Handbook of Nanocelluloses: Classification, Properties, Fabrication, and Emerging Applications 303089620X, 9783030896201
This Handbook covers the fundamental aspects, experimental setup, synthesis, properties, and characterization of differe
178 1 33MB
English Pages 1080 [1081] Year 2022
Preface
Contents
About the Editor
Contributors
Part I: Fundamentals
1 Nanocelluloses: Sources, Types, Unique Properties, Market, and Regulations
1 Introduction
2 Sources and Structure of Cellulose
3 Types and Classification of Nanocelluloses
4 Cellulose Nanocrystals (CNCs)
4.1 Cellulose Nanofibrils (CNFs)
4.2 Bacterial Cellulose (BC)
5 Unique Properties of Nanocelluloses
5.1 Mechanical Strength
5.2 High Binding Capacity
5.3 Low Toxicity
5.4 Biocompatibility
5.5 Biodegradability
6 Global Market
7 International Regulations
8 Conclusion
References
2 Nanocelluloses Toxicological and Environmental Impacts
1 Introduction
1.1 In Vitro Studies
1.1.1 Cellular Uptake
1.1.2 Immunotoxicity
1.1.3 Cytotoxicity
1.1.4 Oxidative Stress
1.1.5 Genotoxicity
2 In Vivo Studies
2.1 Immunotoxicity
2.2 Cytotoxicity
3 Environmental Impacts
4 Conclusion and Future Prospects
References
3 Nanocellulose Production from Different Sources and Their Self-Assembly in Composite Materials
1 Introduction
2 Nanocellulose from Native Sources
3 Nanocellulose from Microorganisms, Tunicates, and Algae
4 Production of Nanocellulose
5 Nanoscale Morphological Properties of Nanocellulose
6 Targeting Specific Applications by Properties
7 Electrostatically Stabilized Nanocellulose-Based Suspensions
8 Self-Assembled Nanocellulose in Composite Materials
9 Conclusions and Future Perspectives
References
4 Physicochemical Characterization of Nanocellulose: Composite, Crystallinity, Morphology
1 Introduction
2 Composites
2.1 Nanocellulose and Biodegradable Polymers Composites
2.1.1 Nanocellulose and Synthetic Biodegradable Composites
Polycaprolactone
Poly (Butylene Succinate) (PBS)
Polyethylene Glycol (PEG)
Poly (Lactic) Acid (PLA)
Polyglycolic Acid (PGA)
Poly (Lactic-co-glycolic) Acid (PLGA)
2.1.2 Nanocellulose and Natural Biodegradable Composites
Starch
Chitosan
Alginate
Protein
Gelatin
3 Crystallinity of Cellulose, Nanocellulose, and Composites
3.1 Cellulose Crystallinity
3.2 Nanocellulose Crystallinity
3.3 Cellulose Nanocomposites Crystallinity and Mechanical Properties
3.4 Cellulose Nanocrystal Liquid Crystal Phases
3.5 Crystallinity Measurements
4 Morphology and Physico-Chemical Properties of Nanocellulose and Composites
4.1 Morphology of Nanocellulose and Composites
4.2 Size, Composition, Physicochemical, and Reactivity Properties
4.2.1 Size
4.2.2 Elemental Analysis
4.2.3 Surface Charge
4.2.4 Surface Chemistry
5 Conclusion and Future Prospects
References
5 Nanocellulose
1 Introduction
2 General Overview on Nanocellulose
3 Cellulose Nanocrystals: Preparation and Characterization
4 Nanofibrillated Cellulose: Preparation and Characterization
5 Bacterial Nanocellulose: Preparation and Characterization
6 Conclusion
References
Part II: Nanofabrication
6 Cellulose Nanosystems from Synthesis to Applications
1 Introduction
2 Micro and Nanocelluloses
2.1 Microfibrillated Cellulose Fibers (MFCs)
2.2 Spherical Cellulose Nanoparticles (SCNs)
2.3 Nanocellulose Crystals (CNCs)
2.4 Cellulose Nanofiber (CNF)
2.5 Bacterial Nanocellulose (BNC)
3 Nanocellulose System
3.1 Cellulose Hydrogels
3.2 Cellulose Aerogels
3.3 Cellulose Polymer Nanocomposites
4 Synthesis of Nanocellulose
4.1 Mechanical Methods
4.2 Cellulose Pretreatment Method
4.3 Chemical Methods
4.4 Biological Methods
5 Applications of Nanocellulose
5.1 Biomedical Application
5.2 Pharmaceutical Application
5.3 Energy Production and Storage
5.4 Flexible Electronic Devices
5.5 Others
6 Future Directions
7 Conclusion
References
7 Synthesis, Characterizations, Functionalizations, and Biomedical Applications of Spherical Cellulose Nanoparticles
1 Introduction
2 Overview of Celluloses and Nanocellulose
2.1 Structure and Source of Celluloses
2.2 Nomenclature and Types of Nanocellulose
3 Spherical Cellulose Nanoparticles
4 Spherical Cellulose Nanoparticle Synthetic Methodology
4.1 Dispersion-Based Techniques
4.1.1 Emulsion-Solvent Evaporation
4.1.2 Nanoprecipitation
4.1.3 Microfluidic Technique
4.2 Polymer Self-Assembly
5 Characterization of Spherical Cellulose-Based Nanoparticles
6 Surface Functionalization Techniques
7 Biomedical Applications
8 Conclusion
References
8 Cellulose Nanocrystals
1 Introduction
2 Structure, Morphology, and Properties of Cellulose Nanocrystals
2.1 Structure and Morphology of CNCs
2.1.1 Effect of Sources and Processing Techniques on Structure and Morphology of CNCs
2.1.2 Effect of Hydrolysis Time on Structure and Morphology of CNCs
2.1.3 Effect of Surface Functionalization on Structure and Morphology of CNCs
2.1.4 Various Morphologies of CNCs: Rods, Spheres, Network, and Core-Shell Structures
2.2 Properties of Cellulose Nanocrystals
3 Preparation of Cellulose Nanocrystals
3.1 Preparation of Cellulose Nanocrystals
3.1.1 Chemical Treatment: Acid Hydrolysis of CNCs
3.1.2 Physical Processes: Ultrasonication Synthesis of CNCs
3.1.3 Enzymatic Synthesis of CNCs
4 Functionalization Techniques
4.1 Extraction-Dependent Functionalization
4.2 Functionalization by Physical Adsorption
4.3 Functionalization by Chemical Modification
5 Physicochemical Characterization
6 Applications
7 Conclusions
References
9 Cellulose Nanofibers
1 Introduction
2 Sources of Cellulose
3 Different Techniques for CNF Synthesis
3.1 Processes for CNF Extraction from Plant Resources
3.2 Alkali and Acid-Chlorite Pretreatment of Cellulose Extraction
3.3 Micro- and Nanofibrillation of Cellulose
3.4 Acid Hydrolysis Synthesis
3.5 Enzymatic Hydrolysis
3.6 Electrospinning of Cellulose Nanofibers
3.7 Bacterial Synthesis of Cellulose Nanofibers
4 Unique Properties of CNF
4.1 Optical Transparency
4.2 Barrier Properties
4.3 Mechanical Properties
4.4 Thermal Features
4.5 Electrical Properties
4.6 Biocompatibility
4.7 Biodegradability
5 Emerging Applications
5.1 CNFs as Reinforcing Materials
5.2 Nanopapers
5.3 Energy Storage, Battery Function, and Flexible Electronic Devices
5.4 Filtration
5.5 Medical, Healthcare, and Cosmetic Applications
6 Conclusion
References
10 Electrospinning of Cellulose Nanofibers for Advanced Applications
1 Introduction
2 Electrospinning Setup
3 Electrospinning Parameters
4 Cellulose Electrospinning
4.1 One-Step Methods
4.2 Two-Step Methods
5 Electrospinning of Cellulose Blends
6 Cellulose Composite Electrospinning
7 Applications of Electrospun Cellulose Nanofibers
7.1 Tissue Engineering
7.2 Drug Delivery Systems
7.3 Food Industry
7.4 Textile
7.5 Separation Process
7.5.1 Membranes
7.5.2 Adsorbent
7.6 Others
8 Future Directions
9 Conclusion
References
11 Bacterial Cellulose Nanofibers
1 Introduction
2 Structure and Unique Properties
3 Biosynthesis Mechanism
3.1 Factors Affecting the BC Biosynthesis Process
3.2 Synthetic Pathway
4 Surface Functionalization
5 Biomedical Applications
5.1 Wound Healing
5.2 Biomedical Scaffolds
5.3 Drug Delivery
5.4 Lenses
6 Environmental Protection and Improvement
6.1 Air Filtration
6.2 Heavy Metal and Dye Wastewater Reduction
6.2.1 Organic Pollutant Removal From Wastewater
6.3 Disinfection of Wastewater
6.4 Water Desalination
7 Energy Applications
8 Packing Applications
9 Future Directions
10 Conclusion
References
12 Emerging Application of Nanocelluloses for Microneedle Devices
1 Introduction
1.1 Insight to Categories and Characteristics of Nanocellulose
2 Preparation of Nanocellulose
2.1 Conversion of Cellulose to Nanocellulose
2.2 Nanocellulose Properties
2.3 Production of Nanocellulose
2.4 Pretreatment Techniques
2.4.1 Alkaline Pretreatment
2.4.2 Bleaching Pretreatment
2.5 Extraction Techniques
2.5.1 Chemical Techniques of Nanocellulose Production
2.5.2 Biological Techniques
2.5.3 Mechanical Techniques
3 Emergence of Nanocellulose for Microneedle (MN) Fabrication
3.1 Microneedle Device and their Categories
3.2 Fabrication Technologies and Characterization of Microneedle
3.3 Application of Microneedle
3.4 Advantage of Microneedle
3.5 Limitation of Microneedle
4 Nanocellulose for Microneedle Fabrication
4.1 Effect of Nanocellulose Combination on Microneedle Fabrication
4.2 Limitation of Nano Cellulose Combination on Microneedle Fabrication
5 Conclusion and Future Aspects
References
Part III: Processing
13 Nanocellulose for Antibacterial, Anti-biofouling Applications: To Antiviral Development in the Future
1 Introduction
2 The Classification of Nanocellulose, Structures, and Properties
3 Biofouling and Microorganisms
4 Application Cases from the Viewpoint of Fouling
4.1 Membranes
4.2 Medical Application
5 Antiviral Characteristics: Future Problems
6 Conclusion and Future Prospects
References
14 Nanoparticle Decoration of Nanocellulose for Improved Performance
1 Introduction
2 Nanoparticles
2.1 Organic Nanoparticles
2.1.1 Polymeric Nanoparticles
2.1.2 Liposomes Nanoparticles
2.2 Inorganic Nanoparticles
2.2.1 Metal-Based Nanoparticles
2.2.2 Metal Oxides-Based Nanoparticles
2.2.3 Ceramic Nanoparticles
2.3 Carbon-Based Nanoparticles
3 Nanocellulose for Flexible Energy and Electronic Device
4 Nanocellulose for Wound Healing Applications
5 3-D Bio-Printed Nanocellulose for Tissue Engineering
6 Nanocellulose for Food Packaging
7 Nanocellulose for Water Treatment
8 Conclusion
References
15 Nanocellulose as Reinforcement Materials for Polymer Matrix Composites
1 Introduction
2 Nanocellulose: Accessibility and its Characteristics
2.1 Cellulose Nanocrystal (CNC)
2.1.1 Potential Sources of Cellulose Nanocrystals
2.1.2 Methods Applied for CNC Preparation
Mechanical Process
Chemical Process
Biological Source
Combined Method
2.1.3 Properties of Cellulose Nanocrystals
2.1.4 Applications of CNC
2.2 Cellulose Nanofiber (CNF)
2.3 Bacterial Cellulose Nanofibers (BCs)
2.3.1 Methods of BC Nanofication
2.4 Cellulose Nanogels (CNGs)
2.5 Spherical Cellulose Nanoparticles
3 Reinforcement of Interactions between Polymer and Nanocomposites
3.1 Tensile Properties of Nanocellulose
3.2 Different Kinds of Covalent Interaction for the Preparation of Polymers and Nanocomposites
3.2.1 Reaction between Hydroxyl Group and Epoxides
3.2.2 Reaction between Hydroxyl Group and Isocyanate
3.2.3 Reaction between Hydroxyl Group and Peptide
3.2.4 Reaction between Hydroxyl Group and Silane
4 Processing Methods of Polymer Nanocomposites
4.1 Hot-Melt Processing
4.2 Wet Processing
5 In Situ Polymerization
5.1 In Situ-Formed Bacterial Cellulose (BC) Nanocomposites
5.2 In Situ Polymerization of Monomer in the Presence of Bacterial Cellulose
5.3 In Situ Growth of Bacterial Cellulose in the Presence of a Polymer
5.4 In Situ Growth of Bacterial Cellulose in the Presence of a Nanofillers
5.5 In Situ-Formed Plant Cellulose (NC) Nanocomposites
6 Conclusion and Future Prospective
References
16 Synthesis and Applications of Organic Framework-Based Cellulosic Nanocomposites
1 Introduction
2 Classification of Plant Nanocellulose and Their Structural Characteristics
3 Synthesis of Various Organic Framework Cellulosic Nanocomposites
3.1 Fabrication of CF composites
3.2 Synthesis of Nanoparticle Immobilized Cellulose Fiber Composites
3.3 Immobilizing MOFs into a Cellulosic Structure
3.4 Synthesis of COF-Grafted Cotton Fiber
3.5 Synthesis of MOF/Cellulose Composite
3.6 Fabrication of Hybrid Films via an In Situ Synthetic Method
3.7 Preparation of MOF Containing Cellulose Paper Composites
3.8 Synthesis of MOF-Incorporated CNF Composites
3.9 Fabrication of MOF-Based CNF Nanopapers
3.10 Fabrication of MOF-CNF Papers by Direct Mixing
4 Characterization
5 Applications
5.1 Adsorption
5.2 Gas Adsorption
5.3 Detection of Metal Ions`
5.4 Iodine Capture
5.5 Extraction of Organics
5.6 Separation
5.7 Wastewater Treatment
6 Bio-application
6.1 Antibacterial Activity
6.2 Drug Delivery
7 Future Perspective and Conclusion
References
Part IV: Biomedical
17 Advances of Nanocellulose in Biomedical Applications
1 Introduction
2 Types of Nanocellulose
2.1 Cellulose Nanofibrils
2.2 Cellulose Nanocrystals
2.3 Bacterial Nanocellulose
3 Properties of Nanocellulose
3.1 Surface Chemistry
3.2 Biodegradibility
3.3 Biocompatibility
3.4 Toxicology
4 Nanocellulose in Biomedical Applications
4.1 Nanocellulose as Medical Biomaterials as Replacements
4.1.1 Blood Vessel Replacement
4.1.2 Soft Tissue-Ligament, Meniscus, and Cartilage Replacements
4.1.3 Nucleus Pulposus Replacement
4.2 Drug Delivery
4.3 Tissue Engineering
4.4 Bone Regeneration
4.5 Wound Healing
4.6 Dental Applications
4.7 Cancer
4.8 Antimicrobial Activity
4.9 Immobilization of Enzymes
4.10 Biosensors and Clinical Diagnosis
5 Conclusion
References
18 Nanocelluloses as a Novel Vehicle for Controlled Drug Delivery
1 Introduction
2 Nanocellulose Biodegradability and Cytotoxicity
3 Nanocellulose Functionalization for Controlled Drug Loading and Release
4 Nanocelluloses in Drug Delivery Systems
5 Nanocelluloses in Drug Delivery System
6 Nanocellulose for Skincare Formulation
7 Nanocelluloses for Oral Drug Delivery
8 Nanocelluloses in Tablet Formulations
9 Nanocelluloses in Cosmetics Formulations
10 Nanocelluloses in Skincare Formulations
11 Nanocellulose Membranes with Drug Delivery Function
12 Nanocellulose Gels for Drug Delivery Applications
13 Nanocellulose Drug Delivery in Wound Healing Applications
14 Nanocellulose Drug Delivery in Antimicrobial Materials
15 Conclusion and Future Prospects
References
19 Nanocelluloses for Tissue Engineering Application
1 Introduction
2 Tissue Engineering Process and Principles
3 Nanocelluloses for Tissue Engineering
3.1 Cellulose Nanocrystals
3.2 Cellulose Nanofibrils
3.3 Bacterial Cellulose
4 Nanocellulose Hydrogels
5 Nanocellulose Scaffolds
6 Nanocellulose 3D Printing
7 Conclusion and Future Prospects
References
20 Nanocellulose for Vascular Grafts and Blood Vessel Tissue Engineering
1 Introduction
2 Criteria of Vascular Grafts and Blood Vessel Tissue Engineering
2.1 Engineering of Different Lumen Diameters and Varying Structures
2.2 Integration of Engineered Vessels with the Host Vessels or Tissues
2.3 Mechanical Properties of the Structure
2.4 Biocompatibility and Hemocompatibility
3 Unique Properties of Nanocellulose
3.1 A Wide Range of Mechanical Properties (Mechanical Reinforcement)
3.2 Surface Chemistry
3.3 Biological Properties
3.3.1 Biocompatibility
3.3.2 Hemocompatibility
3.3.3 Biodegradability
3.4 Patency Parameters of Vascular Grafts
3.4.1 Endothelialization
3.4.2 Mechano-clinical Parameters
4 Nanocellulose for Vascular Tissue Engineering
4.1 Cellulose Nanocrystals
4.2 Cellulose Nanofibers
4.3 Bacterial Cellulose
5 Nanocellulose for Vascular Grafts
5.1 Common Biomaterials for Vascular Grafts
5.2 Fabrication of Bacterial Nanocellulose Grafts
5.3 Composite Forms of Bacterial Nanocellulose Grafts
5.4 Non-composited Bacterial Nanocellulose Grafts
5.5 Other Nanocellulose Types
6 Limitations of the Use of Nanocellulose in Vascular Grafts/Tissue Engineering
7 Conclusion and Remarks
References
21 Nanocellulose Biocomposites for Bone Tissue Engineering
1 Introduction
2 Cellulose and Its Derivatives
2.1 Origin-Based Classification
2.1.1 Bacterial Cellulose
2.1.2 Wood and Plant Cellulose
2.1.3 Algal Cellulose
2.1.4 Tunicate Cellulose
2.2 Morphology-Based Classification
2.2.1 Cellulose Fibers
2.2.2 Cellulose Filaments
2.2.3 Cellulose Micro/Nanofibrils
2.2.4 Crystalline Cellulose
2.3 Cellulose Derivatives
2.3.1 Cellulose Ether
Methyl Cellulose
Carboxymethyl Cellulose
Ethyl Cellulose
Hydroxyethyl Cellulose
Hydroxypropyl Cellulose
2.3.2 Cellulose Ester
Cellulose Acetate (CA)
2.3.3 Cellulose Nitrate
2.3.4 Cellulose Sulfate
3 Bone and Its Components
4 Bone Tissue Engineering (BTE)
5 Nanoentities for BTE
6 Nanocellulose in BTE
7 Nanocellulose Embedded PNCS for BTE
7.1 Spherical Cellulose NPs Embedded PNCs
7.2 CNCs/NCCs Embedded PNCs
7.3 CNFs Embedded PNCs
7.4 BC-NFs Embedded PNCs
7.5 CNW Embedded PNCs
7.6 Nanocellulose Derivatives Embedded PNCs
7.6.1 Carboxymethyl Nanocellulose
7.6.2 Hydroxyethyl Nanocellulose
7.6.3 Cellulose Acetate
7.6.4 Aerogel Cellulose
7.6.5 Oxidized-Cellulose Nanofibers
8 Toxicity and Biocompatibility of Cellulose-PNCS
9 Conclusion
10 Challenges and Future Perspective
References
22 Nanocelluloses in Wound Healing Applications
1 Introduction
1.1 Structure of the Human Skin
1.2 Types of Skin Injuries
2 Wound Healing Stages
3 Ideal Wound Healing Dressings
4 Wound Healing Biomaterials
5 Nanocelluloses for Wound Healing
5.1 Bacterial Cellulose (BC) in Wound Healing
5.2 Cellulose Nanocrystals in Wound Healing
5.3 Cellulose Nanofibers in Wound Healing
5.4 Cellulose Hydrogels in Wound Healing
6 Conclusion and Future Prospects
References
23 Advances in Nanocellulose for Wound Healing Applications
1 Introduction
2 Wound Repair and Regeneration
3 Criteria for Wound Healing Materials
4 Chemical Modification of Nanocellulose for Wound Healing
5 Cellulose Nanocomposites for Wound Healing
6 Nanocellulose Decorated with Nanoparticles for Wound Healing
7 Nanocellulose Functionalized with Antibacterial Agents for Wound Healing
8 3D-Printed Nanocellulose Materials for Wound Healing
9 Future Directions
10 Conclusion
References
24 Nanocelluloses for Tissue Engineering and Biomedical Scaffolds
1 Introduction
2 Tissue Engineering Approaches
3 Polymer Materials Being Used in Tissue Engineering
4 Nanocelluloses for Tissue Engineering
5 Nanocelluloses and Natural Polymers for Tissue Engineering
6 Nanocelluloses and Synthetic Polymers for Tissue Engineering
7 Unique Properties of Nanocellulose for Tissue engineering
8 Nanocellulose for Artificial skin
9 Nanocelluloses for Dental Implants
10 Nanocelluloses for Cornea Replacement
11 Nanocelluloses for Vascular Grafts
12 Nanocelluloses for Bone Tissue Scaffold
13 Nanocelluloses for Orthopedic Implants
14 Nanocelluloses for Wound Dressing
15 Market and Commercial Applications
16 Conclusion and Remarks
References
25 Nanocelluloses in Sensing Technology
1 Introduction
2 Sensors Principle and Assembly
3 Types and Classifications of Sensors
3.1 Cellulose-Based Sensors
4 Nanocelluloses in Chemical Sensors
5 Nanocelluloses in Optical Sensors
6 Nanocelluloses in Gas Sensing Applications
7 Nanocelluloses in Food Sensing Applications
8 Nanocelluloses for Water Monitoring Sensors
9 Conclusion
References
Part V: Environmental
26 Nanocellulose Membranes for Air Filtration
1 Introduction
2 Chemistry of Nanocellulose
3 Types of Nanocellulose for Air Filters
3.1 Cellulose Nanocrystals (CNCs)
3.2 Cellulose Nanofibers (CNFs)
3.3 Bacterial Nanocellulose (BNCs)
4 Types of Nanocellulose Isolation
4.1 Mechanical Treatments
4.2 Chemo-Mechanical Treatment (Kraft Pulping)
4.3 Enzymatic-Mechanical Treatment
5 Properties of Nanocellulose
6 Applications of Nanocellulose
7 Nanocellulose Air Filters
8 Conclusion and Prospects
References
27 Nanocellulose-Based Materials for Wastewater Treatment
1 Introduction
2 Cellulose Sources and Structures
3 Fabrication of Nanocellulose-Polymer Composites
4 General Considerations in Fabricating Cellulose Nanocomposite
4.1 Functionalization of Nanocelluloses to Serve as a Nanofiller
4.1.1 Urethanization Method
4.1.2 Etherification Method
4.1.3 Silylation Method
4.2 Methods for Combining Nanocellulose with a Polymer
4.2.1 Solvent Casting Method
4.2.2 Coprecipitation Method
4.2.3 In Situ Polymerization Method
5 Remarkable Properties of Nanocellulose-Polymer Nanocomposites
6 Cellulose-Nature Polymer Nanocomposites
7 Cellulose-Synthetic Polymer Nanocomposites
8 Removal of Heavy Metals
9 Removal of Organic Pollutants
10 Flocculation and Coagulation
11 Oil/Water Separation
12 Removal of Microbes from Wastewater
13 Conclusion and Future Prospects
References
28 Surface Functionalizations of Nanocellulose for Wastewater Treatment
1 Introduction
2 Wastewater Pollutants in Present Scenario
2.1 Nutrients
2.2 Hydrocarbons
2.3 Heavy Metal Ions
2.4 Microbes
2.5 Organic Dyes
3 Conventional Techniques for Wastewater Treatment
3.1 Chemical Methods
3.1.1 Oxidation
3.1.2 Ozonation
3.1.3 Photocatalysis
3.1.4 Electrochemical Methods
3.1.5 Electron Beam Irradiation
3.1.6 Chemical Extraction
3.1.7 Radiocolloid Treatment
3.2 Physicochemical Methods
3.2.1 Ion Exchange
3.2.2 Coagulation and Flocculation
3.2.3 Filtration
3.2.4 Adsorption
3.2.5 Screening and Flow Equalization
3.2.6 Comminution and Sedimentation
3.2.7 Precipitation
3.3 Biological Methods
4 Nanocellulose Membrane: A Super Adsorbent for Wastewater Treatment
5 Modification of Nanocelluloses for Wastewater Treatment
5.1 Covalent Modification
5.2 Non-covalent Modification
5.3 Mercerization
5.4 Esterification
5.5 Silylation
5.6 Etherification
5.7 Polymer Grafting
5.8 TEMPO Oxidation
5.9 Radiation
5.10 Ionized Gases
6 Grafting of Nanocellulose for Wastewater Treatment
6.1 Nanocellulose for Environmental Application
6.2 Carboxylation
6.3 Amination
6.4 Silanization
6.5 Amidation
6.6 Esterification
6.7 Phosphorylation
7 Decoration of Nanocellulose with Nanoparticles/Composites for Wastewater Treatment
7.1 Nanocellulose Magnetic Nanocomposites
7.2 Nanocellulose/Clay Nanocomposites
7.3 Nanocellulose/Polymer Composites
7.4 Processing of Nanocellulose-Based Polymer Composites
7.5 Properties of Polymer Cellulose Nanocomposites
7.6 Nanocellulose-Based Porous Nanocomposites (Foams)
7.6.1 Polyurethane Foams
7.6.2 Aerogels
8 Future Directions
9 Conclusions
References
29 Nanocelluloses for Removal of Heavy Metals From Wastewater
1 Introduction
2 Environmental Impacts of Heavy Metals
3 Unique Properties of Nanocellulose in Wastewater Treatment
4 Methods of Heavy Metal Removal
4.1 Membrane Separation
4.2 Coagulation and Flocculation
4.3 Chemical Precipitation
4.4 Chemical Oxidation and Reduction
4.5 Ion Exchange
4.6 Electrochemical
4.7 Sonochemical
4.8 Phytoremediation
4.9 Adsorption
5 Nanocellulose in Heavy Metal Removal
6 Surface Modification of Nanocelluloses for Heavy Metal Removal
6.1 Carboxymethylation
6.2 Sulfonation
6.3 Phosphorylation
6.4 Esterification
6.5 Silylation
6.6 Cationization
6.7 Graphting Polymers
7 Conclusion and Future Directions
References
30 Nanocellulose Membranes for Water/Oil Separation
1 Introduction
2 Membrane Technology of Oily Wastewater
2.1 Oil/Water Separation Mechanism-Based Membrane Technology
3 Membrane from Synthetic Polymers for Oil Wastewater
3.1 Electrospun Nanofibers for Oil/Water Separation
3.2 Hydrophilic-Oleophobic Nanofibrous Filtration Membranes for Oil/Water Separation
3.3 Hydrophobic-Oleophilic Nanofibrous Filtration Membranes for Oil/Water Separation
3.4 Electrospun Nanofibrous Sorption Membranes for Oil/Water Separation
3.5 Hydrophobic-Oleophilic Nanofibrous Sorption Membranes for Oil/Water Separation
4 New Generation of Nanotechnology Membrane Prepared from Nanocellulose
4.1 Cellulose and Nanocellulose: Preparation and Properties
4.1.1 Cellulose Nanocrystals (CNCs)
4.1.2 Cellulose Nanofibers (CNFs)
4.1.3 Bacterial Cellulose (BC)
4.1.4 Electrospun Cellulose Nanofibers (ECNFs)
4.1.5 Spherical Cellulose Nanoparticles (SCNPs)
4.2 Cellulose Nanomaterials for Oil/Water Separation
4.2.1 Cellulose Nanocrystals for Oil/Water Separations
4.2.2 Cellulose Nanofiber for Oil/Water Separation
4.2.3 Bacterial Cellulose for Oil Adsorption
5 Conclusions
References
31 Nanocelluloses for Removal of Organic Dyes from Wastewater
1 Introduction
2 Physico-Chemical Characterization of Nanocellulose
3 Different Forms of Nanocellulose in Dye Removal
3.1 Cellulose Nanocrystals (CNCs)
3.2 Bacterial Nanocellulose (BNCs)
3.3 Cellulose Nanofibrils (CNFs)
4 Chemical Modifications of Nanocellulose for Dye Removal
4.1 Carboxylation
4.2 Phosphorylation
4.3 Sulfonation
4.4 Other Chemical Modifications
5 Role of Nanocellulose in Dye Removal
5.1 Nanocellulose Dye Adsorbents
5.1.1 Adsorption of Cationic Dye
5.1.2 Adsorption of Anionic Dye
5.2 Adsorption of Toxic Dye Components
5.2.1 Adsorption of Hg
5.2.2 Adsorption of Cr Ions
5.2.3 Adsorption of Co, Pb, and Ni
5.2.4 Adsorption of Other Dye Constituents
6 Water Treatment and Pollution Management
7 Conclusion
References
Part VI: Constructions and Others
32 Nanocellulosic Materials for Papermaking and Paper Coating Industry
1 Introduction
2 Nanocellulosic Materials Being Used for Papermaking
3 Cellulose Nanocrystals (CNC)
4 Mechanical Methods
5 Homogenization
6 Microfluidization
7 Fine Grinding
8 Freezing Smashing
9 Chemical Hydrolysis
10 Alkali Hydrolysis
11 Acid Hydrolysis
12 TEMPO Hydrolysis
13 Biological Hydrolysis
14 Combined Methods
15 Cellulose Nanofibrils
16 Mechanical Treatment
17 Pretreatments of CNFs
18 Mechanical Pretreatment
19 Enzymatic Pretreatment
20 Chemical Pretreatment
21 Bacterial Cellulose
22 Nanocellulosic Materials Being Used for Paper Coating
23 Cellulose Nanocrystals
24 Cellulose Nanofibers (CNF)
25 Bacterial Cellulose Nanofibers (BC)
26 Advances of Nanocellulosic Materials in Papermaking
27 Solar Cells
28 Paper Membranes
29 Flexible Electronics
29.1 Basic Electronic Components
29.1.1 Paper Electrodes and Circuits
29.1.2 Circuit Switches
29.2 Energy Storage Devices
29.2.1 Supercapacitors
29.2.2 Electrochemical Cells
29.2.3 Biofuel Cells
29.2.4 Lithium-Ion Batteries
29.3 Nanogenerators
29.4 Electrochemical Devices for Accessible Diagnostic Testing
29.4.1 Pressure Sensors
29.4.2 Nanocellulose Paper for Transparent (Opto) Electronics
30 Biodegradability of Nanocellulose Materials
31 Drawbacks in the Characterization of Nanocellulosic Material at the Industrial Scale
32 Market Perspectives
33 Conclusion and Future Prospects
References
33 Nanocelluloses for Sustainable Packaging and Flexible Barrier Film Technology
1 Introduction to Packaging Materials
2 Replacement of Plastics with Nanocelluloses (NC)
2.1 Barrier Property Within NC Film
3 Sources of NC for Packaging Industry
3.1 Pre-treatment and Nanocellulose Isolation Methods
4 Types of Nanocelluloses in Packaging Industry
4.1 Nanofibrillated Cellulose (NFC)
4.1.1 Oxygen Barrier
4.1.2 Oils and Grease Barrier
4.1.3 Water Vapor Barrier
4.1.4 Aqueous Liquid Barrier
4.2 Cellulose NanoCrystals (CNCs)
4.3 Bacterial Nanocellulose (BNC)
4.3.1 Electrospun Cellulose Nanofibers (ECNF)
4.4 Nanocellulose-Based Composites and Bioactive Agents
4.5 Nanocellulose-Polymer Composite
5 Nanocellulose Possibilities in packaging Industry
5.1 Food Packaging
5.2 Confectionery
5.3 Food Freshness Indicator
6 Advantages and Effectiveness of NC in Packaging
7 Smart and Active Packaging
7.1 Active Packaging
8 NC Application for Various Production Technologies
8.1 Nanocellulose in Films and Coatings
8.1.1 Extruded Nanofilms
8.1.2 Nanocellulose Films Casting from Liquids
8.1.3 Filtration and Papermaking Process
8.1.4 Coating Process in Nanofilms Making
8.2 Pharmaceutical and Biomedical Applications
9 Worldwide Market and Industrial Producers of NC
10 Conclusion and Future Prospective
Reference
Index
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Ahmed Barhoum Editor
Handbook of Nanocelluloses
Classification, Properties, Fabrication, and Emerging Applications
Handbook of Nanocelluloses
Ahmed Barhoum Editor
Handbook of Nanocelluloses Classification, Properties, Fabrication, and Emerging Applications
With 280 Figures and 89 Tables
Editor Ahmed Barhoum NanoStruc Research Group Chemistry Department Faculty of Science Helwan University Helwan, Cairo, Egypt National Centre for Sensor Research School of Chemical Sciences Dublin City University Dublin, Ireland
ISBN 978-3-030-89620-1 ISBN 978-3-030-89621-8 (eBook) https://doi.org/10.1007/978-3-030-89621-8 © Springer Nature Switzerland AG 2022 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG. The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland
Preface
Handbook on Nanocelluloses covers all current aspects of nanocellulose technology, from experimental setup to industrial applications. This book provides a comprehensive overview of the different types of nanocelluloses used today in research and commercial applications. The book focuses on the unique properties, synthesis methods, surface modifications, blends with other materials, physicochemical characterization techniques, and current and future applications of nanocelluloses. These handbooks comprise two volumes. Handbook of Nanocelluloses: Fundamentals, Properties, Fabrication, and Characterization (Volume I) covers various classes of nanocelluloses, including spherical nanoparticles, nanowhiskers, nanofibers, aerogels, and hydrogels, especially synthesis methods and self-assembly of nanocelluloses into architectural nanostructures. Special attention is given to characteristic features, bulk and surface functionalization, toxicity, global markets, safety, and regulations. In particular, the following topics are covered in detail: • Types and classifications, unique properties, fabrication, and critical processing parameters • Unique properties developed by adjusting diameter, alignment, morphology, and functionality • Surface chemistry, surface and bulk functionalization, and self-assembly • Mechanical, physical, chemical, and biological synthesis methods • New fabrication techniques and their critical processing parameters • Physicochemical characterization techniques for nanocellulose hybrids Handbook of Nanocelluloses: Emerging Technologies and Industrial Applications (Volume II) covers the potential applications of nanocelluloses in biomedicine (drug delivery, tissue engineering, medical implants, medical diagnostics and therapeutics, biosensors), energy generation and storage (fuel cells, batteries, supercapacitors), environmental protection and improvement (air purification and water treatment), agriculture and food processing, papermaking, textiles, construction, and others. Special attention is given to the environmental impact, safety, and other legal aspects
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Preface
related to the industrial use of nanocelluloses in order to improve and disseminate their commercialization. In particular, the following topics are covered in detail: • • • • • •
Opportunities and challenges for nanocellulose production Nanocellulose hybrids and their critical processing parameters Interaction of nanocelluloses in biological and ecological systems Nature of nanocelluloses in terms of their applicability for industrial purposes Applicability of nanocellulose-based systems in various industries Interdisciplinary perspective of nanocelluloses in science, biology, medicine, and engineering • Challenges of nanocellulose technology and its future markets Handbook of Nanocelluloses shows how the latest developments in the field of nanocelluloses are leading to real innovations in a number of industrial sectors. The book is a valuable reference for materials scientists; biologists; medical, chemical, biomedical, manufacturing, and mechanical engineers working in the research and development industry; as well as academics who want to learn more about future global markets, advanced applications, and the technological challenges of nanocellulose-based systems. Dublin, Ireland July 2022
Ahmed Barhoum
Contents
Part I 1
Fundamentals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Nanocelluloses: Sources, Types, Unique Properties, Market, and Regulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Jaison Jeevanandam, Jordy Kim Ung Ling, Michelle Tiong, Ahmed Barhoum, Yen San Chan, Caleb Acquah, and Michael K. Danquah
2
Nanocelluloses Toxicological and Environmental Impacts . . . . . . . C. Balalakshmi, P. R. S. Yoganathan, K. Tharini, A. Vijaya Anand, A. Murugaesan, Mohammed Jaabir, and Jeyachandran Sivakamavalli
3
Nanocellulose Production from Different Sources and Their Self-Assembly in Composite Materials . . . . . . . . . . . . . . . . . . . . . . Dimitrios Selianitis, Maria-Nefeli Efthymiou, Erminta Tsouko, Aristeidis Papagiannopoulos, Apostolis Koutinas, and Stergios Pispas
4
5
Physicochemical Characterization of Nanocellulose: Composite, Crystallinity, Morphology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . María Luisa García Betancourt and Dahiana-Michelle Osorio-Aguilar Nanocellulose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Abhilash Venkateshaiah, Malladi Nagalakshmaiah, Ramzi Khiari, and Mohamed Naceur Belgacem
Part II
Nanofabrication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6
Cellulose Nanosystems from Synthesis to Applications . . . . . . . . . Syed Baseeruddin Alvi, Anil Jogdand, and Aravind Kumar Rengan
7
Synthesis, Characterizations, Functionalizations, and Biomedical Applications of Spherical Cellulose Nanoparticles . . . . . . . . . . . . . Soroush Soltani, Nasrin Khanian, Taha Rmoodbar Shojaei, Nilofar Asim, Yue Zhao, and Thomas Shean Yaw Choong
1
3
35
51
83 119
143 145
177
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Contents
8
Cellulose Nanocrystals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Tejaswini Appidi, Mudigunda V. Sushma, and Aravind Kumar Rengan
201
9
Cellulose Nanofibers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Amin Meftahi, Mohammad Ehsan Momeni Heravi, Ahmed Barhoum, Pieter Samyn, Hamideh Najarzadeh, and Somayeh Alibakhshi
233
10
Electrospinning of Cellulose Nanofibers for Advanced Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Shahrzad Rahmani, Zahra Khoubi-Arani, Sanaz MohammadzadehKomuleh, and Mahshid Maroufkhani
11
Bacterial Cellulose Nanofibers . . . . . . . . . . . . . . . . . . . . . . . . . . . . Selma Hamimed, Nissem Abdeljelil, Ahmed Landoulsi, Abdelwaheb Chatti, Alaa A. A. Aljabali, and Ahmed Barhoum
12
Emerging Application of Nanocelluloses for Microneedle Devices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Monika Dwivedi, Jyotsana Dwivedi, Shuwei Shen, Pankaj Dwivedi, Liu Guangli, and Xu Xiarong
Part III 13
14
15
16
Nanocellulose for Antibacterial, Anti-biofouling Applications: To Antiviral Development in the Future . . . . . . . . . . . . . . . . . . . . . Hideyuki Kanematsu, Dana M. Barry, Ryo Satoh, Risa Kawai, and Paul McGrath Nanoparticle Decoration of Nanocellulose for Improved Performance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Tabassum Khan and Jahara Shaikh Nanocellulose as Reinforcement Materials for Polymer Matrix Composites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Himani Punia, Jayanti Tokas, Surina Bhadu, Anju Rani, Sonali Sangwan, Aarti Kamboj, Shikha Yashveer, and Satpal Baloda Synthesis and Applications of Organic Framework-Based Cellulosic Nanocomposites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Vasanthakumar Arumugam and Yanan Gao
Part IV 17
Processing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Biomedical
......................................
Advances of Nanocellulose in Biomedical Applications . . . . . . . . . C. Balalakshmi and Sivakamavalli Jeyachandran
263
297
335
361
363
377
407
441
473 475
Contents
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Nanocelluloses as a Novel Vehicle for Controlled Drug Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Alaa A. A. Aljabali, Mohammad A. Obeid, Meriem M. Rezigue, Alaa Alqudah, Nitin Bharat Charbe, Dinesh Kumar Chellappan, Vijay Mishra, Dinesh M. Pardhi, Harish Dureja, Gaurav Gupta, Parteek Prasher, Kamal Dua, Ahmed Barhoum, and Murtaza M. Tambuwala
19
Nanocelluloses for Tissue Engineering Application . . . . . . . . . . . . Balaji Mahendiran, Shalini Muthusamy, Sowndarya Sampath, S. N. Jaisankar, and Gopal Shankar Krishnakumar
20
Nanocellulose for Vascular Grafts and Blood Vessel Tissue Engineering . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Zahra Goli-Malekabadi and Shayan Pournaghmeh
507
543
573
21
Nanocellulose Biocomposites for Bone Tissue Engineering . . . . . . Amandeep Singh, Kamlesh Kumari, and Patit Paban Kundu
597
22
Nanocelluloses in Wound Healing Applications . . . . . . . . . . . . . . . Raed M. Ennab, Alaa A. A. Aljabali, Nitin Bharat Charbe, Ahmed Barhoum, Alaa Alqudah, and Murtaza M. Tambuwala
649
23
Advances in Nanocellulose for Wound Healing Applications . . . . . Kavitkumar Patel, Jahara Shaikh, and Tabassum Khan
677
24
Nanocelluloses for Tissue Engineering and Biomedical Scaffolds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Niloofar Adib Eshgh, Amin Meftahi, Ramin Khajavi, Alaa A. A. Aljabali, and Ahmed Barhoum
25
Nanocelluloses in Sensing Technology . . . . . . . . . . . . . . . . . . . . . . Alaa A. A. Aljabali, Mohammad A. Obeid, Mazhar S. Al Zoubi, Nitin Bharat Charbe, Dinesh Kumar Chellappan, Vijay Mishra, Harish Dureja, Gaurav Gupta, Parteek Prasher, Kamal Dua, Rasha M. Elnashar, Murtaza M. Tambuwala, and Ahmed Barhoum
Part V
Environmental . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
709
745
775
26
Nanocellulose Membranes for Air Filtration . . . . . . . . . . . . . . . . . Maximiliano Rojas-Taboada and María Luisa García Betancourt
777
27
Nanocellulose-Based Materials for Wastewater Treatment . . . . . . Kandasamy G. Moodley, Vasanthakumar Arumugam, and Ahmed Barhoum
809
28
Surface Functionalizations of Nanocellulose for Wastewater Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Amandeep Singh, Jyothy G. Vijayan, and Kandasamy G. Moodley
843
x
29
Contents
Nanocelluloses for Removal of Heavy Metals From Wastewater . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Selma Hamimed, Nejib Jebli, Amina Othmani, Rayene Hamimed, Ahmed Barhoum, and Abdelwaheb Chatti
30
Nanocellulose Membranes for Water/Oil Separation . . . . . . . . . . . Ragab Abouzeid, Hanan S. Fahmy, Hamouda M. Mousa, G. T. Abdel-Jaber, W. Y. Ali, and Ramzi Khiari
31
Nanocelluloses for Removal of Organic Dyes from Wastewater . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Akshaya Radhakrishnan, Mohammed Jaabir, Sivakamavalli Jeyachandran, K. Tharini, A. Vijaya Anand, and A. Murugaesan
Part VI
Constructions and Others
..........................
891
933
971
999
32
Nanocellulosic Materials for Papermaking and Paper Coating Industry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1001 R. Karthika, B. Jayanthi, A. Aruna, and T. Selvankumar
33
Nanocelluloses for Sustainable Packaging and Flexible Barrier Film Technology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1035 B. Jayanthi
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1065
About the Editor
Prof. Dr. Ahmed Barhoum NanoStruc Research Group Chemistry Department Faculty of Science Helwan University Helwan, Cairo, Egypt National Centre for Sensor Research School of Chemical Sciences Dublin City University Dublin, Ireland Ahmed Barhoum is the head of the Nanostruc Research Group, Chemistry Department, Helwan University (Egypt). He obtained his PhD and postdoc fellowship in chemical sciences from the Department of Materials and Chemistry (MACH), Vrije Universiteit Brussel (Belgium). He currently works in the School of Chemical Sciences (SCS) at Dublin City University (Ireland). He is also a member of the National Centre for Sensor Research (NCSR), Fraunhofer Project Centre (FPC), and Nano Research Facility (NRF) at Dublin City University (Ireland). His research interests include the fabrication of nanoparticles, nanofibers, hydrogels, and thin films for electrocatalysis, drug delivery, and electrochemical biosensors. He has won several scientific awards and prizes for his academic excellence: Helwan University Prizes (2020 and 2019), Irish Research Council (2020), Chinese Academy of Science Fellowship (China, 2019), Institut français d’Égypte Fellowships (France, 2018 and 2020), Research Foundation Flanders Fellowships (Belgium, 2015 and 2016), Medastar Erasmus Mundus (Belgium, 2012), Welcome xi
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About the Editor
Erasmus Mundus (Italy, 2012), Gold Medal from Egyptian Syndicate of Scientific Professions (2007), Gold Medal from Helwan University (2007), and many more. Ahmed also acts as an expert evaluator for the National Science Centre (Poland), Czech Science Foundation (Russia), Swiss National Science Foundation (SNSF, Switzerland), and Innovators Support Fund (ISF, Egypt) and examiner for international students’ work (Egypt, India, Australia, etc.). He is the editor of 12 handbooks published by Elsevier and Springer Nature. Ahmed has secured 18 research grants (PI/CoPI of 10 funded projects and member of 8 projects) from Egypt (ASRT & STDF), China (CAS), Japan (JSPS), the USA (NSF & US-Aid), Belgium (SIM & FWO), Germany (AGYA), and France (Imhotep), among others. He was co-organizer of 4 conferences and coauthored 150 publications. He has published in highimpact journals including the Journal of Materials Chemistry A, ACS Applied Materials & Interfaces, Applied Materials Today, Nanoscale, Carbohydrate Polymers, Materials Science and Engineering: C, and the Journal of Colloid and Interface Science, and many of his papers have been highlighted in Research Highlights, News & Views, journal cover articles, and national and international media and press. His handbook Emerging Applications of Nanoparticles, Elsevier, has been featured on CNN, Forbes, and Inc Top Best Nanostructures Books of All Time.
Contributors
G. T. Abdel-Jaber Department of Mechanical Engineering, Faculty of Engineering, South Valley University, Qena, Egypt Nissem Abdeljelil Laboratory of Biochemistry and Molecular Biology, Faculty of Sciences of Bizerte, University of Carthage, Jarzouna, Tunisia Ragab Abouzeid Cellulose and Paper Department, National Research Centre, Giza, Egypt Caleb Acquah Faculty of Health Sciences, University of Ottawa, Ottawa, Ontario, Canada Mazhar S. Al Zoubi Department of Basic Medical Sciences, Faculty of Medicine, Yarmouk University, Irbid, Jordan W. Y. Ali Production Engineering and Mechanical Design Department, Minia University, Minia, Egypt Somayeh Alibakhshi Membrane Department, Hassun Textile Research Center, Tehran, Iran Alaa A. A. Aljabali Faculty of Pharmacy, Department of Pharmaceutics and Pharmaceutical Technology, Yarmouk University, Irbid, Jordan Alaa Alqudah Faculty of Pharmacy, Department of Pharmaceutics and Pharmaceutical Technology, Yarmouk University, Irbid, Jordan Syed Baseeruddin Alvi Department of Biomedical Engineering, Indian Institute of Technology Hyderabad, Hyderabad, India Tejaswini Appidi Department of Biomedical Engineering, Indian Institute of Technology Hyderabad, Sangareddy, Telangana, India Vasanthakumar Arumugam Key Laboratory of Ministry of Education for Advanced Materials in Tropical Island Resources, Hainan University, Haikou, China
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Contributors
A. Aruna PG & Research Department of Biotechnology, Mahendra Arts and Science College (Autonomous), Namakkal, Tamil Nadu, India Nilofar Asim Solar Energy Research Institute, National University of Malaysia, Bangi, Malaysia C. Balalakshmi Department of Nano science & Technology, Alagappa University, Karaikudi, Tamil Nadu, India Satpal Baloda Department of Horticulture, College of Agriculture, CCS Haryana Agricultural University, Hisar, Haryana, India Ahmed Barhoum NanoStruc Research Group, Chemistry Department, Faculty of Science, Helwan University, Helwan, Cairo, Egypt National Centre for Sensor Research, School of Chemical Sciences, Dublin City University, Dublin, Ireland Dana M. Barry Department of Electrical & Computer Engineering, Clarkson University, Potsdam, NY, USA Science/Math Tutoring Center, The State University of New York at Canton, Canton, NY, USA Mohamed Naceur Belgacem University of Grenoble Alpes, CNRS, Grenoble INP, LGP2, Grenoble, France Surina Bhadu Department of Biochemistry, College of Basic Sciences & Humanities, CCS Haryana Agricultural University, Hisar, Haryana, India Yen San Chan Department of Chemical Engineering, Curtin University Malaysia, Miri, Sarawak, Malaysia Nitin Bharat Charbe Departamento de Quimica Orgánica, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, Macul, Santiago, Chile Abdelwaheb Chatti Laboratory of Biochemistry and Molecular Biology, Faculty of Sciences of Bizerte, University of Carthage, Jarzouna, Tunisia Dinesh Kumar Chellappan Department of Life Sciences, School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia Thomas Shean Yaw Choong Department of Chemical and Environmental Engineering, Faculty of Engineering, Universiti Putra Malaysia, Selangor, Malaysia Michael K. Danquah Chemical Engineering Department, University of Tennessee, Chattanooga, TN, USA Kamal Dua Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Ultimo, NSW, Australia Harish Dureja Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak, India
Contributors
xv
Jyotsana Dwivedi Department of Pharmacy, Pranveer Singh Institute of Technology (PSIT), Kanpur, India Monika Dwivedi Lab for Multimolar Biomedical Imaging and Therapy, University of Science and Technology of China, Hefei, China Pankaj Dwivedi Lab for Multimolar Biomedical Imaging and Therapy, University of Science and Technology of China, Hefei, China Maria-Nefeli Efthymiou Department of Food Science and Human Nutrition, Agricultural University of Athens, Athens, Greece Rasha M. Elnashar Chemistry Department, Faculty of Science, Cairo University, Giza, Egypt Raed M. Ennab Department of Clinical Sciences/Vascular Surgery, Faculty of Medicine, Yarmouk University, Irbid, Jordan Niloofar Adib Eshgh Department of Textile Engineering, Faculty of Technical Engineering, Science and Research Branch, Islamic Azad University, Tehran, Iran Hanan S. Fahmy Department of Mechanical Engineering, Faculty of Engineering, South Valley University, Qena, Egypt Yanan Gao Key Laboratory of Ministry of Education for Advanced Materials in Tropical Island, Resources, Hainan University, Haikou, China María Luisa García Betancourt Centro de Investigaciones Químicas, IICBA, Universidad Autónoma del Estado de Morelos, Morelos, Mexico Zahra Goli-Malekabadi Bioengineering Center for Cancer, Department of Mechanical Engineering, Isfahan University of Technology, Isfahan, Iran Liu Guangli Anhui Medical University, Hefei, China Gaurav Gupta School of Pharmacy, Suresh Gyan Vihar University, Jagatpura, Jaipur, India School of Pharmaceutical Sciences, Jaipur National University, Jaipur, India Rayene Hamimed Laboratory of Bioactive Molecules and Applications, Department of Applied Biology, University of Tebessa, Tebessa, Algeria Selma Hamimed Laboratory of Biochemistry and Molecular Biology, Faculty of Sciences of Bizerte, University of Carthage, Jarzouna, Tunisia Mohammed Jaabir Department of Biotechnology and Microbiology, National College, Tiruchirappalli, Tamil Nadu, India S. N. Jaisankar Department of Polymer Science and Technology, Council of Scientific and Industrial Research-Central Leather Research Institute, Chennai, Tamil Nadu, India
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Contributors
B. Jayanthi Department of Biotechnology, Sona College of Arts and Science, Salem, Tamil Nadu, India Nejib Jebli Laboratory of Hetero-Organic Compounds and Nanostructured Materials, Faculty of Sciences of Bizerte, University of Carthage, Jarzouna, Tunisia Jaison Jeevanandam CQM – Centro de Química da Madeira, MMRG, Universidade da Madeira, Funchal, Portugal Sivakamavalli Jeyachandran Department of Biotechnology and Microbiology, National College, Tiruchirappalli, Tamil Nadu, India Anil Jogdand Department of Biomedical Engineering, Indian Institute of Technology Hyderabad, Hyderabad, India Aarti Kamboj Department of Molecular Biology, Biotechnology & Bioinformatics, College of Basic Sciences & Humanities, CCS Haryana Agricultural University, Hisar, Haryana, India Hideyuki Kanematsu Department Material Science and Engineering, National Institute of Technology (KOSEN), Suzuka College, Suzuka Mie, Japan R. Karthika PG & Research Department of Biotechnology, Mahendra Arts and Science College (Autonomous), Namakkal, Tamil Nadu, India Risa Kawai Department Material Science and Engineering, National Institute of Technology (KOSEN), Suzuka College, Suzuka Mie, Japan Ramin Khajavi Department of Polymer and Textile Engineering, South Tehran Branch, Islamic Azad University, Tehran, Iran Tabassum Khan Department Pharmaceutical Chemistry, SVKM’s Dr. Bhanuben, Nanavati College of Pharmacy, Mumbai, Maharashtra, India Nasrin Khanian Department of Physics, Faculty of Science, Islamic Azad University, Karaj, Iran Ramzi Khiari University of Monastir, Faculty of Sciences of Monastir, Laboratory of Environmental Chemistry and Clean Process (LCE2P-LR21ES04), Monastir, Tunisia Univ. Grenoble Alpes, CNRS, Grenoble INP, LGP2, Grenoble, France Department of Textile, Higher Institute of Technological Studies of Ksar Hellal, Ksar Hellal, Tunisia Univ. Grenoble Alpes, CNRS, CERMAV, Grenoble, France Zahra Khoubi-Arani Faculty of Polymer Engineering, Sahand University of Technology, Tabriz, Iran Apostolis Koutinas Department of Food Science and Human Nutrition, Agricultural University of Athens, Athens, Greece
Contributors
xvii
Gopal Shankar Krishnakumar Applied Biomaterials Laboratory, Department of Biotechnology, PSG Institute of Advanced Studies, Coimbatore, Tamil Nadu, India Kamlesh Kumari Department of Chemical Engineering, SLIET, Longowal, Punjab, India Patit Paban Kundu Department of Polymer Science and Technology, University of Calcutta, Kolkata, West Bengal, India Department of Chemical Engineering, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand, India Ahmed Landoulsi Laboratory of Biochemistry and Molecular Biology, Faculty of Sciences of Bizerte, University of Carthage, Jarzouna, Tunisia Jordy Kim Ung Ling Department of Chemical Engineering, Curtin University Malaysia, Miri, Sarawak, Malaysia Balaji Mahendiran Applied Biomaterials Laboratory, Department of Biotechnology, PSG Institute of Advanced Studies, Coimbatore, Tamil Nadu, India Mahshid Maroufkhani Department of Chemical, Materials and Polymer Engineering, Buein Zahra Technical University, Qazvin, Iran Paul McGrath Department of Electrical & Computer Engineering, Clarkson University, Potsdam, NY, USA Amin Meftahi Department of Polymer and Textile Engineering, South Tehran Branch, Islamic Azad University, Tehran, Iran Nanotechnology Research Center, Islamic Azad University, South Tehran Branch, Tehran, Iran Vijay Mishra School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, India Sanaz Mohammadzadeh-Komuleh Department of Chemistry, Shahrood University of Technology, Shahrood, Iran Mohammad Ehsan Momeni Heravi Department of Textile and Fashion Engineering, Mashahad Branch, Islamic Azad University, Mashhad, Iran Kandasamy G. Moodley Department of Operations and Quality Management, Durban University of Technology, Durban, South Africa Hamouda M. Mousa Department of Mechanical Engineering, Faculty of Engineering, South Valley University, Qena, Egypt A. Murugaesan PG and Research Department of Chemistry, Government Arts College, Ariyalur, Tamil Nadu, India Shalini Muthusamy Applied Biomaterials Laboratory, Department of Biotechnology, PSG Institute of Advanced Studies, Coimbatore, Tamil Nadu, India
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Contributors
Malladi Nagalakshmaiah Department of Polymer and Composite Technology & Mechanical Engineering (TPCIM) Institut Mines-Telecom, IMT Lille Douai, Douai, France Hamideh Najarzadeh Department of Textile Engineering, Faculty of Technical Engineering, Science and Research Branch, Islamic Azad University, Tehran, Iran Mohammad A. Obeid Faculty of Pharmacy, Department of Pharmaceutics and Pharmaceutical Technology, Yarmouk University, Irbid, Jordan Dahiana-Michelle Osorio-Aguilar Centro de Investigaciones Químicas, IICBA, Universidad Autónoma del Estado de Morelos, Morelos, Mexico Amina Othmani Faculty of Sciences of Monastir, University of Monastir, Monastir, Tunisia Aristeidis Papagiannopoulos Theoretical and Physical Chemistry Institute, National Hellenic Research Foundation, Athens, Greece Dinesh M. Pardhi School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland Kavitkumar Patel Department Pharmaceutical Chemistry, University of Mumbai, Mumbai, India Stergios Pispas Theoretical and Physical Chemistry Institute, National Hellenic Research Foundation, Athens, Greece Shayan Pournaghmeh Biomedical Engineering Department, Engineering Faculty, University of Isfahan, Isfahan, Iran Parteek Prasher Department of Chemistry, University of Petroleum & Energy Studies, Dehradun, India Himani Punia Department of Biochemistry, College of Basic Sciences & Humanities, CCS Haryana Agricultural University, Hisar, Haryana, India Akshaya Radhakrishnan Department of Biotechnology and Microbiology, National College, Tiruchirappalli, Tamil Nadu, India Shahrzad Rahmani Department of Chemical Engineering, Babol Noshirvani University of Technology, Babol, Iran Anju Rani Department of Biochemistry, College of Basic Sciences & Humanities, CCS Haryana Agricultural University, Hisar, Haryana, India Aravind Kumar Rengan Department of Biomedical Engineering, Indian Institute of Technology Hyderabad, Hyderabad, India Meriem M. Rezigue Faculty of Pharmacy, Department of Pharmaceutics and Pharmaceutical Technology, Yarmouk University, Irbid, Jordan
Contributors
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Maximiliano Rojas-Taboada Centro de Investigaciones Químicas, IICBA, Universidad Autónoma del Estado de Morelos, Morelos, Mexico Sowndarya Sampath Department of Polymer Science and Technology, Council of Scientific and Industrial Research-Central Leather Research Institute, Chennai, Tamil Nadu, India Pieter Samyn Applied and Analytical Chemistry Department, Institute for Materials Research, Hasselt University, Diepenbeek, Belgium Sonali Sangwan Department of Molecular Biology, Biotechnology & Bioinformatics, College of Basic Sciences & Humanities, CCS Haryana Agricultural University, Hisar, Haryana, India Ryo Satoh Department Creative Engineering, National Institute of Technology (KOSEN), Tsuruoka College, Yamagata, Japan Dimitrios Selianitis Theoretical and Physical Chemistry Institute, National Hellenic Research Foundation, Athens, Greece T. Selvankumar PG & Research Department of Biotechnology, Mahendra Arts and Science College (Autonomous), Namakkal, Tamil Nadu, India Jahara Shaikh Department Pharmaceutical Chemistry, SVKM’s Dr. Bhanuben, Nanavati College of Pharmacy, Mumbai, Maharashtra, India Shuwei Shen Lab for Multimolar Biomedical Imaging and Therapy, University of Science and Technology of China, Hefei, China Taha Rmoodbar Shojaei Department of Mechanical Engineering of Agricultural Machinery, Faculty of Agricultural Engineering and Technology, College of Agriculture and Natural Resources, University of Tehran, Karaj, Iran Amandeep Singh Department of Polymer Science and Technology, University of Calcutta, Kolkata, West Bengal, India Jeyachandran Sivakamavalli Department of Biotechnology, National College, Tiruchirappalli, Tamil Nadu, India Soroush Soltani Department of Chemical and Environmental Engineering, Faculty of Engineering, Universiti Putra Malaysia, Selangor, Malaysia Solar Energy Research Institute, National University of Malaysia, Bangi, Malaysia Mudigunda V. Sushma Department of Biomedical Engineering, Indian Institute of Technology Hyderabad, Sangareddy, Telangana, India Murtaza M. Tambuwala SAAD Centre for Pharmacy and Diabetes, School of Pharmacy and Pharmaceutical Science Ulster University, Coleraine, UK K. Tharini Department of Chemistry, Government Arts College, Tiruchirappalli, Tamil Nadu, India
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Contributors
Michelle Tiong Department of Petroleum Engineering, Curtin University Malaysia, Miri, Sarawak, Malaysia Jayanti Tokas Department of Biochemistry, College of Basic Sciences & Humanities, CCS Haryana Agricultural University, Hisar, Haryana, India Erminta Tsouko Department of Food Science and Human Nutrition, Agricultural University of Athens, Athens, Greece Abhilash Venkateshaiah Institute for Nanomaterials, Advanced Technologies and Innovation (CXI), Technical University of Liberec (TUL), Liberec, Czech Republic A. Vijaya Anand Department of the Human Genetics and Molecular Biology, Bharathiyar University, Coimbatore, Tamil Nadu, India Jyothy G. Vijayan Department of Chemistry, M. S. Ramaiah University of Applied Sciences, Bengaluru, India Xu Xiarong Lab for Multimolar Biomedical Imaging and Therapy, University of Science and Technology of China, Hefei, China Shikha Yashveer Department of Molecular Biology, Biotechnology & Bioinformatics, College of Basic Sciences & Humanities, CCS Haryana Agricultural University, Hisar, Haryana, India P. R. S. Yoganathan Department of Biotechnology, National College, Tiruchirappalli, Tamil Nadu, India Yue Zhao School of Mechanical, Materials, Mechatronic and Biomedical Engineering, Faculty of Engineering and Information Sciences, University of Wollongong, Wollongong, Australia
Part I Fundamentals
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Nanocelluloses: Sources, Types, Unique Properties, Market, and Regulations Sources, Types, Unique Properties, Market, and Regulations Jaison Jeevanandam, Jordy Kim Ung Ling, Michelle Tiong, Ahmed Barhoum , Yen San Chan, Caleb Acquah, and Michael K. Danquah Contents 1 2 3 4
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sources and Structure of Cellulose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Types and Classification of Nanocelluloses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cellulose Nanocrystals (CNCs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1 Cellulose Nanofibrils (CNFs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2 Bacterial Cellulose (BC) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Unique Properties of Nanocelluloses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1 Mechanical Strength . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2 High Binding Capacity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3 Low Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4 Biocompatibility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.5 Biodegradability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4 5 7 9 12 14 17 17 19 22 23 24
J. Jeevanandam CQM – Centro de Química da Madeira, MMRG, Universidade da Madeira, Funchal, Portugal J. K. U. Ling · Y. S. Chan Department of Chemical Engineering, Curtin University Malaysia, Miri, Sarawak, Malaysia M. Tiong Department of Petroleum Engineering, Curtin University Malaysia, Miri, Sarawak, Malaysia A. Barhoum (*) NanoStruc Research Group, Chemistry Department, Faculty of Science, Helwan University, Helwan, Cairo, Egypt National Centre for Sensor Research, School of Chemical Sciences, Dublin City University, Dublin, Ireland e-mail: [email protected] C. Acquah Faculty of Health Sciences, University of Ottawa, Ottawa, Ontario, Canada M. K. Danquah Chemical Engineering Department, University of Tennessee, Chattanooga, TN, USA © Springer Nature Switzerland AG 2022 A. Barhoum (ed.), Handbook of Nanocelluloses, https://doi.org/10.1007/978-3-030-89621-8_4
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6 Global Market . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 International Regulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Abstract
Celluloses are insoluble polysaccharides that are formed by glucose monomer chains and are crucial constituents of plant cell walls, vegetable fibers, and bacterial cells. Cellulose polymers can be extracted from natural sources and modified into nanocelluloses via mechanical, chemical, or enzymatic approaches to be utilized in environmental and biomedical applications. However, high molecular weight, cost of production, and lack of compatibility with other materials are the major limitations of celluloses. Thus, this chapter discusses the distinct sources and exclusive properties of nanocelluloses. Additionally, the global market and international regulations that are implemented on the commercial usage of nanocelluloses were elucidated. Keywords
Nanocelluloses · International regulations · Biodegradability · Cellulose nanofibrils · Bacterial cellulose nanofibers
1
Introduction
Recently, several nanomaterials have been introduced as a potential alternative to bulk materials in various fields due to their exclusive properties influenced by their high surface to volume ratio [41]. Nanomaterials are traditionally synthesized via chemical or physical approaches. Though these two approaches yield smaller nanomaterials, their cost of production is prohibitive and requires the use of toxic chemicals [39, 40]. Biosynthesis of nanomaterials via natural sources such as enzymes, biomolecules of microbes, or phytochemicals from plants is highly preferred for numerous applications, especially biomedical applications [39, 40]. Among the wide variety of biosynthesized nanomaterials, nanocelluloses are gaining enormous significance as potential polymeric nanomaterials among researchers. Celluloses are insoluble polysaccharides formed by glucose monomer chains and constitute a crucial element of plant cell walls, vegetable fibers, and bacterial cell walls [10]. However, the relatively high molecular weight, cost of production, and lack of compatibility with other biomaterials are the major limitations of celluloses [82]. As a result, in recent times, cellulose polymers extracted from natural sources are engineered into nanocelluloses via mechanical, chemical, or enzymatic approaches [64]. These nanocelluloses are widely used in both environmental and biomedical applications as shown in Fig. 1. Thus, this chapter describes the distinct variation in sources and exclusive properties of nanocelluloses. Additionally, the global market and international regulations that are implemented on the commercial usage of nanocelluloses are also discussed.
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Fig. 1 Biomedical and environmental applications of nanocelluloses [61]. © Reproduced with permission from Elsevier (2020)
2
Sources and Structure of Cellulose
Cellulose is a ubiquitous polymeric material that is widely used as commercial raw material. Plant fibers, such as cotton, hemp, flax, and jute, as well as wood (about 42 percent cellulose) are crucial sources of cellulose. Further, cellulose is a β-dglucopyranose subunit of homopolymer linked by the (1!4) bond, which is β-1,4-glucan. The β-1,4-glycosidic linkage stereochemistry creates a linear chain of glucan where glucose residue is rotated to 180 . Numerous cellulose chains are combined for the formation of a crystalline or paracrystalline lattice where both intrachain (intramolecular) and interchain (intermolecular) hydrogen bonds are used for stabilization. It can be noted that the intrachain bonds of hydrogen are formed between the oxygen rings with a residue and the C3 hydroxyl hydrogen of an adjacent residue. Hydrogen bonds in the interchain are formed between the atoms of oxygen and adjacent hydroxyl chains with van der Waals forces providing additional stability. Hydroxyl groups in a chain of cellulose bonds result in an inert straight macromolecule which makes them a strong and durable natural material. Besides, cellulose microfibrils in vascular plant primary walls are generally made of 36 β-glucan chains with certain chains having 500 glucose residues, while others have 2500 to 4500 residues. Additionally, individual chains may be stunned with few overlapping neighbors within a microfibril [7]. Cellulose can be extracted from numerous sources such as seed fibers, wood, grasses (bamboo, bagasse), algae, and many more as shown in Table 1. Among these
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Table 1 Sources of cellulose that can be utilized for the fabrication of cellulose nanofibers [54]. © Reproduced with permission from World Scientific (2020) Crop Wood Sugarcane Oil palm fruit Wheat Cotton Barley Almond Jute Coir Sisal Ramie Flax Hemp Abaca
Leading producer country Russia, North America, Africa, South America South America, Asia, North America Asia, South America North America, Russia, Europe, Asia China, India North America North America, Europe Asia, China Asia South America China China, Canada, Russia China, Europe, Russia Asia, South America
Type Stem Bast Seed Bast Seed Bast Seed Bast Seed Leaf Bast Bast Bast Leaf
sources, wood is considered the most common source of cellulose [88, 90]. Wood can be classified as hardwood and softwood. Generally, hardwood requires more mechanical action compared to softwood for equivalent fibrillation [90, 99]. Other than cellulose, wood contains lignin, hemicelluloses, and phytochemicals. Cellulose is the primary structure responsible for the mechanical strength of wood. It has fibrillar element architecture that is composed of cells with several layers (illustrated in Fig. 2), including the middle lamella (ML); the primary wall (P); the outer (S1), middle (S2), and inner (S3) layers of secondary wall; and the warty layer (W). The middle lamella is identified to bind with the neighboring cells and contains a high lignin content. The cell walls are composed of three significant components: matrix, cellulose, and hemicellulose [49, 89]. The prime cell wall is roughly 30–1000 nm in thickness and comprises microfibrils of cellulose that are located diagonally. The minor cell wall has S1, S2, and S3 layers with a distinct microfibril angle according to the axis of the fiber. The alignment of microfibrils is parallel in these layers and is compactly packed in a flat helix. Further, the cellulose fiber mass is based on the secondary wall and has 100–300 nm of thickness in cotton and spruce wood. This fibrous form is a thin watery layer of hemicellulose and lignin located on the inner cell-wall surface. With the advancement of nanotechnology, cellulose can be transformed into nanocellulose at a lower cost with enhanced properties. Nanocelluloses are the extracts from natural celluloses fabricated into nanosized structures. To synthesize nanosized celluloses, different approaches are utilized which result in particles with various properties including hydrophilicity, chirality, biodegradability, comprehensive chemical modifying capacity, and semicrystalline versatile fiber morphology formation. The enhanced fiber surface ratio can lead to robust interactions with the surroundings such as in the incorporation of huge water quantity and sturdy connections with other biomaterials and polymers, including catalysts [22].
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Glycoproteins Helicoidal transitions (cellulose microfibrils)
Bundles of cellulosein amorphous matrix
Sec on cell dary wal l
S1 Hemicellulose S3
S2 Primary cell wall
S2 S1
Pectin Microfibril
Macrofibrils in amorphous region Amorphous domain Crystalline domain Parallel polymer chains
Tree m
Plant cell walls cm/mm
Macrofibril µm
E-1,4-linkedD-glucose
Microfibril nm
Å
Fig. 2 An illustration of the wall layers and composition of wood [30]. © Reproduced with permission from Springer (2018)
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Types and Classification of Nanocelluloses
Generally, the nanocellulose family can be divided into different types such as (1) spherical cellulose nanoparticles; (2) cellulose nanocrystals (CNC), also known as nanocrystalline cellulose; (3) nanofibrils of cellulose (CNF), called nano, microfibrillated cellulose (NFC), (MFC), and nanofibers of cellulose; and (4) cellulose from bacteria (BC), which can be referred to as microbial cellulose (MBC) as shown in Fig. 3. Notably, CNF is under extensive research with greater clarity on its properties relative to CNC and BC. Different types of nanocelluloses pose different distinct properties that impose their feasibility and functionality as displayed in Fig. 4. For example, one of the unique features is the enhanced strength of Young’s modulus (e.g., 10 GPa for CNC) which can be assessed in a variety of aspect ratios depending on the type of component, as well as latent compatibility with other materials such as living cells and polymers [1]. Besides, the material and chemical processing technologies for
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Fig. 3 Classification of nanocelluloses [67]. © Reproduced with permission from [67]
a
b
c
Fig. 4 Structure of different types of nanocellulose. (a) Hierarchal structure of cellulose from meter to nanometer scale, (b) reaction between strong acid and cellulose to form nanocellulose, and (c) structure of bacterial cellulose nanofibers [69]. © Reproduced with permission from Michelin et al. [67]
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Table 2 Nanocellulose materials and their sources [85]. © Reproduced with permission from Elsevier (2019) Type of nanocellulose Microfibrillated cellulose
Selected references and synonyms Microfibrillated cellulose, nanofibrils and microfibrils, nanofibrillated cellulose
Nanocrystalline cellulose
Cellulose nanocrystals, crystallites, whiskers, rodlike cellulose microcrystals Bacterial cellulose, microbial cellulose, biocellulose
Bacterial nanocellulose
Typical sources Wood, sugar beet, potato tuber, hemp, flax
Wood, hemp, cotton, flax, wheat straw, mulberry bark, ramie, Avicel, tunicin, cellulose from algae and bacteria Low molecular weight sugars and alcohols
Formation and average size Delamination of wood pulp by mechanical pressure before and/or after chemical or enzymatic treatment Diameter: 5–60 nm Length: several micrometers Acid hydrolysis of cellulose from many sources Diameter: 5–70 nm Length: 100–250 nm Bacterial synthesis Diameter: 20–100 nm; different types of nanofiber network
nanocellulose fabrication are tremendously adaptable providing an inclusive structural and functional range of possibilities. These have opened up novel fields of cellulose applications such as porous nanosized hydrophilic membranes, composite nano-scaffold materials, and hard and soft tissue repairing medical implants, especially for cardiovascular alternatives [51]. To produce nanocelluloses, novel approaches involving enzymatic/chemical/ physical methodologies to separate them from wood and agricultural residues were utilized via a bottom-up method. A similar method was utilized for the fabrication of cellulose nanofibrils from bacterial glucose. Conventionally, two techniques are involved: (1) bacterial cellulose bio-formation and (2) plant cellulose disintegration via refiner shear forces [50, 71]. The details of sources for each type of cellulose are discussed and presented in Table 2.
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Cellulose Nanocrystals (CNCs)
CNCs, also called whiskers, consist of rodlike crystals of cellulose with 5–70 nm of width and several hundred microns of length. CNCs are mostly engendered using acid hydrolysis and heat-controlled techniques eliminating sections of an amorphous and purified source of cellulose after treating them with ultrasonication. As part of cellulose fiber crystal extract, selective areas of amorphous hydrolyzed cellulose with enhanced crystallinity are fabricated via CNCs from the plant source. Sulfuric acid hydrolyses are negatively charged with half-ester sulfate on the surface of the nanocellulose particle. It is designed to prevent the aqueous aggregation of the particles due to electrostatic repulsion. In addition, the rodlike CNC morphology
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can lead to self-assembled liquid crystalline behavior, depending on their concentration [1]. The cellulose sources are varying, and the dimensions of the created crystals are strongly influenced by their crystallinity degree. For example, 90% of nanosized crystalline rods can be obtained from cotton, wood, and Avicel [17], whereas the generated large polydisperse crystals comparable to those of CNFs can be obtained from tunicin, bacteria, and algae [19, 78, 81, 94]. Though they are similar in size to CNFs, their flexibility is very limited due to the absence of an amorphous region. These CNCs are widely used in drug delivery, barrier coating, and antimicrobial and superhydrophobic agents as displayed in Fig. 5. CNC can be derived from distinct source types such as cell walls of plants, cotton, algae, microcrystalline cellulose, bacteria, and animals (Fig. 6). Conventionally, CNC crystals have exclusive geometries based on their biological sources. It is noteworthy that the membrane of cellulose from algae is rectangle in structure, whereas twisted geometry of ribbon was displayed for cellulose chains from both bacterial and tunicates [44]. The sources of CNC can be divided into two categories: (1) lignocellulosic sources and (2) extracts from algae, animals, and bacteria. The most common source is lignocellulosic sources, also known as woody and nonwoody plants. Further, natural fibers of lignocelluloses are categorized according to the plant origin such as
Fig. 5 Biomedical applications of cellulose nanocrystals [75]. © Reproduced with permission from Michelin et al. [67]
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a
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b
c
Fig. 6 Methods of cellulose nanocrystal fabrication: (A) CNC-based hydrogel beads for methylene blue dye removal in stages, such as (a) hydrogel formation, (b) batch adsorption, and (c) fixed bed adsorption process. (B) CNC for kaolin clay particles via coagulation-flocculation process. (C) Metal ion capture via CNF/CNC with (a) acetone treated membrane, (b) cumulative metal ion capture via CNCs, and (c) SEM image of membrane surface with nucleated metal ions [26]. © Reproduced with permission from Elsevier, 2017
leaf, bast or stem, grass, seed or fruit, and straw fibers. Furthermore, 2000 fiber plant species have been reported till now. On the other hand, ocean tunicates are identified as the only animal cellulose source. There are three classes for tunicates; however, only two classes, namely, Ascidiacea and Thaliacea, contain tunics, which is an exclusive integumentary tissue that covers the entire animal epidermis. Besides, the resultant cellulose was identified as chemically identical to cellulose extracted from plants. Nevertheless, there are differences in terms of their structure due to the variety of tunicate families and species. Likewise, the yield of production is directly proportional to the extract and tunicate-extracted cellulose usage. It should be noted that the tunicate species belongs to the Ciona intestinalis and can be used for the formation of CNC at high ocean densities, which leads to the large-scale production of cellulose [76]. Thus, tunicates are considered as a unique candidate for the synthesis of CNCs. Besides, algae could also be used to produce CNC. For instance, Gelidium red algae have been reported to have a high quantity of carbohydrates and are readily available for commercial applications [43, 48]. In addition, green algae, which belong to the order of Valonia or Cladophora, exhibit crystallinity of 95%. On the other hand, Gram-negative bacteria producing acetic acid are considered as the
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Table 3 Sources of CNC Sources Woody plants Nonwoody plants Animal Algae Bacteria
Examples Softwood, hardwood Sawdust wastes, flax fibers, oil palm, peanut shells, potato peel, jute fibers, kenaf, hemp, bagasse, corn, pineapple leaf, white coir, alfa, bamboo, sunflower, garlic straw Tunicates (especially Ciona intestinalis tunicate species) Red algae (e.g., Gelidium), green algae (e.g., Valonia, Cladophora) Gluconacetobacter
most efficient for CNC particles using the bacterial glucose, named Gluconacetobacter. This source is explained in-depth in Section 4.2: Sources of BC. Overall, the sources of CNC are listed in Table 3.
4.1
Cellulose Nanofibrils (CNFs)
Unlike CNCs with ca. 90% of crystals, CNFs are fibrils with entangled micrometer length and cellulose domains of both amorphous and crystalline nature. The lengthy particles provide enhanced suspensions by improving the viscosity of the aqueous medium at moderately low concentrations. The manufacture of CNFs can be traced back to the late 1970s and early 1980s pioneered at ITT Rayonier, USA [31]. The suspension force by wood-based cellulose fibers through high-pressure homogenizers can produce CNFs. This mechanical treatment can split the fibers and liberate the microsize fibrils which have an enhanced aspect ratio with the characteristic of a gel in water, as shown in Fig. 7. Other than mechanical treatment such as homogenization, grinding, and ball milling, CNFs can be extracted from cellulosic fibers through other processes involving mechanical and/or chemical approaches. In contrast to BC, pure cellulose structure isolation with 1–100 nm dimensions from wood and plants requires multistage disintegration processes. One of the processes is high pressure homogenization of pulps (Fig. 8) based on ITT Rayonier procedures [31]. Besides, pulps can also be produced from wood by chemical treatments. There are two types of pulp: (1) kraft pulp (by mixing sodium hydroxide and sodium sulfide), which is also known as pure cellulose fibers, and (2) sulfite pulp (pulverizing with salts of sulfurous acid), with several cellulose fiber by-products. Regardless of the pulp type, the use of homogenizers is energy intensive and can lead to extensive clogging. Hence, a delamination process associated with the addition of hydrophilic polymers such as poly (acrylic acid), methyl cellulose, carrageenan, and guar gums is essential to reduce the tendency to clog and enable enhanced consistency of the pulp [96]. Nevertheless, five to ten passes through homogenization are required to provide gel-like characteristics for CNF. Compared to kraft pulps, the delamination process is simple among sulfite pulps with a high content of hemicellulose and/or dense charge to ease the delamination process. It is astonishing to note
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Fig. 7 Surface area of nanocelluloses. From left to right: cellulose microfibril network, cellulose nanocrystals, and cellulose nanofibers [35]. © Reproduced with permission from Elsevier (2019)
Fig. 8 High pressure pulp homogenization approach for cellulose nanofibril fabrication [45]. © Reproduced with permission from Elsevier (2019)
that CNFs of about 27000 kWh per ton are needed to fabricate gel-like CNFs from the suspension of a sulfite pulp [60]. Besides, completely delaminated CNFs can be fabricated through carboxymethyl group introduction. This group of CNFs will
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1 Purification
> 50 types of CNF
– homogenization; – grinding; – refining; – extrusion; – blending; – ultrasonication; – cryocrushing; – steam explosion; – ball milling; – aqueous counter collision.
2 Mechanical pretreatment – blending; – refining; – grinding.
3 Biological/chemical pretreatment – enzymatic hydrolysis; – carboxylation; – carboxymethylation; – quaternization; – sulfonation; – solvent-assisted pretreatment.
4 Principal mechanical treatment
cooking and bleaching
5 Post-treatment – chemical modification; – fractionation.
1 raw material wood, plants etc.
Fig. 9 Schematic diagram of CNF process conditions [73]. © Reproduced with permission from American Chemical Society (2016)
become swollen pulps after being exposed to sodium salts which have lower cellwall cohesion, making them easier to delaminate. According to Iwamoto et al. [36], another kind of pulp that is easy to delaminate is holocellulose with anionic polysaccharides [36]. In recent times, researchers focus on sustainable synthesis approaches that are energy-efficient to produce CNFs. This is done by pretreating CNFs via physicochemical and enzymatic techniques prior to homogenization to minimize the consumption of energy. In fact, many protocols are followed for a delamination process such as elevated refining of shear, microfluidizers, crushing of cryogenics in numerous configurations [98], refiner-type treatments [72], a combination of beating, rubbing and homogenization [74], ball mills and ultrasonification [105]. However, it is still not conceivable to judge which treatment types are the best as the energy efficiency determination and the delamination extent for certain energy types are not quantitatively accessible at present. Different production mechanisms require different sources as summarized in Fig. 9.
4.2
Bacterial Cellulose (BC)
BCs are fabricated from numerous carbon sources, such as mono- or oligosaccharides, organic acids, and alcohol [34, 65]. Their yields from distinct carbon sources are tabulated in Table 4. BC is formed through fermentation which opens up a way for in situ shaping of cellulose, also known as bio-shaping. During bacteria cultivation, a variety of shapes including flat materials, i.e., fleeces and foils, fibrils (Fig. 10a), hollow bodies (Fig. 10b), spheres, fibers, and coatings, can be obtained through bio-shaping with great effectiveness.
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Table 4 Bacterial cellulose productivity from various carbon sources [47]. © Reproduced with permission from African Journals online (2005)
Carbon sources Fructose Saccharose Inositol Glycerol Galactose Ethanol Methanol
15
Yield, % (compared to 1% glucose) 95 69 85 155 24 25 22
Fig. 10 Morphology of bacterial cellulose: (a) fibrils and (b) hollow bodies. © [5] under Creative Commons Attribution License (CC BY)
BC can be obtained from microbes extracellularly, and the most competent cellulose producing microbe is Gluconacetobacter xylinum (an aerobic acetic acid bacteria), which can yield up to 40% depending on the carbon source, e.g., glucose [52]. These bacteria are commonly cultured in aqueous media with nutrients, e.g., sugar after fermentation and plant carbohydrates. The processing time is identified to range from a day to 2 weeks [23]. BC is labeled as an exopolysaccharide that interacts with atmospheric air. Even though BC possesses similar chemical composition compared to plant cellulose, BC has free functional groups with only alcohol and does not require pretreatment to eliminate hemicellulose and lignin prior to hydrolysis. Further, it is fabricated as pure cellulose with average molecular weight, enhanced crystallinity, and excellent mechanical stability. Furthermore, it is designed as a nanomaterial and polymer via processes of biotechnological assembly from carbon sources such as D-glucose with low molecular weight and requires no isolation from cellulose sources. This is also known as white biotechnology of
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cellulose. BC nanofibers normally have an average diameter of 20–100 nm enclosing up to 99% water. It has a polymerization degree of 3000–9000 and a distinctive crystallinity of 80–90%. The resulting unique features of BC can entangle to form stable network structures that can form with novel functionalities, properties, and nanocellulose applications. One of the well-known examples is its ability serve as a superior in vivo tissue scaffold which provides a novel vista for implants in the medical field to repair hard and soft tissues [52, 53]. Flat products from bacterial cellulose are usually produced via static cultivation in an aqueous medium with nutrients or in cultivation with a thin layer on phases of solid such as silicone, agar, rubber, and other membranes with pores. For fleeces and foils specifically, strain type, culture medium volume, and cultivate time are the main factors in controlling their size and thickness [51]. On the other hand, the matrix application in the static culture leads to tube formation which is appropriate as medicinal vascular implants. The BC formation can be in the shape of spheres and fibrils under the condition of frantic cultivation, which is regulated by the agitation intensity and type. However, there are certain limitations such as only bacterial strains of Gluconacetobacter, i.e., ATCC 53582 and Komagataeibacter sucrofermentans, are adaptable to rapid mutations for the formation of BC with altered properties and structures as shown in Fig. 11 [32].
a
b
GIc 6CF-GLc
Chemical synthesis 6CF-GIc
Fermentation medium
Komagataeibacter sucrofermentans
c
Lamellar structure
Primary structure Cellulose chain Micro fiber
Bacterial cellulose
e
d
Fig. 11 Formation of bacterial cellulose with cellulose chain via simple chemical approach [21]: (a) molecules of glucose and 6-cellulose fiber, (b) fermentation of microbe, (c) bacteria-mediated cellulose fiber formation, (d) BC microstructure, and (e) microbial fermentation-mediated BC pellicle formation. © Reproduced with permission from Nature (2019)
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Unique Properties of Nanocelluloses
Nanocellulose exhibits diverse, remarkable properties, and these properties can be usually categorized into three parts, mainly, mechanical, chemical, and biological properties [58]. Owing to these properties, nanocellulose has been employed in numerous applications like composite reinforcement, paper additive, drug delivery, and functional material [56, 91].
5.1
Mechanical Strength
Cellulose elementary fibrils consist of a varying portion of crystalline (ordered) regions and amorphous (disordered) fraction, depending on their origin, and the modulus of these alternating regions characterized the mechanical nanocellulose properties. Crystalline cellulosic domains contribute to the material’s elasticity and stiffness, whereas the amorphous fraction contributes to the materials’ plasticity and flexibility [58]. Further, the various nanocellulose types with modulus are expected to contribute to the mixing of regions with crystallinity and amorphous nature. That said, the variations in the mechanical properties are inevitable as the fraction of crystallinity and amorphous nature in nanocellulose is distinct. For example, CNC, which exhibits more crystalline region, has a higher stiffness compared to the fibrillated cellulose such as cellulose microfibrils (CMF) and cellulose nanofibrils (CNF) with both cellulosic regions of amorphous and crystalline nature [70]. The properties of mechanical strength, mainly Young’s modulus of the nanocellulose, have been examined through either numerical simulations or measurements using experiments. However, to date, a wide distribution of values has been reported, and there is no recognition of a standard value since there are limited metrology techniques available. Also, the mechanical properties are sturdily affected by several factors, predominantly, the composition of chemicals and plant location [70], as shown in Fig. 12. Remarkably, most works have been intensified on the swiftly measurable elastic properties in the material’s axial direction. It is worth pointing out that the axial mechanical properties decline with an increment in the angle of microfibril (MFA), i.e., the average angle between the microfibril direction and the axis of the axials. A wide value range for the CMF modulus (involving CNF) was reported, and it is generally accepted that the average modulus is around 100 GPa [58]. In most cases, atomic force microscopy (AFM) was utilized to quantify the CNF elastic modulus via a three-point bending test where the filament in the center is disturbed by a force with a known value, as illustrated in Fig. 13. For example, Cheng et al. [12] identified that the modulus of elasticity at an axial direction for regenerated Lyocell CMF, pulp CMF, and commercial CMF was 98, 81, and 84 GPa, respectively. Besides that, Iwamoto et al. [37] also employed AFM to estimate the modulus of single CMF from tunicate (Halocynthia papillosa) prepared by 2,2,6,6-tetramethylpiperidine-1-oxyl radical-oxidation (TEMPO-oxidation) and acid hydrolysis and revealed that the modulus was around 145 and 150 GPa, respectively. Recently,
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b
c
Fig. 12 Mechanical properties of various cellulose nanofibrils [3]: (a) isotherms of nanofibrillated cellulose (NFC) moisture sorption, (b) Young’s modulus plot of NFC and NFC composite, and (c) stress-strain curves of NFC and different concentration of NFC composite. © Reproduced with permission from Elsevier (2014)
Parvej et al. [77] studied the transverse modulus of a single strand of CNF using AFM, and the transverse modulus of elasticity was calculated to be around 6.9 GPa. Similarly, the values of an extensive elastic modulus range were described for CNC, and these values generally fall between 110 and 220 GPa, which is significantly higher than CMF [70]. For example, Wu et al. [103] obtained the elastic modulus value of 139.5 GPa by using atomistic simulations. Aside from that, Tanaka et al. [92] evaluated the natural cellulose crystal elastic modulus value via molecular simulation technique and found that the modulus values were between 124 and
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Fig. 13 Schematics of a three-point bending test using atomic force microscopy (AFM) [18]. © Reproduced with permission from Walter de Gruyter GmbH & Co KG (2017)
155 GPa. On the other hand, Lahiji et al. [55] used AFM to calculate the modulus of CNC in a transverse direction where they compared the experimental curves of force-distance with calculations of 3D finite elemental analysis. The transverse modulus was estimated to be between 18 and 50 GPa. The transversal modulus is comparatively lower as there are about tenfold discrepancies between total bond energies that are acting in the direction of axial and transverse angles of cellulose crystals [33]. The different values reported for CNC are collected in Table 5. Owing to the impressive modulus of elasticity and tensile strength, nanocellulose, mainly CNC, is often regarded as a perfect model for reinforced polymer composite processing techniques. Some of the reinforcement composite materials are summarized in Table 6. Based on Table 6, CNC with 1.6 g.cm-3 of density is considered as a material with lightweight; nonetheless, they possess stronger tensile strength as compared to Kevlar fiber, carbon fiber, and steel wire. Notably, CNC only has approximately 25% of the strength of carbon nanotube (strongest nanofiber produced today); however, it is worthy to note that the costs for carbon nanotube are much higher as compared to nanocellulose, which makes nanocellulose more attractive for certain applications [9].
5.2
High Binding Capacity
Cellulose is a β-1,4-linked anhydro-D-glucose unit of homopolysaccharide in which these units rotated about 180 , similar to its neighbors, with repeated glucose dimer segments. One of the special features of cellulose is that the cellobiose monomer is borne with three hydroxyl group, which allows strong hydrogen bond formation with the adjacent unit of glucose in the same chain (intramolecular hydrogen bonding), and with distinct chain (intermolecular hydrogen bonding), as depicted in Fig. 14 [58, 79]. Owing to these available hydroxyl groups, nanocellulose exhibits
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Table 5 Axial and transverse modulus of nanocellulose Axial modulus, EA (GPa) 98 81 84
Transverse modulus, Et (GPa) -
AFM
145–150
-
AFM
-
6.9
Atomistic simulation Molecular simulation AFM
139.5
-
Material Lyocell MFC Pulp MFC Commercial MFC TunicateCMF CNF
Method AFM
CNC Cellulose crystals CNC-wood
124–155 -
18– 50
Reference Cheng et al. [12]
Iwamoto et al. [37] Parvej et al. [77] Wu et al. [103] Tanaka et al. [92] Lahiji et al. [55]
Table 6 Properties of cellulose and several reinforcement materials [70]. © Reproduced with permission from Royal Society of Chemistry (2011) Material Kevlar-49 fiber Carbon fiber Steel wire Clay nanoplatelets Carbon nanotubes Boron nanowhiskers Crystalline cellulose
Density, ρ (g cm-3) 1.4 1.8 7.8 -
Tensile strength, σf (GPa) 3.5 1.5–5.5 4.1 -
Elastic modulus in axial direction, EA (GPa) 124–130 150–500 210 170
-
11–63
270–950
-
2–8
250–360
1.6
7.5–7.7
110–220
a reactive surface. It is important to point out that the hydroxyl group’s reactivity on various positions is heterogeneous. The hydroxyl groups located at the sixth position behave like primary alcohol, whereas the hydroxyl groups attached at carbon atoms 2 and 3 act as the secondary alcohols. Interestingly, the hydroxyl group reactivity at the sixth position is ten times rapid than the other OH group, while the hydroxyl group reactivity at the second position is twice compared to the third position [58]. With the presence of these groups of hydroxyl compounds, nanocellulose provides an exclusive platform for novel material synthesis via chemical alterations such as esterification, polymer granting, and oxidation. These chemical functionalizations are mainly due to the introduction of stable negative/positive charges of electrostatics on the surface of the nanosized cellulose surface or by tuning the surface energy [27]. Among the chemical modification approaches, esterification,
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Fig. 14 Intramolecular ( ) and intermolecular ( ) hydrogen bonding networks in cellulose structure [79]. © Reproduced with permission from Elsevier (2018)
Fig. 15 Schematics of surface-stearoylated cellulose nanoparticle synthesis [100]. © Reproduced with permission from WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim (2015)
which was the first technique to synthesize cellulose derivatives, remains one of the most prominent techniques (Wang et al. 2018a, b). For instance, esterification of nanocellulose successfully overcome the poor dispersibility of nanocellulose in nonpolar solvents. A typical example of esterification of nanocellulose is the synthesis of novel surface-stearoylated nanocellulose from microcrystalline cellulose (presented in Fig. 15), where the synthesized surface-esterified nanocellulose demonstrated good dispersibility in various nonpolar organic solvents (Wang et al. (2015). The surface-esterified nanocellulose significantly promoted their compatibility with nonpolar compounds and demonstrated a great promising attribute in the construction of multifunctional materials. Apart from reactive groups, surface charges of nanocellulose are another important aspect in surface chemistry, commonly known as sulfate esters (“-“ OSO 3 ) with a negative charge on CNC. The negative esters of sulfate are fabricated via cellulose hydrolysis with sulfuric acid (H2SO4), where the sulfuric acid reacts with the surface hydroxyl groups of cellulose [58]. The charges in the group of negative particles promote the dispersion of the nanocellulose in a liquid medium. For instance, it was found that with more negative sulfonic group content, the sulfated nanocellulose
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exhibited a lower zeta potential value (more negative surface), which indicated good phase stability of nanocellulose dispersion [58]. Nonetheless, it is noteworthy that the existence of negative surface charged sulfonic groups can alter the characteristics of nanocellulose, mainly its stability toward temperature, which is relatively significant in the melt processed synthesis approach. However, it has been identified that the nanocellulose which contains a negative sulfonic group is less thermostable than the nanocellulose, which does not contain sulfonic group (prepared by hydrochloric acid hydrolysis) [33]. Therefore, studies on optimizing the hydrolysis conditions are of great interest and important to obtain thermostable nanocellulose.
5.3
Low Toxicity
Low toxicity is also a remarkable chemical property of nanocellulose. Although nanocellulose is yet to be designated as generally recognized as safe (GRAS), researchers have proven that nanocellulose exhibits a low risk of toxicity, as shown in Fig. 16, allowing its wide usage for future benefits. For instance, Jeong et al. [42] studied the toxicity of nanocellulose in vitro and in vivo and found that the nanocellulose was not toxic to the endothelial cells of umbilical vein from humans and there were no negative effects on mice. Another in vivo study also reported that intake of 7 wt%, 14 wt%, and 21 wt% of nanocellulose suspension has been identified to be hazardous in the metabolism of animals [2]. Moreover, DeLoid et al. [16] also utilized a stimulator in the tract of the gastrointestine for the digestion of ingested nanocellulose to confirm that nanocelluloses (CNF and CNC) have low toxicity. Additionally, the research team also performed in vivo toxicity test and realized that there are no hematology variations, markers of serum, and histology Production and chracterization
Toxicological studies In vitro
Cellulose nanofibrils (CNFs) Size and shape Surface chemistry
Cellular uptake
No uptake into cells No oxidative stress
Immunotoxicity
Charge functionalization Cellulose nanocrystals (CNCs)
Main outcomes
In vivo
No relevant cytotoxicity Possible genotoxicity
Cytotoxicity Aspect ratio Crystallinity
Oxidative stress
Low uptake into cells, but internalized into phagocytic cells
Genotoxicity
No relevant cytotoxicity
Aggregation
Inflammation
Fig. 16 Characteristics and toxicological study-dependent benefits of nanocelluloses (cellulose nanofibrils and cellulose nanocrystals) for biomedical applications [97]. © Reproduced with permission from Springer Nature (2020)
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between rats and controls given with suspension of CNF, indicating that the ingested nanocellulose is likely nonhazardous. Despite these studies confirming that nanocellulose does not generate concerns toward cytotoxicity, high evaluations are still obligatory to ascertain the safety of nanosized cellulose commercialization.
5.4
Biocompatibility
Nanocelluloses are highly biocompatible for varied biomedical applications. Biocompatibility describes the ability of a material to be compatible with living tissues in the body. The biocompatibility of nanocellulose is evidenced in numerous researches. Particularly, Hakkarainen et al. [28] investigated the NFC from wood for the dressing of wounds. They found that the NFC dressing did not cause any allergic reactions or inflammatory response and demonstrated high biocompatibility with the skin graft donor sites. Another biocompatibility testing was performed recently by Han et al. [29] where they prepared novel polyaniline-cellulose nanofiber-polyvinyl alcohol hydrogel and evaluated their biocompatibility using L929 cells by MTT assay. It was realized that in all tested concentrations of hydrogel extracts, the cell viability of the group reached above 90%, confirming the excellent biocompatibility of CNF-based hydrogel. It is interesting to highlight that bacterial nanocellulose (BNC) is often regarded as a better biocompatible material than other nanocellulose types. This is attributed to its gel network and the coating via BNC gels with external surfaces [23]. For example, Wang et al. (2018a, b) assessed the in vivo biocompatibility test of BC scaffold using a rabbit model and found that all the BC scaffolds did not provoke a reaction in the external surface of the body and the adjacent tissue in the subcutaneous region that are cohesive with all implanted scaffolds. This finding suggests that the BC scaffolds are potentially good to be used as a biocompatible material. Besides, Zang et al. [104] examined the biocompatibility of BC tube for the application of vascular tissue engineering (artificial blood vessel material). The authors found that tubes made up of BC are without any adverse effects on the vessel surface culturing cells and, interestingly, the tubes of BC exhibit comprehensive endothelialization with a layer of confluent endothelial phase. Further, there is no macroscopic sign in the implant inflammation indicating that the BC tubes are highly biocompatible and appear to be prominent as an artificial blood vessel material. Aside from being biocompatible, nanocellulose also exhibits excellent biodegradable properties. Owing to this property, nanocellulose is often used in the preparation of environmentally benign polymeric materials. Several articles focusing on the biodegradability of nanocellulose have been published. For instance, Bagde et al. [6] fabricated composite films based on starch and evaluated their biodegradability using ISO 17556:2003(E) method. The research team found that the film incorporated with CNC showed a higher biodegradation percentage as compared to control. Additionally, Singh et al. [87] compared the biodegradation rate of H2SO4 hydrolyzed CNC with microcrystalline cellulose by using two environmentally
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relevant consortia and found that the hydrolyzed CNC degraded faster than microcrystalline cellulose, suggesting greater biodegradability.
5.5
Biodegradability
Another important point worthy to note is that nanocelluloses are not fully biodegraded in vivo due to the absence of cellulase in most species and their enhanced crystallinity [95]. Even so, the nonbiodegradable feature has been explored in the development of scaffolds to provide support for the long term such as cardiovascular and cartilage implants. For example, Ávila et al. [4] prepared hydrogels using BNC as a material for auricular cartilage implant, and the in vivo studies showed nonbiodegradation of BNC even after implantation for 12 weeks. Nonetheless, researchers have proposed various approaches to improve the biodegradability of nanocellulose, especially hydrogels of nanocellulose, to suit different applications, as illustrated in Fig. 17. For example, Li et al. [57] modified the BNC using periodate oxidation to form 2,3-dialdehyde BNC and found that the synthesized nanocellulose demonstrated excellent biodegradability when verified in simulated fluids of the body and solutions buffered with phosphate. In another study, chemical modification of BNC was achieved through periodate oxidation mineralized with nanohydroxyapatite to replace the native inorganic bone tissue component. The degradation research via in vitro studies revealed that the modified
Fig. 17 Various applications of biodegradable nanocellulose hydrogel [14]. © Reproduced with permission from Elsevier (2019)
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composite experienced mass changes after incubation in a simulated body fluid condition for 14 days, confirming the biodegradation of oxidized nanocellulose.
6
Global Market
Numerous national and international projects have been developed to industrialize nanocellulose. Consequently, the market of nanocellulose has experienced significant development and applications. This is evidenced in the recent reports published where M&M [62] highlighted that the market of nanocellulose is registered to an enhanced compound annual growth rate (CAGR) of 18.4% during the forecast period between 2018 and 2023. By 2023, it is projected to reach 661.3 million US dollars (USD). Similarly, FM [20] also estimated a high CAGR of 18.8% of the global market of nanocellulose in the forecast period of 2018–2025 reaching 1,076.43 million USD by 2025. On the other hand, Biobased Market estimated that in 2018 the production of nanocellulose was around 40,000 metric tons and is anticipated to rise at a 30% CAGR to reach 250,000 metric tons by 2025 [68]. The progress can also be ascribed to the increased demand for nanocellulose for numerous applications spanning from medical to construction. According to Shatkin et al. [86], the application of nanocellulose can be categorized into high and low volume and novel applications based on the overall production of each sector. The application of nanocellulose and its categorization are tabulated in Table 7. The authors pointed out that the greater volume potential for use of nanocellulose is the packaging and paper applications. They furthered their study to estimate the latent necessity of annual nanocellulose tonnage and estimated that less than 10% of the annual total nanocellulose is consumed for low volume applications compared to the high-volume applications [13]. In another market study, the application segment Table 7 Identified applications of nanocelluloses and their categorization [86]. © Reproduced with permission from TAPPI journal (2014) High-volume applications Cement Automotive body Automotive interior Packaging coatings Paper coatings Paper filler Packaging filler Replacement-plastic packaging Plastic film replacement Hygiene and absorbent products Textiles for clothing
Low-volume applications Wallboard facing Insulation Aerospace structure Aerospace interiors Aerogels for the oil and gas industry Paint-architectural Paint-special purpose Paint-OEM applications
Novel and emerging applications Sensors-medical, environmental, industrial Reinforcement fiber-construction Water filtration Air filtration Viscosity modifiers Purification Cosmetics Excipients Organic LED Flexible electronics Photovoltaics Recyclable electronics 3D printing Photonic films
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is subcategorized into paints, processing of papers, gas and oil, food, cosmetics, pharmaceutical, composites, and others [66]. Notably, the paper processing and composites industry held the largest market segment (highest revenue share) due to the excellent properties of nanocellulose [83, 93]. The rising demand for nanocellulose in the biomedical and food industry over the past few years is propelled by the requirement of “green” material [15]. Among the type of nanocellulose, the BNC segment is anticipated to provide the highest (25.7%) CAGR growth rate during the 2018–2025 period of forecast [20]. The growth and market of BNC and its products, primarily in the medical, food, and cosmetic applications, is burgeoning. Additionally, Sharma et al. [85] also mentioned that in 2016, the universal BNC is measured at 207.36 million USD and it was predicted to reach 497.76 million USD by 2022. On the other hand, due to the income generated in the nanocellulose manufacturing industry, MFC/CNC embraces one of the uppermost shares of 35 million USD in 2016. It was forecasted to grow by more than 7% CAGR, surpassing 1 billion USD by 2024 [24]. With these swift protuberant applications, the industry of nanosized cellulose throughout the world is considered to involve a deep portfolio of commercialization in recent times. The industrialization and commercialization of nanocellulose is constantly emerging as it demonstrates huge possibilities. European countries are expected to account for the largest share of the global market as the demand for pulp and paper is increasing and massive R&D investments are being conducted in this region [63]. The market report was considered feasible considering the number of progress recorded by some commercial facilities. For instance, the public-private partnership between the European Union and the Bio-Based Industries Consortium, known as Bio-Based Industries Joint Undertaking (BBI JU), was established with a total of €3.7 billion funding [68]. BBI JU funded numerous projects such as NeoCel (Novel processes for sustainable Cellulose-based materials), which developed techno-economically feasible processes for the production of sustainable cellulose-based materials to propel the regional nanocellulose market [8]. Besides that, a new report on the nanocellulose market provides a succinct analysis of the market size which was also published by Pulidindi et al. [80]. The authors indicated that North America accounted for a majority share in the global market of nanocellulose, as presented in Fig. 18. The revenue size is anticipated to reach over 155 million USD in 2026 due to increasing research projects along with regaining momentum in the commercial construction sector. Furthermore, the interest by companies and universities in the production of nanocellulose adds more credence to the market potentials. For that, many applications of nanocellulose were documented as publications or filed as patents. Specifically, many inventions involving nanocellulose are being claimed every year with an increase in the number of patents. Charreau et al. [11] conducted systematic research on the search of the number of patents published between 2010 and 2017 and found almost 950 documents involving CNC, about 1700 documents involving CNF, and almost 1800 documents involving BNC that have been published. The evaluation of the annual number of published patents involving nanocellulose since 2010 is illustrated in Fig. 19. It was realized that nearly 70% of the published patent
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Nanocelluloses: Sources, Types, Unique Properties, Market, and Regulations
Fig. 18 The global nanocellulose market revenue size [80]. © Reproduced with permission from Global Marker Insights (2020)
27
Global Nanocellulose Market By Region (USD Million) North America
Middle East & Africa
Europe
Asia Pacific
Latin America 2019
b 500 450 400 350 300 250 200 150 100 50 0
20 09 20 10 20 11 20 12 20 13 20 14 20 15 20 16 20 17 20 18
11 20 12 20 13 20 14 20 15 20 16 20 17 20 18
20
20
20
10
Number of patents
500 450 400 350 300 250 200 150 100 50 0
09
Number of patents
a
2026
Publication year
Publication year
20
20
10 20 11 20 12 20 13 20 14 20 15 20 16 20 17 20 18
500 450 400 350 300 250 200 150 100 50 0
09
Number of patents
c
Publication year
Fig. 19 The annual number of published patents involving (a) CNC, (b) CNF, and (c) BC from 2010 to 2017 [11]. © Reproduced with permission from Elsevier (2020)
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were published within 2015–2017, showing that the market of nanocellulose is constantly growing. Interestingly, in the same report, applications data indicates that the countries with the highest interest for a patent application for CNC are China, the United States, and Canada, whereas patent offices of Japan, China, and the United States are the top 3 countries for claiming the patents involving CNC; the vast majority of patent documents for BNC were filed in China. The trends observed clearly illustrate the dynamics of the growing nanocellulose fields all over the world.
7
International Regulations
The international regulations of nanomaterials apply to the use of nanocelluloses in commercial biomedical or environmental applications. The United States and European Union have drafted and implemented strong regulations, laws, protocols, and rules for the handling, production, and labeling of nanomaterials, including nanocelluloses for commercial applications. In the United States, agencies such as the Institute for Food and Agricultural Standards (IFAS); Food and Drug Administration (FDA) with Federal Food, Drug, and Cosmetic Act (FFDCA) and Voluntary Cosmetic Registration Program (VCRP); and Personal Care Products Council (PCPC), as well as the US Environmental Protection Agency (USEPA) are responsible for regulating the usage of nanocelluloses in commercial applications. Similarly, the European Chemicals Agency (REACH), the European Regulation on the Classification, Labelling, and Packaging (CLP) of Chemicals, the Scientific Committee on Emerging and Newly Identified Health Risks (SCENIHR), the European Union Cosmetics Products Notification Portal (CPNP), and the European Medicines Agency (EMEA) are the authorities and government agencies that regulate the incorporation of nanocelluloses in biomedical and environmental applications. In addition, the Scientific Committee on Consumer Safety (SCCS), International Cooperation on Cosmetic Regulation (ICCR), and individual countries have specific laws and regulations such as the UK Soil Association, the Biological Farmers of Australia, and the Canada General Standards Board which monitor and regulate the incorporation of nanocelluloses in industrial and commercial usages [38]. Further, the Technical Association of the Pulp and Paper Industry (TAPPI) and the International Organization for Standardization (ISO) have proposed a strategy to standardize methodologies related to nanocelluloses. According to their regulations, the term “nanocellulose” can be used only for nanosized fibrils that are isolated from plants or agricultural sources [25]. Furthermore, Finnish experts in the field of nanocelluloses have analyzed the suitability of these nanomaterials to be accepted by the REACH regulatory board in the European Union. They identified that certain properties of nanocelluloses such as varying toxicity depending on the cell and live model types are contradicting the REACH regulations to accept nanosized celluloses as a safe material for commercial applications [46]. However, it must be noted that there is no proper regulatory board or committee for the global monitoring and standardization of nanocellulose usage in commercial applications. Thus, it is significant to form a global governing body to monitor and regulate the usage of nanomaterials,
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especially nanocelluloses, in specific and desired applications. Moreover, standardization of toxicity determining assays for the identification of nanocelluloses’ cytoor genotoxicity is highly essential to elevate their large-scale commercial production.
8
Conclusion
Nanocelluloses are widely used in various applications ranging from biomedical to environmental fields. These novel nanosized celluloses possess low toxicity, enhanced binding capacity, mechanical strength, biocompatibility, and biodegradability, which makes them a unique material compared to other bulk and nanosized materials. However, nanocelluloses are not widely included in commercial or largescale applications due to the lack of extensive research to identify their toxic levels among different microbes, plants, animals, and humans. Further, global standardization authority and regulatory boards are required in the future to regulate the efficiency and compatibility of nanocelluloses to be used in commercial applications without any adverse effects on the environment, humans, and other species of organisms.
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Nanocelluloses Toxicological and Environmental Impacts C. Balalakshmi, P. R. S. Yoganathan, K. Tharini, A. Vijaya Anand, A. Murugaesan, Mohammed Jaabir, and Jeyachandran Sivakamavalli
Contents 1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1 In Vitro Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 In Vivo Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1 Immunotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2 Cytotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Environmental Impacts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Conclusion and Future Prospects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Abstract
The desire to achieve environmental sustainability stimulates research on novel cellulose-based polymers for a wide range of uses across various industries. Recently, nanomaterials based research is blooming and versatile applications of nanomaterials were recorded in the various research platforms. The toxicological characteristics of CNMs, which are exposed to increasing concentrations of C. Balalakshmi Department of Nano science & Technology, Alagappa University, Karaikudi, Tamil Nadu, India P. R. S. Yoganathan · J. Sivakamavalli (*) Department of Biotechnology, National College, Tiruchirappalli, Tamil Nadu, India K. Tharini Department of Chemistry, Government Arts College, Tiruchirappalli, Tamil Nadu, India A. Vijaya Anand Department of the Human Genetics and Molecular Biology, Bharathiyar University, Coimbatore, Tamil Nadu, India A. Murugaesan PG and Research Department of Chemistry, Government Arts College, Ariyalur, Tamil Nadu, India M. Jaabir Department of Biotechnology and Microbiology, National College, Tiruchirappalli, Tamil Nadu, India © Springer Nature Switzerland AG 2022 A. Barhoum (ed.), Handbook of Nanocelluloses, https://doi.org/10.1007/978-3-030-89621-8_6
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nanomaterials for a certain duration, have been studied in vitro mainly through mammalian cell lines. Several outcomes have been evaluated, including cell death, immune response activation, inflammation, oxidative stress, and genetic damage. These endpoints, along with the physical and cell-internalizing characteristics of CNM, provide crucial insights on the possible detrimental consequences and associated processes of CNM in live organisms. Among the cellulosic nanomaterials obtained from various sources and with varying functionalization are being produced for usage in a variety of applications, in pure and composite, ranging from consumer goods to pharmaceutics and healthcare materials. At the same time nanocellulose-based materials also bring the toxic effects to the environment, based on prior knowledge of the potential adverse health effects of other nanomaterials with a high aspect ratio and biopersistency in body fluids, e.g. As with carbon nanotubes, the nanometric size of nanocellulose is expected to increase its toxicity when compared to bulk cellulose. Several toxicological studies were performed, either in vitro or in vivo, with the goal of predicting the health consequences produced by nanocellulose exposure. The purpose of this study is to identify and link the toxicological effects elicited by nanocelluloses created using a top-down strategy from vegetal biomass, namely, cellulose nanocrystals and nanofibrils, to the physicochemical properties of nanocellulose.
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Introduction
Since the birth of nanotechnology as a distinct fascinating research area, an everincreasing number of novel nanomaterials have been produced, with applications ranging from healthcare items to high-performance engineering materials. Several nanomaterials have been utilized for various purposes among, nanocellulose is defined as products or extracts of natural cellulose (found in plants, microbes, and animals) that have a nanoscaled structure material. CNMs’ toxicological characteristics have mostly been studied in vitro, with mammalian cell lines exposed to increasing concentrations of the nanomaterial for a certain amount of time. Several outcomes were measured, including cell death, immune response activation and inflammation, oxidative stress, and genetic damage. These endpoints, in combination with the CNM’s physicochemical qualities and cell internalization, provide critical information on the CNM’s possible negative impacts and related pathways in live beings. Although previous research has shown that nanocellulose has low or no toxicity (such as table salt) when utilized as a biomedical material, these natural nanomaterials’ toxicological and safety problems should be highlighted. Since its beginning more than 20 years ago, nanotoxicology research for nanoparticles has developed a comprehensive evaluation system for metallic nanoparticles (Au, Ag nanoparticles, quantum dots, etc.) and carbon nanotubes. However, nanocellulose and nanocellulose-based biocomposites are still in the early stages of toxicology study (mostly in terms of cytotoxicity). Table 1 summarizes the recent reports of toxicology experiments and results for nanocellulose. Overall, at the cellular and genetic level, there is no evidence of serious influence or damage of nanocellulose in vivo organ and animal experiments. However, inhalation of large amounts of
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Table 1 Toxicological studies of nanocellulose Type CNCs
CNF
BC
Toxicological experiment Acute lethal test Multi-trophic assays L929 cells were used to test cytotoxicity The L929 cell lines were evaluated for cytotoxicity Human monocytes and mice macrophages were used to test cytotoxicity The enzyme comet assay was used to test in vitro genotoxicity Nerve and its modular effects on a nematode model Bovine fibroblasts cells were used to test cytotoxicity Osteoblast cells and L929 fibroblast cells were used to test cytotoxicity Human umbilical vein endothelial cells were used to test cytotoxicity A male C57/Bl6 mouse was used in an animal experiment Human umbilical vein endothelial cells immunoreactive in vitro
Outcomes Possibility of low toxicity Low risk to the environment At low CNC concentrations, cytotoxicity is low No cytotoxic effects
[1] [1] [2] [3]
No evidence of cytotoxicity or inflammatory effects
[4]
There is no indication of significant DNA damage. Low or no cytotoxicity
[5]
At low CNF concentrations (0.02–100 g/mL), cytotoxicity is low No cytotoxicity
[7]
There is no toxicity, in vitro and in vivo Non-immunogenicity and non-toxicity Non-immunogenicity and non-toxicity
[6]
[8] [9] [10] [10]
nanocellulose (especially CNC) can trigger pneumonia due to the easy selfassimilation and degradation of nanocellulose in the animal body. Toxicity of a substance describes its potential for harm to a living organism and is an essential part of evaluating the effect of nanomaterials on humans or the environment by making assessments of the risks. Toxicity is determined by dosage and reaction, as well as the types and intensity of adverse effects, the mechanism of action, and the duration of exposure (Shatkin 2013). In the case of fibers, the macrophage is too long to phagocytize, i.e too long for the macrophage cell to swallow it completely, that will trigger inflammatory factors, leading to cancer or fibrosis (Endes et al. 2016) (Fig. 1). The technology based on nanomaterials (NMs) has been identified as a major enabling technology due to its potential to enhance numerous goods and processes of importance to crucial sectors such as healthcare, energy, environment, and manufacturing. Many existing products contain nanometric materials, such as silver, titanium dioxide, or synthetic amorphous silica, and many additional NMs, such as cellulose nanomaterials, are being developed (CNMs). CNMs have a wide range of significant industrial applications, including papermaking, coatings, food, nanocomposite formulation, and reinforcement, as well as the potential for novel biological applications, including as drug delivery carriers, antimicrobial materials, and tissue healing and regeneration [11]. Furthermore, as its production and application grow, it may result in inadvertent human exposure; both for customers and employees, and concerns about its possible impacts on human health have developed.
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Fig. 1 In vitro & In vivo toxicological analysis of different types of Nanocelluloses based on their characteristics
Toxicological studies attempt to produce data that helps anticipate the health consequences of exposure to a certain chemical, such as nanocellulose, allowing humans to be exposed to less risk. To determine the toxicological properties of a drug in a short period of time, tests in mammalian cell lines (in vitro) or animal models (in vivo) are being employed (Table 2). The data provided allows for hazard identification, which supplements exposure evaluation by epidemiological research within the context of risk assessment. Prior to in vivo investigations, in vitro toxicological studies are usually performed to see if the substance/material interacts with cellular components or functions, causing a disruption in cell homeostasis and a quantifiable impact. Conventional toxicological assays assess, among other things, the effects of a substance on cell viability (cytotoxicity), which leads to cell death generally through apoptosis, and the direct or indirect damaging effects on DNA or chromosomes, such as gene, which can eventually lead to carcinogenicity (genotoxicity) (Table 2). Inflammation is another common symptom of persistent nanofibers. Inflammation is an important immunological response to adverse stimuli such as infections, tissue injury, toxicants, or radiation, and it allows survival through infection or damage while preserving tissue homeostasis (Fig. 2). Inflammatory inducers, sensors that detect them, inflammatory mediators produced by the sensors, and target tissues that are impacted by the inflammatory mediators make up a typical inflammatory response [17]. The inflammatory response to aspirated fibrous particles, such as CNT and CNMs, typically peaks on days 1–7 and then declines after the first week postexposure (Park et al. 2018). Nanofiber phagocytosis causes mitochondrial damage, which leads to the formation of reactive oxygen species (ROS). ROS can cause DNA or chromosomal damage, which is a main genotoxic impact. In addition, high aspect ratio nanomaterials can rupture lysosomes and release cathepsin B into the cytosol. ROS production causes oxidation of the redox-active thioredoxin (TXN), which separates it from the thioredoxin-interacting protein (TXNIP), and TXNIP in its free form can activate the NLRP3 inflammasome. With
CNCs, CNF
CNCs
CNCs
Nanocellulose type BC NCC
Test system 3T3 fibroblasts Rainbow trout, vibrio fischeri Multi-trophic assays C57BL/6 mouse model RAW 264.7 macrophages
n/a
+
Cytotoxicity
n/a
+
n/a
Inflammatory n/a n/a
Cell free +, in vitro
+
n/a
Oxidative stress n/a n/a
n/a
+
n/a
Genotoxicity
Male rats exhibit a more adverse lung effect compared to female rats Biodurability is high
Main outcomes Beware of material modification No toxicity and low environmental risk Low environmental risk
[16]
[15]
[14]
References [12] [13]
Table 2 Cytotoxicity, inflammatory response, oxidative stress, and genotoxicity are some of the most common biochemical endpoints addressed in the area. For each endpoint, there was a+ response and a no response (n/a not examined). The last column features a succinct, well-considered explanation of the study’s findings. The studies are listed in the order in which they were released into the public domain
2 Nanocelluloses Toxicological and Environmental Impacts 39
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the goal of identifying the toxicological effects induced by CNMs derived from vegetal biomass (top-down method), either in vivo or in vitro, which may lead to detrimental health consequences, this work explains: In addition to their unique physicochemical properties, they have an environmental impact, which includes cytotoxicity, oxidative stress, immunotoxicity, genotoxicity, and reprotoxicity.
Fig. 2 The processes involved in inflammation activation are simplified to be represented
Method In vitro
In vivo
Cells cultured One or more cell types are cultured (epithelial, endothelial, fibroblastic, etc.) Extraction of organs and tissues (liver, heart, lung, blood)
Observable Outcomes Cytotoxic Genotoxic Viability and Aneuploidy, proliferation polyploidy, of cells have clastogenicity changed DNA mutations, DNA strand breaks
Immunotoxic Immune cell counts changes in chemokines
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As CNMs, in vitro and in vivo toxicological methods are used to investigate the negative impacts of a chemical or item. Because there are many more in vitro studies on nanocellulose-biological system interactions than in vivo studies, and most of them are only focused on one type of nanocellulose, the in vitro toxicological studies are first reviewed for each type of CNM considered, i.e., CNCs and CNFs.
1.1
In Vitro Studies
1.1.1 Cellular Uptake CNC cellular uptake has been investigated in order to assess their potential as carriers for macromolecules (drugs, DNA, etc.) delivery or as part of toxicological studies. Two separate investigations found that the degree of FITC-labeled CNC absorption by distinct mammalian cell lines (epithelial, endothelial, fibroblasts, and macrophages) was relatively low, considering their use as nanocarriers (Roman et al. 2009; Dong et al. 2012) [18]. Similarly, Hosseinidoust et al. (2015) observed that just a small amount of six different CNCs were up taken by various cell lines utilizing dark field hyperspectral imaging for bare CNCs and confocal microscopy for fluorescein amine conjugated CNCs, despite a clear time- and dose-dependent internalization. Because macrophages’ cell membranes were intact, their presence inside the cells suggested an active or passive transport mechanism. Furthermore, the soft, amorphous, and highly carboxylated CNC poles appeared to improve their uptake, indicating that the increased transport of CNCs with a higher charge is mediated by a contact of these carboxyl-rich chains with the cell membrane [19] found murine alveolar MH-S macrophage uptake of a pristine CNC in the context of toxicological studies, with CNCs in gel being more internalized than those in powder; internalization might have happened by phagocytosis or macropinocytosis. After 4 h of treatment, spherical negatively charged FICT-labeled CNC produced from oil palm empty fruit bunch exhibited negligible cellular accumulation on either C6 rat glioma or NIH3T3 murine fibroblasts. Menas et al. [17] found no CNC uptake in human alveolar epithelial A549 cells. The lung clearance of the longer CNCs was lower than that of the shorter CNCs. They were remained evident on the apical surface of the cell layer 48 h after exposure. They were then removed from the cell surface within 24 h of exposure. A new study has shown that at a low level, CNC internalization and accumulation in cells happens. The uptake of NMs by macrophages is regulated by their size and surface characteristics, such as charge, as well as cell type and function. Macrophages uptake is higher than epithelial cells in the body’s immune system. The uptake of these NMs has been shown to be linked to a number of factors. 1.1.2 Immunotoxicity Interleukin (IL)-1b and IL-18 proteolytic activation is controlled by inflammasomes, which are huge intracellular multiprotein signaling complexes that respond to external stimuli and govern the proteolytic activation of interleukins. It is thought that needle-like NMs, such as CNT. CNCs and CNFs exhibit certain properties with asbestos fibers and carbon nanotubes, such as high aspect ratio, insolubility, and
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biopersistency, and therefore may be able to activate the NLPR3-inflammasom [16]. Other characteristics such as surface charge may potentially influence CNCs’ capacity to activate an immune response. A modified CNC was able to increase the secretion of IL1b in mouse macrophages (J774A.1) and human peripheral blood mononuclear cells (PBMNC) primed with lipopolysaccharide (LPS) and nonprimed. This increase in IL1b was associated with the increased formation of mitochondrial ROS and extracellular adenosine. Triphosphate (ATP), is related to its ability to activate the NLRP3 inflammasome. The NLRP3/IL-1b inflammatory pathway was not activated by any of the other cationic CNCs studied. The molar ratio of monomers [aminoethylmethacrylate (AEM) or aminoethylmethacrylamide (AEMA)] to hydroglucose units differed across the CNCs, resulting in cationic polymer brushes that were more or less cationic. In terms of CNC hydrophobicity, uncoated hydrophilic CNCs evoked a stronger inflammatory response than their lignin-coated hydrophobic counterpart [20]. Human monocyte-derived macrophages (THP1 cells) were exposed to the uncoated CNC for 24 h (50 lg/mL) and showed an increase in cytokines and chemokines was identified; the response was enhanced after 72 h of exposure. In contrast, the hydrophobic CNC only raised the levels of 5 of those cytokines after 24 h, and their levels returned to normal after 72 h. In contrast, after 6 h of exposure, pure cotton-derived CNCs (average length 135 5 nm; width 7.3 0.2 nm) did not activate IL-1b or TNF-a in THP-1 cells. Another research found that pure CNC did not induce macrophage polarization and that M0 macrophages expressed very low levels of cytokines and chemokines. In terms of size , Cellulose three CNCs of varying sizes generated a significant inflammatory response in A549 cells [17] after 24 and 72 h of exposure, with a direct connection between the size of the CNCs and the amplitude of reaction. The various immunological responses elicited by different CNCs (Table 1) demonstrate that variations in physicochemical properties (size, charge, etc.) are essential to their immunotoxicity and should be considered when contemplating biological applications or human exposure, such as inhalation.
1.1.3 Cytotoxicity Because researchers are interested in discovering the potential of CNCs as drug carriers, in chemotherapy, or in patches, their cytotoxicity has been studied in numerous publications utilizing various cell lines and functionalized CNCs. No cyotoxicity was detected for 0.05 wt% CNC suspension tested in several human epithelial and endothelial cells and mouse cell lines. For 24, 48, and 72 h [21], there was no evident loss of cell viability in A549 cells exposed to 1.5, 15, and 40 lg/cm2 and in human brain microvascular endothelial cells (HBMEC) exposed to 10, 25, and 50 lg/mL CNCs. In macrophages exposed to pristine CNCs in gel or powder, just a low cytotoxicity was found (Erdem et al. 2019). A recent use of CNCs with negatively charged carboxylic groups in hydrogel membranes with Na?, Ca2?, and Mg2? as gelling cations was developed for use in active patches for photodynamic treatment of melanoma [22]. This hydrogel biocompatibility was proven by cytotoxicity testing (MTT, morphological alterations, organelle integrity) utilizing two cell lines of melanoma and one cell line of human primary cutaneous fibroblasts
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exposed to the CNC membrane via direct and indirect contact tests. CNCs evaluated in various cell types, such as S/9 insect cells and V79 Chinese hamster lung fibroblasts, exhibited no substantial cytotoxicity. The results revealed that these CNCs had the ability to cause cell death, but only at extremely high concentrations. In this study, exposure to macrophages (RAW 264.7) and HaCaT cells resulted in a dose-dependent decrease of cell viability, although there was no toxicity up to 700 lg/mL.
1.1.4 Oxidative Stress In terms of oxidative stress induction, A549 cells were exposed to three distinct CNCs showed no significant reduction in glutathione (GSH) levels, a hallmark of oxidative stress [22]. In the [17] investigation on the new CNCs made from rubber wood and Kenaf bast fibers, nitrite production by RAW264.7 murine cells was one of the endpoints tested, and there was a nearly fourfold increase in the concentration of nitrite in macrophages, which correlated with their viability loss. Lower doses of CNCs were deemed non-toxic since the quantity of generated nitrite was comparable to that of LPS (Tuerxun et al. 2019). ROS production was also evaluated in [23] research of digested CNC, and a modest increase in ROS production was seen with CNCs at 1.5% w/w, but the impact was lost when this CNC was disseminated in a standardized food matrix (DeLoid et al. 2019). 1.1.5 Genotoxicity Few research has looked at the genotoxicity of CNCs to the best of our knowledge. Cotton CNCs (average length 135 5 nm; width 7.3 0.2 nm) were exposed to human bronchial epithelial BEAS-2B cells in a concentration range of 2.5–100 lg/mL, and chromosomal damage was assessed using the micronucleus assay, which yielded negative results. The vast majority of research addressing the possibility for a wide variety of CNCs from various sources and with various characteristics to induce cell death attest to the absence of substantial cytotoxic effects in a variety of mammalian cell lines when taken together. Nonetheless, certain harmful effects were identified either at extremely high concentrations that are unlikely to be attained in the organisms or in highly sensitive cells such as macrophages. Surface charge is a crucial variable to consider when designing new CNCs, particularly for biomedical applications.
2
In Vivo Studies
2.1
Immunotoxicity
Yanamala et al. (2014) evaluated the local and systemic inflammatory potential of two types of wood derived CNC in a 10 wt% gel/suspension or in powder in adult female C57BL/6 mice (7–8 week old) exposed by pharyngeal aspiration to 50–200 lg/mouse, and compared it to that of asbestos [24]. The overall number of cells in the BAL fluid increased 24 h after exposure, with faster recruitment of neutrophils, lymphocytes, and eosinophils, and a dose-dependent increase in polymorphonuclear neutrophils.
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Overall, powder CNCs was able to produce a greater increase in BAL cells, as well as the formation of eosinophils, whereas suspension CNCs induced more oxidative stress. The range of CNC in suspension was 90.2 3.0 nm (length) and 7.2 2.1 nm (width), while in powder it was 207.9 49.0 cm (length and width) and 8.2 (length), respectively. This difference could be partially due to the differences in the dimensions of the CNC dimensions. When compared to asbestos, the overall larger numbers of PMNs and other inflammatory cells after CNC exposure indicated that CNC evoked a more severe acute inflammatory response. Mice exposed to CNC suspension, on the other hand, exhibited a type 1T helper cell (Th1) immunological response and a higher acute inflammatory response, whereas CNC powder-exposed animals exhibited type 2T helper cell (Th2) responses, i.e., allergic inflammation. Surprisingly, in mice exposed to asbestos, the pattern of up-regulated cytokines/ chemokines was less apparent. Mice exposed to CNC suspension, on the other hand, exhibited a type 1T helper cell (Th1) immunological response and a higher acute inflammatory response, whereas CNC powder-exposed animals exhibited type 2T helper cell (Th2) responses, i.e., allergic inflammation. Surprisingly, in mice exposed to asbestos, the pattern of up-regulated cytokines/chemokines was less apparent. White blood cell counts increased significantly following exposure to both types of CNC (200 lg/mouse), indicating acute systemic inflammation. These findings suggest that the shape and size of CNCs may be important determinants in determining the kind of innate immune inflammatory response in the lungs, and that the immune response differs by gender. A follow-up research with C57BL/6 female and male mice (7–8 weeks) was carried up by the same group to investigate gender differences in response to CNC longer doses [25]. For 3 weeks, mice were exposed to wood pulp-derived CNC (length 158 97 nm; width 54 17 nm) through pharyngeal aspiration twice a week. After 3 months of treatment (a cumulative dosage of 240 lg/mouse), there was a substantial increase in total cell counts and macrophages in the BAL, with female mice exhibiting a greater increase in total PMN and lymphocytes than male mice. Female mice had a more significant inflammatory response to CNC than male mice, according to histological evaluation and identification of proinflammatory cytokines and chemokines in BAL fluid. A similar pattern was observed in terms of oxidative stress indicators, with CNC exposure linked with a greater drop in antioxidant defense reserves in females compared to males, despite the fact that both genders were impacted. Overall, increased oxidative stress, increased TGF-b, and collagen deposition in the lungs of CNC-exposed mice were significantly higher in female mice than in male mice, indicating gender differences in the pulmonary response to CNC exposure.
2.2
Cytotoxicity
Although cellulose and its derivatives are frequently employed as thickeners and fillers in foods and medicines, a recent semi-chronic research was conducted to assess the toxicological consequences of ingested CNF [26]. Male Wistar Han rats (12 weeks old) were given either alone or in a feeding matrix a CNF (mean width 64 nm)
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prepared by mechanical grinding of dried sheets of softwood bleached kraft fiber. In addition, as previously described in the in vitro portion, a triculture was employed in parallel. There were no significant differences in blood counts, hematological measurements (hematocrit, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, and platelet count), serum markers (HDL, LDL, and free fatty acid), hepatic function markers (AST, ALT, ALP, total protein, and albumin), or renal function markers (total bilirubin, creatinine). Histopathology did not disclose any significant findings, suggesting that CNF has acute toxicity and is presumably harmless when consumed in small amounts. In the case of CNC, LDH activity, a measure of cell membrane injury, increased up to 1.63-fold and 1.57-fold in the lungs of adult female C57BL/6 mice after pharyngeal aspiration of a 10% CNC gel/suspension and powder, respectively [24]. The presence of 4-hydroxynonenal (4-HNE) and protein carbonyl production were used to assess oxidative damage. After being exposed to CNC, there was a dose-dependent increase in the accumulation of protein carbonyls, with the solution having a greater impact than the powder CNC. 4-HNE levels rose in both CNC formulations, although at greater quantities (100 and 200 lg per mouse). Overall, oxidative damage was more apparent in the lungs of CNC-treated animals than in those of asbestos-treated mice [24]. The same mice were exposed to a wood pulp-derived CNC by pharyngeal aspiration twice a week for 3 weeks, resulting in pulmonary tissue damage as measured by LDH and total protein activity in BAL (cumulative dose of 240 lg/mouse) after 3 months [25].
3
Environmental Impacts
Nanocellulose’s many appealing characteristics have sparked increased interest in the material from both academic and industrial area in recent years, with the material showing promise for both industrial and consumer applications. This will unavoidably result in more nanocellulose being released into the environment. Although nanocellulose is often considered as non-toxic, there are still gaps in our understanding of its effects on the environment and human health, and data is sparse. The aim of the study was to assess the environmental risk associated with this new material while taking into consideration projected future production expansion. The findings of this study add to the increasing corpus of environmental risk evaluations of nanomaterials and pave the path for the safe commercialization of nanocellulosecontaining goods. Nanocellulose is a promising material with a wide range of possible uses and numerous unique characteristics. Pilot-scale development for commercialization has begun because to the unique and useful materials that may be developed utilizing nanocellulose. As a result, a complete understanding of nanocellulose’s environmental effect, which spans the whole life cycle, provides the cornerstone for its long-term viability. In this work, four similar lab scale nanocellulose manufacturing processes were assessed using the Eco-Indicator 99 method for a cradle-to-gate life cycle assessment (LCA). The results showed that the bulk of the environmental effect of nanocellulose manufacturing is reliant on both the chemical modification and mechanical treatment approach used for the
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chemical–mechanical fabrication routes. When it comes to sonication, the mechanical treatment takes precedence over the chemical changes. Because TEMPO oxidation had a smaller impact than carboxymethylation, the optimum technique based on unit mass production was 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) oxidation followed by homogenization. Despite the fact that the production method of nanocellulose has a huge environmental footprint when compared to its raw material extraction process (kraft pulping), it still has significant environmental benefits over other nanomaterials such as carbon nanotubes. To avoid subsequent environmental concerns in wastewater treatment, the optimum chemical feedstock utilized to synthesis the adsorbents should be ecologically benign (i.e., non-toxic). Nanocellulose, the most common organic biopolymer on the planet, meets several requirements for a very safe but effective adsorbent. Recent developments, are higlighted in this study by expalining the techniques currently in use for such designs and provides a comprehensive overview of these technologies in order to stimulate more focused research for nanocellulose-based adsorbent materials in the future. The activity of nanocellulose can lead to many different effects in environment, since human and, to a lesser extent, environmental exposure to nanocellulose has been shown to cause a significant increase in normal airborne particle concentrations [26], as well as concerns about the potential hazards associated with HARN and nanomaterials in general, a better understanding of the structure–activity relationship of nanocellulose is required [9]. In the context of nanotechnology, these dangers revolve around the possibility for manufactured nanomaterials to have negative environmental consequences if they are widely used. Given the most common exposure pathways and the restricted extent of their usage, nanomaterial exposures and health consequences are unlikely to represent a significant concern to public health. However, as the quantity and varieties of artificial nanomaterials utilized in society grow, so does the risk of unexpected environmental effects. The use of finding the environmental impact is to provide the overview of the research work whether it is pointed toward exploring the biological impact of nanocellulose and the potential hazard which was caused by the nanocellulose. Along with the physical properties of the nanocellulose under investigation, the description of the test method used and the results of the experiments designed to assess cytotoxicity, the inflammatory response following nanocellulose exposure, the oxidative stress level of the biological system are also under study, Possibilities for expression of nanocellulose genetic toxicity [27]. These endpoints are widely considered as the most significant drivers of nanomaterial toxicity in the area of particle and fiber toxicology. This is a way that we are understanding the environmental impact of nanocellulose and the form of nanocellulose.
4
Conclusion and Future Prospects
According to the study on the possible hazards posed by various types of nanocellulose, particularly to human and environmental health, the present knowledge of its structure–activity link is ambiguous and incoherent. While several studies suggest
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that nanocellulose is generally safe, some emphasizes the possibility of negative consequences. A wide range of analyzed disparities can contribute to differences in the cellular environment including, the source of nanocellulose, synthesis technique, its characterization methods, dosage, and concentrations exposed to the cellular system, the exposing methodology, or even the gap of acknowledging the characteristics before administering the nanocellulose composites to the biological system under analysis. Some research points to inhalation as one of the primary entry pathways for particles in industrial settings [28–30]. Others consider immune cell reactions to be significant drivers of toxicity. Some of the reported cellular responses are the consequence of severely overloaded systems, and the consequences are thus attributed to the dosage rather than the nanomaterials themselves [31]. So far, most trials have used a broad hazard assessment approach with minimal attention for realistic exposure dosages, particle properties during exposure, time frames, or exposure situations. Furthermore, due to the structure of nanocellulose, tracking it throughout absorption and destiny is difficult due to a lack of analytical tools capable of measuring nanocellulose in biological systems. As a result, the morphological impact or organ distribution following exposure is restricted. A thorough understanding of the exact physical and chemical characteristics of currently manufactured and utilized nanocellulose, as well as realistic exposure dosages, is critical and unavoidable. Finally, data in acute exposure scenarios reported upon the structure–activity relationship of nanocelluloses indicate that they do not pose as greater risk to human (and environment) health as other HARN currently being produced and potentially used in similar applications (e.g. CNTs) [32]. Until more research elucidates the potential for harmful health/ environmental impacts posed by nanocellulose, the best approach to protect yourself is to prevent exposure using specific personal protective gear and discharge. Clarity must be achieved on the health consequences of low dosage, chronic, and recurrent exposure to nanocellulose in its many forms, since this holds the key to their potential beneficial usage across a wide range of disciplines and applications.
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22. Meschini, S., Pellegrini, E., Maestri, C.A., Condello, M., Bettotti, P., Condello, G., Scarpa, M.: In vitro toxicity assessment of hydrogel patches obtained by cation-induced crosslinking of rod-like cellulose nanocrystals. J. Biomed. Mater. Res. B Appl. Biomater. 108(3), 687–697 (2019). https://doi.org/10.1002/jbm.b.34423 23. Tuerxun, D., Pulingam, T., Nordin, N.I., Chen, Y.W., Kamaldin, J.B., Julkapli, N.B.M., Lee, H. V., Leo, B.F., Johan, M.R.B.: Synthesis, characterization and cytotoxicity studies of nanocrystalline cellulose from the production waste of rubber-wood and kenaf-bast fibers. Eur. Polym. J. 116, 352–360 (2019). https://doi.org/10.1016/j.eurpolymj.2019.04.021 24. DeLoid, G.M., Cao, X., Molina, R.M., Silva, D.I., Bhattacharya, K., Ng, K.W., Loo, S.C.J., Brain, J.D., Demokritou, P.: Toxicological effects of ingested nanocellulose in in vitro intestinal epithelium and in vivo rat models. Environ. Sci. Nano. 6, 2105–2115 (2019). https://doi.org/10. 1039/C9EN00184K 25. Yanamala, N., Farcas, M.T., Hatfield, M.K., Kisin, E.R., Kagan, V.E., Geraci, C.L., Shvedova, A.A.: In vivo evaluation of the pulmonary toxicity of cellulose nanocrystals: a renewable and sustainable nanomaterial of the future. ACS Sustain. Chem. Eng. 2, 1691–1698 (2014). https:// doi.org/10.1021/sc500153k 26. Donaldson, K., Tran, C.L.: An introduction to the short-term toxicology of respirable industrial fibres. Mutat. Res. 553(1–2), 5–9 (2004). https://doi.org/10.1016/j.mrfmmm.2004.06.011 27. Stone, V., Miller, M.R., Clift, M.J.D., Elder, A., Mills, N.L., Moller, P., et al.: Nanomaterials vs ambient ultrafine particles: an opportunity to exchange toxicology knowledge. Environ. Health Perspect. 125(10), 106002 (2017). https://doi.org/10.1289/EHP424 28. Endes, C., Mueller, S., Kinnear, C., Vanhecke, D., Foster, E.J., Petri-Fink, A., et al.: Fate of cellulose nanocrystal aerosols deposited on the lung cell surface in vitro. Biomacromolecules. 16(4), 1267–1275 (2015) 29. Endes, C., Schmid, O., Kinnear, C., Mueller, S., Camarero-Espinosa, S., Vanhecke, D., et al.: An in vitro testing strategy towards mimicking the inhalation of high aspect ratio nanoparticles. Particle Fibre Toxicol. 11(1), 40 (2014) 30. Clift, M.J.D., Foster, E.J., Vanhecke, D., Studer, D., Wick, P., Gehr, P., et al.: Investigating the interaction of cellulose nanofibers derived from cotton with a sophisticated 3D human lung cell coculture. Biomacromolecules. 12(10), 3666–3673 (2011) 31. Pereira, M.M., Raposo, N.R.B., Brayner, R., Teixeira, E.M., Oliveira, V., Quintao, C.C.R., et al.: Cytotoxicity and expression of genes involved in the cellular stress response and apoptosis in mammalian fibroblast exposed to cotton cellulose nanofibers. Nanotechnology. 24(7), 075103 (2013) 32. Endes, C., Camarero-Espinosa, S., Mueller, S., Foster, E.J., Petri-Fink, A., Rothen-Rutishauser, B., Weder, C., et al.: A critical review of the current knowledge regarding the biological impact of nanocellulose. J. Nanobiotechnol. 14(1), 78 (2016). https://doi.org/10.1186/s12951-0160230-9
3
Nanocellulose Production from Different Sources and Their Self-Assembly in Composite Materials Dimitrios Selianitis, Maria-Nefeli Efthymiou, Erminta Tsouko, Aristeidis Papagiannopoulos, Apostolis Koutinas, and Stergios Pispas
Contents 1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Nanocellulose from Native Sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Nanocellulose from Microorganisms, Tunicates, and Algae . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Production of Nanocellulose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Nanoscale Morphological Properties of Nanocellulose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Targeting Specific Applications by Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Electrostatically Stabilized Nanocellulose-Based Suspensions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Self-Assembled Nanocellulose in Composite Materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 Conclusions and Future Perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
52 54 56 61 64 68 70 72 75 76
Abstract
Cellulose derived from lignocellulosic biomass or microorganisms via fermentation can be transformed into nanocellulose (NC), i.e., cellulose nanofibrils (CNFs) and cellulose nanocrystals (CNCs), applying mechanical, chemical, and enzymatic processes or a combination of the aforementioned methods. NC production from bacterial cellulose derived from renewable resources will be presented. This chapter will also focus on the colloidal properties of NC and its stability and interactions with other components at a nanoscale level. Preparation
The authors D. S. and M.-N. E. contributed equally to this work D. Selianitis · A. Papagiannopoulos (*) · S. Pispas Theoretical and Physical Chemistry Institute, National Hellenic Research Foundation, Athens, Greece e-mail: [email protected]; [email protected]; [email protected] M.-N. Efthymiou · E. Tsouko · A. Koutinas Department of Food Science and Human Nutrition, Agricultural University of Athens, Athens, Greece e-mail: [email protected]; [email protected] © Springer Nature Switzerland AG 2022 A. Barhoum (ed.), Handbook of Nanocelluloses, https://doi.org/10.1007/978-3-030-89621-8_7
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methods to obtain NC or high-performance nanomaterials will be discussed with special attention to ex situ structural modification of bacterial cellulose, highlighting advances over the last 10 years. Properties of these nanomaterials will be illustrated as an indispensable part of their electrostatic stabilization in NC suspensions and self-assembly into nanostructures either in pure NC or in nanocomposites. Results that are based on light scattering (LS), small angle scattering (SAS), and rheology techniques will be presented. This chapter attempts to give insight on correlation aspects between structure, dynamics, and interactions at the nanoscale and the properties of NC that are attractive for a broad spectrum of applications including sectors of biomedicine, food science, materials and characterization fields, and environmental science. Keywords
Bacterial cellulose · Renewable resources · Nanocellulose · Small angle scattering · Rheology Abbreviations
CNCs CNFs LS NC SANS SAS SAXS
1
Cellulose nanocrystals Cellulose nanofibrils Light scattering Nanocellulose Small angle neutron scattering Small angle scattering Small angle X-ray scattering
Introduction
Environmental and societal concerns are gradually shifting research from petroleumbased materials to sustainable and renewable counterparts that show great potential for process scalability. Recovery of NC from renewable biomass or fractionation and microbial bioconversion of lignocellulosic residues to NC could sustain chemical and biochemical intermediates that are further supplied into a variety of other end products leading to economic efficiency and low environmental footprint [1]. Industrial biotechnology including the development and establishment of innovative technologies and biotechnological pathways is the key for sustainable production of polymeric nanomaterials. NC market will grow at a CAGR of 20.4% within the forecast period of 2019–2027, reaching from USD 247.2 million to USD 1.1 billion by 2027 [2]. Rising packaging industry along with persistent necessity for sustainable production will boost NC market over the projected timeframe (Fig. 1). Cellulose is a versatile polysaccharide that can be modified combining mechanical, chemical, or enzymatic strategies to obtain nanofibrils and micro- and nanocrystals. NC is found in plant-based feedstock, algae, and tunicates, or it can be produced by acetic acid bacteria via fermentation (bacterial cellulose). In situ practice
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Fig. 1 Mapping market potential of NC by region and by type
to control specific properties of bacterial cellulose could be achieved employing different fermentation strategies and bioreactor configuration, selecting highly efficient bacterial strains, as well as formulating fermentation media that fulfill metabolic requirements of strains. Media supplementation with exogenous molecules, i.e., polymeric materials, comprises a novel approach for in situ bacterial cellulose modification with tailored properties. Ex situ structural modification of cellulose could offer high added value to cellulose involving mechanical, chemical, and enzymatic processing or combination of the aforementioned techniques [3]. Crystallite sizes, size distribution, surface characteristics, thermal stability, and dispersion capacity of cellulose nanocrystals as well as aspect ratios, fibrillar orientation, and mechanical properties of cellulose nanofibrils could render them appropriate for targeted applications in domains of nanoparticle science such as sustained drug delivery [4] and nanocomposite materials science [5], preparation of nanostructured bulk materials for applications in gas sensors [6], and tissue engineering [7]. As the interest in NCs increases, the study of their nanostructure and relevant properties is crucial. The fundamentals of the relation between structure and properties and the ability to control and design NC-based materials for specific applications call for the use of modern and powerful experimental methods. Indeed, experimental techniques such as small angle scattering and microscopy [8] are often used to investigate the morphology of NCs at the nanolevel. Recent studies illustrate that the behavior of NCs shares common features with “traditional”
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colloidal systems as, for example, the rich phase behavior of nanoscopic rigid rods of high aspect ratio which readily can be oriented by flow or may form liquidcrystalline phases solely based on their mutual interactions and the concentration in aqueous suspensions [9]. In a similar manner, the 3D network structures in NCFs are fascinating examples of hierarchically organized natural materials that can be described by the notions of the mesh-size and fractal morphology which has been used in polymer science and soft matter physics for decades. Moreover, these nanoscopic features are used to describe the dynamic behavior of the new systems in terms of flow properties, viscoelasticity, and mechanical strength. The ability to modify the surface of NCs appears to be a very useful tool because it allows to tune the interparticle interactions in suspensions and specifically in aqueous ones. Addition of charges and polymeric entities or a combination of the two in the form of polyelectrolytes opens a wide range of possibilities to exploit the previous knowledge on electrostatically and sterically stabilized nanosystems and to introduce NCs in the relevant fields of applications [10]. Surface modification in NCs not only facilitates their stability in relevant media but also defines their interactions with other components and in this way allows the design of new composite and nanocomposite materials. Consequently, NCs are a class of nanomaterials with great potential in modern nanomaterial, biomedical, and food science. This chapter presents the application of NCs in new biocompatible materials with focus on self-assembled nanostructures with advanced properties. A comprehensive description is attempted by including the sources and production methods of NCs. Their structure at the nanoscale is explained through current literature and in the framework of colloidal and soft matter physics. Specific applications based on the NC properties are analyzed. The electrostatic stabilization of NCs in aqueous media is discussed so that their importance in suspension and in hydrogel applications is illustrated. This chapter may serve as an inclusive reference for nanostructured biomaterials based on NCs.
2
Nanocellulose from Native Sources
There is a wide variety of plant-based resources that can serve as feedstock to produce NC (Table 1) through cellulose release from the lignocellulosic matrix and its subsequent treatment applying specific methodologies. Among natural sources, wood constitutes the most important industrially used source of cellulose, corresponding to 90–95% of cellulosic pulp produced worldwide [11]. Cellulose in wood occurs in thin microfibrils that are assembled in larger structures. Cellulose domains are embedded into hemicellulose and surrounded by lignin, leading to a recalcitrance lignocellulosic structure. Wood species can be classified into softwoods (Gymnosperms) and hardwoods (Angiosperms) according to their structural characteristics. The length of softwood fibers varies between 3 and 3.6 mm, while hardwood fibers are more rigid ranging from 0.9 to 1.5 mm [12, 13]. Cellulose production from hardwoods is a cost-intensive process due to high energy demands that are required to treat this highly heterogeneous and complex raw material.
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Table 1 Plant-based cellulose sources for the production of NC and variation of their lignocellulosic content (% w/w) based on literature-cited publications Cellulose source Wood Wood fibers Non-wood Calotropis plants procera Sisal Hemp Flax Kenaf Pineapple leaf fibers Bamboo Bleached bamboo pulp Agroforestry Wood residues chips Branches Pine needles Cotton stalks Wheat straw Rice straw Corncob Areca nut husk Industrial Banana processed peels agricultural wastes Agave bagasse Sugar beet pulp Lemon seeds
Cellulose % 46.4 4.3
Hemicellulose % 27.1 3.3
Lignin % 25.0 22
Reference [18]
45.0 1.5
35.0 1.6
11.5 2.7
[19]
62.6 2.8 70.6 3.6 66.3 3.5 61.2 0.8 62.5
12.5 2.5 15.6 2.9 18.8 2.7 18.5 1.5 13.9
7.9 1.0 4.2 0.8 2.2 0.1 12.9 0.7 15.9
[20]
[21] [22]
41.8 1.9 79.3 2.1
27.2 4.3 15.1 1.3
23.2 2.7 0.08 0.003
[18] [23]
39.8 0.3
26.3 0.7
26.3 0.3
[17]
30.9 0.4 23.5 0.5
21.3 0.1 16.0 0.6
31.0 0.7 33.0 2.0
36.1
22.7
30.9
[24]
44.8-22.3
33.4-14.4
8.75-18.7
[25, 26]
36.5 2.1 44.1 34.2 1.9
38.0 1.6 32.7 20.8 0.7
22.0 2.7 19.9 31.6 2.4
[27] [28] [29]
16.6
7.3
4.0
[30]
42.0
18.0
14.0
[31]
45.0 0.1
25.4 2.1
11.2 1.7
[32]
19.2 0.8
13.3 0.5
9.1 0.6
[33]
Equivalent fibrillation could be achieved through milder mechanical treatments in the case of softwoods [14]. Extensive mechanical fibrillation is required for the disruption of the S1 secondary wall layer to access the S2 inner layer [15]. NC derived from mechanically processed plant cellulose is characterized by linear or branched chains with diameter of 4–50 nm and length values greater than 50–500 nm [16]. Low extraction yields of NC from bleached wood pulps combined with high
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wood demands from paper, construction, and furniture industries restrict its use in industrial nanocomposite production [14, 17]. Therefore, seeking for alternative sources of cellulose is a rising research sector in the wide literature. Non-wood plants, i.e., agricultural crops, grasses [23], and agroforestry residues, offer a cheap feedstock for NC production with high production rates. Cotton ranks among the most widely available cellulosic fibers with a cellulose content higher than 80% [16, 34]. Other potent NC sources classified as bast fibers include annual plants, i.e., hemp, sisal, flax [20], kenaf [21], jute, or perennials [16, 34]. Agroforestry residues include the biomass fraction derived from forest maintenance, post crop harvesting field residues, and waste streams from industrial processing of crops and forestry resources. Current valorization practices mainly include composting, animal feed supplementation, and combustion for energy production. Under the viewpoint of promoting sustainability and profitability, the valorization of forestry residues for NC production has been suggested [17]. Other potent NC sources that have been investigated are agricultural residues, i.e., empty fruit branches, pineapple leaves [22], banana peels [30], corncob [28], wheat straw [26], rice straw [27], residues and by-products from sugar beet pulp processing [32], sugarcane bagasse, lemon seeds [33], tomato peels, and agave bagasse [31]. Non-wood plants possess relatively low lignin contents (up to 25%), while cellulosic microfibrils show loosened assembling patterns in the primary cell wall [15]. Hence, delignification and purification could be achieved through the implementation of mild and sustainable techniques rendering the whole process economically and environmentally viable [13]. Limitations of industrial-scale transferability of NC production from agroforestry residues are interlinked with seasonality and local production of these renewable resources that could affect continuous and sufficient supply to the industrial sector. Fig. 2 presents a vast majority of cellulose sources, so far treatments for its transformation to nanostructures, their properties, and their potential value added applications.
3
Nanocellulose from Microorganisms, Tunicates, and Algae
Bacterial cellulose constitutes a nanocellulosic biopolymer produced extracellularly by numerous bacterial species, i.e., Gluconoacetobacter (formerly Acetobacter), Rhizobium, Agrobacterium, and Sarcina [14]. The ultrastructure of bacterial cellulose synthesis has been descried in A. xylinum which is considered as a model strain. More specifically, glucan chains are secreted from extrusion pores that exist in the longitudinal axis of bacterial cells. Cellulosic ribbons with width values in the range of 40 to 60 nm are produced from bacterial cells in parallel with their lengthwise axis. Cellulose ribbons are then secreted in the outer bacterial membrane through extrusion sites in the form of microfibrils. Microfibrils of 1.5 nm width are self-assembled into 3 to 4 nm microfibrils through the crystallization of glucan chains resulting in bundles of microfibrils and eventually in larger cellulosic ribbons [35]. Bacterial cellulose presents a three-dimensional ultrafine network with average diameter values lower than 100 nm and length of around 100 μm [36]. Cellulose fibrils of Gluconacetobacter present mainly Iα crystal structure, while the Iα/Iβ ratio, width of nanofibers,
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Fig. 2 Schematic diagram illustrating sources of cellulose, basic treatments toward nanoscale particles, properties, and applications
morphology, and properties are highly dependent on culture macro- and microenvironment [37]. The average length and diameter are in the range of 100–1500 nm and 10–50 nm, respectively, with longer length particles being classified as nanofibers (CNFs) and the shorter ones as nanocrystals (CNCs) [36]. Bacterial cellulose shows similar molecular structure with plant cellulose, while it possesses superior physicochemical properties including high degree of polymerization, absolute purity (absence of lignin, hemicellulose, and pectins), high crystallinity (up to 95%), high water holding capacity, permeability to gases, enhanced mechanical and thermal stability, as well as biocompatibility. Bacterial cellulose is produced by various fermentation strategies, i.e., static and agitating mode. To date, lab-scale production includes static fermentation with cellulose pellicle being synthesized at the air-liquid interface [36]. The main drawbacks for industrialscale production are the long-term cultivation required and high costs associated with large facilities and low bacterial cellulose production rate. Specific bioreactor configurations mostly focusing on a proper impeller design combined with the addition of several additives could lead to enhanced bacterial cellulose concentrations. Aeration and agitation are also critical due to the fact that oxygen supply is directly associated with the aerobic metabolism of Gluconacetobacter xylinus. Several bioreactor systems including rotation disk reactors, stirred-tank reactors, and airlift reactors have been thoroughly presented [38]. Agitating conditions have been reported to alter bacterial cellulose macroscopic morphology resulting in spherical-shaped or irregular granules of bacterial cellulose with different sizes. Cellulose-negative mutants (Cel-) may contribute to reduced bacterial cellulose
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yields especially in the case of agitated cultivations. The presence of Cel- in the culture medium favors the formation of different by-products, i.e., acetan depending on the bacterial stain applied as the biocatalyst [38]. Chen et al. [39] employed a 75 L stirred-tank reactor equipped with one pitched blade impeller and two marine impellers. The system was stirred at 30 rpm and the aeration was set at 0.5 vvm. It was demonstrated that the scale-up of fermentation to 75 L fermenter affected negatively bacterial cellulose productivity and yield, thus enhancing production rate compared to lab-scale practice. Large-scale production resulted in improved crystallinity indices (83%), higher degree of polymerization and crystallite size, as well improved tensile strength compared to 400 mL shake flask cultivation. Cheng et al. [40] reported a bacterial cellulose production of 13.0 g/L when A. xylinum ATCC 700178 was cultivated in plastic composite support biofilm reactor at 100 rpm and oxygen supply of 1 vvm. The addition of carboxymethyl cellulose in the culture medium significantly contributed to this enhanced bacterial cellulose concentration. Ιn situ modification of bacterial cellulose altering fermentation conditions, i.e., addition of water-soluble polysaccharides, cellulose derivatives, and proteins, could induce desired properties and structural characteristics [41]. Dayal and Catchmark [42] evaluated the effect of several additives on bacterial cellulose properties. In the case that fermentation media were supplemented with 3% w/v pectin, bacterial cellulose showed the highest modulus of elasticity (142 kPa), while maximum tensile modulus (21 MPa) was observed in the case of 1% w/v gelatin addition. Crystallinity and crystallite size of bacterial cellulose were highly affected. CMC and gelatin-based media resulted in bacterial cellulose with reduced values of crystallinity (60–71%), while bacterial cellulose obtained from pectin-based media was highly crystalline (83%) with small crystallite size. The valorization of cost-effective carbon and nitrogen sources derived from renewable resources could further improve the efficiency of bacterial cellulose fermentation. Related studies have been illustrated in Table 2. The fermentation media represent approximately 30% of total production cost of the bioprocess for the production of bacterial cellulose. Bacterial cellulose concentrations varying between 2.8 and 13.3 g/L have been reported when waste and by-product streams of the agroindustrial sector were implemented (Table 2). Lin et al. [45] reported a bacterial cellulose concentration of 7.0 g/L when G. hansenii CGMCC 3917 was cultivated on waste beer yeast hydrolysate as the sole nutrient supplement. Cheng et al. [49] proposed a green bioprocess for bacterial cellulose production (2.9 g/L) utilizing corn stalk hydrolysates that were subjected to acetic acid pretreatment followed by detoxification. SEM analysis revealed the nanoscale dimensions of bacterial cellulose. In another study, bacterial cellulose synthesis was evaluated using aqueous extracts from citrus processing waste discarded from open markets as well as citrus juices from whole fruits [51]. The highest bacterial cellulose production of 6.7 g/L was attained when K. sucrofermentans DSM 15973 was cultivated in grapefruit juice-based media. Waste and by-product streams from biodiesel and confectionery industries have been reported to sustain efficient bacterial cellulose production as the sole sources of nutrients. Bacterial cellulose concentrations up to 13.3 g/L were achieved, while properties analysis demonstrated enhanced water holding capacities
Renewable resources Grape bagasse Wheat straw hydrolysate Waste beer yeast hydrolysate Flour-rich waste hydrolysate Crude glycerol, sunflower meal hydrolysate Molasses Pawpaw juice Corn stalk hydrolysate Cashew tree residues Citrus juices Citrus peel extracts Raisins aqueous extracts Batch static Batch static Batch static Batch static Batch static Batch static
K. sucrofermentans DSM 15973
Fermentation mode Batch static Batch agitated Batch static Batch static
G. intermedius SNT-1 A. pasteurianus PW1 A. xylinus ATCC 23767 K. rhaeticus K. sucrofermentans DSM 15973
Bacterial strain G. xylinus NRRL B-42 G. xylinus ATCC 700178 G. hansenii CGMCC 3917 K. sucrofermentans DSM 15973 12.6 7.7 2.9 6.0 6.1–6.7 2.9–5.2 2.8
Bacterial Cellulose production (g/L) 8.0 10.6 7.02 13.0 13.3 1.8 0.31 0.41 0.86 0.55–0.61 0.26–0.47 0.31
Productivity (g/L/d) 0.57 1.51 0.70 0.87 0.89
[52]
[47] [48] [49] [50] [51]
Reference [43] [44] [45] [46]
Table 2 Bacterial cellulose production using various renewable resources based on literature-cited publications that have achieved the highest bacterial cellulose concentration combined with enhanced productivity values
3 Nanocellulose Production from Different Sources and Their Self-Assembly in. . . 59
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Fig. 3 Bioprocess development for bacterial cellulose production from various renewable hydrolysates, its transformation to NC, and value added application based on pillars of circular economy
(102–138 g water/g bacterial cellulose), high degree of polymerization (1889.1–2672.8), and enhanced tensile strength (72.3–139.5 MPa) of the produced biopolymer [46]. Figure 3 illustrates a bioprocess development based on a circular economy-oriented approach for the production of bacterial cellulose from various renewable resources and its transformation to NC for further value added applications, i.e., biodegradable films for active packaging. This alternative, could value waste streams as sustainable resources ensuring that they will be re-introduced into food value chains. NC can also be obtained from tunicates (mainly Ascidiacea) which belong to invertebrate marine animals. Tunicates are invasive species with high reproduction rates, and they can forthright change the marine biodiversity irreversibly threatening at the same time the aquaculture industry. Alternatively, tunicates could serve as promising candidates for commercial scale production of NC (so-called tunicin). Cellulose in tunicates can be found in tunic tissue which dominates in exoskeleton structure and cell walls of internal organs. Tunicin, isolated as almost pure (76–90%) Iβ-type crystals, exhibits a helically organized network [53]. NC from tunicates presents higher aspect ratio (50–100) compared to plant cellulose (10–20) with an average length of 100–4000 nm and diameter of 20 nm [1]. A prehydrolysis-kraft cooking-bleaching method was applied to isolate NC from tunicates with a yield of 32% [54]. NC showed a high crystallinity index of 89% with an average length of 1567 nm and aspect ratio of 90. The same group [1] carried out the largest-scale isolation of cellulose nanocrystals (CNC) derived from tunicate that has been reported to date. Twenty kilograms of tunicates were processed by strong H2SO4
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Nanocellulose Production from Different Sources and Their Self-Assembly in. . .
61
hydrolysis followed by diafiltration and concentration to obtain 12.2% CNCs based on dry weight of the tunic powder. The onset temperature of thermal degradation varied between 180 and 290 C depending on the concentration of H2SO4 that was applied and the hydrolysis duration. Aspect ratio of tunicate-derived CNCs and crystallinity were determined to be equal to 65 and 75%, respectively. Algae, including multicellular macroalgae (brown, red, and green algae) and unicellular microalgae, are an abundant source of aquatic biomass rich in carbohydrates, lipids, proteins, vitamins, and other bioactive compounds, while their chemical composition is strongly influenced by origin and species. They are traditionally applied in cosmetics, pharmaceuticals, and food industries [55]. NC could be obtained from invasive green algae (Cladophorales, Chlorella, Spirogyra, and Chaetomorpha) which are the main contributors to severe eutrophication phenomena observed in coastal areas as well as from traditional algae processing residues. NC recovery from several algal species employs chemical treatment or combined methods of mechanical refining, acid hydrolysis, and TEMPO-oxidation [56]. Acid hydrolysis was employed to obtain NC from Cladophorales with a width of 20–30 nm, high specific surface area, and crystallinity up to 100% [57]. Waste biomass derived from red and brown algae (Gelidium elegans, Laminaria japonica) that accumulate high amounts of lipids, agar, and alginates is not favorable for NC production. This is attributed to the low cellulose content present in their biomass combined with the necessity for extraction of these compounds prior to cellulose recovery employing solvents and alkali and thus rendering the whole process inefficient in terms of economics and environmental impact. Indicatively, cellulose nanofibers (CNFs) were isolated from L. japonica with combined enzymatic hydrolysis followed by TEMPO-oxidation [58]. The produced CNFs exhibited width values of 10–20 nm and length of 0.6–1 μm, while crystallinity was relatively low (65%). In another study, NC was extracted from Chaetomorpha antennina using bleaching, while NC was mainly found in the form of Iα allomorph, and it showed a highly organized orientation with a crystallinity index of 85% [59].
4
Production of Nanocellulose
The properties of NC are highly rendered by the initial feedstock and the preparation method that is applied. Table 3 depicts selected literature-cited publications that deal with NC production using plant-based cellulose and bacterial cellulose. Preparation method and properties are also included. NC recovery from plant-based feedstock includes pretreatment of the raw material and the recovery of NC. The pretreatment process of raw cellulosic fibers aims to remove noncellulosic components contained in the plant matrix, i.e., lignin, hemicellulose, pectins, and waxes, facilitating subsequent processing [37]. Conventional pretreatment of lignocellulosic biomass includes pulping via acid, alkaline, or enzymatic hydrolysis, while bleaching is carried out applying oxidative techniques using hydrogen peroxide or sodium chloride as bleaching agents most frequently [64].
Flax/NCs Sisal/NCs Hemp/NCs Wood/NFs Bamboo/NFs Wheat straw/NFs Flax/NFs
Soybean straw/ NCs or NFs
Bacterial cellulose/NFs
Source/type Bacterial cellulose Bacterial cellulose/NCs Bacterial cellulose/NCs
Ultrasonication (0.5 h)
50% wt H2SO4 and oxidation with 2% H2O2 (3 h, 45 C) 50% wt H2SO4 (1 h, 45 C) 60% wt H2SO4 (1 h, 45 C) 34% wt H2SO4 and 24% HCl wt (1 h, 45 C) 55.4% w/v H2SO4 (2 h, 50 C) 50.7% wt H2SO4 (48 h, 50 C) 50.7% wt H2SO4 (0.7 h, 70 C) Endoglucanases, xylanases, ultrasonication 32% wt H2SO4 (0.75 h, 45 C)
Preparation method High shear homogenization
18.5 5.3 9.4 3.3 9.4 3.3
567 296 100–600 – 15–45 10 5 20–50 10–20 10–40 15–35 15–100
57
29.6 10.4
882 544
400 403 159 580 – – – –
95.3
44.3 18
1322 189
87 78 88 71.0 64.9 63.4 81.6
50
80.4
83
89
-
-
– 336 285 308 332.9 331.7 332.2 347.4
– – – – – – –
350
226.7
212.3
24.5
28.8
–
–
263
218
53.6 0.7 43.9 0.8
223
33.6 1.5
350
34.8
89.6 91
Decomposition temperature ( C) 305
ζ-Potential (mV) 26.5
Crystallinity index (%) 75.1
33.7 14
Diameter (nm)
622 100
Length (nm)
Table 3 Selected literature-cited studies on NC production from plant-based feedstock or microorganisms
[40]
[20]
[63]
[62]
[61]
Refs [60]
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The identification of an effective method is mainly dependent on the origin of the lignocellulosic matrix. Cellulose isolation avoiding the formation of internal hydrogen bonds in both crystalline and amorphous regions requires delamination of cellulosic fibers under intense mechanical shearing [13]. Mechanical techniques include high-pressure homogenization under 50–2000 MPa, micro-fluidization which is based on constant shearing stress, as well as grinding and milling that are based on shearing and friction to achieve fibrillation [64]. Mechanical practice is widely used in industrial-scale production, and it is highly efficient for disintegration of cellulose pulps into their microfibrillar and crystalline structures [13]. NC obtained from sugarcane bagasse through high-pressure homogenization showed diameter values of 10–20 nm, while the recovery yield was determined equal to 90% under the optimum refining condition [65]. The scalability potential of high-pressure homogenization has been related to high energy demands of the process reaching 70 MW h/t [13]. The isolation of NC fibers from previously chemically treated poplar and wheat straw using an ultrafine grinder was studied [66]. The obtained CNFs presented an average diameter of 43–45.2 nm. Another approach to obtain NC from bleached bamboo pulp was ball milling coupled with maleic acid hydrolysis [23]. This combination led to a higher recovery yield of CNCs (up to 24.5%) compared to acid hydrolysis alone (2.8%). Cryocrushing is another mechanical method that involves the exposure of cellulosic fibers to liquid nitrogen prior to crushing under high shear forces and ultrasonication [64]. CNFs isolated from chemically pretreated banana peels using high-intensity ultrasonication (HIUS) presented average length and diameter values in the range of 263.9–589.0 nm and 20–35 nm, respectively [30]. In another study, ultrasonication applied on wood, bamboo, and wheat straw led to NF diameters of 10–35 nm, while in the case of flax, variations were higher (10–100 nm). Decomposition temperatures were between 332 and 347 C, while crystallinity indices showed great variations with the lowest values obtained by bamboo and wheat straw NC (63–65%) [40]. Electrospinning using electrical discharge has been also reported [14]. Robles-García et al. [31] used the electrospinning technique for NC recovery from agave bagasse to obtain nanofibers with enhanced thermal properties and diameter values of 54.6–171 nm. Acid hydrolysis mostly with H2SO4 and HCl is widely applied for the production of NC. Amorphous regions of cellulose chains are easily hydrolyzed, while crystalline domains remain intact and can be isolated as nanocrystals [64]. The final properties of nanocrystals are highly affected by the raw material and the hydrolysis conditions, i.e., stirring, temperature, reaction time, acid concentration, and acid/ cellulose ratio. Woody chips, branches, and pine needles were subjected to H2SO4 hydrolysis for 40 min to produce nanocrystalline cellulose. The obtained nanocrystals exhibited high aspect ratios combined with high crystallinity (84–93%) as well as moderate thermal stability with maximum decomposition temperature varying from 272 C to 277 C [17]. H2SO4 hydrolysis of bacterial cellulose has been reported to yield cellulose nanowhiskers, with high aspect ratios from 20 to 50 [62] as well as highly crystalline (89.6%), rodlike BCNs with enhanced thermal stability [60]. Combined H2SO4 (34% wt) and HCl (24% wt) hydrolysis of bacterial cellulose
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has been reported to yield CNCs with length and diameter values of 1322 nm and 44.3 nm, respectively [61]. In the case of plant-based cellulose, combined acid hydrolysis resulted in NCs with higher aspect ratios than the aforementioned, while crystallinity ranged between 78 and 88% and the decomposition temperature was in the range of 285–336 C [20]. Enzymatic hydrolysis of cellulose is a heterogeneous bioprocessing employing enzymes, i.e., cellulases for degradation or modification of cellulosic fibers. In the case of lignocellulosic biomass, the synergy of cellulases and xylanases has been reported as xylan which is the primary component of hemicellulose that could still remain in the crude cellulosic pulp. The enzymatically produced NC exhibits diameter values in the range of 5–110 nm and length of few micrometers, while they are structured in bundle of fibrils [63]. The eco-friendly nature of enzymatic hydrolysis and the mild operative conditions could lead to sustainable and costeffective production of NC with low environmental impact. Endoglucanases were applied as a mild alternative to improve cellulose nanofibrillation of pretreated waste wheat straw that was previously subjected to disk grinding. CNFs with lower average height (37.3 nm) were obtained in this case compared to CNFs derived without enzyme involvement [26]. NC was recovered from pretreated soybean straw via acid or enzymatic hydrolysis. H2SO4 hydrolysis led to CNCs of 10 nm diameter and 300 nm length with a crystallinity index of 57%, while enzymatic hydrolysis (xylanases and cellulases) resulted in CNFs of similar diameter, length higher than 1 μm, lower crystallinity index (50%), and higher thermal stability [63].
5
Nanoscale Morphological Properties of Nanocellulose
Current investigations show great interest in the properties of celluloses at the nanoscale. Powerful tools such as small angle scattering methods resolve spatial correlations at length scales between 1 and 100 nm and in several cases up to several μm. These methods are nondestructive and provide average characteristics over macroscopic sample volumes. Small angle neutron scattering in particular [67, 68] exploits the difference in scattering contrast between hydrogen and deuterium to obtain high scattered intensities, highlights specific parts of the sample (contrast matching), and extracts the scattering length density spatial distribution in detail (solvent contrast variation). Microscopy methods (TEM and SEM) are complementary to small angle scattering and provide accurate information on the shape and size of NCs. A summary of examples from recent literature on the morphological characterization of NCs is presented in Table 4. Cellulose from dry wood pulp was TEMPO-oxidized to obtain cellulose nanofibers (TOCN) or hydrolyzed using strong H2SO4 to obtain nanocrystals. The nanoscale morphology of all cellulosic materials was studied. Crystalline cellulose in its natural state exists in the Ia and Iβ polymorphs, and its crystallographic packing typically creates rods of rectangular cross section. Indeed, small angle neutron scattering (SANS) and small angle X-ray scattering (SAXS) form factors without details of the cross section, e.g., infinitely thin rods did not give adequate fits of the
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Table 4 List of works on morphological characteristics of NCs at the nanoscale including experimental methods and extracted parameters NC TOCNs, CNCs NFCs CNCs
CNCs CNCs, CNFs Crosslinked NC foams
Experimental methods SAXS, SANS, DLS, TEM SANS, SAXS SAXS on levitating drop, SEM SAXS, laser diffraction, AFM Scanning microbeam SAXS, TEM SANS, SAXS, cryo-SEM
Morphological characteristics Cross-sectional dimensions
Ref. [8]
Correlation length, fractal exponents of network Mean interparticle distance
[69] [70]
Mean interparticle distance, helical pitch
[9]
Orientation distributions, mean interparticle distance, cross-sectional dimensions
[71]
Large and small correlation lengths, fractal exponents, persistence length, cross-sectional dimensions/shape
[72]
Fig. 4 SAS profiles from the three form factors discussed in the text for a ¼ 2 nm and b ¼ 8 nm. Reprinted with permission from [8]. Copyright 2017 American Chemical Society
scattering profiles [8]. The form factor of rodlike particles with dimensions L, b, and a under the assumptions that L b a and sin2x/x2 ≈ exp (x2/2.59) was provided by the Gaussian approximated parallelepiped model [8]. This model provided similar form factors with the ones of the full form factor of the parallelepiped model and the ribbon model where L b a (Fig. 4). The characteristic powerlaw dependence of scattered intensity as a function of scattering wave vector q, i.e., I(q)~qn, is the one expected for rigid and linear objects at low q with n ¼ 1 and the one for sharp interfaces at high q with n ¼ 4. The values of the extracted dimensions from SANS and SAXS were a ≈ 2 nm and b ≈ 8 nm. This result was explained by the crystallization of individual cellulose chains into microfibrils that contain a small number of unit cells within the cross
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section. The asymmetry of the fibrillar cross section (b > a) was attributed to possible preferred direction of the oxidation that was induced by TEMPO and the sheetlike conformation of cellulose in the crystalline phase [8]. Only a lower limit for the nanofiber length Lmin ≈ 150 nm could be extracted because of limitations of SANS and SAXS at low q. The high concentration of H2SO4 and the elevated temperature caused decomposition of cellulose chains and also led to higher cross section and shorter lengths in the cellulose nanocrystals (CNCs). TEM imaging showed compatible results regarding the geometry of the NCs. The small angle scattering results were complemented by dynamic light scattering (DLS) where the translational and rotational diffusion coefficients were measured and the length of the NCs was estimated to be about 170 and 140 nm for the nanofibers and nanocrystals, respectively. The hydrolysis of nanofibrillated cellulose (NFC) was investigated by SANS and SAXS at different xylan contents. In particular, the network structure of the enzymatically hydrolyzed NC was tested [69]. The small angle scattering data were modeled by an empirical model [73, 74] that consisted of two terms. A power-law term I(q)~qn that dominates at low q gives information on the self-similarity of the formed network that is expressed by a characteristic fractal exponent n. Another term I(q)~(1 + (qξ)m)1 that describes the correlations within the network is used to extract a correlation length ξ (network mesh-size) and a high-q power-law exponent m [75]. The characteristic q ≈ 1/ξ is related to a “shoulder” that is evident in the I(q) data. The correlation length decreased as hydrolysis degree increased either at low xylan (from 40 to 13 nm) or high xylan (from 13 to 9 nm) content. Additionally, the fractal exponent n increased from about 2 which is characteristic of loose mass fractal to about 3 indicating a more compact network [69]. The assembly of CNCs by evaporation of water was monitored in situ by SAXS in a straightforward experiment [70]. Ultrasonic waves were used to levitate an aqueous drop between two pressure nodes. The drop volume was measured by imaging with a USB camera. The concentration in the water drop increased by more than one order of magnitude from 1.5% to 25%. A characteristic main scattering peak increased in q-position and intensity as concentration increased. A mean interparticle distance between CNCs was extracted by the position of the peak qpeak by d ¼ 2π/qpeak. This distance dropped from about 50 nm to 5 nm as concentration increased. Interestingly, the power-law scaling of d as a function of concentration changed from d~c1/3, to d~c1/2, to d~c2/3, and finally to d~c1. These concentration regimes corresponded to isotropic colloidal arrangement, biphasic state, gel/unidirectionally compressed phase, and nematic phase, respectively [70]. The order parameter that was extracted by the anisotropy 2D scattering data reached a maximum at 20 vol%. This work illustrated the power of small angle scattering techniques to quantify phase transitions in self-assembling NCs. In another study, the nematic liquid crystal phase of CNCs was investigated by SAXS and laser diffraction [9]. The dimensions of CNCs were independently evaluated by atomic force microscopy (AFM). Their length and diameter were about 180 nm and 5 nm, respectively, with relatively high polydispersities of the order 40%. These results were consistent with SAXS experiments where the form
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factor could be fitted by both a cylindrical and a rectangular prism model. The average center-to-center distance between CNCs was determined by the q-position of scattering peaks in the SAXS profiles that were observed at the volume fraction range roughly from 1 to 7%. This distance was found to drop from 50 to 25 nm as a function of concentration. The results supported the formation of chiral nematic phase [9]. The pitch of the helical morphology was estimated by laser diffraction, and it was found to decrease from 15 to 2 μm as volume fraction increased from 2.5 to 6.5 %. Additionally, the twist angle between closest neighbor CNCs was calculated to increase from 1 to 4 . Scanning microbeam SAXS coupled with a flow cell was employed to resolve the alignment of CNCs and CNFs in confined flow [71]. Flow direction was on the z while beam direction was on the x axis. Scattered X-rays were collected on a 2D detector which was placed vertically to the beam direction, i.e., on the yz plane. Isotropic scattering profiles were obtained at low flow-rates. The characteristic power-laws of I(q)~q2 (flat object) and I(q)~q1 (rigid rod) were obtained for CNCs and CNFs, respectively, at low q (0.1–0.2 nm1) which corresponds to about 10–5 nm in direct space. At higher concentrations, a correlation peak emerged indicating the mutual arrangement of the scattering particles. At increased flow-rates, anisotropic SAXS patterns were collected as the scattered intensity depended on both the magnitude of q and the polar angle χ (on the yz plane). The distributions of orientations were extracted by subtracting an isotropic contribution and averaging in a q range of 0.25–0.45 nm1. The anisotropically scattered intensity was plotted as a function of χ in several heights spanning the flow channel. The orientation distributions were found dependent on the size and shape of the NC structures as they determine the collective dynamics in CNC and CNF semidiluted dispersions. The experiments were combined with rheo-optical measurements and numerical simulations [71]. NC foams were produced from bleached pulp by TEMPO-oxidization. Fibrillated cross-linked hydrogels were subsequently prepared, and their swelling and absorption properties were tested [72]. Foams with incorporated polyethyleneimine (PEI) as a physical cross-linker and hexamethylenediamine (HMDA) as a partially chemical cross-linker were investigated. The authors showed that the small angle scattering data could be fitted with three different models. A Debye-Bueche/Lorentz function model provided a large and a small correlation length. A mass fractal model interpreted the data as a superposition of a surface fractal (large fibrillar structures) and mass fractal aggregates of spherical objects. This model provided a radius for the spherical model, a cutoff length, and the characteristic dimension for the mass and surface fractals. Finally, the stiffness (persistence length), axes of cross section, and contour length were extracted from the scattering function of flexible cylinders with elliptical cross section. Persistence length (~ 10 nm) and mass fractal dimension (~ 1.5) increased with the addition of PEI and HMDA which demonstrates that fibers become stiffer and the network becomes more compact. The cutoff length (15–30 nm), which was proven equivalent to the dimension of the swollen fiber bundle, increased in the presence of PEI and decreased in the presence of HMDA [72]. Similarly, the large correlation length (70–90 nm) increased for PEI and decreased for HMDA in comparison with pure NC network. This length scale
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was attributed either to large pores or fiber bundles. On the other hand, the small correlation length (3–5 nm) was identified as the size of an elementary fibrillar unit. Small angle scattering techniques were also used to follow the transformation of the network structure in the foams upon hydration. High-resolution scanning electron microscopy revealed the network morphology up to the scale of 10 μm, while it confirmed the existence of pores of 50–200 nm in size and cellulose fibers with diameters of 10–30 nm.
6
Targeting Specific Applications by Properties
Natural polymers constitute indispensable biomaterials in life science. Their origin, production methods, and final properties define targeted applications. Cellulose is the most abundant polysaccharide in nature. Cellulose’s great availability, biocompatibility, and renewability are the pillars for further consideration of this polymer in specific and value added applications. Nanotechnology preferentially combined with green chemistry could offer alternative and environmentally friendly routes for the development of renewable and sustainable end products [76]. NC could be an ideal building block due to its unique structure which gives rise to properties such as high Young’s modulus and enhanced mechanical strength. Its incorporation into final products determines the final properties according to the morphology and surface properties of the former. Ultimate biodegradable and nontoxic NC-based materials could be fabricated to serve highly demanding sectors, i.e., catalysis, super adsorbents, elastic conductors, pharmaceuticals, medicine, tissue engineering, drug delivery systems, and the food and biopolymer industry in the form of aerogels, hydrogels, micro- and nanoparticles, nanocomposites, emulsions, and membranes/films [7]. Conventional formulations of some of the aforementioned lag behind in mechanical strength which can be controlled by involving NC in the form of nanofibers or nanocrystals. The fibrillar arrangement of the structure, the high aspect ratio, low density, and the enhanced mutual hydrogen bonds of properly modified NC lead to final products with enhanced mechanical ductility and flexibility as well as a highly porous matrix [77]. Indicatively, polymeric nanocomposites require the implementation of reinforcing fillers with high aspect ratios that can improve stress transfer. High aspect ratios can also promote viscosity modification and reduce required amounts in suspensions for efficient gelation [1]. NC presents excellent gas permeability and water holding capacity/absorbency due to the thick crystalline structure of the nanoparticles meeting requirements of the packaging sector. NC-based coating could be applied for the production of biofilms with enhanced flexibility and optical transparency providing at the same time an alternative for the substitution of nondegradable plastic coatings that have been so far used in packaging [78]. Modified with polyvinyl alcohol, bacterial NC was incorporated into silver nanoparticles to produce food packaging films. The improved oxygen barrier properties of films were attributed to the dense threedimensional network of bacterial NC crystals [78]. Starch nanocomposite films
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were reinforced with cellulose nanocrystals obtained after chemo-mechanical treatment of sugar beet pulp. The incorporation of nanocrystals into the films enhanced their tensile strength and modulus of elasticity [79]. Nanocrystals obtained from acid hydrolysis of bacterial cellulose were used as reinforcing fillers to fabricate edible gelatin films. The presence of nanocrystals in the gelatin matrix decreased its water affinity and enhanced the mechanical properties of nanocomposites, thus favoring edible packaging applications [80]. Specific structure characteristics of NC create great potential in colloid formation, crating 3D networks via hydrogen bond cross-linking, covalent bonding, or ionic interactions with various functional compounds, i.e., metals and polymers [7]. NC, in the form of crystals obtained from cotton, has been efficiently employed in sustained drug release as composite in alginate-based hydrogels [81]. Electrostatic interactions and ionic cross-linking created by positively charged nanocrystals and anionic carrier or delivery agents, i.e., alginate, could provide stable hydrogel structures. The ζ-potential values of NC higher than +38.9 mV could be a strong indicator for functional colloidal systems of this type [81]. Novel hydrogels were fabricated with CNCs derived from tunicates and poly(acrylic acid). The incorporation of CNCs into the hydrogel network favored mechanical performance of the latter in terms of strength, ductility, and toughness [82]. Another crucial factor is the minimum decomposition temperature of NC and thus of the final applications that demands high temperature values. It has been reported that NC preparation using strong H2SO4 and TEMPO-oxidation results in NCFs of low thermal degradation with minimum decomposition temperatures varying between 120 and 210 C. This is attributed to charged sulfate groups and sodium carboxylate groups introduced on the NCF surfaces, respectively, initiating thermal degradation faster [83]. Cellulose from poplar wood and cotton was treated via four different methods to produce different types of NCFs. Strong acid hydrolysis with HCl or H2SO4 led to an increase in crystallinity (~90%) of CNFs with lower aspect ratios compared to the HIUS and TEMPO-oxidation. HIUS resulted in the formation of interconnected bundles which could be avoided if TEMPO-oxidation was preceded, thus obtaining NCFs with high aspect ratios. Aerogels produced from HIUSand TEMPO-oxidized NCF showed enhanced water absorbability, good flexibility and rigidity, as well as enhanced potential to remove dye pollutants. Also, high thermal degradation temperatures (336–342 C) were observed in the case of HIUSand HCl-NCF aerogels [84]. High crystallinity index of NC is correlated to good thermal stability of the molecule. Crystallinity indices of nanocellulose derived from various renewable lignocellulosic biomass vary between 60% and 80% [77], while higher values up to 95% have been reported for bacterial NC [38]. As a consequence, source of origin should be carefully selected based on the required application. NC presents an easily amendable amphiphilic character demonstrating its strong capacity as emulsion stabilizer. The good emulsifying performance of NC is also demonstrated by its ζ- potential absolute values higher than 35 mV, allowing satisfying water dispersibility via the creation of strong repulsion forces [60]. NC derived from H2SO4 hydrolysis of bacterial cellulose showed better thermal stability and emulsifying performance after incorporation in olive oil Pickering emulsion due
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to superior properties of the former including initiating decomposition temperature of 350 C, crystallinity index of 89.6%, and ζ-potential of 34.8 mV [60]. NC from lemon seeds has also been proposed as a stabilizer in Pickering emulsion, while the emulsifying potential of nanocrystals was highly affected by the intensity of the method that was employed to produce them [33]. Water-in-oil Pickering emulsions valorizing CNFs that were obtained via enzymatic hydrolysis of algal biomass followed by TEMPO-oxidation resulted in small and homogeneous oil droplets showing good stability after 30 days of storage. CNFs showed the ability to emulsify 50% of sunflower oil [58].
7
Electrostatically Stabilized Nanocellulose-Based Suspensions
Interaction of surface hydroxyl units of NC with water favors its dispersion in aqueous media; however, the strong interfiber hydrogen bonding drives aggregation between the CNFs [85]. Dispersion can be assisted by ultrasonication or highpressure homogenization although to some restricted extent. Surface modification by introducing charges or polymeric chains effectively stabilizes NC by electrostatic or steric forces, respectively. Dispersion stability by surface charging may be described by the ζ-potential of the nanoparticles. A value of 10 mV has been found not enough to overcome hydrogen bond forces [86]; however, good dispersion [87] was achieved by a ζ-potential of about –30 mV. Sulfuric acid hydrolysis is commonly used to introduce surface charges in the form of sulfate groups. Carboxyl groups are also introduced by routes that may include oxidization of hydroxyl groups and physical adsorption [88]. Interactions between NCCs can be regarded within the framework of rodlike colloids [89]. Surface charge affects interactions and stabilization among other parameters such as aspect ratio and size and induces ionic strength dependence on the charged colloids. Modifications with cationic charges are also possible, i.e., with amine [90] and quaternary ammonium [91] groups that present a degree of ionization sensitive or not to pH. Combination of steric and electrostatic stabilization could be also achieved by grafting of polyelectrolytes [92]. CNCs were prepared from cotton slurry and hydrolysis with sulfuric acid at fiber/ acid ratio of 1/20. CNC powders were mixed with deionized water at a broad range of concentrations to prepare nanorod suspensions [10]. The morphology of CNCs was compared to the one of cotton with SEM imaging. Images from cotton showed large fiber bundles that incorporated micro-sized fibrils. Cotton fibers were not dispersible in water due to their large size and strong hydrogen intermolecular bonds. These clusters of fibers had diameters of several μm. On the other hand, in CNC samples, images showed nm-sized rodlike particles with length about 300 nm and diameter about 25 nm. H2SO4 hydrolyzes regions of amorphous cellulose preferentially, while crystalline regions are not accessible for hydrolysis. The authors constructed a phase diagram for CNCs from steady-shear viscosity measurements (Fig. 5). Shear-thinning behavior was characterized by the broadly used Carreau
Nanocellulose Production from Different Sources and Their Self-Assembly in. . .
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1000 Isotropic
100
Isotropic+Liquid Crystal
Gel 0.8
10
0.1s-1 1s-1 10s-1 100s-1
1 0.1
0.6
0.4
non-Newtonian Index
Fig. 5 Flow properties of CNC suspension viscosity as a function of concentration. Reprinted from [10]. Copyright 2015, with permission from Elsevier
Viscosity (Pa•s)
3
0.01 0.2 1E-3
c2 0.1
C1 1 Concentration(wt%)
10
equation for the viscosity (η) which at intermediate and high shear rates (_γ ) is simplified to a power-law ηðγ_ Þ γ_ n1 . Plots of viscosity and non-Newtonian index (n) versus concentration revealed two critical concentrations. At the lower critical concentration (0.6%), which was also near the calculated critical overlap concentration, the viscosity scaling changed from the isotropic and dilute dispersion scaling η~c1 to a weaker concentration dependence. The index n showed a strong drop at this concentration. At the higher critical concentration (10%), viscosity scaling became stronger while non-Newtonian index kept decreasing. The authors identified the three concentration regimes as “isotropic,” “isotropic + liquid crystal,” and “gel” from lower to higher concentration [10]. Screening electrostatic interactions with addition of salt caused a drop in the viscoelastic moduli of the suspensions. This was connected with the polyelectrolyte nature of the hydrolyzed CNCs and illustrated the importance of electrostatic interactions in their stabilization. Hydrolysis of cellulose derived from plants leads to the production of charged rodlike particles that are expected to have a complex phase diagram. The interaction between individual NCCs in suspension depends on their orientation and ionic strength. Freeze-dried hydrolyzed NCC was dispersed in water to investigate the effect of concentration, salt content, and pH on the interactions and self-organization [89]. Surface charge of nanoparticles was quantified by ζ-potential measurements which was about 45 mV in the absence of salt and dropped in absolute value as salt content increased. Viscosity versus salt content showed a minimum at about 10 mM NaCl. This was explained by a reduction of the effective volume of the particles caused by a shrinkage of the electrostatic double layer and a subsequent domination of attractive interactions that promote network formation. AFM measurements confirmed the rodlike shape of the particles that had average length of about 210 nm and diameter of 15 nm. Size distributions obtained by DLS revealed the presence of nanoparticles of hydrodynamic diameter in the order of 100 nm in the absence of salt that were identified as the NCC particles. Upon addition of salt, size distribution shifted to higher values confirming the interparticle aggregation. A phase diagram was drawn by combining with rheological measurements. Increase
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in NCC concentration gradually led from a predominantly viscous fluid (isotropic suspension) to an ordered fluid (anisotropic suspension) and to a predominantly elastic viscoelastic fluid at even higher concentrations. The boundaries between the phases shifted to lower critical concentrations as salt content increased [89]. Surface modification of NCs can be carried out by adsorption of surfactants as well as with polyelectrolytes. These non-covalent interactions are guaranteed by the development of hydrogen bonds, electrostatic interactions, or van der Waals forces [93]. A typical example was published by Larsson et al. [94] concerning the production of thermoresponsive NFC with the adsorption of a thermoresponsive block copolymer onto NFC. Using ATRP polymerization, three diblock copolymers were synthesized consisting of a quaternized poly(2-(dimethylamino) ethyl methacrylate) (qPDMAEMA) and a thermoresponsive block poly(di(ethylene glycol) methyl ether methacrylate) (PDEGMA). The PDMAEMA segment was quaternized to produce positively charged amino groups, and then the block copolymer was adsorbed onto the negatively charged NFC showing excellent water solubility. In this way, complexes were formed between a thermoresponsive polyelectrolyte block and the NFCs in aqueous media without using any chemical reaction on the NFC [94]. Unmodified NFCs (u-NFCs) or modified NFCs were evaluated to maintain the pliability of PPy-NFC electrodes with high gravimetric and volumetric capacitances. NFC modifications were made by introducing carboxylate or positively charged amine groups resulting in the formation of fibers with anionic (a-NFCs) or cationic (c-NFCs) surface charges. Measurements of the ζ-potential at pH 7 gave the values 12, 41, and +31 mV for (u-NFCs), (a-NFCs), and (c-NFCs), respectively, confirming the successful surface modification of a-NFCs and c-NFCs with carboxylate or quaternized amine compounds [95]. The gradual surface modification of CNCs by sulfonation has been reported, investigating the self-assembly behavior of the nanoparticles in aqueous suspensions. The surface modification of the CNCs was conducted by changing hydroxyl groups in the periphery with charged sulfate ester groups. The ζ-potential measurements showed that with gradual increase of surface modification of CNCs, values for all samples were negative with an increasing trend in absolute value, demonstrating stability improvement and better molecular dispersion in aqueous suspensions. The SEM images illustrated the self-organization of the modified CNCs in the solid films. The increase in the degree of replacement resulted in a better self-assembly of rodlike nanoparticles in the solid films. Surface modification of CNCs can be controlled avoiding destructive effects on the crystallinity of CNC nanoparticles [96].
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Self-Assembled Nanocellulose in Composite Materials
The self-assembly of materials has been considered an important parameter to form well-defined structures by physical interactions above a critical concentration. It has been reported that after a certain period of time, thermal treatment of cellulose fibers in acidic solution could lead to degradation; thus, it could be controlled through
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strong acid hydrolysis. Colloidal suspensions of acid-hydrolyzed cellulose fibers can be optimized using ultrasonication, to yield microcrystalline cellulose [4, 97]. This process leads to the formation of cellulose nanowhiskers (CNWs) which are colloidal systems with remarkable lateral dimensions of 5–10 nm and length of 50–300 nm depending on the plant source [4]. These particles are excellent rodlike nanofibers as they have the ability to self-assemble and form a chiral nematic phase. CNW nanoparticles could be candidates for biomedical, tissue engineering, and drug delivery applications. The first study to report self-assembly of CNWs into a chiral nematic liquidcrystalline phase was carried out in 1992 [98]. Since then, production and selfassembly research of CNWs has become widespread in the scientific field. Khandelwal et al. [99] dealt with the biosynthesis of bacterial cellulose and cellulose from tunicates as well as the self-assembly behavior of CNWs derived from these sources. The first organization was made by cellulose chain synthesized bacteria with dimensions of about 1.5 nm in diameter and protons of 3–4 nm in diameter. Subsequently, these nanostructures were organized to form crystalline microfibrils of 20 nm width which will be connected in ribbons of 80–120 nm in widths and a very long length in the order of micrometers [99]. Self-organization of CNWs under the concept of different morphologies was evaluated [100]. A series of raw CNCs with a wide range of dimensions (1–1700 nm) were produced when acid hydrolysis was applied. The raw CNCs were then fractionated by membrane filters leading to narrower size ranges and the subsequent formation of size-unified CNCs. FTIR, TGA, and XRD analysis of the self-assembly of CNCs revealed that size-unified CNCs exhibit differences in thermal stability as well as in cholesteric nematic liquid assembly. This fractionation of CNCs could provide enhanced thermal stability, higher crystallinity, and more effective selforganization than raw CNCs, which contain small and large fibers [100]. Another study presented self-organization through different amphiphilic interactions between natural and synthetic segments. Carbon quantum dots (CQDs) were utilized as a fluorescent shell assembled around the CNC core to form a chiral fluorescent CQD/CNC nanostructure. This formation through amphiphilic interactions can lead to the self-assembly of these hybrid materials into the fluorescent chiral liquid-crystalline phase and maintain this morphology by forming flexible CNC films. The films exhibited remarkable fluorescent fingerprint and allowed selforganizing CQDs/CNCs to form chiral morphologies rather than being randomly distributed in the CNC matrix [101]. NC-based gels are a new class of soft materials that are distinguished into hydrogels and aerogels. They are characterized as low cost, biocompatible, and biodegradable. CNC hydrogels were prepared by ionic gelation in CNC suspensions and tested under the addition of the metal chlorides NaCl, MgCl2, AlCl3, CaCl2, and SrCl2. A minimum 1.5 wt% in CNC was required for gel formation in all cases. Gel strength increased as Debye length decreased, indicating that at screened electrostatic repulsions, van der Waals attractions and hydrogen bonding dominated. This was the cause of gelation and it was achieved at lower salt contents for salts with higher valency [102]. TEMPO-oxidized CNF hydrogels have been prepared by
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electrostatic complexation with lysozyme. Protein globules acted as ionic crosslinkers at neutral pH where protein and CNF carboxylate groups are oppositely charged. The networks that were created were soft and fragile under deformation and the gelation was pH tunable [103]. Zhang et al. [104] presented the preparation and self-organization of bio-hybrid hydrogel (BHH) and bio-hybrid aerogel (BHA) obtained from NC and nanochitin in order to create an innovative biohybrid gel for water purification. The self-assembly of BHH 3D structure was achieved through hydrogen bonds and electrostatic interactions between the negatively charged groups of TEMPO-oxidized cellulose nanofiber and positively charged groups of deacetylated chitin nanofiber. BHAs were obtained from the lyophilized BHHs and presented a highly porous physically linked network structure which ensures the availability of its internally active site for the adsorption of toxic metallic and organic pollutants [104]. A supramolecular aerogel (SA) which was self-organized into supramolecular structure by hydrogen bonding in combination with polyaniline in 3D lightweight aerogel of NC has been reported. More specifically, 3D structures of SA with impressively high porosity presented high conductivity and capacity. This innovative material could be used as an electrode and toxic gas sensor and in various other applications [6]. Aerogels can readily be formed by the selforganization of CNWs [105]. Different concentrations of cellulose nanowhiskers can lead to aerogel density alterations from 0.078 to 0.155 g cm3. These formulations showed significant stability over time [105]. Two types of hydrogels in aqueous media of CNF at different NaOH concentrations were produced and evaluated. At 6–9 wt% NaOH concentration, hydrogels were formed by the aggregation of individual fibers in the original morphology cellulose I. At 15 wt% NaOH, the coalescence of CNFs led to the network formation presenting the highly crystalline structure cellulose II [106]. Recent studies have shown that CNC-based nanocomposites could increase their tensile strength and transparency depending on the aspect ratio of CNC. Tensile properties also depend on the adaption of cellulose nanofibers into the polymeric matrix, making processing conditions critical [76, 107, 108]. Poly(vinyl alcohol) (PVA) was modified in linear and cross-linked form utilizing different ratio of bagasse-extracted NC, thereby forming nanocomposite PVA films. PVA is a biodegradable polymer that develops strong hydrogen bonds with the NC hydroxyl groups, resulting in the formation of PVA-cellulose whiskers. Linear PVA and cross-linked PVA showed an increase of roughly 50% in the tensile strength by the addition of 7.5 wt% and 5 wt% NC, respectively, while the study using TGA showed that cross-linked PVA with NC had higher thermal stability as opposed to linear PVA [109]. Poly(ethylene glycol) (PEG) hydrogels were cross-linked in situ with CNCs from pulp fibers to produce a reinforced nanocomposite material. CNCs were functionalized by chargeable sulfate groups under a sulfuric acid hydrolysis scheme. CNCs were found to adhere to the produced PEG network which had characteristics of a gel even in the absence of the nanorods. Its swelling degree decreased significantly as a function of added CNC amount showing a strong attraction between the two materials. Mechanical properties such as Young’s modulus, fracture stress, and
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fracture energy increased with increasing CNC concentration, while tensile strength decreased. These findings were attributed to the breakable hydrogen bonds between CNCs and PEG network [5]. The interactions between the cationic native nanofibrillated cellulose (C-CNF) and the anionic montmorillonite (MTM) have been reported to lead to self-assembly by a simple centrifugation process to produce a bio-based 3D bulk nanocomposite material with high compressive strain and low density [110]. Multilayered NC/polymer thin films are promising functional materials with potential in drug delivery, flexible electronics, and membrane technology [111]. The complexation between chitosan (CS) and CNWs was approached through the layer-by-layer (LBL) process. The hydrogen bonds as well as the electrostatic interactions between the negatively charged sulfate groups on the CNW surface and positively charged amino groups of CS led to the development of multilayered films. The surface of CNW/CS film was characterized as relatively smooth with roughness values lower than 11 nm. The average thickness of a single bilayer of the film was measured to be 7.0 nm, and the amount of chitosan transported in each cycle was 14.7 mgm2 [112]. Another scientific study of particular interest dealt with self-assembly between nanofibrillated cellulose and cationic amphiphilic diblock copolymer micelles with soft core. The target was to complex carboxymethylated nanofibrillated cellulose and micelles formed in aqueous solution from poly(1, 2-butadiene)-block-poly (dimethylaminoethyl methacrylate). As a result, a biomimetic nanocomposite was formed between colloidal fiber and spherical colloidal micellar with nanodimensions and rubbery core [113]. Aqueous dispersions of anionic and cationic cellulose I nanofibrils have been utilized to form alternating multilayers with the layer-by-layer technique. Films were found to be less hydrated and contain higher adsorbed amount and less energy (work of adhesion) for surface separation in comparison with layers formed by the anionic NC with a cationic polyelectrolyte polyethyleneimine [114]. In another study, layer-bylayer deposition of cellulose I nanofibrils and poly-(N-isopropylacrylamide-co-acrylic acid) copolymer microgels produced multilayers with porous structure which facilitated the penetration of dye molecules. The presence of poly(N-isopropylacrylamide) enriched the films with thermoresponsive release kinetics of the dye molecules [115].
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Conclusions and Future Perspectives
Α thorough review on the so far available sources of NC was presented with specific emphasis on bacterial cellulose. Additionally, methods that are employed for the preparation of nanocellulosic fibers or crystals were included, while extensive discussion on properties and targeted applications covering a vast majority of industrial sectors was quoted. Increased public awareness and the establishment of strict policy regulations for fossil-based production have paved the way toward alternative resources that provide clean energy, green chemicals, and materials with high biodegradability. It should be highlighted that the application of
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agricultural and industrial waste streams in the nanotechnology field should further be investigated to attain economic feasibility while introducing renewability, biodegradability, and sustainability concepts that could give rise to a new bio-economy era. High value added applications of nanocellulosic materials as nanocomposites, hydrogels, and aerogels successfully serving sectors of food biopackaging, biomedicine, and biopolymers could contribute to this. Self-assembled nanocomposite materials do not require any chemical reaction and therefore avoid the drawbacks of toxicity. Therefore, they are a very attractive field for the application of the biocompatible and biodegradable NCs. The design of NC-based functional materials requires their investigation with advanced noninvasive techniques such as small angle scattering. Current knowledge in the broad fields of food science, biomedicine, and soft biomaterials will definitely be the basis for new self-assembled nanocomposite materials based on NCs.
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Physicochemical Characterization of Nanocellulose: Composite, Crystallinity, Morphology María Luisa García Betancourt and Dahiana-Michelle Osorio-Aguilar
Contents 1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Composites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1 Nanocellulose and Biodegradable Polymers Composites . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Crystallinity of Cellulose, Nanocellulose, and Composites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1 Cellulose Crystallinity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2 Nanocellulose Crystallinity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3 Cellulose Nanocomposites Crystallinity and Mechanical Properties . . . . . . . . . . . . . . . . 3.4 Cellulose Nanocrystal Liquid Crystal Phases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5 Crystallinity Measurements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Morphology and Physico-Chemical Properties of Nanocellulose and Composites . . . . . . . 4.1 Morphology of Nanocellulose and Composites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2 Size, Composition, Physicochemical, and Reactivity Properties . . . . . . . . . . . . . . . . . . . . 5 Conclusion and Future Prospects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Abstract
Cellulose is one of the most important organic polymers in terms of its production and industrial applications. Cellulose found in nature is obtained from a big assortment of natural sources such as plant fibers, tunicates, and also obtained from bacteria. It makes it the most abundant organic polymer on the earth. Nanocellulose is a material derived from cellulose. For successful applications of nanocellulose, specific knowledge of properties by characterization is fundamental. Different morphologies of nanocellulose combined with biodegradable polymers extend the applications by increasing their mechanical properties. Some
M. L. García Betancourt (*) · D.-M. Osorio-Aguilar Centro de Investigaciones Químicas, IICBA, Universidad Autónoma del Estado de Morelos, Morelos, Mexico e-mail: [email protected] © Springer Nature Switzerland AG 2022 A. Barhoum (ed.), Handbook of Nanocelluloses, https://doi.org/10.1007/978-3-030-89621-8_9
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applications are biofilters, biosensor strips, tissue engineering, aerospace industry, automotive components, electrical industry, lubricants, heavy metal removal from aquatic media, lithium-ion batteries, and so forth. The crystallinity properties of nanocellulose studied by X-ray diffraction are fundamental to conjugate them with composites. These studies accompanied by other spectroscopic techniques such as nuclear magnetic resonance, Raman, and Infra-Red give precisely additional structural characteristics. Morphology characterization by atomic force, scanning, and transmission electron microscopy becomes important since nanocellulose originates from bottom-up or top-down methodologies. The morphology and dimensions vary according to parameters used in the direct synthesis from cellulose. The morphologies may be nanowhiskers, nanofibers, or bacterial nanocellulose, which are different from each other. Keywords
Nanocellulose · Nanocellulose biopolymer composites · Nanocellulose crystalinity · Nanocellulose characterization · Characterization techniques for nanocellulose
1
Introduction
Cellulose is a hydrophilic, odorless, and tasteless polysaccharide found in the structure of plants. It is a renewable and recyclable natural resource recently adapted to industrial applications because of its renewability, biocompatibility, biodegradability, and anti-microbial properties. Cellulose is an organic linear polymer with a molecular repeat unit comprised of glucose monosaccharide, the acetal linkage is β-1,4, and it is the major component of plant cell walls. Its general formula is (C6H10O5)n and has a density of 1.50 g/cm3. Each monomer bears three hydroxyl groups, the ability of these groups to form hydrogen bonds plays a significant role in the crystalline and other physical properties of cellulose. Each cellulose fiber is formed by the union of fibrils, which are long threadlike bundle of molecules laterally stabilized by intermolecular hydrogen bonds. Each cellulose fiber is formed by the union of fibrils, which are long thread-like bundle of molecules laterally stabilized by intermolecular hydrogen bonds. Cellulose fibers consist of different structured cell walls, so when undergoing chemical and mechanical treatments, it is possible to affect the morphology in size and appearance (smooth or rough). It has been observed that cellulosic fibers are composed of individual microfibers linked by lignin and when subjected to chemical treatments their size is reduced and the surface roughness modifies. This is attributed to the removal of components such as hemicellulose, lignin, and waxes [1]. Nanocellulose is defined as a cellulose material having dimensions of 100 nanometer (nm) or less with a particularly high specific area, high porosity with excellent pore interconnectivity, high stiffness, high biodegradability, and a low density
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(around 1.6 g/cm3). The increasing environmental concerns provided the usage of biodegradable reinforcements such as nanocellulose for diverse polymers. The natural synthetic biopolymers also have the same properties of renewability, biocompatibility, and biodegradability. Some of these polymers are polycaprolactone, poly (butylene succinate) (PBS), polyethylene glycol (PEG), poly (lactic) acid (PLA), polyglycolic acid (PGA), copolymer poly (lactic-co-glycolic) acid (PLGA), starch, chitosan, alginate, protein, and gelatin. They come from chemical synthesis or natural resources; the synthetic biopolymers produced chemically come from biosynthesis of living organisms or biological material [2]. For successful applications of nanocellulose, it is important to characterize the samples to know the degree of polymerization, morphology, shape, aspect ratio, dimensions, charge, crystallinity, purity, and structural and thermal properties. And for nanocellulose biodegradable composites, it is important to know the correct immersion of nanocellulose in the matrix, as well as the mechanical properties [3]. A previous review provided a detailed description and evaluation of characterization according to the needs and origin of the specimen by detailing the best practice for respective techniques [4]. This book chapter contains relevant information of physicochemical properties of nanocellulose and composites of nanocellulose with biodegradable synthetic (PBS, PEG, PLA, PGA, and PLGA) and natural (starch, chitosan, alginate, protein, and gelatin) polymers. The first section contains a resume of biopolymers composites with nanocellulose and a review of characterization properties. In this section, the effect of the immersion of nanocellulose in the biodegradable polymeric matrix is disused. The second section focused on crystallinity properties contains facts on crystal structure Iα and Iβ of cellulose polymorphs and nanocellulose. The effect of crystallinity conferred to nanocellulose composites by nanocellulose, revised in this section, discuses some examples. The third section contains resumed information about microscopy, textural, mechanical, and other properties of nanocellulose and nanocellulose composites. This last section presents specific properties of nanocellulose and composites.
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Composites
Composites or nanocomposites produced employing nanocellulose is nowadays a field widely studied due to the opportunity to develop useful and eco-friendly materials. Sustainability is a key part of the research interest over the scientific community. Considering that the combination of polymers with nanocellulose not only reduces the cost, volume of production, and energy consumption, but also reduces the residual waste released to the environment. The nanocellulose surface possesses multiple OH groups which reduces the interaction with polymers. To overcome this issue, the modifications of those groups and surface functionalization promotes the interaction, either covalent or non-covalent bonds with polymer matrix [5].
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The main characteristics of nanocellulose which make ideal for composites can be listed. (1) Nanocellulose is low cost and biocompatible material due to is natural resource; (2) contains multiple modifiable hydroxyl groups that are modified, improves the interaction thanks to good dispersion and compatibility with the polymer matrix; (3) the low density of cellulose, not only reduces the density of composite, but also produces lightweight materials; (4) the nanostructural dimensions of nanocellulose increases the surface area; (5) the phase change of nanocellulose from solid to liquid induces change properties (hydrophilic nature, non-toxicity, and self-assembly), allowing the formation of other structures and interaction with polymers [6, 7]. Nanocellulose-reinforced plastic composites can be divided into two types: biodegradable and non-biodegradable polymers (Fig. 1). This section focuses on nanocellulose-reinforced plastic composites and their main characterization properties of composites. The cited biodegradable polymers include natural and synthetic. The synthetic polymers are polycaprolactone, poly (butylene succinate) (PBS), polyethylene glycol (PEG), poly (lactic) acid (PLA), polyglycolic acid (PGA), and copolymer poly (lactic-co-glycolic) acid (PLGA). And the natural biopolymers cited in this review are starch, chitosan, alginate, protein, and gelatin.
2.1
Nanocellulose and Biodegradable Polymers Composites
The nanocellulose and biodegradable polymers composite emerged as an alternative for reinforced biodegradable polymers, as well as an improvement in mechanical properties [8, 9]. The biodegradable polymers have important properties for sustainability, the most important, biodegradability. They are also easy to process, can be recycled, and are accessible [7].
2.1.1
Nanocellulose and Synthetic Biodegradable Composites
Polycaprolactone Polycaprolactone (PCL) is a synthetic biodegradable polyester partially crystalline, having a low melting point (60 C) and a glass transition temperature of 60 C, and hydrophobic. It can be prepared by ring-opening polymerization of ε-caprolactone, which is commonly derived from fossil carbon [10]. As a biopolymer, PCL has been recognized for its industrial potential. In assessment to traditional plastics like polypropylene (PP) and polyethylene (PE), each of which require at least hundreds of years to absolutely degrade, PCL biodegrades into naturally occurring products in only a few years [10, 11]. In the last decade, the synthesis of PCL and cellulose nanofibers has been thoroughly studied and shows how the blending of those two fibers, for example, via co-electrospinning, results in a firm fibrous web with an improved wicking rate, comparing it with the lack in water retention that PCL presents [12]. To carry out with this method, cellulose acetate (CA) is used as a precursor to fabricate cellulose through the removal of the acetyl groups, a deacetylation.
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Fig. 1 Schematics of different biodegradable polymers to form nanocellulose composites
Some authors reported the wicking rate for different blend ratios of PCL/CEL, which suggested that increasing the CEL ratio in the blend enhanced the wicking front height, though this increase also resulted in a decreased crystallinity, according to the XRD patterns. Therefore, the resultant nanofibers may be used as biofilters and biosensor strips. Other authors, following a similar procedure that involves the in situ regeneration of cellulose chains into the PCL fibers, reported that the nanofibers exhibit structural integrity, high wettability, and enhanced mechanical properties and proposed them as a potential candidate for tissue regeneration application [13]. Poly (Butylene Succinate) (PBS) Poly(butylene succinate) (PBS) is a thermoplastic polymer resin of the polyester family that presents a great advantage over others since it can be either obtained from petroleum sources or from renewable resources [14], as both succinic acid and 1,4-butanediol can be bio-derived. The main interest in Poly (butylene succinate) PBS or polytetramethylene succinate and its copolymers is their balanced mechanical properties like polypropylene, but with exceptional characteristics of biodegradability. PBS is a thermoplastic polyester with repeated units of butylene succinate (C8H12O4) [9]. The success of PBS as thermoplastic materials is linked to its properties, PBS is a semicrystalline polymer with high crystallization ability and its melting temperature is one of the highest among poly (alkylene dicarboxylates). The glass transition temperature is well below room temperature; hence, PBS possesses a broad workability range which allows its processing through extrusion, injection molding, and thermoforming. The main uses of PBS regard environmental purposes, such as mulching films, compostable bags, nonwoven sheets & textiles, catering products, and foams. However, the lack of enough mechanical properties leads to the limitation in the
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engineering fields, such as the aerospace industry, automotive components, and electrical industry, so it is necessary to reinforce the PBS in order to extend its application area. Sustainable and biodegradable nanocomposites were prepared using PBS and INF. The dispersion state of INF within the resulting PBSINF composites was investigated using TEM and static tensile properties (i.e., modulus, strength, and toughness) were measured at room temperature (~25 C) and atmospheric conditions (relative humidity: ~50 5%) using an Instron Universal Testing Machine. All specimens tended to follow ductile fracture mode, as evidenced from the stress-strain curves. Addition of INF was observed to lead to an increase in resilience, tensile, and flexural moduli of PBS-INF nanocomposites, but was accompanied with a decline in toughness and strain-at-break of the nanocomposites. INF showed a promising reinforcing ability by enhancing both tensile and flexural strengths up to 1.5 phr INF loading. However, beyond this level of loading, both the strength parameters were observed to decline due to possible agglomeration of INF. Thus, the optimum INF loading for enhanced (tensile and flexural) stiffness and strength properties was found to be 1.5 phr [15]. Polyethylene Glycol (PEG) Polyethylene glycol (PEG) is a polyether formed by repeated ethylene glycol units [(CH2CH2O)]. The synthesis methods for production of PEG are anionic polymerization of ethylene oxide and any hydroxyl initiators, and ring-opening polymerization from epoxyethane. PEG is a USFDA-approved biopolymer with wide use in pharmaceutical applications because of the exceptional tunable properties and safety profile. Tunable properties such as biocompatibility, high structure flexibility, amphiphilicity, devoid of any steric hindrances, and high hydration capacity are attributed to the multiple configurations PEG may take. The configurations are surface dependent; it means that may be grafted in a planar or spherical surface. The layer thickness depends upon the molecular weight, conformation and graft density of PEG. The main configurations are brush, mushroom, and loops. For a spherical surface, the configurations occur by adsorption, entangled or conjugated [18]. PEG forming composites with cellulose is a field studied because of the potential to produce sustainable products. PEG is a nontoxic, biocompatible, immunogenic, non-antigenic, and biodegradable plasticizer for cellulose, and it elevates the rate of cellulose biodegradation. The use of PEG in composite fabrication incremented the flexibility, increased the impact resistance, the elongation at break, and film elongation due to the plasticizing effect of PEG [19]. Different studies about composites using nanocellulose and PEG as plasticizer were previously reported. Banana pseudo-stem-based nanocellulose was plasticized with PEG, adding nanoclay and graphene oxide nanofillers in order to increase the film properties; and improvement on the tensile strength was observed when using nanoclays, indicating good interaction with the clay. In another work, wood
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cellulose was employed for nanofibrillation adding PEG, observing a development of the mechanical properties (higher flexibility and thus higher potential conformability) after wetting, which is an important factor in wound bend; the composite was proposed for liquid absorption in wounds, but recommend posterior investigation for final use [20]. Other applications for composites including cellulose, nanocellulose or nanostructures, and PEG are green lubricants [21], heavy metal removal from aquatic media [22], tissue engineering [23], and lithium ion batteries [7]. Poly (Lactic) Acid (PLA) Despite poly(lactic) acid (PLA) has a poor commercial purpose due to its availability not comparable with derived petroleum-based composites, in the last years the interest has increased due to the awareness of nonbiodegradable polymers [9]. The physical, chemical, and mechanical properties of PLA are transparent, crystalline, compostable, high mechanical strength, thermoplastic characteristics, biocompatibility, and processability. PLA can be produced by the condensation polymerization or via ring-opening polymerization of the lactic acid and can be derived from natural raw material such as potatoes, corn, starch, rice, sugar beet, and sugar cane [8, 9]. This biopolymer exhibits high mechanical strength, thermoplastic characteristics, and biocompatibility. Yet, the thermal instability, low elongation at break, poor water vapor barrier properties, and brittleness of PLA limit its performance in various industries. Polylactide cellulose-based and nanocellulose-based nanocomposites (PLA/CNC) achieved their fabrication after long and exhaust work due to interaction is difficult because of the hydroxyl groups on cellulose surface, and nanocellulose particles agglomeration in polymeric matrix. Nanocellulose is hydrophilic, while PLA is hydrophobic [6]. Fortunately, hydroxyl groups are easily modifiable, which allows the dispersibility and compatibility with PLA matrix. Then, functionalization, the use of hybrid methods and the addition of surfactant or compatibilizers, suggested to enhance the dispersion in PLA and improved the mechanical properties [16]. Main techniques of PLA/CNC nanocomposites are focused on the best dispersibility of CNC on PLA matrix with improved interaction are melt mixing, solution casting, electrospinning, pickering emulsion, and hybrid approaches [16, 17]. Other techniques, such as the reinforcement of PLA/CNC with natural fibers, are based on the commercial availability, research interest, sustainable production, and natural abundance such as flax, hemp, jute, kenaf, and other fibers with high potential are roselle, mulberry, and kenaf [9]. Polyglycolic Acid (PGA) Poly (glycolic acid) (PGA) is a biodegradable, thermoplastic polymer and the simplest linear, aliphatic polyester. It can be prepared starting from glycolic acid by means of polycondensation or ring-opening polymerization. PGA is a low-cost tough fiberforming polymer TM; it has a glass transition temperature between 35 C and 40 C and its melting point is in the range of 225–230 C. PGA also exhibits an elevated degree of crystallinity, around 45–55%, thus resulting in insolubility in water [18]. The
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solubility of this polyester is somewhat unusual, polyglycolide is soluble in highly fluorinated solvents like hexafluoroisopropanol (HFIP) and hexafluoroacetone sesquihydrate, that can be used to prepare solutions of the high-MW polymer for melt spinning and film preparation. Fibers of PGA exhibit high strength and modulus (7 GPa) and are particularly stiff, but one major limitation is its hydrolytic instability [19]. PGA nanoparticles have been widely used as polymer-carriers for Controlled drug delivery systems (CDDSs) due to their superb biodegradability and biocompatibility properties, which are being utilized for the targeted delivery of poorly soluble or unstable bioactive compounds bringing about low side effects and high drug loading efficacy [20]. Other applications of PGA include the fabrication of disposal bags, diapers, and eating utensils. It also can be used to create geo-textiles and plant pots, and it is suitable for thermoformed blown bottles and injectionmolded objects [21]. Poly (Lactic-co-glycolic) Acid (PLGA) Poly (lactic acid) (PLA) and poly (glycolic acid) (PGA) are the most used biodegradable polymers in tissue engineering for the design of three-dimensional scaffolds. The copolymer poly (lactic-co-glycolide) (PLGA) is also employed. PLGA is a block copolymer of linked segments of grafts of PLA and PGA [22]. Those biopolymers exhibit a high degree of biodegradability, biocompatibility, and sustained-release properties. They are also approved by the US FDA and European Medicine Agency for medical applications such as tissue engineering, drug delivery, and medical and surgical devices [22]. Main disadvantage of PLGA is the low hydrophilicity and low surface energy which disrupts the cell adhesion and penetration for tissue growth. For overcoming this issue, bioactive agents are added to PLGA to form three-dimensional scaffolds [23]. The synthesis of PLGA is by random melt co-polymerization at high vacuum from lactide and glycolide, followed by ring-opening polymerization [22]. Cellulose provides reinforcement for nanocellulose-PLGA composite [7]. The union of nanocellulose, a PLGA offers better control by the enhancement of degradation and mechanical properties of the composite. One of the fabrication methods is via freeze-drying or lyophilization that consists in the ultrasonication of blended suspensions. This method allows the control of properties by means of variation of nanocellulose ratio [23, 24]. Besides, nanocellulose-PLGA has better biocompatibility than pure PLGA, because it promotes proliferation, spreading, and adhesion of cell fibroblasts. However, high load of nanocellulose (7 wt.% with respect of) produces composites with poor mechanical properties equivalent to pure PLGA [24]. The fabrication of three-dimensional porous tissue engineering scaffolds is the main application of PLGA. Tang and coworkers investigated composites assembling cellulose nanofibers and PLGA by freeze-drying an ultrasonically blended suspension. They studied the effect on the morphology, porosity, and mechanical properties by modifying their mass ratio of cellulose and biopolymer and observed the cell viability of NIH 3 T3 fibroblasts. Scaffolds showed a porosity greater than 95% for all mass ratios, homogeneous, and pore size distribution and pore interconnection for
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a specific mass fraction of nanocellulose and PLGA of 5:1, an increment of mechanical strength when increasing nanocellulose was observed, equivalent to that of the cartilage tissue, and cell still viable and attached after 2 weeks of cultivation on the scaffold [23].
2.1.2
Nanocellulose and Natural Biodegradable Composites
Starch Starch is a carbohydrate mostly used in the human diet, considered as the main energy resource due to its natural abundance. Plants also obtain energy from starch, and storage in roots, stems, grains, and fruits [25]. And finally, the carbohydrates for human diet come mainly from cereal grains, such as corn, wheat, sorghum, and tubers, and roots, such as potato, tapioca, arrowroot, etc. [26]. The two forms of starch synthesized by plants are amylopectin and amylose. The common starch contains mostly amylopectin (between 70% and 85%), which contains chains of glucose units linked by α-1,4 glycosidic bonds, and small glucose branches [25]. The other 1530% of common starch is amylose, which contains linear chain of α-1,4 glucans with minimal branches. Starch has countless industrial uses because it possesses food attributes, such major reserve carbohydrate in plants, fruits, grain, roots, and stems. It gives texture and sensorial properties to packed food as well; as a hydrocolloid, it has exceptional functional characteristics. The main presentation of starch is in grain with different architectures, used in other applications than food because of interaction of surface carbohydrates with other molecules such as, proteins and lipids [26]. The extracting and refining starch methods are drying, grinding, and sieving. The granule may exhibit multiple size and morphologies, depending on these processes [25]. Starch combined with nanocellulose achieve a green biocomposite. Nanocellulose acts as a reinforcement in starch-based thermoplastics, incrementing the life use, enhancing the water sensitivity and mechanical properties. After the life use, the biocomposite serves as a composting for plants and animals [27]. The methods for starch-based nanocomposites are solvent casting method and compounding or extrusion method. The first method is frequently used for starch-based nanocomposites preparation and depends on the type of matrix, mixing the polymer solution with dispersed nanocellulose. And the second incorporates the cellulose with starch and mixing by extrusion; it usually has poor dispersion of nanocellulose. The first method produces composites with superior mechanical properties due to the low agglomeration of nanocellulose, as compared with composite obtained by extrusion [27]. Thermoplastic starch (TPS) has low applicability limitations for packaging and protective films because it has inferior mechanical properties such as easy deformation and low tensile strength. In addition, TPS has excessive hygroscopicity to overcome the disadvantages; the use of nanocellulose as a reinforcement in the starch matrix is an effective way. TPS presents by itself, for example, the use of nanocellulose fillers enhances the film water sensitivity which is a useful feature for food packaging applications. In comparison with their conventional micro-
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composite counterparts filled by micro-scale cellulose fibers, these nanocomposites show some great properties because of the nanometer-size effect [28]. The applications of starch and nanocellulose are paper coatings [29], antiviral and antibacterial films [30], flexible optoelectronic and scaffolds for tissue regeneration, and bio-based packaging [27]. The bio-based packing is the promising substitute for the extensive use of polymers in current industrial presentation for shopping bags, one use dishes, films for packaging food, fruits and vegetables, and medical uses [27]. The main disadvantage of composite starch and nanocellulose is that mechanical properties are inferior to the commercial polymers. However, in the last years the interest in research incremented for cellulose and packaging because of the big problem caused by petroleum-based polymers to the environment [27].
Chitosan Chitosan (CS) is a natural biopolymer extracted from natural chitin via deacetylation. Chitin is a natural polysaccharide found in the shell of crustaceous (crawfish, shrimps, crabs, etc.) [31]. CS has been extensively studied for various applications because of its biocompatibility, biodegradability, muco-adhesiveness, and derivability from abundant and inexpensive biomass. It is obtained from the partial deacetylation of chitin, where the difference between chitin and chitosan relies on the degree of acetylation (DA), with chitin having DA values over 50%, and chitosan having lower percentages. Despite their various benefits and distinctive properties, chitosan-derived materials, and particularly their films, show poor mechanical performance that hampers their use for more exigent applications. Such properties and alternative functionalities can be improved through the preparation of composites with natural fibers or blends with other polymers [32]. Chitosan-cellulose mixtures are of specific interest as a result of the structural similarity, leading to compatible composite materials that combine the physicochemical properties of chitosan with the wonderful mechanical properties of cellulose fibers [33]. As described above, the mechanical strength of chitosan is so poor that practically it cannot be utilized by itself for applications based on its distinctive properties. One interesting way of obtaining this composites is using [BMIm+Cl], an ionic liquid (IL), as a green solvent to dissolve and prepare the [CEL + CS] composites [3], where a majority of the IL (>88%) is recovered by distilling the aqueous washings of [CEL + CS], so the method is considered as recyclable. The authors reported that measurements were made to determine tensile strength of pure chitosan film and (CS + CEL) composite films with different cellulose concentrations so as to determine it by adding CEL into CS, the [CEL + CS] composite material would have adequate mechanical strength for sensible applications [34]. Results obtained clearly indicate that adding CEL into CS considerably increase its tensile strength. For example, up to 5 increase in tensile strength will be achieved by adding 80% of CEL into CS, and that the tensile strength of the composite material can be adjusted by adding considered amount of CEL. More importantly, the tensile strengths of [CS + CEL] composite materials are comparable with those of existing CS materials
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as well as those prepared by either grafting or copolymerization with different chemicals [31], Polyglycolic acid (PGA). As mentioned above, better dispersion of nanocellulose in PLA increments the mechanical properties of PLA/CNC nanocomposites. The main methods for studding not only the mechanical, but also the physicochemical properties are according to the destination of the composite, but they can be divided by thermal, spectroscopic, microscopic, and rheological. For example, Khoo, Ismail, and Chow [35] reported the synthesis of cellulose nanocrystals (CNC) from microcrystalline cellulose by acid hydrolysis for mixing with PLA by solution casting technique; the nanocomposite exhibited a needle-like structure. They also demonstrated that up to 5% of CNT is capable to nucleate the PLA, and the PLA/CNC decomposes at higher temperature than pure PLA, indicating better thermal stability. More recently, Wang and coworkers [6] proved that spectroscopic analysis was crucial to determinate the degree of polymerization and the degree of hydroxyl substitution; those are important parameters for successful composite PLA/CNC production. In addition, the degree of crystallization was promoted by grafted nanocellulose crystal acting as a nucleating agent for PLA, leading to a better tensile strength of the composite than PLA, from 41.9 MPa to 53.9 MPa. According to previous results, the PLA/CNC composite is an ideal candidate for packaging field, as it acts as a high-barrier, and antioxidant for food preservation and transportation, and nanocomposites incorporated with bioactive compounds for the preservation of refrigerated products [36–38]. Alginate Alginates (algin) are a linear anionic polysaccharide polymer of β-(1-4)-Dmannuronic (M-blocks) and α-L-guluronic acid (G-blocks). These uronic acids are often arranged in heteropolymeric fashions that have a close to equal proportion of the monomers and homopolymeric blocks, it has significant rheological properties, such as gelling, viscosifying, and stabilization of dispersions, which depend on the alginate chemical structure [39]. Alginate is obtained from different sources of macroalgae (seaweeds), which is naturally available in several coastal areas of many countries. The cell wall of a brown seaweed contains a vast quantity of alginate (alginic acid) when compared to other (red, green) macroalgae, and it is an insoluble salt. Alginate can be extracted from macroalgae within the form of water-soluble alginate by employing several methods to reinforce its applicability in advanced applications. Alginate and alginate-based biocomposites have been used as, for example, adsorbents for ionic dyes, antibacterial films, packaging, wound healing materials, and stimulus response drug releasing materials [40]. Although alginate-based biocomposites have robust potential to be used as an example in packaging applications, they typically lack the required mechanical properties, such as high strength. To increase the mechanical properties of alginate-based biocomposites, nanocellulose has been studied as reinforcement agents in alginate films. Nanocelluloses are natural materials with a minimum of one dimension in the nanoscale. They combine vital cellulose properties with the
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features of nanomaterials and open new horizons for materials science and its applications [40, 41]. It is convenient to subdivide nanocelluloses into three categories: bacterial nanocellulose (BNC, also referred to as microbial cellulose or biocellulose), cellulose nanofibrils (CNFs, also referred to as nano/microfibrillated cellulose), and cellulose nanocrystals (CNCs, also referred to as nanocrystalline cellulose). BNC is generated wherever the fermentation of sugars and plant carbohydrates via microorganisms takes place. This type of cellulose has unique properties such as high purity (pure cellulose), a nanofiber network structure, and a high-water content of 99% in the form of mechanically, thermally stable hydrogel bodies and the fact that it is categorized as a highly biocompatible material. This last one characteristic makes BNC useful in the biomedical sector, especially for tissue engineering, where BNC is used with alginate in a novel bilayer BNC scaffold for auricular cartilage tissue engineering, for example. This bilayer BNC scaffolds are composed of a dense nanocellulose layer joined with a macroporous composite layer of nanocellulose and alginate [42]. This study demonstrated that bilayer BNC scaffolds offer good mechanical stability and maintain a structural integrity while providing a porous architecture that supports cell ingrowth. In a different study, the two sides of a BNC membrane were modified asymmetrically with different biomaterials for cell encapsulation, one side was modified with collagen for the improvement of cell adhesion and the other side was coated with alginate to protect transplanted cells from immune rejection [41]. In regards to CNF materials, there is a broad palette of engineering applications including composite materials for the automotive, building (cement and plastic reinforcement), packaging (coatings, films, paper, and filler reinforcement) sector, air, and water filtration. This is basically due to their high specific surface area, high strength, and ease of functionalization and environmental friendliness. Recently, composite materials of alginate and cellulose nanofibrils (CNF) have shown promising results for bioprinting and tissue engineering applications. In particular, the shear-thinning properties of CNF combined with the viscous alginate that form hydrogels with divalent cations at physiological conditions are enticing for bioprinting. Where the alginate contributes with elastic properties and increased mechanical resistance at large deformations. The cellulose nanofibrils reduces the syneresis of the alginate gels and contributes to increased resistance against compression at small deformations as seen by an increase in Young’s modulus [43]. Nanocrystalline cellulose is mostly used as interface stabilizers, rheological modifiers, as films/coatings and reinforcing agents in polymer composites, but also are nontoxic and show great potential in biomedical devices as well. The authors claim results obtained, such as mechanical properties, morphology, cytocompatibility, bioadhesion, and cell proliferation, suggest that CNC and alginate gels can be a potential candidate to find applications in tissue engineering area as, for instance, in tissue repair and wound healing [44].
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Protein Proteins are large sized molecules (macromolecules), polymers of structural units known as amino acids. A total of 20 different amino acids exist in proteins and tons of these amino acids are attached to each other in long chains to make a protein [1]. Amino acids can be released from proteins by hydrolysis, the cleavage of a covalent bond by addition of water in adequate conditions. Soy protein isolate (SPI), the main component of soybean, has been used to prepare biodegradable materials, such as adhesives, plastics, and numerous binders in recent years [2]. Although the SPI plastics typically possess good biodegradability, their application is restricted by poor flexibility and water resistance. To obtain flexible SPI plastics with a high tensile strength, fillers must be used, such as cellulose whiskers because they have useful properties, such as a high aspect ratio and a large interface area. Cellulose whiskers now have been successfully used as a new kind of filler, as a reinforcing phase in both synthetic polymeric matrixes and natural ones. The effects of the whisker content on the morphology and properties of the glycerol-plasticized SPI composites were investigated and the authors reported that, with the addition of 0–30 wt.% of cellulose whiskers, strong interactions occurred both between the whiskers and between the filler and the SPI matrix, reinforcing the composites and preserving their biodegradability [2, 3]. Furthermore, the incorporation of the cellulose whiskers into the SPI matrix led to an improvement in the water resistance for the SPI-based composites. Gelatin Gelatin (GL) is an animal protein which can be obtained by the controlled hydrolysis of the fibrous insoluble collagen present in the bones and skin generated as waste throughout animal slaughtering and processing. It can be pictured as a copolymer build-up from triads of α-amino acids with glycine at every third position (soft blocks) and triads of hydroxyproline, amino acid, and glycine (rigid blocks), with a slim molar mass distribution [1]. Gelatin can form films and coating with good optical properties, adequate mechanical properties, and excellent gas barrier properties at low relative humidity able to act as bio-packaging materials. It possesses properties of an ideal biomaterial for many in vivo healthcare applications, such as good biocompatibility, low immunogenicity, and biodegradability [45, 46]. Due to the abundant active groups on the molecular chains, for example, amino groups, hydroxyl groups, and carboxyl groups, gelatin can be easily modified chemically to improve its chemical and physical properties. Gelatin can be fabricated in various forms like films, microparticles and nanoparticles, fibers, and hydrogels. Gelatin has been extensively employed in food, cosmetic, pharmaceutical, and medical applications, thanks to its low antigenicity, good biodegradability, nontoxicity, and low cost [47]. Gelatin hydrogel has great potential for biomedical applications such as cartilage, wound dressing and adhesive due to its biocompatibility, biodegradability, and highwater content capacity. However, gelatin hydrogels typically have relatively weak
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mechanical strength that limits the applications of gelatin hydrogels in several areas [48]. Nanofiber cellulose (NFC) is used as a reinforcement to hydrogels due to the advantages it presents, such as high aspect ratio, crystallinity, stiffness and specific surface area, and low percolation threshold. A specific property of cellulose- based compounds is the high density of hydroxyl groups which provides the hydrophilic nature of these materials, making them good candidates for hydrogels, which has played an important factor in food fields, for example. The authors reported that NFC reinforcement provides an efficient approach to tailor gelatin gel properties and has the potential as a food aid for gelatin additive in restructured foods [49].
3
Crystallinity of Cellulose, Nanocellulose, and Composites
3.1
Cellulose Crystallinity
Considering that the abundancy of nanocellulose is enough around the world, the extraction of crystalline regions allows the cellulose nanocrystals. They exhibit different shapes such as microcrystallites, nanofibers, whiskers, and nanowhiskers. The cheaper and available sources of nanocellulose nanocrystals are plants. Other sources of cellulose for the production of nanocrystals are bacteria, algae, and marine animals. So the most crystalline cellulose ~95% is usually found in algae. Marine animals have crust rich in cellulose, while bacteria produce it [50]. The so-called elementary crystallites of cellulose form nanocrystals in different fashions. Microcrystals, nanoparticles, nanowhiskers, or nanofibers self-assemble when glucan chains are combined. The glucan chains or elementary fibrils are macromolecules aggregated in microfibrils. They have five or more unities due to Van der Waals interactions or inter and intramolecular networks of H-bonds. The elemental fibers formed by polymerization of glucose residues with D configuration get a degree of polymerization (DP) depending on the resource type. For example, cotton reaches a DP of greater than 10,000, wood has a DP within the range of 300–1700, and plant fibers obtain 800–10,000. Cellulose conformed of bonded by C-1 and C-4 adjacent glucose units with β-(1-4) glycosidic linkage of D glucose (Fig. 2a). The hydroxyl groups locate at the C-2, C-3, and C-6 position of anhydroglucose and reducing and non-reducing end groups found on C-1 and C-4 positions, respectively [50]. Cellulose structure contains crystalline and noncrystalline phases with undefined boundaries considered as two-phase crystal produced with uniaxial molecular orientation fabricated by an enzyme complex in the biological system [51]. Figure 2b presents a schematic of cellulose with crystalline and noncrystalline regions. The crystalline arrangements or elementary crystallites form by intra- and intermolecular hydrogen bonds of cellulose macromolecules which have hydroxyl groups (Fig. 2c) [52, 53]. The crystalline regions depend on the packing of cellulose, which is mainly parallel; the configuration of cellulose links by intra- and intermolecular hydrogen bonds (Fig. 1c). The aligned arrangement of cellulose has four different polymorphs (I, II, III, IV). Which is the result of wide variation of molecular orientation and hydrogen bonding network within the crystalline region. The most stable structure is
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Fig. 2 (a) Cellulose linked by glucose units with β-(1–4), (b) schematics of cellulose showing crystalline and amorphous regions, (c) adjacent macromolecules of cellulose presenting intra- and intermolecular hydrogen bonds. Reproduced with permission [53]. (d) Cell units for Triclinic unit cell and Monoclinic unit cell. Monoclinic angle g is obtuse. (Reproduced with permission of [58])
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cellulose II and has a monoclinic crystal structure. The most studied polymorphs are cellulose I and II because the intra-sheet bonds of cellulose II lattice are the same as that in cellulose I, forming multiple inter-sheet hydrogen bonds. It allows the conversion of stable cellulose I into cellulose II, but not inversely. Cellulose I is the native cellulose in nature, while cellulose II is the second study obtained from the cellulose I by regeneration or mercerization. In this transformation, cellulose is solubilized in a solvent and precipitated to obtain cellulose II. And mercerization uses sodium hydroxide (NaOH) by swelling the cellulose I followed by trying to remove the swelling agent to give cellulose II. The first process of regeneration allows better crystallinity and thermal stability during cellulose dissolving. The dissolving occurs due to the supramolecular bonds between the hydrogen bonds and between hydroxyl groups disruption. In the second process, mercerization, solubilization does not exist, implying cellulose structure maintains intact. This process is the best for interdigitation of polarities for adjacent microfibrils, which means that parallel cellulose II chain may convert to antiparallel cellulose II [54]. Cellulose I has two types of crystalline structures; one-chain triclinic and two-chain monoclinic unit cells, corresponding to Iα and Iβ, respectively [55]. The triclinic unit just receives an individual macromolecule chain for a single-unit cell, while the monoclinic receives two bi- unit cells, as seen in Fig. 2d [56]. Iβ is the poly form predominant in plants coexisting with the Iα in different rates depending on the cellulose nature and structure [57]. And proportion is dependent on the origin of cellulose; Iβ is the main polymorph found in the cell wall of plants, and Iα is mainly present in bacterial cellulose [55]. The coexistence of both polymorphs Iα and Iβ gives the semicrystalline nature of cellulose. Then, the best way to obtain crystalline cellulose is to transform the native Iα into Iβ by hydrothermal treatments using an alkaline solution [56]. Parallel up and parallel down are the two types of packing of nanocellulose defined by Gardner and Blackwell for the directionality for unit cells in cellulose chains; the parallel up would be the most probable for both types of polymorphs Iα and Iβ [56].
3.2
Nanocellulose Crystallinity
Cellulose has a nanostructured organization promoting the nanocomponents isolation by mechanical and chemical treatments. The crystalline and amorphous give nanofibers, nanofilaments, nanocrystals, and amorphous nanoparticles separated from cellulose. Being cellulose, a suitable feedstock for nanomaterials production [3]. The crystalline domains of nanocellulose removed by chemical process produce cellulose nanocrystals (CNC), also called cellulose nanowhiskers, and usually present a needle-like shape. These nanocrystals are the crystalline domains removed from plants or wood by acid hydrolysis attacking the amorphous region. The highly crystalline domains resist the acid treatment keeping the whisker or rod-like morphology. The cellulose nanofibrils (CNF) results from mechanical treatment and has a fibber-like shape [53]. Mechanical methods reduce the degree of crystallinity
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because of the damage to the microfibril structure. CNF has a longer aspect ratio than cellulose nanowhiskers between 30 and 300, and CNC may have 10–50 [59]. The degree of crystallinity depends on the treatment conditions; however, it remains lower than CNC. The bacterial nanocellulose (BNC), also known as biocellulose, or microbial nanocellulose has a ribbon-like shape; such ribbons are linked nanofibers and assembled by hydrogen bonds [53]. The hairy cellulose nanocrystalloids (HCNC) are similar to CNC, however, contain different-ending polymers. The procedure converts cellulose to derivative cellulose soluble in water; the first step consists of oxidation of cellulose fibers using periodate. And the second step is the addition of inert salt, accelerating the process of cellulose solubilization. After that, a heat treatment at 80 C the production of sterically stabilized SNCC occurs [55]. Regardless of the type of nanocellulose and crystallinity, they belong to the cellulose nanoparticles (CNs) classification. The purity and crystal structure are the main differences between nanofibrillated cellulose (NFC) and bacterial nanocellulose (BNC). NFC produced from wood pulp usually contains hemicellulose, while BCN is cellulose in its pure state. NFC has mainly the Iβ polymorph, while BNC has Iα cellulose [57]. The differences in nanostructured nanocellulose are due to the kind of synthesis. However, differences also depend on crystallinity and origin. Top-down and bottom-up are the main approaches for nanocellulose synthesis. The top-down approach is when separate nanocellulose from the cellulosic source. The production of CNC and cellulose nanofibrils CNF is a top-down approach. The bottom-up method consists of the self-assembly of molecules or atoms to form an architecture, for the case when bacterial species produce bacterial cellulose [53]. The crystalline assembly and hydrogen bonds of nanocellulose enhance the properties such as particular rheology, large aspect ratio, flexibility, low density, and stiffness. In addition, their abundance and intrinsic biodegradability make them interesting for diverse applications of CNs. For example, substituent of petroleumbased materials, including binders and adhesives [53]. For a successful application, considering that chemical, mechanical, and physical properties of nanocellulose are fundamental [60].
3.3
Cellulose Nanocomposites Crystallinity and Mechanical Properties
Thanks to biodegradability, renewability, low density, and low cost of lignin-based materials could be used as composite reinforcement. This approach combines bio-based/renewable and renewable reinforcement, decreasing the use of petroleum-based materials. For this approach, the main goal is the size reduction of fibers due to high dimensions from 10 to 100 mm have some disadvantages such as limited processing temperature, lower tensile strength, variability from batch to batch, and high-linear coefficient of thermal expansion (LCTE) [57]. To overcome these issues, nanocellulose is extensively used as composite reinforcement,
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combining renewability, biodegradability, low density, and low cost with better properties strength, chemical, thermal, and reproducibility properties. The cellulose crystals own cellulose molecules formed by extended chains. This arrangement confers high tensile strengths between 0.3 and 22 GPa and crystal stiffness of 300 GPa. For a single cellulose crystal, the axial modulus is between 58 and 180 GPa. Those values estimated theoretically are the major drivers to apply nanocellulose in composites [57]. The mechanical properties mixed with the crystallinity of nanocellulose rise the composites reinforcement. Despite the crystallinity of nanocellulose being variable depending on the natural source. As mentioned above, the higher crystalline nanocellulose is the bacterial Iα type. The techniques for determining the tensile modulus of nanocellulose fibers were X-Ray diffraction and Raman spectroscopy. For a single fibril, the tensile moduli resulted between 100 and 160 GPa according to estimated theoretically. However, the experimental tensile strength resulted in more variables, observing values between 1.6 and 3.0 GPa for NFC obtained from wood by TEMPO oxidation. The tunicate whispers exhibited a mean strength between 3 and 6 GPa. Such differences concerning the theatrically estimated were due to sliding fracture or failure mechanism caused by sonication-induced fragmentation. Although the difference in the tensile strengths between NFC and BNC was due to fragmentation level. Observing that BNC did not fragment in the same level as NFC, they do not have the same packaging either crystallinity [57]. BNC is an outstanding reinforcement component for thermosets and thermoplastics exhibiting tensile moduli 21 GPa and strength 320 MPa still using high loadings of BNC at 65 wt.%. The values 400 MPa achieved for nanocomposites containing BNC showed higher performance in BNC-reinforced materials. Although BNC-reinforced polymer composites are now not available, still under investigation to increase BNC production. The cost of production, the need for energy consumption to maintain the growth of cellulose produced by bacteria, low yield, and the purifications of BNC are the main facts to overcome the uses and applications of BNC with a better degree of crystallinity and better mechanical properties [57]. Nanofibrillated cellulose (NFC) and nanocrystalline cellulose (NCC) have more availability from natural resources than bacterial nanocellulose BNC. Despite not having the same crystallinity as BNC, they are an excellent alternative for reinforcing polymers to improve the resistance of biodegradable polymers such as starch, polybutylene succinate (PBS), polyhydroxybutyrate (PHB), polyhydroxy acids (PHA), and biopolymer polylactic acid (PLA). The tensile strength and thermal conductivity properties improved by the addition of nanocellulose to the composite synthetic polymers. For example, in the combination in thermoset reinforcement, the cellulose fibers in nanoscale dimensions increase the mechanical properties as compared with normal cellulose. The increment in properties is mainly due to the crystallinity, but also due to the high surface area, improved interfacial properties, and mechanical properties [61]. In another example, the nanocellulose crystals acted as nucleation agents that promoted the crystallization of biodegradable polymers such as poly (L-lactic acid) (PLLA) matrix, showing an increment of crystallization rate with respect to the pure PLLA; this phenomenon was also observed for PLA. In
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this work, lactic acid (LA) assembled uniformly on the surface of nanocellulose to promote the crystallization of PLA [6].
3.4
Cellulose Nanocrystal Liquid Crystal Phases
Cellulose nanocrystals (CNCs) belong to the rod-like family of lyotropic substances and classify as 1D nanostructures. However, the properties of CNCs are different from other lyotropic materials, such as the micelle-forming surfactant type. The main properties are because of interparticle interaction and colloidal complexity. Interparticle interaction contains a twisted structure along the axis. Colloidal complexity by the chemically anisotropic and highly hydrated surface. The edge has hydrophilic sites from the equator and axially extending O-H and C-H functional groups, thereby leading to anisotropic swelling [4]. Then, in general, the main disadvantages when dispersing the nanocellulose are that molecules at the surface or the interface become disordered and consequently partially crystalline [51]. Despite of hydrophilic sites at the edges and the partial loss of crystallinity when dispersing nanocellulose in water, they self-assembly into liquid crystalline or colloidal-hierarchic architectures [4]. The liquid crystal self-assemble by its rod-like nature and inspires optic and printing electronic applications [62, 63]. The principal cause of the isotropic assemble of CNC into liquid crystalline phases are the length scales of nanocellulose, which is dependent on the source. For example, the CNCs derived from wood usually have 3–5 nm in diameter and 100–300 nm in length. The interparticle attraction also leads to liquid crystals due to CNC surfaces reached in hydroxyl groups generating hydrogen bonding in water suspension [4]. The liquid crystal ordering of CNC assembles isotopically when diluted in water suspension, even though the final organization depends on the concentration (Fig. 3).
Fig. 3 Cellulose Nanocrystal Liquid Crystal Phases assemblies using random and oriented induced state at variable concentration [4]
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The semidilute and concentrated isotropic assembly are due to increased concentration. For high concentration, the assemblies become liquid crystal microdomains called tactoids. Tactoids are liquid crystal microdomains or microdroplets that nucleate spontaneously in isotropic dispersions. They are the primitive phases of macroscopic anisotropic phases developed after assembly [64]. Such structures found in colloidal liquid crystals are in a transitional state, in the middle of isotropic and macroscopic liquid crystalline phases. Typical colloidal liquid crystals are part of cellulose nanocrystals, polymers, molecules, and some viruses. The biphasic phase reached an equilibrium with order domains with isotropic and liquid crystallites. Finally, at higher concentration, the gel state formed by the interaction occurs due to antiparticle attraction and concentration, leading to absolute liquid crystalline order. The anisotropic-isotropic order determines the transitional structure in the phases of CNC. Using positive ions either H+ or Na+ in CNCs, colloidal solutions containing sulfate half-ester groups gave rise to percolation, aggregation, and colloidal stability [64]. The tactoids, usually characterized by optical microscopy, are usually deformable and now form part of diverse new materials and structural investigations [64]. Furthermore, the ability to form liquid crystals at high concentrations depends on the characteristics of CNC allowing the new chiral liquid crystalline state. The polarized confocal microscopy and circular dichroism characterization techniques are ideal for the characterization of this peculiar state of dispersing CNC [4].
3.5
Crystallinity Measurements
The crystallinity of cellulose and nanocellulose is a measurable property that depends on the weight fraction of the crystalline regions. X-ray diffraction is the common characterization technique to study the crystalline cellulose structure [65]. Additional to this technique, near-IR FT-Raman spectroscopy determined precisely additional structural characteristics [60]. The crystallinity index (CI) is the measurable parameter that determines the crystallinity of a material. The CI is the mass ratio of the crystalline material contained in the dry sample based on the two-phase single crystal model [51]. The crystallinity index is the parameter that depends on the measurement technique, which usually are X-Ray diffraction (XRD), solid-state nuclear magnetic resonance (CP/MAS 13C NMR) spectroscopy, and analytical process [51]. Nevertheless, the evaluation of nanostructured is complicated due to the diversity in morphologies and chemical composition, and then the characterization is not defined with a single method [51]. The factors that affect the CI values are purity, morphology, interface between bundled cellulose microfibrils [51]. This parameter is useful to determine the cellulose transformation. For example, the polymorphic transformation of cellulose I to cellulose II from Agave americana studied by X-ray diffraction revealed a modification in the crystalline index during the alkali process in the mercerization method varying the NaOH proportions. At 5–10% of NaOH
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concentration, started the transformation from cellulose I to cellulose II, and the complete transformation occurred at 15% alkali concentration. The alkali treatment 2% (w/v) increased the crystallinity index, and the excess of NaOH >2% (w/v), decreased the crystallinity index. The unit cell parameters also varied with the NaOH concentration due to the generation of alkali celluloses [65]. The two approaches to calculate the crystallinity index consist of the calculation with respect to the total area under diffractograms or with respect to the main peak (200) [65, 66]. In the first approach, the crystalline index Cr. I. is Cr:I: ¼
Acryst Atotal
Where Acryst is the sum of crystalline band areas, and Atotal is the area under all the peaks of the complete diffractogram. The second approach is an empirical method described with respect to the main peak as follows Cr:I: ¼
I 200 I am 100 I 200
Iam is the intensity of the peak at 18 2θ, and I200 is the intensity of the (200) index. For the best results in X-Ray diffraction analysis, sample preparation and spectrum analysis should be careful. The sample preparation for powder X-Ray diffraction requires milling after laceration with a scalpel manual to faction the big pieces. The ball milling only makes a mixed powder with different crystallite orientations, without inducing the crystallite fracture. After recording the spectrum from 2Ɵ ¼ 5 to 2Ɵ ¼ 40 , peak analysis would give much information about crystal using the next equations [65]. For this part, an empty holder will measure a spectrum for air scatter and polarization correction. After correction, the background should be removed. • Correction for the air scattering ðI 1 Þ2θ ¼ ðI Þ2θ ðI air Þ2θ eμt= cos θ μt ¼ 1.2 is the optical density of the cellulose specimen, (I )2θ is the intensity of the peak at specter, and (Iair)2θ is the intensity at the same value for the air scatter specter. • Correction for the polarization effect ðI 2 Þ2θ ¼
ðI 1 Þ2θ : 0:5ð1 þ cos 2 2θÞ
• Fitting and spectral analysis To get data information from peaks, use the Pearson VII function
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I ðxÞ ¼ h
A
i μ 1 þ ððx XC Þ=wÞ2 21=μ 1
I(x) is the intensity at x ¼ 2θ, A is the profile amplitude, w is the profile width, XC is the profile center, and μ is the shape factor. • Lattice spacing The Bragg equation determines the lattice space dh k lfor each fitted peak position XC nλ ¼ 2d sin θ θ is the angle of diffraction for the central value (2θ ¼ XC), d is the lattice space (distance between the atomic layers), λ is the wave length of incident X-rays, and n is an integer number chosen according to the order of reflection. Iα polymorph has three main lattice plans (110), (010), and (100) and monoclinic Iβ the lattice plans are (200), (110), and (110). Both share d-spacings of 0.39 nm, 0.53 nm, and 0.61 nm for each lattice plan, respectively. The difference between d-spacings for respective Miller index along (110) and (200) is due to the relative displacement of cellulose sheets at (110) in Iα polymorph, while the hydrogenbonded planes along chain axis direction at monoclinic Iβ. The relative displacement at Iα between subsequent hydrogen plane is c/4, and c/4 is the alternated displacement at Iβ by van de Walls interactions [66]. The lattice parameters (the angles and unit cell dimensions) of cellulose and nanocellulose depend on the cell type, triclinic (Iα) or monoclinic (Iβ). And also depend on the source of nanocellulose and its taxonomy. Table 1 presents a list of different lattice parameters for both types Iα and Iβ. Accurate characterization shows general values for monoclinic and triclinic, respectively [67, 68]. Other values were reported for bacterial cellulose [69]. Recently, experimental values for garlic and agave nanoparticles calculated for both Iα and Iβ types of nanocellulose presents all the cell parameters [70].
4
Morphology and Physico-Chemical Properties of Nanocellulose and Composites
4.1
Morphology of Nanocellulose and Composites
The morphology of nanocellulose is commonly determined by transmission electron microscopy (TEM), scanning electron microscopy (SEM), and atomic force microscopy (AFM). The different geometries and dimensions of nanocellulose show the strong dependence on the source of obtaining and the conditions of the treatments used for its isolation. In the production of nanoparticles, three shapes have been reported: bars, spheres, and whiskers (Different preparation methods
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Table 1 Different values of lattice parameters of both triclinic (Iα) and monoclinic (Iβ) Triclinic (Iα) Cellulosic material General values [68]
Garlic cellulose nanoparticles [70]
Monoclinic (Iβ) Lattice parameters a ¼ 6:72 A b ¼ 5:96 A c ¼ 10:40 A α ¼ 118.081 β ¼ 114.801 γ ¼ 80.3751
a ¼ 3:82 A b ¼ 4:89 A c ¼ 5:96 A α ¼ 115.57 β ¼ 90.30 γ ¼ 62.99
Cellulosic material Cellulose microcrystals from tunicin [67]
Bacterial cellulose [69] Agave cellulose nanoparticles [70]
Lattice parameters a ¼ 7:78 A b ¼ 8:20 A c ¼ 10:38 A γ ¼ 96.5
a ¼ b ¼ 9:33 A a ¼ 3:64 A b ¼ 4:92 A c ¼ 6:02 A α ¼ 106.07 β ¼ 101.89 γ ¼ 81.41
and properties of nanostructured cellulose from various natural resources and residues: a review). The shapes of cellulose nanoparticles can be categorized into three subcategories according to Fig. 4. Although all types are similar in chemical composition, they are different in morphology, particle size, crystallinity, and some properties due to the difference of the extraction method used and the source. The three main types are: cellulose nanofibers (CNFs), cellulose nanocrystals (CNCs), and bacterial nanocellulose (BNC). Cellulose nanocrystals (CNCs), also called cellulose nanowhiskers (CNWs) or nanocrystalline cellulose (NCC), are extracted from cellulose fibers, and it usually consists of an acid-induced restructuring process. Thus, their geometrical dimensions depend on the origin of the cellulosic substrate and hydrolysis conditions. Usually, they present a relatively broad distribution in length, and the average length is of the order of a few hundred nanometers while the width is of the order of a few nanometers. CNCs have a high aspect ratio, relative low density (1.6 g/cm3), and a reactive surface of side groups -OH that ease the grafting of different species to obtain different surface properties (surface functionalization). Surface functionalization permits self-assembly, controls dispersion within polymer matrices and particle-particle and matrix-particle adhesion resistance [71]. Cellulose nanofibers (CNF) are the entangled, long, and flexible nanocellulose, they form an extended flexible web-like fiber network that can be produced from cellulose fibers subjected to mechanical processes using both shear and thermal forces. The key characteristic is the size of the cellulose nanofiber, which are typically less than 100 nm in diameter and several micrometers long. CNFs can be recognized through their architecture, which contains extended masses of rudimentary nanofibers with reciprocating anisotropic and isotropic areas [71]. Bacterial
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Fig. 4 Morphology of cellulose nanocrystals, cellulose nanofibers, and bacteria nanocellulose. (This diagram was adapted from references [72] and [73])
nanocellulose (BNC) is a natural biopolymer synthesized by various bacteria species, particularly Gluconacetobacter xylinus. It has a three-dimensional structure that has a complex highly entangled and ribbon-like structure, and it is considered a hydrogel since it is mostly composed of water in its native state (99%) [42]. Starch is a promising biopolymer for manufacturing biocomposite materials since it is renewable, fully biodegradable, and available at a low cost. Some authors studied the effect of nanocellulose fiber (NCF) concentration on the properties of TPS. They used TPS as a matrix with water and glycerol as a plasticizer and with 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, and 1% NCF as reinforcements. Observing by microscopy showed that the diameter of the fibril was 242 158 nm. Micrographs of the samples showed fractured fibers under liquid nitrogen for 0.4 wt.% NCF-filled TPS and 1 wt.% NCF filled TPS, respectively. For each material, different magnifications were used to show both the cellulose dispersion inside the TPS matrix and therefore the surface adhesion between the composite components. The strong interfacial adhesion is a result of their good dispersion within the matrix. In the case of 1 wt.%, showed poor interfacial
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adhesion between the NCF and the TPS matrix. This reduced interfacial adhesion is the consequence of agglomeration of NCF. Usually, nanocellulose reinforcing PLA composites help in the improvement of tensile strength and elastic modulus. However, the hydrophilic nanocellulose and hydrophobic PLA are incompatible, forming weak matrix bonding. To improve the compatibility and dispersion state of PLA/nanocellulose, surface characteristics of nanocellulose need some chemical and mechanical modifications. Sullivan et al. (2015) made PLA/NCC bio-nanocomposite films via melt blending and compression molding at 175 C for 3 min. The SEM pictures showed that the bio-nanocomposites films have more surface fracture events when contrasted with pure PLA, which demonstrated that the addition of NCC added to a more fragile PLA. In general, NCC went about as a nucleating agent by increasing the polymer matrix crystallinity, improving the crystallization and more fragile properties.
4.2
Size, Composition, Physicochemical, and Reactivity Properties
Cellulose nanomaterials posse unique features such as high aspect ratio due to the fibril structure, nanosize, surface reactivity, specific dispersibility, and so forth, that require proper characterization to extend the application related to these unique properties. The accurate, detailed, and careful characterization is the key to the upgrade in applications correlated to the mentioned features attributed to the nanoscale. The specific characterization followed by consistent protocols extended the market for nanocellulose materials application. For example, the thixotropic additives/agents are one of the mentioned applications (Current characterization methods for cellulose nanomaterials-1). In this application, the nanocellulose has diverse functions in drilling, like cleaning and keeping the drill fresh while drilling, letting debris go out to the surface, avoiding gas and liquid filtering within the hole, and incrementing the yield stress of drilling mortar slurry (Cellulose Nanoparticles as Modifiers for Rheology and Fluid Loss in Bentonite Water-based Fluids). In this example, nanocellulose had multifunction attributed to the physicochemical properties for immersion and combination with other materials like chemical functionalization to distribute uniformly into the matrix to confer an improvement of mechanical properties. Other examples also include the composites fabrication extending the market toward paper manufacture to enhance its strength and appearance, in food packing to include carrier flavors, and to increase shelf life. In medicine, the use of nanocellulose is focused on the design of improved mediums for human cell growth. Before this application, further treatments are required such as purification and homogenization for better consistent and posterior treatments, as well as for the controlled fragmentation of molecule chain cellulose. For cleaving the chains, acid hydrolysis cleaves the disordered regions for stiffing the CNCs. The hydrolysis condition determines the aspect ratio, charge, and surface chemistry of CNCs [74]. The high shear used in mechanical treatments confers flexibility to CNFs. The degree of branching, particle width, charge, surface chemistry, and aspect
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Table 2 List of characterization and property measurements mentioning their respective procedure, technique, or method utilized in the cited review [75]
Characterization Size Size Composition
Property measurements Size Dispersibility Dimensions Aspect ratio Elemental analysis
Physic properties
Surface charge
Chemical properties
Surface chemistry Reactivity
Procedure, technique, or method DLS SEM and TEM EDS XPS SIMS ICP CHNS EA Polyelectrolyte (PE) titrations Conductometry titration Zeta potential
Comments This technique is limited due to the nanocellulose aspect ratio. SEM and TEM allow the analysis of individual crystals. EDS is fast and simple method measured in SEM. Detailed quantification provided by XPS, SIMS, or CHNS are accurate. Polyelectrolyte (PE) titration is a long method and get no reliable final data. Conductometry titration improved PE titration by protonating the CNF surface. Zeta potential measures the surface charge of nanocellulose.
Fluorescence labeling
ratio are the parameters determined by the mechanical shear process, pretreatments, and posterior TEMPO oxidation. FROM tempo oxidation results in finer fibrils. The best properties modulation of CNFs and CNCs responding to the environment, the characterization follows their correct interaction. For this issue, the surface chemistry dictated by bond strength, polymer interfacial interaction, agglomeration, selfassembly, and dispersion are the critically fundamental parameters for successful application. The check list provided previously [75] for samples characterization describes as follows: (1) Type of cellulose nanomaterial, (2) drying method or suspension concentration, (3) surface charge group type/density, (4) Counterion/ pH, (5) used additives, (6) source of nanocellulose, and (7) batch number/date of production. This information is needed to determine the impact the redispersion of nanocellulose for characterization. Table 2 describes the characterization and required procedure to determine the dimensions, composition, surface charge, surface chemistry, reactivity, and dispersibility.
4.2.1 Size For dimension determination of nanocellulose the first step is the dispersion that depends on the sonication intensity. Mostly, CNC are dispersible in water at low sonication and low known concentration. This step is needed to separate nanostructures to get their own properties from CNC powders. However, dispersion needs high energy to achieve the separation; probe sonication provides the required energy to mechanically separate the efficiently individual nanocellulose. After
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dispersion, the technique Dynamic Light Scattering (DLS) measures an apparent particle size by hydrodynamic in suspension using the equation Stokes-Einstein equation. The limitation of this technique is that nanocelluloses have aspect ratio, and the technique assumes that the samples have a single constant rate of diffusion or are spherical. Then DLS becomes a better approach to determinate the dispersion quality or the state of aggregation. Scanning Electron Microscopy and Transmission Electron Microscopy are ideal to determine dimensions of nanocellulose. These techniques confirm the existence of nanocellulose, and also the purity, dispersion, estimation, and quantification of aspect ratio. The resolution of SEM may be a limitation to differentiate individual CNC due to the cellulose interaction showing an unclear morphology. Fortunately, the improved resolution of TEM perhaps the observation of individual CNC.
4.2.2 Elemental Analysis The composition analysis was performed by different techniques such as Energy dispersive X-ray spectroscopy (EDS), X-ray photoelectron spectroscopy (XPS), auger electron spectroscopy (AES), Secondary ion mass spectrometry and time of flight (SIMS), and atomic emission spectroscopy techniques including Inductively coupled plasma (ICP), Carbon hydrogen nitrogen-sulfur elemental analysis (CHNS EA) and (CHNS). EDS performs at the same time as SEM on surfaces visible on the respective micrographs. The main advantages are that it gives instant measurement and quantitative chemical composition. The limitations of EDS are that it doesn’t measure low elements and can’t measure clusters. EDS only measures usually C, O, and S. In addition, this method doesn’t have the sensitivity to measure trace elements. XPS affects the chemical analysis in detail because it gives quantitatively the carbon bonds to other elements, and differentiates the kind of bonds with such elements. It also characterizes the oxidation state of metal nanoparticles and cellulose nanomaterials. In particular, XPS determines the changes on the surface associated to non-carbon elements. AES carries out the chemical composition due to the specific energies of each element. XPS and AES are quantitative techniques. However, the sample handling, preparation, contamination, calibration, accurate work function, beam damage, and charge compensation affects the data. Then, a proper methodology is fundamental. The main inconvenience of these techniques is that the sample must be solid, which is an inconvenience for cellulose nanomaterials. Another inconvenience is that both XPS and AES don’t have sensitivity to measure trace elements. And finally, the measurements are only carried out over the surface, not from the bulk material. SIMS consists of the sample bombardment with ions. Sputtering the sample with primary ions of alkali metal ions, gallium ions (Ga+), or argon ions (Ar+). Dynamic SIMS, scanning SIMS, and static SIMS are the modes of SIMS. This technique fundamentally determines the surface functionalization of cellulose nanomaterials. The presence of chemical modification, lateral distribution amino acid, identification of individual amino acids were the characteristics determined by SIMS [76]. The modification with fatty acyl chain modification in CNMs was the studied
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characteristic in SIMS, indicated by covalent bond between fatty acids and the cellulose nanomaterials [77]. SIMS also determined the surface chemistry modification by acetylation [78]. The unique limitation of SIMS for the output is not simple quantifiable, so that, other methods like CHNS or XPS should accompany the analysis. In ICP, a plasma ionizes sample atoms posteriorly analyzed by atomic emission spectroscopy (AES) or mass spectrometry (MS). The ICP technique identifies salt compounds, metallic particles, or impurities present in nanocellulose materials. It is ideal for heavy elements; but for lighter elements, it would be accompanied with XPS. Additionally, ICP-MS/AES requires liquid sample and measures trace elements. The elemental analysis by CHNS determines the presence of elements present in an organic compound. The quantitative elemental analysis bases in the Dumas method consisting to put oxygen at an elevated temperature (more than 1000 C). The elements carbon (C), hydrogen (H), nitrogen (N), sulfur (S), and oxygen (O) are moved by means of helium, inert gas, toward the combustion chamber at the mentioned temperature. The oxygen at this temperature reacts with each element forming CO2, H2O, NO, NO2, and NOx. Sophisticated equipment, with additional detectors, allows to determine additional substances containing halogens using silver nitrate for CHNS-O, oxygen using carbon and copper oxide (CHNS-O) and through sulfur using barium sulfate (CHNS). The sample sometimes contains elements different than C, H, N, S, and O. These contaminants are undesirable products to remove by adsorbents after initial ignition forming combustion products, for example, hydrogen chloride forms from chlorine. This technique is useful for determining sulfur groups in acid hydrolysis [79]. It also results crucial in the determination of functional groups of sulfurated and nitrogenated bases [80, 81]. And the technique also determined the chemical leaching in polymers containing cellulose nanomaterials [82]. The method requires a dry sample before analysis. The limitations of elemental analysis by CHNS are the percentage limit of C and N present in the sample above 0.05%, at low loading levels the uncertainty has a limit between 200 and 300 ppm, and systematic deviations when samples have sulfur. And for nanocellulose samples, the results are difficult to measure C, O, or H because of the background of cellulose structure.
4.2.3 Surface Charge Direct or indirect polyelectrolyte (PE) titrations are the traditional methods to determine the surface charge of nanocellulose materials. The Pe titration consists of the absorption of a polyelectrolyte on the CNF surface to reach the material isoelectric point. Taking into account the amount of surface charges on the CNF is the same amount of surface charge. The method takes a long time, is tedious, the adsorption of polyelectrolyte is not sure, and may create aggregates such that the obtained value was not reliable. Conductometry titration resulted to overcome the issues previously mentioned. The method consists of varying the pH NaOH solution and HCl solution to control gelatinization. Before the titration, the groups
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deprotonate completely so that the deprotonation controls the conductivity by adding NaCl. Zeta potential of cellulose nanostructures measure the colloidal stability of cellulose nanomaterials, which depends on the surface charge. The presence/type of electrolytes in the suspension, temperature, and pH affect the measurement of nanocellulose by Zeta potential due to its measures of the electrophoretic mobility. Then, the sample preparation is a decisive parameter since the measurement depends on the dispersion. And also record the data in one mode as well as measure always at the same temperature.
4.2.4 Surface Chemistry The surface chemistry of cellulose nanomaterials impacts their interaction with surrounding media. It determines the degree of dispersion of CNM in polymers or solvents to achieve self-assembly and interfacial bond, but avoiding the aggregation. Fluorescent imaging techniques afford accurate techniques for accessing to matrix composites and surrounding environment where nanocellulose immersed, including biological media. The imaging techniques using fluorescence alternatively offer structural information about the immersion media (polymers or biological media). The techniques quantify the size and aggregates to inform about quality of dispersion [83] and other mentioned properties such as monitoring of chemical process like exfoliation, orientation, and distribution of probe molecules along any material, and distribution of co-polymers in a composite [84, 85]. Another mode of fluorescence is FLIM or fluorescence lifetime imaging microscopy. FLIM allows a variety of processes due to its intrinsic property of fluorophore forming, the Forster resonance energy transfer (FRET) that consists in the formation of a couple of the fluorophore. This phenomenon only appears at short long scales, providing information of interphase and interface regions. The processes are motion restriction, confinement, dye aggregation, location of interfacial regions, changes of the local environment, and dynamic processes. The chemical studies for surface chemistry of nanocellulose using fluorescence are covalent bonds, ion exchange, and physisorption labeling. Covalent labeling studies uses the fluorophore of covalent bond in the nanocellulose. Ion exchange labeling tracks and quantifies cellulose nanomaterials. In this process, the electrostatic bonds are formed. Physisorbed labeling is a simple process using diverse fluorophores and serves for determination of lignin, for fluorescence properties determination of nanocellulose composites, amount of dye adhered to cellulose, etc.
5
Conclusion and Future Prospects
This work presented a critical review of nanocellulose and composites using nanocellulose considering that successful production depends directly on their properties. The main advantage of nanocellulose is its natural origin having biodegradability, biocompatibility, non-toxicity, and antimicrobial properties; the natural origin determines these properties.
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Despite the low solubility, mixing with polymers overcomes this disadvantageous characteristic. The natural and synthetic biodegradable polymers reinforced with cellulose nanostructures provide an enhancement of mechanical properties, extending the opportunity for applications, mainly that uses diverse packaging. Other important applications which have an impact on the environment are biofilters, biosensor strips, heavy metal removal from aquatic media, lithium-ion batteries, etc. The applications impacting other fields indirectly with the environment are tissue engineering, aerospace industry, automotive components, electrical industry, lubricants, and so forth. The crystallinity of nanocellulose depends on different factors being origin, kind of nanocellulose, and synthesis methods. Nanocellulose may originate directly synthesized by bacteria using bottom-up approach or by top-down synthesis extracting the nanocomponents from plants. The kind of nanocellulose depends on the type of plants, wood, or cotton. In addition, the synthesis method affects the crystallinity. For example, the mechanical methods affect considerably the crystallinity because of the damage to the microfibril structure. The level of crystallinity is a measurable and important property estimated by the crystallinity index which is the weight fraction of the crystalline regions. Beyond the known morphology of cellulose nanocrystals, cellulose nanofibers, and bacterial nanocellulose, it becomes important to characterize the morphology due to successful mixing with polymers and to notice if the combination resulted in better mechanical properties.
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Nanocellulose Sustainability and Preparation Abhilash Venkateshaiah, Malladi Nagalakshmaiah, Ramzi Khiari, and Mohamed Naceur Belgacem
Contents 1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 General Overview on Nanocellulose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Cellulose Nanocrystals: Preparation and Characterization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Nanofibrillated Cellulose: Preparation and Characterization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Bacterial Nanocellulose: Preparation and Characterization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Abstract
Nowadays, the incremental demands on utilization of renewable biomass has emphasize the importance of cellulosic materials. This can be justified by the large number of publications as well as the new generation of materials made from biosource residues. Cellulosic fibers present many potential advantages: the most important of them are their bio-renewable character, their ubiquitous A. Venkateshaiah Institute for Nanomaterials, Advanced Technologies and Innovation (CXI), Technical University of Liberec (TUL), Liberec, Czech Republic M. Nagalakshmaiah Department of Polymer and Composite Technology & Mechanical Engineering (TPCIM) Institut Mines-Telecom, IMT Lille Douai, Douai, France R. Khiari (*) University of Monastir, Faculty of Sciences of Monastir, Laboratory of Environmental Chemistry and Clean Process (LCE2P-LR21ES04), Monastir, Tunisia Univ. Grenoble Alpes, CNRS, Grenoble INP, LGP2, Grenoble, France Department of Textile, Higher Institute of Technological Studies of Ksar Hellal, Ksar Hellal, Tunisia Univ. Grenoble Alpes, CNRS, CERMAV, Grenoble, France M. N. Belgacem University of Grenoble Alpes, CNRS, Grenoble INP, LGP2, Grenoble, France © Springer Nature Switzerland AG 2022 A. Barhoum (ed.), Handbook of Nanocelluloses, https://doi.org/10.1007/978-3-030-89621-8_3
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availability in a variety of sources, and their low cost. This chapter presents a general overview of the preparation and characterization of nanocellulose from various sources. These products have recently acknowledged considerable attention as a potential source to produce nanomaterials with higher excellent performances. The preparation and characterization of cellulose nanocrystals (CNC), nanofibrillated cellulose (CNF), and bacterial nanocellulose (BNC) were discussed. Keywords
Natural fiber · Cellulose · Nanocellulose · Cellulose nanocrystals · Nanofibrillated cellulose
1
Introduction
Recently, with the growing understanding of environmental conservation, the use of renewable, sustainable, green materials for the production of high-value products has become increasingly relevant owing to its low environmental impact [1]. As natural biomaterials emerge as a viable solution to the rapidly depleting nonrenewable sources, global warming, environmental pollution, and energy crisis, the research on biomaterials has drawn considerable attention. Renewable materials derived from plants (lignocellulosic biomass, starch, gums), animals (chitin, chitosan, gelatin), and microbes (alginates, bacterial cellulose, polyhydroxyalkanoates) have been considered as promising candidates in terms of their ample supply and environmental benignity [2]. Among them, lignocellulosic biomass represents the most abundant renewable materials available on earth [3]. Lignocellulosic biomass refers primarily to plant-based materials that contain various organic compounds of natural origin. Biomaterials derived from lignocellulosic biomass can substitute petroleum-derived polymers in a wide range of applications [3]. The composition of the cell wall of lignocellulosic biomass consists primarily of lignin, hemicellulose, and cellulose groups. Around 10–25% of the dry weight of the lignocellulosic biomass is accounted for by lignin, and hemicellulose accounts for about 20–35%, while cellulose constitutes the major proportion of about 35–50% and is mainly localized in the plant cell wall [4]. Cellulose, with a projected annual production of 75 billion tons, constitutes the most abundant renewable polymer material on earth [5]. This inexhaustive amphiphilic polysaccharide possesses excellent physicochemical properties that enable its use in a wide variety of applications. Low cost, abundant availability, rich surface chemistry, biodegradability, biocompatibility, and environmental benignity have made these materials stand out as an alternative for fossil fuel–derived materials. Historically, cellulosic materials have been of significant importance for thousands of years in various applications and continue to be used in paper and textile industries worldwide [6]. Chemical constituents of cellulose include the linear chains of β-D-glucopyranose repeating units covalently connected via β-1,4 glycosidic bonds. Additionally, the presence of a large number of intramolecular and intermolecular hydrogen bonds
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imparts cellulose with different structural configurations. In the crystalline sections of cellulose fibrils, these hydrogen-bonding networks are orderly and densely packed, resulting in water-insoluble strong fibers with high tolerance to most organic solvents [7]. This orderly packing imparts high stiffness and mechanical strength to the cellulose. The disordered amorphous domains contribute to the flexibility of the bulk material. Cellulose can be found as various polymorphs, i.e., celluloses I, II, IIII, IIIII, IVI, and IVII, on the basis of molecular orientations, intramolecular, intermolecular, and van der Waals interactions, extraction, and treatment processes [8]. These polymorphs can be converted to one another via thermal and chemical treatments. Cellulose is composed of highly ordered crystalline regions and disordered amorphous regions. Depending on the source and the extraction process used for its isolation, cellulose’s crystallinity can range from 40% to 70%. While the dense crystalline domains are more immune to mechanical, chemical, and enzymatic reactions, the less dense amorphous domains are susceptible to such reactions [9]. Cellulose can be directly derived from natural plants (wood, cotton, agricultural crops, hemp) or can be obtained via microbes (bacteria, algae, or fungi) [4]. The most popular of these is wood-based cellulose, and it is typically used in the form of wood pulp. The characteristics of cellulose depend on its origin, source, maturity, pretreatment techniques, processing procedures, and reaction conditions. In general, the removal of noncellulosic components from lignocellulosic sources is through the elimination of extractive components (fatty acids, tannins, flavonoids, free sugars, terpenoids, terpenes, waxes, fats, resin, and rosin), delignification, and bleaching [10, 11]. Pretreatments constitute the majority of the overall cost of manufacturing and can be done using multiple physical, chemical, and biological processes and enable the disruption of the lignocellulosic compact structure and its recalcitrance [3]. However, in the case of bacterial cellulose, pretreatments are not necessary as they do not contain any lignin, hemicellulose, or extractives [12]. Literature review of articles from past decades reveals that most of them have focused on the development, optimization, and scaling up of nanocellulose production. However, recent studies have targeted the search for new uses and the enhancement of the properties of existing materials based on nanocellulose in diverse applications. This chapter aims at providing a brief summary of the use of nanocellulose, with a special emphasis on CNC, CNF, and BNC as illustrated in Fig. 1.
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General Overview on Nanocellulose
Over the past few decades, nanotechnology concerning cellulosic materials has generated considerable interest. Broadly termed as nanocellulose (Fig. 2), these materials exhibit low density, lightweight, exceptional strength, high surface-tovolume ratio, low thermal expansion coefficient, biocompatibility, biodegradability, and non-toxicity [13–15]. Their Young’s modulus is around 20–50 GPa and possesses a surface area of hundreds of m2/g making them an ideal nanomaterial for numerous applications [16]. Nanocellulose encompasses several cellulosic materials of identical chemical composition; however many properties like morphology, crystallinity, and particle
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As carbon source Pulp
Pretreatment Mechanical Process
Pretreatment Chemical Process
Acid Hydrolysis
Nanofibrillated cellulose
Biological Process
Acid Hydrolysis
Cellulose nanocrystals
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Physicochemical and thermal analysis
Particle analysis
Morphological analysis • Scanning electron microscopy • Transmission electron microscopy • Atomic froce microscopy
• X-ray diffraction • Fourier-trasnform infrared spectroscopy • Thermogravimetric analysis
• Fiber analyzer • Dynamic light scattering • Size analyzer
Fig. 1 Schematic representation of different nanocellulose preparation and characterization
Cellulose
Different cellulosic precursors
Plants
Softwood
Composition of extracted cellulose
Morphology of extracted nanocellulose
Fig. 2 (continued)
Microorganisms
Hardwood
Algae
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Fungi
Cellulose (40−44%) Hemicellulose (25−29%) Lignin (25−31%)
Cellulose (43−47%) Hemicellulose (25−30%) Lignin (16−24%)
Cellulose (60−70%) Hemicellulose (35−45%) Lignin (1.5−2%)
Pure cellulose
Length: 3−7 mm Width: 15−20 mm Crystalinity: 49−95%
Length: 1−2 mm Width: 15−20 mm Crystalinity: 90−95%
Length: 200−550mm Width: 10−25mm Crystalinity: 70−80%
Length: 1−9 µm Width: 3−5 mm Crystalinity: 49−75%
Tunicates
Cellulose (2−20%) Chitin < 0.5%
Crystalinity: 7−19%
Cellulose (65−65%) Nitrogen containing components (25−35%)
Length: 600 nmseveral µm Width: 15−20 mm Crystalinity: 89−95%
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Secondary wall S3 Lumen
Secondary wall S2
Helically arranged crystalline microfibrils of cellulose
Secondary wall S1 Primarry wall
Amorphous region mainly consist of lignin and hemicellulose
Disorderly arranged crystalline cellulose microfibrils networks Microfibrillated cellulose
Cellulose Lignin
Crystalline region
Mechanical shear
CNFs Diameter: 5-60 nm Length: > 1 µm
Ele
Amorphous region
me n fibr tary ils
Hemicellulose
Crystalline region Amorphous region
Hydrolysis with strong acid
CNFs Diameter: 5-70 nm Length: > 100-200 nm
Fig. 2 Few common sources of cellulosic materials along with the schematic representation of hierarchical structure and the degree of processing challenge to obtain them [13]. (Reprinted with permission from Dhali et al. (2021))
size vary depending on the natural source and extraction methods. In the literature, numerous terminologies have been used to categorize nanocellulose, which inevitably leads to confusion. The Technical Association of the Pulp and Paper Industry (TAPPI) has recently proposed standardized terminology and descriptions for cellulose nanomaterials (Fig. 3) [17]. Herein, we will discuss mainly the nano-object
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Fig. 3 Standardized terms to classify cellulose nanomaterials according to TAPPI W13021
Fig. 4 Transmission electron microscopy images of CNC, CNF, and BNC [19–21]. (Reprinted with permission from Fan et al. (2019), Hassan et al. (2017), and Núñez et al. (2020))
category which comprises cellulose nanocrystals (CNC), nanofibrillated cellulose (CNF), and bacterial nanocellulose (BNC) (Fig. 4). A top-down approach is employed to obtain CNC and CNF which involves the disintegration of plant matter through chemical or mechanical treatments, whereas BNC is obtained via a bottom-up approach using bacterial cultures [18]. Plants biosynthesize cellulose-forming fibers composed of both crystalline and amorphous phases. To produce the expected nanocellulose, acid hydrolysis or mechanical shearing would have to be employed to first soften and break the least crystalline areas. A highly crystalline rodlike CNC of nanometric length is obtained via acid hydrolysis, while mechanical shearing yields CNF of micrometer length. The structure of cellulosic fibers consequently results in two families of cellulosic nanoparticles which, depending on the researcher, can be referred to by many different names as illustrated in the Fig. 3. Indeed, we are focused on following the clearest way to distinguish between these cellulose nanoparticles which is to consider the steps involved in their preparation. The main steps involved in the preparation of cellulose nanocrystals and microfibrillated celluloses as well as bacterial nanocellulose (BNC), along with the terminologies, are presented.
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Cellulose Nanocrystals: Preparation and Characterization
Cellulose nanocrystal (CNC) is a term used to describe nanocrystals of cellulose with rodlike morphology and/or spherical cellulose nanoparticles (Fig. 5). CNC are often termed nanowhiskers, nanocrystalline cellulose, rodlike cellulose crystals, or nanorods in literature from vegetal plants and/or spherical shape from starch. As mentioned earlier, strong acid hydrolysis is the predominant method used in the production of CNC, wherein amorphous regions of the native cellulose are removed, while the crystalline domains remain unaltered followed by high-intensity mechanical or ultrasonic treatment producing short rodlike structures. Concentrated sulfuric acid is the most frequently used acid in the isolation of CNC. CNC produced via sulfuric acid hydrolysis impart a negative particle charge due to the formation of sulfate ester groups, which improves the phase stability of the nanocrystalline particles in an aqueous medium. CNC exhibit a high level of crystallinity in the range of 54–88% and as a result a very limited flexibility [22]. The dimensions of CNC are all in nanometric range and vary with the nature of the source of cellulose and the extraction procedure. Typically, the diameter is in the range of 3–50 nm, while the length is in the range of 50–500 nm. CNC derived from BNC and tunicates have been reported to have larger particle size as compared to the CNC produced from cotton or wood. This is due to the higher crystalline nature of BNC and tunicates with longer nanocrystallites [23]. CNC possesses a unique set of properties such as large surface area, high specific strength, very high modulus, exceptional stability, and excellent optical properties. CNC are known for their exceptional mechanical properties. Young’s modulus of CNC is theoretically estimated to be 167.5 GPA along its cellulose chain axis. This modulus value is similar to that of Kevlar and much higher than that of steel. The properties of the CNC are also dependent on the nature of the source; CNC obtained from tunicates exhibit a modulus of 143 GPa while that of cotton is around 105 GPa. Other outstanding CNC properties include high tensile strength of ~9 GPa, high thermal stability up to 260 C, lower thermal expansion coefficient of 0.1 ppm/K, and low density (1.5–1.6 g/cm3). In general, the isolation of CNC from plant sources is carried out in several steps. The first step involves the milling of fibers from different sources to reduce the particle size and to improve the contact surface area for subsequent treatments. The powder is then washed with distilled water to dissolve and remove any impurities. The next step is the isolation of pure cellulose from the lignocellulosic biomass by eliminating noncellulosic material. This can be done by alkali treatment using strong bases like sodium hydroxide or potassium hydroxide. This stage enables the partial dissolution of hemicellulose fractions; removes waxes, pectin, silica ash, and fats; and exposes cellulose crystals for subsequent processes [26]. This is followed by bleaching or delignification with sodium chlorite or hydrogen peroxide. This enables the complete removal of hemicellulose as well as lignin. All of the abovementioned steps are often repeated to obtain a higher purity of the product. The next step involves the elimination of amorphous domains via a chemical treatment and isolates the crystalline regions followed by mechanical or ultrasonic treatment. Different chemical treatments used to isolate CNC will be discussed in the following sections.
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a
b
WHPL
c
WCPL
d
WCPB
WHPB
f
e
NS (x5000; scale bar = 5µm)
SN (x5000; scale bar = 5µm)
Fig. 5 Transmission electron micrographs from diluted CNC suspensions: (a) ¼ WHPF, (b) ¼ WCPF, (c) ¼ WHPP, (d) ¼ WCPP, (e) ¼ NS, and (f) ¼ SN. (Reprinted with permission from Bettaieb et al. (2015) [24] and Xiao et al. (2019) [25])
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Table 1 Preparation of CNC from various natural raw materials and synthesis techniques Raw material Flax Cotton Industrial waste cotton Wood Sisal Chili leftover Cotton Medical absorbent cotton Whatman no. 1 filter paper Eucalyptus pulp Birch and maple Kraft pulp Microcrystalline cellulose Microcrystalline cellulose Sugarcane bagasse Tunicate Bamboo pulp Wood pulp board Microcrystalline cellulose
Isolation method H2SO4 acid hydrolysis at 45 C for 4h H2SO4 acid hydrolysis at 50 C for 5h H2SO4 acid hydrolysis at 50–60 C for 8 h H2SO4 acid hydrolysis at 50–60 C for 25–45 min H2SO4 acid hydrolysis at 60 C for 15 min H2SO4 acid hydrolysis at 45 C for 45 min HCl acid hydrolysis at 110 C for 3 h H3PO4 acid hydrolysis at 48 C for 1.5 h HBr acid hydrolysis at 100 C for 1 h Formic acid hydrolysis at 95 C for 6h Maleic acid hydrolysis at 120 C for 90 min H2SO4 + HCl acid hydrolysis at 68 C for 10 h HCl + HNO3 acid hydrolysis at 110 C for 3 h Cellulase enzymatic hydrolysis at 110 C for 3 h Endoglucanase enzymatic hydrolysis at 50 C for 2 h Phosphotungstic solid acid hydrolysis at 90 C for 4.7 h Tetrabutylammonium acetate ionic liquid treatment at 65 C for 2 h BmimHSO4 ionic liquid treatment at 70–90 C for 1 h
Dimensions (l) nm (d) nm 100–500 10–30
References [32]
450
25
[33]
180 60
10 1
[34]
100–300
3–5
[35]
150–350
3–5
[36]
90–180
4–6
[37]
279 6 –
20 5 10
[38] [39]
100–400
7–8
[40]
50–200
5–20
[41]
200–450
10–30
[42]
–
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[43]
187 18
14 4
[44]
193–246
14–18
[45]
–
17 3
[46]
200–300
25–50
[47]
300–500
20–30
[48]
50–300
14–22
[49]
The most common and widely used chemical treatment to prepare CNC is the mineral acid hydrolysis technique. Several mineral acids including sulfuric acid, hydrochloric acid, phosphoric acid, hydrobromic acid, nitric acid, formic acid, maleic acid, and their combined mixtures have been used for the hydrolysis process [26] (Table 1). The basic mechanism involved in acid hydrolysis is the digestion of disordered amorphous regions as they are easily accessible due to the low-density regions resulting from randomly oriented cellulose chains. During the hydrolysis,
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Fig. 6 Schematic representation of the acid hydrolysis mechanism to obtain CNC
acids release hydronium ions which easily target the amorphous regions and attack the glycosidic bonds with oxygen elements (Fig. 6). The protonation of the oxygen between two anhydroglucose moieties causes the C1-O bond to cleave. The produced carbocation is stabilized by electronic delocalization of the glycoside ring oxygen adjacent to C1. A nucleophilic attack on the C1 caused by the water molecule regenerates the acid terminating the depolymerization generating CNC. The properties of the obtained CNC are dependent on the type of acid used for hydrolysis. For example, upon using sulfuric acid, the sulfate groups will react with cellulose surface hydroxyl groups producing negatively charged sulfonic groups. This negative charge facilitates the easy dispersion and stabilization of CNC in water. When hydrochloric acid is used, the CNC agglomerate due to the absence of any surface charge [27]. However, the sulfuric acid–hydrolyzed CNC show lower thermal stability as the sulfate groups incorporated accelerate cellulose degradation, which might not be ideal for many applications. Utilizing phosphoric acid imparts flame resistance and higher thermal stability to the CNC [28]. The synthesis parameters such as time and temperature play a crucial role in determining the CNC characteristics. Longer reaction times are often associated with shorter CNC lengths, and higher temperatures have been known to result in de-esterification of sulfate groups [29]. Additionally, the raw materials have been known to impact the CNC properties, namely, dimensions and degree of crystallinity. Further, the concentration of acids is known to influence hydrolysis kinetics. It has been reported that acid concentration below 58 wt % may cause the depolymerization of cellulose and its subsequent conversion to soluble sugars, thereby affecting the CNC yield [30]. The hydrolysis reaction is terminated by adding an excess of deionized water. CNC are isolated and purified via centrifugation to remove the excess acid, and the final product is subjected to dialysis to remove any salts and impurities and to attain the required pH [31].
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While acid hydrolysis is commonly used for the processing of CNC, some issues, such as hazardous nature, high energy consumption, corrosion of equipment, and health and environmental risks, need to be addressed. As a result, recent research has focused on replacing liquid acids with a solid acid. The use of concentrated phosphotungstic acid for hydrolysis yielded CNC with rodlike morphology with 15–40 nm diameter and had higher thermal stability than the liquid acid hydrolysis. The solid acid used could be recovered by extracting using diethyl ether. Solid acids have the advantages of easy recovery and recyclability, low corrosion of equipment, and fairly safe working conditions. The recovered solid acid retains its reactivity and can be used for several cycles of CNC production. Despite the advantages, solid acids are expensive and require a longer reaction time and offer low yields. Gaseous acids have also been used in the hydrolysis of CNC. Different types of gaseous acids, such as hydrochloric, nitric, and trifluoroacetic acids, have been used for the hydrolysis [17]. Typically, wet cellulose containing high moisture content (~80%) is exposed to gaseous acids. The gaseous acids get absorbed by the wet fibers resulting in a high local concentration of acid leading to an increased rate of hydrolysis of the amorphous phase and local inter-fibril contacts. This technique is less hazardous than conventional acid hydrolysis and does not require a copious amount of water. Additionally, the yield of the product is higher and with higher purity [17]. Several other techniques have been explored to obtain CNC including enzymatic hydrolysis, ionic liquid treatment, and (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) oxidation (Table 1). Usually, these methods are used in conjunction with other physical, chemical, or mechanical treatments. Enzymatic hydrolysis utilizes various enzymes such as cellobiohydrolase, endoglucanase, exoglucanase, and pectate lyase to degrade lignin and hemicellulose contents and to obtain CNC. Enzymatic hydrolysis requires mild reaction conditions and is more environmentally friendly as compared to acid hydrolysis. Ionic liquid treatment involves the use of green solvents like 1-butyl-3-methylimidazolium hydrogen sulfate to dissolve lignocellulosic matter. These nontoxic, low boiling point, thermally stable, nonvolatile, environmentally friendly solvents have been used to obtain CNC with 14–22 nm diameter and 50–300 nm length [49]. CNC has been obtained via the TEMPOmediated oxidation process of cellulose fibers. This technique incorporates a large number of carboxylate groups into the CNC ensuing excellent dispersion in aqueous solutions. This treatment is usually carried out in aqueous solutions under mild reaction conditions and compared to CNC obtained using the traditional hydrolysis process; the TEMPO-oxidized CNC reveal smaller sizes, higher viscosity, higher shear stress, and better transmittance. Since the properties of CNC depend on many variables, it is necessary to analyze for a better understanding of the material before its use. A plethora of characterization techniques are used in the analysis of CNC including X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), atomic force microscopy (AFM), N2 adsorption, mechanical testing, and dielectric spectroscopy. XRD is used to obtain the crystallinity index, which regulates the physical and mechanical properties of CNC. The percentage of crystallinity is
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derived from the peak position (2θ) and diffraction intensity of the (002) lattice plane corresponding to the crystalline domains and the intensity of diffraction between (002) and (101) lattice peaks corresponding to the amorphous domains [50]. SEM, TEM, and AFM enable the analysis of morphology and in the evaluation of CNC dimensions including length and diameter [50]. The characterization involving N2 adsorption analysis will obtain precise surface area. The dispersion stability of CNC is expressed by the zeta potential value [51], which measures the surface charge, and the thermal stability of the material can be analyzed by thermogravimetric analysis [37].
4
Nanofibrillated Cellulose: Preparation and Characterization
Nanofibrillated cellulose (CNF) is a class of cellulose nanomaterial obtained via fibrillation of cellulose fibers via intensive mechanical processes. CNF were first successfully obtained, in 1982, via high-speed homogenization of eucalyptus pulp; however, about 20 years after their discovery, these materials began to attract recognition. CNF are characterized by high aspect ratios with their diameters in nanoscale and lengths up to several micrometers. Numerous terms have been used in the literature to describe CNF including microfibrillated cellulose, cellulose nanofibers, and nanocellulose fibers. As opposed to CNC, CNF are flexible long fibers containing both amorphous and crystalline domains obtained through the mechanical disintegration of cellulose fibers. A higher shear force is generated in this process, leading to the extraction of CNF from the pretreated fibers along the longitudinal direction. Typically, this processing technique inducing fiber delamination is correlated with high energy consumption. This energy consumption has been reported to decrease by up to 98% by chemically pretreating the cellulose fibers [52]. Effective cellulose fiber pretreatments facilitate the breaking of hydrogen bonds, alter the crystallinity, and provide easy accessibility of hydroxyl groups, thus improving the fiber reactivity [53]. CNF exhibit high transparency, high oxygen barrier property, outstanding mechanical properties, and biocompatibility. Despite these advantages, the commercialization of CNF is hindered due to some limitations. CNF have a large specific surface area and abundant surface hydroxyl groups. Thus, hydrogen bonds are formed between fibrils by these surface hydroxyl groups forming a strong agglomeration of fibers resulting in a gel-like structure. A great deal of energy is required in the form of mechanical force to shear and isolate the fibers. Moreover, the temperature generated due to the mechanical shearing effects can alter the crystal structure of the CNF, influence the gel behavior, and damage their network structure, inadvertently affecting the final product properties [54]. Cellulose fibrillation must be done in liquid, and the product is stored as a dispersion as irreversible hydrogen bonds are formed between the CNF upon drying [55]. CNF is mostly stored as aqueous dispersion with very low solid content, which complicates the storage, transportation, and further usage of the CNF. The high hydrophilicity of CNF is another drawback, which restricts its use in many applications. Several
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strategies have been employed to overcome these drawbacks. Cellulase hydrolysis is used to cut and strip off the fibers and promote eventual mechanical separation. Another method is via replacing the surface hydroxyl groups of CNF by using coupling agents or to oxidize the surface hydroxyl groups using TEMPO to create aldehyde or carboxyl groups. To reduce the cohesion between fibers, a surface charge may also be introduced to allow fibers to repel each other [56]. Defibrillation of CNF is an energy-intense process, which involves the mechanical disintegration of native cellulose fibers to obtain nanofibrils. The dimensions of the CNF are dependent on the disintegration power wherein the diameters are usually in the range of 10–100 nm while the lengths are up to several microns. Depending on the raw material and the degree of processing, certain chemical pretreatments are performed to reduce the energy requirements. Different mechanical processes have been used over the years to obtain CNF (Table 2), and some of the most common methods will be discussed below. The longest and most widely used method of preparation for CNF is highpressure homogenization. It involves the injection of pretreated cellulose slurry at room temperature through a micron-size hole under high pressure and velocity. The high shear forces generated due to the high pressure and velocity, interparticle collisions, and turbulent forces reduce the size of the fibers to the nanoscale. The high-pressure homogenization technique is simple and highly efficient and does not involve organic solvents. This technique is also ideal for large-scale manufacturing as it guarantees high CNF output with uniform physical properties. However, to obtain CNF the slurry needs to undergo several passes through the micro nozzle and thus requires more energy and time. The energy requirement is calculated to be 7.5 kWh/g for 30 high-pressure homogenization passes [57]. The clogging problem, because of the very small orifice size, is another problem associated with highpressure homogenization. Hence, it is necessary to reduce the fiber size prior to homogenization through mechanical pretreatment. Additionally, the crystalline structure of CNF can suffer excessive mechanical damage [58]. Microfluidization is a technique similar to high-pressure homogenization. The microfluidizer operates at a steady shear rate, unlike the homogenizer, which operates at constant pressure. The microfluidizer consists of an intensifier pump capable of generating high pressures to push the slurry of pretreated cellulose pulp through an interaction chamber. The interaction chamber houses specially designed microchannels of fixed geometry wherein the slurry attains high velocity. This generates high shear forces capable of defibrillating the fibers [59]. Further, the impact forces, colliding streams, turbulence forces, high-frequency vibration, and pressure drop break the intramolecular and intermolecular hydrogen bonds and assist in the formation of CNF [60]. To increase the degree of fibrillation, the procedure must be repeated many times, and chambers of varying sizes must be used. The product is directed through a heat exchanger upon leaving the chamber; either can be recirculated again for further processing or directed externally to the next stage [53]. CNF preparation via ball milling is a technique used for its low cost and simplicity as it operates at ambient temperature and pressure. Ball milling involves the production of CNF utilizing planetary balls inside a rotating drum. The frictional
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Table 2 Preparation of CNF from various natural raw materials and synthesis techniques Raw material Sugarcane bagasse Empty fruit branch Dry softwood pulp Kenaf bleached pulp Hardwood Kraft pulp Softwood Kraft fibers Pinecone biomass Softwood Kraft pulp Cellulose powder Napier fiber Cotton stalks Corn cob Water hyacinth Poplar wood powder Wood, bamboo, wheat straw Coir fibers Sunflower stalks
Isolation method High-pressure homogenization at 80 MPa pressure for 30 cycles High-pressure homogenization at 50 MPa pressure for 30 cycles High-shear homogenization 22,000 rpm for 2 h Grinder and high-pressure homogenization at 50 MPa pressure for 40 cycles Microfluidization for 20 cycles
Dimensions (l) nm –
(d) nm 10–20
References [61]
–
5–40
[62]
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16–28
[63]
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15–25
[64]
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5–20
[65]
50–200
4–10
[66]
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[67]
Microfluidization at 160 MPa pressure for four cycles Grinding with 0.1 mm disk gap and 500 rpm for nine passes Microgrinding with 0.1 mm disk gap for nine passes for 2 h Ball milling at 400 rpm for 2 h
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15–40
[68]
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10–25
[69]
Ball milling at 840 rpm for 180 min TEMPO oxidation for 1 h TEMPO oxidation Cryocrushing
– 10–100 438 173 –
16–35 3–15 2.1 1.1 20–100
[70] [71] [72] [73]
Ultrasonic treatment at 1200 W for 20 min Ultrasonic treatment at 1000 W for 30 min
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4–12
[74]
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10–40
[75]
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5–50
[76]
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5–10
[77]
Steam explosion at 100–150 C for 1 h at 137 pa Steam explosion at 180 C for 1.5 h at 137 pa
and shear forces created between the balls break the cellulose fibers and reduce the fiber size to the nanoscale. The defibrillating forces are generated under the action of colliding balls and friction between the balls and walls of the rotating chamber [61]. Despite its simplicity and low cost, the use of this method has many drawbacks. The production efficiency of milling techniques is low, and the product lacks uniformity [78]. Further, the ball milling technique generates tremendous heat due to the frictional forces and thus cannot be used for a long time. A significant volume of metal or quartz debris is introduced by the collision and the rubbing between balls and chamber wall, which affects the purity of nanocellulose.
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Grinding is another simple, low-cost, low-energy-consuming technique used in CNF preparation. It is ideal for the large-scale CNF production from plant fibers and suitable for industrial applications [24]. Grinding involves cellulose fibers being constantly pressed and sheared between a static and a rotating disk or two rotating disks while the distance between the grinding disks reduces; this enables the particle size of the cellulose fibers to decrease to small sizes to achieve defibrillation [8]. Similar to the homogenizer and the microfluidizer, several passes are required to produce CNF, and the final product quality and properties are dependent on the number of grinding passes, the distance between the disks, and the morphology of the disks. However, the CNF isolated via grinding exhibit low crystallinity and mechanical strength as the high-intensity mechanical shearing destroys the crystalline regions of cellulose [79]. As is the case for ball milling, high-speed grinding disks might collide or even erode due to prolonged usage and generate impurities that will be introduced into the product [54]. The grinding procedure is not susceptible to clogging and can handle a large volume of raw materials at one time, so it is also used for pretreatment to homogenize large volumes of cellulose to reduce the size of fibers [80]. Cryocrushing is a technique used in the mechanical defibrillation of frozen cellulose slurry. Prior to cryocrushing, the fibers are chemically treated to remove noncellulosic impurities followed by swelling in water. The swollen fibers are then frozen in liquid nitrogen and then subjected to high shear forces to enable mechanical defibrillation. Owing to the strain applied by the ice crystals arising from the high shear forces on the frozen cellulosic fibers, the cell wall ruptures and contributes to mechanical defibrillation. Even though this technique has been used to obtain CNF of 5–100 nm diameter [81], it has a low yield and is not capable of producing very fine CNF [82]. Additionally, the use of this technique is restricted by its high energy consumption and expensive nature. High-intensity ultrasonication is a technique used to produce CNF via disruption of the cell wall in an aqueous medium. When the water molecules absorb ultrasonic energy, it creates microscopic gas bubbles, which then grow and finally implode generating efficient cavitation. In addition to cavitation, sound flow conduction and acoustic waves in the water contribute to the defibrillation process. The pulp under these hydrodynamic forces resulting from the ultrasound causes the defibrillation of cellulose fibers. CNF obtained via ultrasonic treatment had a wide particle size distribution, with diameters ranging from 20 nm to several microns [83]. This suggests that not all nanofibers are separated from the cellulose fibers. The crystalline structure of certain CNF has also been shown to be altered by ultrasonic therapy. Several parameters have been known to affect the final CNF properties. Higher ultrasonic power and temperature ensured better fibrillation, while higher pulp concentration and increased distance between the probe and the beaker were disadvantageous. Additionally, the ultrasonic probe was found to be more efficient than the ultrasonic bath in the production of CNF [53]. It has also been reported that the combination of ultrasonic treatment with other processes such as high-pressure homogenization, microfluidization, and TEMPO oxidation provides a higher yield of CNF [53].
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The steam explosion technique to obtain CNF utilizes high-pressure steam to penetrate the cellulose fiber and to disrupt the internal structure from the inside out. The typical process begins with high-pressure steaming of the raw material, accompanied by rapid decompression [84]. The sudden release of pressure generates shearing force capable of hydrolyzing the glycosidic and hydrogen bonds to produce CNF [85]. Steam explosion technique is environmentally friendly and is comparatively cheaper; however, the CNF prepared are nonuniform [86].
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Bacterial Nanocellulose: Preparation and Characterization
Bacterial nanocellulose (BNC) is an excellent natural polymer with a wide range of scientific and technical uses. BNC owing to its biodegradability, excellent biocompatibility, and environmentally friendly synthesis route makes it an ideal eco-friendly material. Often termed bacterial cellulose, BNC was first discovered by Adrian J. Brown in 1886 via fermentation process by Bacterium aceti [86]. Many species of bacteria can produce cellulose nanofibers as extracellular secretion; however, Acetobacter xylinum, a gram-negative, nonpathogenic, aerobic bacterium, also known by the names Komagataeibacter xylinus or Gluconacetobacter xylinus, is considered the most effective and most extensively studied source of BNC [87]. Several other species of bacteria that produce BNC are Acetobacter, Aerobacter, Agrobacterium, Azotobacter, Rhizobium, Sarcina, and Pseudomonas [88]. BNC is obtained via incubating bacteria cultures for some days in aqueous media containing different carbon sources. The molecular formula of BNC is the same as the plant-biomass-derived cellulose; however, it is distinguished by its special 3D network with porous structure. BNC also possesses several characteristics, which makes it unique. BNC has very high purity as compared to plant-based cellulose due to the absence of lignin, hemicellulose, and other noncellulosic matter. This saves a lot of energy, chemicals, and costs associated with the product purification; thus this is environmentally friendly as well. This enables its use in applications such as biomedical purposes where high purity is a prerequisite. Besides, its interpenetrating 3D structure with very high hydrophilicity and physical strength is ideal for biomedical purposes to be used as wound dressings, artificial skins, scaffolds, and tissue engineering [89]. BNC exhibits a high degree of polymerization and high thermal stability arising from its high degree of crystallinity (84–89%) [90]. BNC nanofibers have diameters in the range of 20–100 nm, while its length can exceed 1–9 μm, thus exhibiting a high aspect ratio. BNC has a higher surface area than their plant-based counterparts and demonstrates high flexibility. A single nanofiber of BNC possesses Young’s modulus of 118 GPa, similar to that of steel [91]. BNC can be produced in various shapes and dimensions as aggregates, disks, and pellicles and hence is a versatile material. The development of environmentally sustainable goods is becoming increasingly important; nanocellulose production by microbial pathways is beneficial in this sense. Industrial processing of BNC-utilizing microorganisms is relevant since certain microorganisms demonstrate rapid development, enabling high yields and
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product availability throughout the year. Bacterial nanocellulose (BNC) is produced from the nucleotide-activated glucose in bacterial membrane [92]. BNC is then channeled through the cell membrane pores in the form of fibrils made up of D-glucose units connected by β-1,4-glycosidic linkages. The fibrils are linear and continuous with narrow size distribution. The abundant hydroxyl groups form intraand intermolecular hydrogen bonding between the lateral and unidirectional aligned chains forming insoluble nanofibrils [93]. Furthermore, these nanofibrils assemble into ribbon-shaped fibrils with 100 C). Researchers are using ionic liquid to solubilize cellulose biomass as a part of pretreatment. The liquid ions can dissolve cellulose biomass at room temperature with comparatively less time. The ionic liquid becomes more advantageous for solubilizing cellulose biomass, as it can be used in reaction to process cellulose [103]. Li et al. [104] have used ionic liquid, 1-butyl-3-methylimidazolium chloride ([Bmim]Cl), to isolate nanocellulose from sugarcane [104].
4.4
Biological Methods
CNFs could be obtained by culturing cellulose secreting bacteria. Nanosystems obtained with biological methods are of high purity and do not require further purification process. Cellulose nanosystem properties can be controlled by bacterial strain and culturing environment. Patricia marín et al. obtained bacterial nanocellulose culturing bacterial strain in the presence of naphthalene crystals (Fig. 8a–e) [105]. This study reports that BNC production requires an enriched carbon source. The utility of toxic naphthalene suggests that industrial and domestic waste also could be used as a source of carbon in BNC production. Erminda tsouko et al. used culture media derived from industrial waste and by-products; this method reduces production costs and is eco-friendly [106].
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Applications of Nanocellulose
5.1
Biomedical Application
Biomaterials are the materials derived from either natural or synthetic origin: bioactive and potential cell modulation. These properties of the biomaterials allow their use for tissue regeneration and repair. Cellulose, having derived from natural sources (plants), has found its application as a biomaterial for various applications due to its biocompatibility, cell adhesion, and integration. The failure of clinical implants is one of the major reasons leading to multiple revision/correction surgeries. The fibrotic tissue development on the implanted devices often results in the malfunctioning of the devices. In an attempt to prevent fibrotic tissue growth on the implanted devices, cellulose-based pockets have been adopted. FrancescoRobotti
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a
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Fig. 8 Biofilm developed by strain Starkeya sp. strain N1B when growing with naphthalene crystals as the sole carbon source. Cultures in a flask containing two (a) or five naphthalene crystals (b). Appearance of a wet cellulose pellicle after collection, with visible naphthalene remnants (c) and after lyophilization (d). SEM images of Starkeya sp. strain N1B biofilm formed during growth on naphthalene (E and F), Ref. [105]
et al. have reported a protective wrapping based on cellulose for the implantable cardiac pacemaker [107]. The in vivo studies revealed that the protective wrapping was intact with no signs of chemical or mechanical damage, suggesting the employability of cellulose-based wrapping material to improve the implant’s life. The injectable cellulose-based construct entrapping magnetic nanoparticles has been explored to apply in tumor ablation, as Fengjuan Wang et al. [80] reported. The cellulose-based hydrogel displayed localized hyperthermia under the magnetic field’s influence and prevented thermal damage to surrounding normal tissue structures. As cellulose forms hydrogel, various CNF hydrogels have been proposed for tissue regeneration and repair. Kun-Chih Cheng et al. reported a composite hydrogel derived from natural sources (cellulose and chitosan) as a prospective platform for neural cell differentiation and repair [108]. Similarly, Natalie Geisel et al. reported a
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molded bacterial cellulose construct that resulted in aligned multilevel microstructures as a substrate for neuronal cell growth [109]. Evelyn Yun Xi Loh et al. reported a composite hydrogel derived from bacterial cellulose to deliver human keratinocytes and fibroblasts as a wound dressing for skin lesions. The in vivo study revealed significant wound healing potential for cellulose hydrogels with/ without cells compared to control [110]. The cell delivery and wound healing potential were attributed to the hydrogel’s cell attachment and water holding capacity. The cellulose-based composites have been well studied for their application in skin regeneration and repair. However, Fengcai Lin et al. have reported a natural skin mimetic hydrogel derived from cellulose nanocrystals (CNCs) exhibiting selfhealing, super stretchability, and electromechanical stimuli sensitivity [111]. The smart hydrogel construct was a composite of plant-derived CNCs and polyphenol (tannic acid), encompassing silver nanoparticles. The hydrogel displayed cross-linking by both borax (used as a cross-linker for tannic acid) and hydrogen bonding, resulting in a superelastic, electroconductive smart hydrogel. The plant-based native cellulose structures have been explored as a scaffold for 3D cell culture. Ryan J. Hickey et al. reported a scaffold derived from decellularized apple slices for culturing [112]. The native hierarchy of the cellulosic structure was coated with collagen for achieving cell growth, as shown in Fig. 9. The cells were cultured for 2 weeks, and when the scaffolds were implanted in vivo, angiogenesis was observed. The native collagen construct derived from spinach leaves has also been explored in a similar attempt to generate a vascularized cell mass. Joshua R. Gershlak et al. have reported an innovative and inexpensive strategy to culture vascular endothelial cells in decellularized spinach leaves (Fig. 10) [113]. The spinach leaf ECM exhibited inherent vascular structures; the cardiomyocytes cultured for 21 days showed contractility. The scaffolds derived from plant sources have also been evaluated for bone regeneration. Jennifer Lee et al. reported cellulose constructs derived from the decellularization of various fruits and vegetables like apple, broccoli, and carrot (Fig. 11) [114]. These scaffolds displayed varying porosity that supported the growth of osteoblasts. Among all the tested scaffolds, only decellularized apple showed significant support to the osteoblast culture, attributed to its resemblance to the bone porosity. Moreover, when the scaffold was implanted in vivo, it exhibited excellent osseointegration.
5.2
Pharmaceutical Application
The inert activity and excellent biocompatibility of cellulose have extended their application in the pharmaceutical industry. Various cellulose-based derivatives have been used as an excipient in a formulation like oral dosage forms and transdermal and transmucosal drug delivery systems [115, 116]. Due to the lack of enzymes responsible for cellulose degradation, it is not used for intravenous administration. The most prominent use of cellulose and its derivatives is as a coating for tablets. The drug dissolution rate from the solid dosage form can be controlled by ester/ether derivatives of cellulose coatings on the tablets [117]. The cellulose coating is hydrophilic, and when it comes in contact with water, it forms a hydrogel by absorbing
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Fig. 9 Decellularized apple slices for myoblasts culturing (2 weeks) (a) grown in culture media, (b) grown in gelatin coated scaffolds, (c and d) grown in collagen coated scaffolds. Nuclei (blue), cell membrane (green), and cellulose (red). Scale bar (1000 μm). Ref. [112]
a
b
Fig. 10 Cellulose based vascular scaffols derived from spinach leaves. (a) before and (b) after perfusion of Ponceau Red. Ref. [113]
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a
b
c
d
e
Fig. 11 (a) Schematic representing the decellularization protocol and cell culturing (b and c) photographs of fruits and vegetable and their respective scaffols (d) Phase contrst imaging of scaffols; (e) SEM imaging. Ref. [114]
water. The porous hydrogel formed on the surface controls the drug release by diffusion and dissolution. The insoluble cellulose derivatives like cellulose acetates exhibit pH-dependent solubility, and these coatings are used as targeted delivery systems or pH-triggered delivery systems [118]. Cellulose and its derivatives are known for the mucoadhesive potential; localized mucosal delivery is warranted in treating various inflammatory conditions. Flavia Laffleur et al. reported a mucosal adhesive patch fabricated by a solvent evaporation method; the resultant patch exhibited significantly enhanced mucoadhesive potential and also mucoprotective properties [119]. Similarly, Georgios K. Eleftheriadis et al. reported a buccal film based on hydroxypropyl methylcellulose (HPMC) for unidirectional and localized delivery of ketoprofen and lidocaine. The prepared films exhibited
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Fig. 12 (a) Image of compartmental micro needle array patch. (b) Pink and blue colour coded needles with two separate monovalent antigens. (c) Antigen loading on microneedles. Ref. [122]
complete drug release within 3 h and were biocompatible with the human buccal cell line. Cellulose-based films have also been investigated for treating chronic skin inflammatory conditions like psoriasis. In order to treat the chronic localized inflammation, a CNF-based patch entrapping curcumin was fabricated by Naewon Kang et al. [120]. The drug-loaded CNFs patch exhibited a significant reduction of inflammation when tested in vivo. Eun Kima et al. fabricated a microneedle patch for the delivery of the recombinant coronavirus vaccine. The dissolvable microneedles were cast with carboxymethylcellulose (CMC); when the prepared films were tested in vivo, significant immune stimulation was observed [121]. Interestingly, bivalent antigen delivery has also been attempted by employing cellulose (CMC)-based microneedles for immunization against influenza [122]. The two antigens were administered intradermally through cellulose microneedles without mixing through a compartmental array, as shown in Fig. 12. The preclinical evaluation of the fabricated patch resulted in enhanced survival and enhanced neutralizing antibodies. The major advantage of cellulose-based intradermal vaccine delivery compared to conventional intramuscular delivery is the presentation of antigens to immune cells, which results in superior immune stimulation. These studies highlight the application of cellulose and its derivatives in the pharmaceutical industry.
5.3
Energy Production and Storage
Cellulose has been recently investigated for its application in energy storage. It is reported that cellulose composite separators employed in the sodium-ion battery have exhibited superior performance when compared with conventional glassbased separators [123]. It has exhibited significant thermal resistance, with the temperature reaching 300 C and thickness of 50 μm. These superior properties displayed by cellulose composite separators have opened newer avenues for cellulose application in batteries. Hyeyun Kim et al. reported that the carboxylated cellulose, when fabricated into mesoporous films and used in lithium-ion battery separator, exhibited significant electrochemical cycling stability and a high discharge rate with repeated charge/discharge cycles [124]. The assembly of asymmetric porosity of the fabricated cellulose membranes between the electrodes played a crucial role in enhancing the system’s stability (Fig. 13). The cellulose is also explored as a sustainable and environmentally friendly alternative for the
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a
b
Fig. 13 (a) Schemes representing the arrangement of porocity (b) The charge discrage cycling of different pattens. Ref. [124]
current collectors used in Li batteries. N. Delaporte et al. reported a hybrid current collector made out of cellulose fibers, which is sustainable and economical compared to the conventional Al-/Cu-based current collectors (Fig. 14) [125]. The as-prepared self-standing hybrid Li-ion electrodes exhibited enhanced cyclic stability for 1000 cycles. In addition to it, the toxic binders used in the conventional electros were avoided, thus preparing an economical alternative by using cellulose. N. Pavlin et al. reported a cellulose nanofiber-based separator for Li-ion battery [126]; these separators were compared with commercially available polyolefin-based separators. The results demonstrated that the cellulose-based separators outperformed the commercial-grade separators in multiple aspects. The battery life improved due to the separator’s excellent wettability and electrolyte uptake and prevented degradation of the anode material. The electrostatically assembled carbon black nanoparticles on the CNFs has also been reported by Yudi Kuang et al. [127]. The composite high-density electrode exhibited a robust and fast charge transfer and was superior to the conventional lithium iron phosphate-based batteries. The integration of conductive polymers and CNFs has promised to fabricate inexpensive, scalable, recyclable, and environmentfriendly electrode materials. Gustav Nystrom et al. have reported a paper-based battery wherein the cellulose fibers derived from algae are coated with polypyrrole (an electroconductive polymer) with a thickness of 50 nm [128]. The resulting aqueous-based batteries showed high charge capacities and cyclic stability with minimal loss. It opens up newer avenues in developing cost-effective, economical, commercially scalable, and sustainable materials to develop high-performance batteries and flexible electronics.
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Fig. 14 Schematic representinf self standing Li-ion hybrid electrode material derived from cellulose. Ref. [125]
5.4
Flexible Electronic Devices
The cellulose nanofibers (CNFs) are extensively investigated for application in flexible electronic devices. Inherently, the CNFs are nonconductive, and thus for electronic applications, it is functionalized by various conductive components. Weiqian Tian et al. reported electroconductive and flexible nanocellulose-based composite films [129]. The CNFs were combined with highly conductive MXenes, and the resultant films exhibited significant mechanical strength (imparted by CNFs) and electroconductivity (imparted by MXenes). Owing to the excellent mechanical strength imparted by CNFs, its applicability as flexible electrode material by the interfacial synthesis of MOF (metal-organic framework) on CNFs was reported by Shengyang Zhou et al. [130]. The CNFs extracted from green algae were used as a substrate, and MOF was grown on nanofibers. The controlled synthesis resulted in a uniform coating of electroconductive material on the CNFs resembling a core-shell structure with a 5–7 nm thickness. Moreover, the fabricated composite material exhibited high cycle stability of more than 103 charge/discharge cycles. Nanocellulose has also been explored as a promising material for flexible perovskite solar cells (PSC). L. Gao et al. reported a transparent cellulose-based biodegradable substrate for PSC, unlike the petroleum-based polymer-based substrates (Fig. 15) [131]. The nanocellulose-based flexible solar cells exhibited a high power per weight ratio and retained >80% of its efficacy after repeated bending of the solar cell. This can aid in developing wearable electronic high-performance devices with sustainability and recyclability. The cellulose-based flexible pressure sensors were fabricated by H. Zhang et al. by combining multiwalled carbon nanotube (MWCNT) with cellulose fabric [132]. The prepared composite material exhibited sensitivity in the range of 0–20 kPa with a response/recovery time of 20 ms. These materials can be further explored in developing smart fabric and medical diagnosis. Similarly, the
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Fig. 15 Schematic representation of flexable solar cells developed from nanocellulose based substrate as an alternative to the conventional petroleum based substrates. Ref. [131]
cellulose was combined with carbon nanotubes (CNT) and was developed as a composite film for e-skin (electronic skin) application [133]. The prepared films exhibited high tensile strength and were nontoxic and biocompatible. Q Fu et al. reported wood-based flexible films made from naturally aligned cellulose fibers showing superior tensile strength [134]. These films were printed with electroconductive ink derived from lignin and showed higher performance. These systems are scalable, economical, and biodegradable and can further explore developing smart packaging and wearable electronics. In an attempt to develop a sustainable, economical wearable sensor material, X Cui et al. explored cellulose-based hydrogel for flexible, soft composite material [135]. The hydrogel was prepared from okara cellulose, which is a by-product obtained from the food industry. The hydrogel exhibited biocompatibility and mechanical property used as a wearable strain sensor (Fig. 16). Thus, the cellulose offers an economical and sustainable alternative for developing advanced high-performance wearable electronics.
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b
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Fig. 16 (a) Tensile strain applied on okara based cellulose hydrogel (0 to 60%). (b) The change in resistance upon bending at varying angles (30 , 60 and 90 ) (d). (c) effect of finger bending on resistanc. Ref. [135]
5.5
Others
Cellulose has also been explored for developing high-density jet fuel, as reported by Y Liu et al., the conversion of cellulose to poly cycloalkanes [136]. The reaction scheme resulted in fine-tuning the yield into methyl cyclopentane, which can be adopted as a gasoline additive. This has resulted in a cheaper fuel production source with minimal reaction steps and mild reaction conditions and may minimize the CO2 emission from aviation. The cellulose nanofiber-based composite has also been explored as lightweight and impact-resistant material for possible use in aircraft and automobiles [137]. Thus, cellulose in the field of aerospace can be an excellent example for all green structure materials.
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Future Directions
The current technological advancements and innovations lead to the emergence of newer hybrid cellulose-based materials. These composite materials have shown promise in applying nanocellulose in various fields as an efficient, sustainable, and economical alternative. Nanocellulose-based smart material for high-performance
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next-generation batteries can truly revolutionize energy storage and may emerge as a green alternative. The development of printable conductive inks based on nanocellulose can help produce large-scale high-performance devices that are efficient and economical. Nanocellulose-based packaging materials have also emerged as an alternative that is now rapidly adopted to minimize the environmental catastrophe caused by nondegradable plastic materials. The development of innovative nanocellulose-based materials for biomedical applications like tissue engineering and regeneration can also be explored to provide precise control at the cellular level. All in all, the research in nanocellulose-based materials has advanced at a rapid pace and has shown promise in resolving long-standing issues; thus, further research may enable sustainable development.
7
Conclusion
This chapter has discussed current methods employed for isolation and bulk production of cellulose-based nanosystems by either chemical or physical processes. The various preprocessing chemical treatments and diverse sources of cellulosebased systems have also been discussed in detail. Later, the current research for applying multiple cellulose-based composite systems is also discussed, encompassing biomedical, pharmaceutical, and electronic applications. This gives a comprehensive overview and state-of-the-art research in developing nanocellulose-based materials for advanced prospective future applications.
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Synthesis, Characterizations, Functionalizations, and Biomedical Applications of Spherical Cellulose Nanoparticles Soroush Soltani, Nasrin Khanian, Taha Rmoodbar Shojaei, Nilofar Asim, Yue Zhao, and Thomas Shean Yaw Choong
Contents 1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Overview of Celluloses and Nanocellulose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1 Structure and Source of Celluloses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2 Nomenclature and Types of Nanocellulose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Spherical Cellulose Nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Spherical Cellulose Nanoparticle Synthetic Methodology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1 Dispersion-Based Techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2 Polymer Self-Assembly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Characterization of Spherical Cellulose-Based Nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Soroush Soltani and Nasrin Khanian contributed equally with all other contributors. S. Soltani (*) Department of Chemical and Environmental Engineering, Faculty of Engineering, Universiti Putra Malaysia, Selangor, Malaysia Solar Energy Research Institute, National University of Malaysia, Bangi, Malaysia N. Khanian Department of Physics, Faculty of Science, Islamic Azad University, Karaj, Iran T. R. Shojaei Department of Mechanical Engineering of Agricultural Machinery, Faculty of Agricultural Engineering and Technology, College of Agriculture and Natural Resources, University of Tehran, Karaj, Iran N. Asim Solar Energy Research Institute, National University of Malaysia, Bangi, Malaysia Y. Zhao School of Mechanical, Materials, Mechatronic and Biomedical Engineering, Faculty of Engineering and Information Sciences, University of Wollongong, Wollongong, Australia T. S. Y. Choong Department of Chemical and Environmental Engineering, Faculty of Engineering, Universiti Putra Malaysia, Selangor, Malaysia © Springer Nature Switzerland AG 2022 A. Barhoum (ed.), Handbook of Nanocelluloses, https://doi.org/10.1007/978-3-030-89621-8_11
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6 Surface Functionalization Techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Biomedical Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Abstract
Throughout the last two decades, cellulose, as the most available green and nontoxic biomacromolecule, has gained increasing interests in any form of nanostructures owing to its superior characteristics consisting of high crystallinity, high specific surface area, surface chemical reactivity, amphiphilic nature, high aspect ratio, stiffness, excellent thermal stability, better mechanical properties, nontoxicity, easy processing renewability, biodegradability, and biocompatibility. The presence of hydroxyl functional groups eases the functionalization process through chemical, physical, and biological reactions, bringing about the enhancement of a variety of nanomaterials with a tunable structure which builds up new opportunities in terms of nanomaterial fabrication. Moreover, many structures of nanocelluloses (NCs), such as cellulose crystallites, nanocrystalline cellulose, nanorods, nanowires, nanoplatelets, nanoyarns, nanospheres, and cellulose nanowhiskers, can be prepared over various industrialized methodologies using a broad range of applications. In this chapter, the latest advances in the synthesis, functionalization, and promising biomedical applications of spherical cellulose nanomaterials were described and elaborated. It was started with a brief background of cellulose, its structural association, and also classification of cellulose nanomaterials for beginners in this field. Afterward, diverse experimental processes for the fabrication of cellulose nanospheres, their characteristics, and characterization techniques were discussed. Moreover, recent and emerging applications of spherical cellulose nanoparticlesin biomedical were presented. Keywords
Cellulose-based nanoparticles · Amorphous nanocellulose · Spherical cellulose nanoparticles · Cellulosic nanospheres · Characterization techniques · Biomedical applications
1
Introduction
Nowadays, using renewable and sustainable materials, such as cellulose, chitin, chitosan, alginate, starch, and gelatin, has drawn the attention of the researchers for generating promising alternative eco-friendly candidates to combat swiftly depletion of natural resources, energy crisis, global warming, and environmental pollution [1, 2]. Among the various resources, cellulose has been revealed to be the most plentiful renewable raw material which can be obtained from plants, tunicates, algae, and certain bacteria [3–6]. The inexhaustive chain of cellulose bundle together generates highly polymeric sites which can be successively isolated as cellulose nanomaterials known as nanocelluloses. These fascinating compounds possess
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incredible physicochemical characteristics such as low density, high strength, excellent stiffness, dimensional stability, low coefficient of thermal expansion, and capability to functionalize the surface chemistry [7–9]. Nanocelluloses (NCs) are typically classified into two main categories: (i) nanostructured materials and (ii) nanofibers [10, 11]. The structural and morphological features of each nanocellulose group are associated with the origin and maturity of cellulose, the separation process, reaction parameters, and potential pre- or post-functionalization methods. The advantages of a three-dimensional hierarchical structure of NCs, as well as their unique physicochemical properties, have raised demands on industrial scales in various applications such as batteries, biomedical products, antimicrobial films, food coatings, cosmetic, catalytic supports, separation membranes, nanocomposite materials, wood adhesives, cement, template for electronic components, electroactive polymers, supercapacitors, paper products, and many more developing usages [12–15]. Up to date, a huge number of literature review articles have been published, focusing on fabrication, characterization, functionalization, and applications of nanocelluloses. Here, we aid to make a summary of some of the most recent findings and developments of NCs, especially spherical cellulose nanoparticles (SCNPs), which have not been addressed in recent publications. Initially, a brief overview of NC classification, its separation from a number of feedstocks, and its characteristics is presented. In the subsequent parts, the most recent employment of SCNP fabrication, functionalization, and characterization on biomedical applications is discussed to present readers with a comprehensive summary of the advancement of cellulose nanospheres.
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Overview of Celluloses and Nanocellulose
2.1
Structure and Source of Celluloses
Cellulose is considered as the most available polymeric raw material in the planet with an annual production of 1010 to 1011 tons. Cellulose is basically formed by duplicating β (1,4)-bound D-glucopyranosyl components in the 4C1-chain structure, where each and every individual unit is coiled at 180 linked with its adjacent [16]. These units are interconnected together to construct a crystalline structure of cellulose well-known as basic fibrils. These latter are pushed and joined together to form microfibrils and macro-fibrils. It should be noted that the characteristics of cellulose highly depend on the length of polymeric chains and the intensity of polymerization. Figure 1 displays a schematic illustration of cellulose contained in plants with a hierarchical structure from the meter to the nanometer scale. Natural cellulose contains both amorphous and crystalline domains where the crystallinity may vary from 40% to 70%. The crystallinity degree is associated with feedstocks and the extraction procedures. In comparison with the crystalline zones, the amorphous ones possess low density and are more likely to react with other molecular clusters [18, 19]. On the other hand, the amorphous domains are less
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Fig. 1 A schematic illustration of cellulose contained in plants with hierarchical structure from the meter to the nanometer scale [17] (Reprinted with permission of MDPI, 2020)
resistant to any sort of physical and chemical treatments as being compared with crystalline ones. Various polymorphs of cellulose (I, II, IIII, IIIII, IVI, and IVII) can be found in accordance with van der Waals force, molecular orientations, inter- and intramolecular interactions, isolation method, and treatment process. These polymorphs can be altered from one to another over chemical or thermal treatments. Up to now, various feedstocks are known as sources of cellulose such as hardwood, softwood, plants and agricultural residues, animal, bacteria, waste paper, and algae [20, 21]. The removal of noncellulosic modules can be carried out over various biological, physical, chemical, and combined pretreatment methods through the exclusion of extractive particles, delignification, and bleaching procedures. These pretreatment procedures maximize the separation of crystalline (pure) cellulose, ensure the crackdown of the ties between noncellulosic and cellulose composites, decline the polymerization degree, elevate the ease of access to cellulose-rich portion, improve the porosity, and increase the inner surface and reactivity [22–25]. However, it is frequently reported that applying multiple pretreatment steps may bring about some dire consequences such as the formation of toxic wastes, incomplete separation, and degradation as well as loss of cellulose. Besides, employing a number of pretreatments will increase the total procedure expenses. In this regard, a large number of researches are still in progress globally to identify the phenomena that typically take place throughout the pretreatment processes, and then it will be practical to optimize the efficiency of the procedures and lessen their expenses and environmental consequences.
2.2
Nomenclature and Types of Nanocellulose
Nanoscale materials, possessing a diameter of ~100 nm in at least one dimension, have brought about a revolution in several industrial fields due to promising biological, optical, physicochemical, and magnetic characteristics [26, 27]. Throughout the last two decades, NCs have been widely studied as prominent and outstanding nanomaterials with remarkable properties such as high surface area, low coefficient
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of thermal expansion, hydrogen-bonding capacity, high tensile strength, renewability, eco-friendliness, biocompatibility, and absence of toxicity components [28]. According to the Technical Association of the Pulp and Paper Industry (TAPPI; WI 3021), NCs are typically classified into two main categories: (i) nanostructured materials, including cellulose microfibrils and cellulose microcrystals, and (ii) nanofibers, including cellulose nanocrystals, cellulose nanofibrils, and bacterial cellulose [10, 11]. Each class is distinctive, possessing unique properties, aspect ratio, diameter, crystallinity, and structure. Cellulose nanocrystals (CNCs) were initially fabricated over acid hydrolysis approaches which possessed 54–88% crystallinity index with rod-shaped nanoparticles within the range of 100 to 6000 nm in length and 4 to 70 nm in width [29]. Over the last 20 years, a wide range of nanoscale size cellulose was established and reported consisting of cellulose crystallites, nanocrystalline cellulose, nanorods, nanowires, nanoplatelets, nanoyarns, nanospheres, and cellulose nanowhiskers [30–32]. On the other hand, nanofibrillated cellulose, commonly fabricated over mechanical procedures, possesses a network structure with the flexibility of above 10,000 nm in length and 20–100 nm in width [33]. The amorphous nanocellulose (ANC) is a new type of nanocellulose of spherical to egg-shaped with a diameter within the range of 80–120 nm. Cellulose and cellulose-based nanospheres are typically produced over acid hydrolysis method with following ultrasound breakdown from regenerated celluloses. These nanomaterials can be directly gained from cellulose solution through a physical suspension, shaping, and renewal procedure [34, 35]. Over the hydrolysis process, the cellulose microfibrils in the parent cellulose will be inflated and separated into nanocrystalline cellulose particles in different shapes, i.e., sphere, rods, nanowires, and nanoplatelets, where the shapes of nanocrystals cannot be formed through simple filtration and centrifugation procedures. The rod-shaped nanocrystalline cellulose typically possesses longer length with several micron and width ranging from 30 to 50 nm. It was reported that spherical cellulose nanoparticles, with the diameter of 10 to 100 nm, can be shaped via self-assembly of small rod-shaped nanocrystalline cellulose over interfacial hydrogen bonds. However, the structural network can be extended in ethanol media (in comparison with aqueous media) in several microns in both the width and length orders which brings about formation of the less isolated cellulose nanocrystals. The strong hydrogen bonding between cellulose nanocrystals may prevail the repulsion of surface negative charges, bringing about the development of self-assembled porous structure. The cumulative specific surface area of the cellulose nanocrystals is several times larger than original cellulose powder. The pore size of cellulose-based nanospheres is much smaller than the amorphous pores presented in original cellulose, which can be corresponded to the presence of the inter-crystal voids resulting from the evaporation of hydroxyl groups and the resultant driving force to progress isolated cellulose nanocrystals closer. However, this porosity could not be observed in other shapes of nanocrystalline cellulose particles. Among different shapes of nanocrystalline cellulose particles, cellulose-based nanospheres possess dispersive behavior with insignificant aggregation in extended networks which makes them
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highly desirable for various biomedical applications. The emphasis of subsequent sections on this chapter was placed on spherical cellulose nanoparticles where synthesis methodologies, characteristics, surface fictionalization, and recent biomedical applications were discussed.
3
Spherical Cellulose Nanoparticles
Contrasting cellulose nanoparticles, nanospheres form from cellulosic by-products present in amorphous, colloidal positions that result from the construction of nanospheres distributed in liquid phases where several diffusion and self-assembly procedures take place. It corresponds to the insolubility of cellulose in water (hydrophobic) and to its restricted solubility in the majority of organic solvents. Generally, spherical cellulose nanoparticles proved to possess noticeable crystallinity and limited porosity, and therefore, the functionalization procedures take place on the surface of the particles. Nanosphere celluloses fabricated via nanoprecipitation, emulsion, self-assembly, or microfluidics methods are more likely to provide occasions for integration and release of tiny guest particles. It should be mentioned that the small proportion of particle capacity might be captured by solvent and, hence, integration and release of guests altered by reaction parameters such as pH, pressure, time, temperature, and humidity [36]. The very first type of spherical cellulose nanoparticles was prepared by Li et al. who employed the acid hydrolysis method for hydrolysis of native cellulose over sonication [37]. In another research, Zhang et al. diluted swelling cellulose fibers into NaOH and then employed mixed-acid hydrolysis over sonication to fabricate spherical cellulose nanoparticles with a size of 85 nm [38]. It is worthy to mention that nanospheres with an aspect ratio of 1 gave very insignificant specific surface area (SBET); however, asymmetric nanoparticles in disk or needle forms offered large SBET. It implied that surface loading per gram of particles was associated with the SBET. Moreover, the formation of spherical cellulose nanoparticles highly depends on cellulose origin and alterations in reaction conditions [39]. Thakore and coworkers synthesized cellulose triacetate nanospheres with a mean diameter of 25–30 nm using an acid hydrolysis process without sonication under ambient conditions in order to gain hydrophobic nanoscale derivatives [40]. Xiong et al. fabricated spherical cellulose nanoparticles with a particle size of 10–65 nm through the conversion of cotton fabric to microcrystalline cellulose over acid mixed- sulfuric and nitric acids hydrolysis procedure to develop the nanosphere material [41]. The polymerization degree of the synthesized spherical cellulose nanoparticles was reported 144, while the polymerization degree of the raw cotton was 1200. It implied that fabricated nanospheres were polycrystalline because they were highly bigger than the crystalline domains. On the other hand, Voskoboinikov et al. isolated the spherical cellulose nanoparticles using colloid dispersion where neither sonication nor alkaline hydrolysis was needed. It was reported that the structural characteristics and diameter of the nanospheres are mainly linked to the starting cellulose precursor [42]. To sum up, employing the
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method to fabricate spherical cellulose nanoparticles has not been optimized yet as the results were not in accordance with the other ones.
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Spherical Cellulose Nanoparticle Synthetic Methodology
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Dispersion-Based Techniques
4.1.1 Emulsion-Solvent Evaporation The surfactant-assisted method has been broadly employed for the fabrication of polymeric nanospheres [43–45]. Surfactants possess both hydrophobic and hydrophilic domains which ease phase separation of the distributed particles in the reaction mixture [46–48]. In other words, the surfactant-assisted method facilitates effective encapsulation of complex hydrophobic and lipophilic composites [49–51]. Typically, the evaporation of the organic solvent is carried out under reduced pressure which involves the formation of an emulsion of the nonmiscible organic solution including an aqueous solution of surfactant and hydrophobic-derived cellulose. Next, the polymeric chains start forming as soon as the surfactant-coated nanospheres spread in the aqueous phase. Later on, the purification of formed nanospheres takes place in order to eradicate unreacted surfactants and polymers. According to the reports, employing the solvent evaporation method causes a narrow size distribution of spherical cellulose-based nanoparticles (with a diameter of 50–300 nm) in water [52]. Moreover, it has been stated that the solvent evaporation method results in the fabrication of nanospheres via a dynamic procedure consisting of a conceivable combination of emulsion droplets as the organic solvent infuses from the interior sites of the nanoparticles. In this regard, the diameter of the final product can be alerted by the configuration of polymeric chains in the organic solvent and the diameter of the primarily shaped emulsion droplets [53]. On the other hand, the size of nanospheres is irrelevant to the chemical structure and molecular weight of the feedstock or guest particles [54]. Studies cited that the type of surfactant and input energy over emulsion formation are the two most considerable and effective elements in droplet size regulation. Wondraczek et al. reported that intensifying the sonication energy and prolonging the process resulted in a reduction of the diameter of the final spherical cellulose nanoparticles from 250 to 206 nm [55]. However, reductions in sonication energy facilitate the narrow size distribution of broader particles. As hydrophilic particles are insoluble in oil phases, hydrophilic drugs can take the advantage of the oil-oil emulsions. For instance, Lokhande et al. confirmed that metformin HCl and ethyl cellulose (as carrying material) were both dissolved in methanol; thus, nanospheres were constructed as the co-solution, and paraffin light oil was mixed under constant stirring. Following blending the material with hexane, centrifugation took part to eradicate oil with 97.66% encapsulation efficiency. It implied that 97.66% of the metformin mass was trapped in the ethylcellulose particles [52].
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In another research, Ubrich et al. employed the multiple emulsification procedure as a promising method to entrap hydrophilic particles where an aqueous mixture of water-soluble particles was mixed in a lipophilic organic polymer phase. The next stage was to prepare an aqueous solution of surfactants using water-oil-water emulsion. Afterward, the two prepared emulsions were mixed, and then evaporation of organic solvent took part to form spherical nanoparticles. It should be highlighted that a pressure homogenization device was employed to ensure the homogenous distribution of particles in nanoscale. The final nanospheres possessed low molecular weight hydrophilic drugs with 67% encapsulation efficiency [56]. To avoid using an organic solvent, salting out of the emulsion technique can be used instead of the emulsification of oil-water. In this process, a water-mixable organic phase is dissolved into an intense salt solution. This method gave a platform to increase the miscibility of the miscible organic with water by reducing the strength of dispersed salt in the water in the presence of an appropriate surfactant. Perugini et al. prepared primary emulsion via a combination of a saltsaturated aqueous phase with a water-miscible organic solution. Next, a large amount of water was applied to dilute the initial emulsion and extract the organic solvent, which brought about the formation of SCNPs. In order to eradicate the salt, prolonged dialysis time was required, let to a loss of guest particles. SEM photomicrographs of SCNPs over emulsion-solvent evaporation approach are depicted in Fig. 2 [57]. To minimize the energy input, the phase inversion approach can be employed over constant temperature. In this procedure, water was added to the organic solvent in the presence of a proper surfactant under vigorous stirring. An oil-water emulsion was being created since the organic phase was highly lower than the aqueous fraction. It could be because of the aqueous fraction [58, 59]. It is worthy to mention Fig. 2 SEM photomicrographs of SCNPs over emulsion-solvent evaporation approach [57] (Reprinted with permission of Elsevier)
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that besides the restrictions on the amount of added water, there was a constrained state inside the three-component phase plan where phase reversal may take place [60].
4.1.2 Nanoprecipitation However, the emulsion-solvent evaporation technique is proven to be efficient, and there is no arguing with the fact that this method has its cons such as harmful effects on human health and the environment, due to the use of organic solvents, requiring large quantities of surfactant, huge energy consumption, and costly purification process. Nanoprecipitation has been alternatively employed to fabricate nanoparticles which offers a number of advantages consisting of the nonexistence of a surfactant, low viscosity, production simplicity, high reproducibility, and low cost of production because of less input energy requirements [61, 62]. Nanoprecipitation provides the formation of nanospheres by instant nucleation of hydrophobic polymer chains in the presence of a large volume of hydrophilic liquid like water and an appropriate polymer like cellulose ester. The mixing procedure can be altered via either the dropwise addition of water or dialysis. Typically, nanoprecipitation takes place in a diluted zone of the polymer where an excess amount of polymer may cause the formation of a broad distribution of nanoparticles [63]. Nanospheres synthesized by nanoprecipitation using either cellulose esters or ethers were reported to have a uniform diameter of 100 to 250 nm. However, the size of final products should be controlled by altering the process parameters such as mixing intensity and parameters, the volume fraction of the organic solvent, and the chemical structure of the used polymer. For instance, to gain a smaller size of nanoparticles with narrower diameter distribution, it was essential to control the mixing process to fabricate homogeneously supersaturated groups. Kulterer et al. observed that the size of cellulose acetate nanoparticles dropped in the presence of an excess amount of the tetrahydrofuran fraction afterward mixing [64]. In addition, variances in the derivatization of cellulose resulted in deviations in the solubility of polymer, which consequently changed the supersaturation level. On the other hand, it was reported that the degree of substitution (DS) value is also reported to have a huge impact on the characteristics of the products and the size of nanoparticles where Hornig et al. observed that altering DS from 1.65 to 3.0 increased the size of particles from 86 to 368 nm. Nevertheless, high magnification of scanning electron microscopy (SEM) revealed the different shapes of nanoparticles where dialysis of a N, N-dimethylacetamide (DMAc) solution led to the formation of spherical nanoparticles (Fig. 3a) while dialysis in the presence of acetone caused irregularly shaped particles (Fig. 3b). Bean-shaped particles were formed by dropwise addition of water into the acetone solutions of the polymer (Fig. 3c and d). However, the concentration of the acetone solutions of the polymer had no impact on the final features of the nanoparticles. Hence, dialysis of DMAc solutions was suggested when regularly shaped nanospheres are required. Because of the fact that simultaneous adjusting of the degree of polymerization and degree of substitution required two unique hydrolysis reactions, it was extremely difficult to measure the role of chemical structure in controlling the diameter of particles over nanoprecipitation procedure. It was also
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Fig. 3 SEM images of nanoparticles of cellulose acetate on a mica surface fabricated via dialysis of (a) polymer dissolved in DMAc (c ¼ 4 mg CA/mL) and (b) polymer dissolved in acetone (c ¼ 4 mg CA/mL), (c) 1 mg CA/mL, and (d) 4 mg CA/mL [65] (Reprinted with permission of American Chemical Society, 2008)
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Fig. 4 SEM photograph of nanocellulose spheres over nanoprecipitations approach [66] (Reprinted with permission of Elsevier, 2019)
recommended that cellulose triacetate should not be employed over the procedure to avoid the possible risk of crystallization of the triacetate [65]. In another research, Agi et al. [66] studied the impact of nanoprecipitations approach on the crystalline formation of spherical cellulose nanoparticles over ultrasonic-assisted weak-acid hydrolysis. The spherical shape of the synthesized samples is proven by SEM photograph as demonstrated in Fig. 4. The smooth surface suggested that the preparation method caused insignificant physical
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damages. Furthermore, the presence of hollow-shaped particles corresponded to granular swelling and then collapse through the synthesis process. Up to now, a wide range of steady and hydrophobic spherical cellulose nanoparticles were fabricated with diameters within the range of employing nanoprecipitation method using different cellulose solution with the diameter within the range of 80–160 nm used for various applications, especially biomedical ones [67]. Moreover, derivatized renewed pure SCNPs were synthesized and reported using a supercritical antisolvent mechanism based on the nanoprecipitation structure [68–71]. A comparison study was done once by Wondraczek et al. between nanoprecipitation and conventional solvent evaporation methods through characterizing the formed spherical nanoparticles. However, both approaches resulted in the narrow size distribution of nanospheres, and nanoprecipitation was strongly recommended for its low input energy requirement and surfactant-free mechanism [55].
4.1.3 Microfluidic Technique Microfluidic, as a substitute technique for the nanoprecipitation process, typically employs a microfluidic device to have a harmonized and speedy mixing process in a tunable and constant way in millisecond scale using three or probably more separate input flows in the presence of polymer stream to fabricate nanospheres with complex constructions. As was mentioned earlier, the nanoprecipitation method of dropwise addition of water or hydrolysis resulted in a slower mixing process under restricted conditions. Microfluidic devices offer a tunable and rapid mixing process below one millisecond by adjusting the flow ratio of incoming fluids as well as raising the channel width while a mixture of the aqueous and organic is streaming. The microfluidic procedure has been vastly employed in the preparation of functionalized and non-functionalized spherical chitosan nanoparticles [72, 73]. Karnik et al. employed quick and tunable microfluidic channels to tune nanoprecipitation of poly(lactic-coglycolic acid)-b-poly(ethylene glycol) diblock copolymers. It was reported that changing flow ratio, mixing time, as well as polymer concentrations and conditions were the main contributors to optimizing the size of particles ranging from 50 to 300 nm (depends on the further application) as well as developing polydispersity [74]. In another research, Majedi et al. increased the size of fabricated spherical chitosan nanoparticles from 110 to 219 nm by increasing the mixing rate [72]. Later, they employed a T-shaped PDMS microfluidic device using a highly stable flow to maximize the control interfacial penetration of ions into the polymer fellow. The functionalized hydrophobic chitosan nanospheres possessed a diameter of 50– 180 nm where the larger particle size was achieved over raising the flow rate [73]. According to the reports, it is quite challenging to fabricate and develop the bulk of polymeric spherical nanoparticles while dealing with complex multicomponent since the charges distribute regularly at the mixing interface [75]. For instance, Tresset et al. synthesized surfactant-polyelectrolyte cellulosic nanospheres, with hydrodynamic diameters tunable in the range of 50–300 nm, using a microfluidic device over the microfluidic-assisted self-assembly method. The used methodology brought about well control of the particle size with repeatable size dispersals and polydispersity overregulated mixing kinetics and regular dissemination of charges at the mixing boundary [76].
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Polymer Self-Assembly
It is known that cellulose ethers and esters are naturally amphiphilic, possessing both hydrophobic and hydrophilic groups. These temperature-sensitive polymers were self-assistant to structure metastable nanocoils in an aqueous solution. Gao et al. found out that at a temperature above the lower critical solution temperature (LCST), ranging from 41 to 44 C, self-assembly of hydroxypropyl cellulose (HPC) took place and resulted in the formation of metastable spherical nanoparticles with the diameter in the range of 150–200 nm which were later alleviated through the covalent in situ cross-linking procedure and structured nanospheres of 300 nm [77]. Figure 5 displays a schematic illustration of changing HPC chains over the in situ cross-linking procedure at 42 C. Afterward, studies were concentrated on temperature-dependent HPC over selfassembly fabrication of nanospheres. Results demonstrated that interaction between hydroxyl groups of cellulose derivatives and carboxylate groups as well as protonaccepting or proton-donating companies brought about a reduction in the LCST of the polymer [78, 79]. For instance, hydroxypropyl methylcellulose (HPMC) has an LCST of 60 C in water, while hydrophilic acrylic acid (AA) molecules are quickly dispersed in water. The phase transition of the HMPC was associated with the hydrophobic-hydrophilic equilibrium of the HPMC arrangement. Over this mechanism, hydrogen bonding structured between AA, as a proton donor, and HPMC, as a proton acceptor, molecules interacted which led to a reduction in the LCST of the
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Fig. 5 Schematic illustration of changing HPC chains over the in situ cross-linking procedure at 42 C [77] (Reprinted with permission of American Chemical Society, 2001)
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Fig. 6 Schematic hydrogen bonding between the HPMC and AA [80] (Reprinted with permission of Journal of Nanomaterials, 2011)
hydrophilic HPMC and subsequently the phase transition at a narrow temperature (as illustrated in Fig. 6) [80]. Fujisawa et al. [81] synthesized ultrathin and homogeneous nanocellulose shell layers on polymer microparticles using the polymer self-assembly method (see Fig. 7). In this research, CNFs with a width of around 3 nm were initially fabricated from wood cellulose by (2,2,6,6-tetramethylpiperidine-1-oxyl) TEMPO-mediated oxidation. The surface CNF shells showed pH-sensitive drug loading/releasing properties, which suggested the potential for a range of therapeutic and biomedical applications. Because of the fact that characteristics of spherical cellulose-based nanoparticles are application-dependent, an understanding of both physical characteristics, including particle morphology, particle size, and distribution, and chemical characteristics, including surface chemistry and cross-linking within nanospheres, is vital. Table 1 summarized the pros and cons of spherical cellulose-based nanoparticles synthesized over the above-discussed methods.
5
Characterization of Spherical Cellulose-Based Nanoparticles
Because of the fact that spherical cellulose-based nanoparticles are applicationdependent, knowing both physical characteristics, e.g., pore size, particle size, dispersal, and morphology, and chemical characteristics, e.g., cross-linking among
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Fig. 7 (a) Schematic design of the synthesis of CNF-shelled microparticles. (b) Illustration and (c) SEM images of CNF-shelled microparticles (left and top right) and surface (bottom right). (d) Illustration and (e) SEM images of the cross section of the microparticles embedded in acrylic resin. Black arrows indicate the CNF shell [81] (Reprinted with permission of Royal Society of Chemistry, 2019)
nanospheres and surface chemistry, becomes particularly a matter of importance [82–84]. For instance, knowing particle size and dispersal is especially essential for tuning secondary characteristics as narrower distributions give the advantage of well-regulated release ratios. Therefore, to achieve high responses in particular applications, spherical cellulose-based nanoparticles should meet the required performance standards. In this section, some key characterization techniques are briefly discussed.
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Table 1 Pros and cons of spherical cellulose-based nanoparticles synthesized over the abovediscussed methods Method Emulsionevaporation
Pros • Uncomplicated and inexpensive • Small particle size • Uniform size distribution • Easy to tune particle size
Nanoprecipitation
• Uncomplicated and inexpensive • Less utilization of surfactants • Reusability • Proficient setup of the target
Microfluidics
• Easy to control process • Easy to tune particle size • Small particle size • Uniform size distribution • Possible control of particle surface characteristics in molecular level
Polymer selfassembly
Cons • High energy utilization • Presence of surfactants • Need for organic solvents • Complicated purification procedure • Not easy to tune particle size • Less yield of nanospheres • Difficulty with hydrophilic polymers • Expensive • Need for advanced devices • Complex process • Complicated purification procedure • Large size particles • Large size distribution
According to nanomedical research outputs, nanoparticle size and narrow size dispersals are two main contributors affecting nanospheres’ bio-dispersal where nanospheres may agglomerate inside tissues. The structure of nanospheres and their morphology may additionally impact their binding capability with guest particles. Atomic force microscopy (AFM), TEM, SEM, and dynamic light scattering (DLS) techniques are being regularly employed to evaluate size ranges, morphology, and structure of nanospheres fabricated under various conditions by providing illustrations of particular nanoparticles under vacuum. However, it is incredibly important to seek which methods are most appropriate to get more accurate results in particular applications. For example, number-average radii acquired by numerical evaluations of well-settled nanoparticle illustrations are reported to be drastically tinier in comparison with the mass-average hydrodynamic radii gained by DLS over an evaluation of distribution figures for the same samples. Electron microscopy of spherical cellulose-based nanoparticles confirms the formation of spherical or near-spherical structures; however, cryptic nanoparticles could be artifacts of drying tensions linked with the clearing of the sample slot or accumulation of unstable nanospheres [68]. Clustered nanoparticles regularly demonstrate complex boundaries among nanoparticles, causing a wider size distribution. Size and size dispersal of the nanospheres can be evaluated by the DLS technique which offers an implicit dimension of hydrodynamic level according to the dispersal of dispersion coefficients. It has been reported that the DLS assessment quality was associated with size dispersal and concentration of nanoparticles as well as
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interactions among nanoparticles. To gain accurate DLS data, the concentration of nanoparticles should be satisfactorily weak to lessen multiple scattering impacts. On the other hand, sample preparation by cryo-TEM technique encounters nanoparticles to a high vacuum which may cause a decrease in size because of the reduction of volatiles. In comparison with the TEM method, DLS offers simple and short sample preparations that allow characterizing the size of dispersed nanoparticles in the liquid phase. In order to utilize spherical cellulose-based nanoparticles for nanomedical applications, such as fragrances and drug carriers, it is important to know about entrapment efficiency (EE) which is identified by means of matching data to kinetic patterns. The EE value is depending on the preparation technique as well as the chemical characteristics of the drug particles [55]. Release behaviors that are measured over experimental circumstances are supportive to realize and assess the carrier medium construction where the drug nanoparticles are entrapped [85]. For illustration, a quick primary release reveals that the guest particles are attached to the exterior surface of nanoparticles while a gradual reduction in release at the last step associates with dispersion and suspension in the polymer. For economic purposes, characterizing stability is a crucial element for shelf life and dispensing of nanospheres to the desired target. A turbidity experiment is a straightforward mathematical approach for observing the solidity of nanosphere suspensions. Accumulation of nanospheres may bring about a reduction in the numbers of nanoparticles and a simultaneous drop in dispersed light strength and turbidness. Each DLS or visible light transmittance can be employed for this evaluation process.
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Surface Functionalization Techniques
Generally, spherical cellulose nanoparticles possess minimal surface charge density which reveals adequate electrostatic repulsion to make them colloidally steady in aqueous suspension. In this regard, the surface charge density can be regulated to affect surface activity, thermal stability, physicochemical interactions, metallic interactions, as well as energy consumption. The surface group and charge density are highly essential in the synthesis of nanocomposites and hybrid spherical cellulose nanoparticles since they influence the capability of the nanoparticles to dissolve and develop a certainly and uniform product. Therefore, knowing the surface functional group and charge density is crucial for the characterization of spherical cellulose nanoparticles [8]. As it is reported, spherical cellulose nanoparticles have conventionally been separated through the hydrolysis process in the presence of mineral acids, which resulted in the attaching of certain functional groups on the hydroxyl groups on the surface of cellulose nanospheres, or via oxidation to supply carboxyl and aldehyde groups. However, as-synthesized spherical cellulose nanoparticles can be further
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post-functionalized to maximize their functionalities by introducing commonly carboxy or carboxymethyl groups. Irrespective of the isolation technique or postfunctionalization process, the surface functionality of spherical cellulose nanoparticles can be resulted from attaching charged compounds to the surface of nanoparticles as hydroxyl species are not accountable for the surface charge because of being protonated over typical solution conditions. It should be mentioned that the surface charge density of functionalized spherical cellulose nanoparticles highly depends on the nature and properties of the applied surface functional groups, whether the group is a weak or strong base/acid, the functionalization process, starting materials, as well as physical, textural, and structural characteristics of the nanoparticles [8]. Chemical modification of hydroxypropyl cellulose (HPC) is a promising approach to ease the fabrication of spherical nanoparticles via specific interactions where no additional reagent is required. Tan et al. synthesized thiolated HPC nanospheres in the range of 88–160 nm and stabilized it through the cross-linking procedure in the absence of additional reagents [86]. As another example, the presence of anionic styrene sulfonate groups and cationic trimethylammonium groups successfully modified ionic derivatives of HPC over polyanion-polycation interactions, resulting in the formation of nanospheres with the size of 150 nm through the self-assembly process [87]. Similarly, amphiphilic HPC nanospheres were modified by Bagheri et al. using atom transmit radical polymerization [82]. Transmission electron microscopy (TEM) image of novel amphiphilic grafted HPC nanospheres containing polycholesteryl methacrylate side chains is illustrated in Fig. 8a. It should be mentioned that enhancing solubility of grafted HPC in water ensured the solidity of spherical nanoparticles in vivo which made them highly applicable as a drug carrier [52]. Figure 8b shows the core-shell structure of iron/ ethylcellulose (EC) nanoparticles synthesized over the emulsion-evaporation method in presence of 5-fluorouracil where iron nuclei were coated by a polymeric shell of around 30 nm thickness [88].
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Fig. 8 (a) TEM image of novel amphiphilic grafted HPC nanospheres containing polycholesteryl methacrylate side chains [82] (Reprinted with permission of Springer, 2013). (b) Dark-field highresolution TEM image of iron/ethylcellulose (core-shell) nanoparticles [88] (Reprinted with permission of Elsevier, 2010)
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Biomedical Applications
Cellulose and cellulose derivatives, such as hydroxypropyl cellulose, ethylcellulose, and cellulose acetate, as biodegradable and biocompatible materials, are nontoxic in nature and are being extensively utilized in pharmaceutical applications. These materials can be purchased for less than one dollar per pound in bulk, indicating that these nanoparticles can efficiently compete with synthetic polymers and polylactic acid [89]. Precise-release features of spherical cellulose-based nanoparticles make them broadly applicable for drug loading and measured drug release for both hydrophilic and hydrophobic drug particles [90]. Spherical EC nanoparticles reported possessing high drug-to-polymer mass ratios with exceptional persistent release properties for both hydrophilic and hydrophobic drugs with encapsulation proficiency of around 80% [91]. In a research done by Ubrich et al., a comparison study was carried out for encapsulation of hydrophilic drugs using EC, polycaprolactone (PCL), and Poly (lactic-co-glycolic acid) (PLGA) nanospheres, indicating that EC nanospheres had the lengthiest drug release [56]. Lately, in vivo analysis in C57BL/6 mice of clarithromycin-loaded spherical EC nanoparticles against free clarithromycin revealed the improved function of the nanospheres against contamination via Helicobacter pylori where drug-loaded nanoparticles disallowed the bacteriological infections through sticking to the cell wall, therefore constraining bacteria bonding while affording continuous drug release [83]. In another research, spherical cellulose nanoparticles with covalently attached fluorescent dye particles persisted for 7 days in human fibroblast cells, although with no bonding to any receptor. It was also stated that a quick mixing process over the microfluidics method presents lengthier, more durable drug release in comparison with similar nanospheres synthesized through bigger-capacity batch mixing [73]. Multifunctional spherical cellulose-based nanoparticles, prepared over nanoprecipitation and solvent evaporation techniques, presented a combination of simultaneous drug loading, targeting, and release in a particular fragment that can be successfully employed for complex nano-delivery systems [92]. Iron/EC core-shell structure nanoparticles were synthesized by Arias et al. over the emulsionevaporation method in presence of 5-fluorouracil where the integration of 5-fluorouracil into the magnetic compounds brought about an elevated drug loading and generated a lengthier drug release summary, in comparison with single 5-fluorouracil surface adsorption. The magnetic field was provided by the iron response for targeting delivery to tumor cells, while the EC shell boosted drug volume and monitored release by providing a polymeric matrix. The outcomes implied that the synthesized spherical iron/ethylcellulose nanoparticles were promising carriers for the effective delivery of 5-fluorouracil to cancer [88]. It is worthy to state that spherical cellulose-based nanomaterials, as a nanocarrier, have generally enhanced the functionality of nanocomposites in comparison with conventional materials by enhancing the steadiness of photodegradation over the fabrication process, by enriching the engagement of target particles to compound sensors, and by improving the chemical characteristics of entrapped particles [93].
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Kulterer et al. fabricated spherical cellulose nanoparticles along with trapped pH-sensitive fluorescence sensors to identify suspended ammonia. The small size of nanospheres as well as their high surface-to-volume proportion improved the dispersion rate of ammonia into the sensor membrane and significantly lessened the detection time in comparison with conventional materials [64]. Recently, the utilization of spherical nanoporous cellulose esters by lauric acid substituents proved brilliant hydrophobicity of lotus leaves which significantly enhanced the functionality of these materials in nanomedical applications [94].
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Conclusion
The formation of spherical cellulose nanoparticles highly depends on cellulose origin and alterations in reaction conditions. Nanosphere celluloses are typically fabricated via nanoprecipitation, emulsion, self-assembly, or microfluidics methods. In terms of synthesis methodology, the majority of experiments are based on maximizing the production yield/efficiency over environmentally friendly procedures through the following considerations: reducing or minimizing the usage of organic solvents, reducing the consumption of energy, adjusting the size and distribution of nanoparticles, and maximizing reproducibly. Because of the fact that cellulose-based nanospheres are mostly applicable for restricted-release carriers of drugs, fragrances, and chemicals, these parameters become highly influential over the direct fabrication of spherical nanocelluloses using acid hydrolysis approaches consisting of nanoprecipitation, emulsion, self-assembly, or microfluidics methods. In the future, studies should be based on the interaction mechanism between spherical cellulose nanoparticles and other materials. Apparently, from this chapter and those cited in previous literature, there are still several challenges to conquer to develop industrial applications of cellulose nanospheres. The spherical cellulosebased nanomaterials will have a bright future with the progress of nanoscience and nanotechnology. Acknowledgments The authors would like to extend their profound gratitude to the Ministry of Higher Education (KPT), Malaysia, for the financial support and funding this research work through Fundamental Research Grant Scheme FRGS/1/2020/TK0/UPM/01/2 (03-01-20-2250FR). We also would like to convey our deepest gratitude and appreciation to Dr. Maryam Shad for her ceaseless support. Conflicts of Interest There are no conflicts to declare.
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Cellulose Nanocrystals Synthesis, Functionalization, and Applications Tejaswini Appidi, Mudigunda V. Sushma, and Aravind Kumar Rengan
Contents 1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Structure, Morphology, and Properties of Cellulose Nanocrystals . . . . . . . . . . . . . . . . . . . . . . . . . 2.1 Structure and Morphology of CNCs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2 Properties of Cellulose Nanocrystals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Preparation of Cellulose Nanocrystals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1 Preparation of Cellulose Nanocrystals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Functionalization Techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1 Extraction-Dependent Functionalization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2 Functionalization by Physical Adsorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3 Functionalization by Chemical Modification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Physicochemical Characterization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Abstract
Among different types of nanomaterials, cellulose nanocrystals (CNCs) have attained great attention for their attractive and excellent properties, such as high surface area, colloidal stability, low toxicity, and high mechanical strength. These nanocrystals are obtained from different cellulose sources: wood pulp, microcrystalline cellulose, straw, bacterial cellulose, algae, and plant fibers. CNCs are generally isolated by a top-down approach and can be functionalized to develop advanced materials with improved properties for potential applications in various T. Appidi · M. V. Sushma Department of Biomedical Engineering, Indian Institute of Technology Hyderabad, Sangareddy, Telangana, India e-mail: [email protected]; [email protected] A. K. Rengan (*) Department of Biomedical Engineering, Indian Institute of Technology Hyderabad, Hyderabad, India e-mail: [email protected] © Springer Nature Switzerland AG 2022 A. Barhoum (ed.), Handbook of Nanocelluloses, https://doi.org/10.1007/978-3-030-89621-8_12
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fields. This chapter elucidates the synthesis approaches (physical, chemical, and enzymatic) and discusses the functionalization techniques (via synthesis, adsorption, and chemical modification). CNCs possess unique and outstanding physicochemical and biological properties. This chapter also discusses the unique and relevant functional (mechanical, thermal, rheological, optical, and biological) properties (cytotoxicity, biocompatibility, biodegradability) of CNCs for various applications. The scope of CNCs as biosensors, scaffolds, liquid crystals, and smart devices and in antimicrobial and food packaging applications is discussed in detail. Keywords
Cellulose nanocrystals (CNCs) · Isolation · Acid hydrolysis · Biocompatibility · Drug delivery · Food packaging application Abbreviations
3D AFM Ag NPs BMDC CMCs CNCs CNWs CPL CTAB DMSO EDS F-CNCs FTIR H2SO4 KHz NaOH PLLA PMMA PSt PVA STAC TEM TEMPO TGA UV-visible spectra XRD
Three-dimensional Atomic force microscopy Silver nanoparticles Bone marrow-derived dendritic cells Cellulose microcrystals Cellulose nanocrystals Cellulose nanowhiskers Circular polarized luminescence Cetrimonium bromide Dimethyl sulfoxide Energy-dispersive X-ray spectroscopy Functionalized CNCs Fourier transform infrared Sulfuric acid Kilohertz Sodium hydroxide Polylactic acid Poly(methyl methacrylate) Polystyrene Polyvinyl alcohol Stearyltrimethylammonium chloride Transmission electron microscopy 2,2,6,6-tetramethylpiperidine-1-oxyl radical Thermogravimetric analysis Ultraviolet-visible spectra X-ray diffraction spectra
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Introduction
Cellulose is an abundant natural polymer which is considered as crucial, inexhaustible renewable source for meeting the ever-increasing demand for green and biocompatible multifunctional products. Cellulose nanocrystals (CNCs) are the crystalline nanostructures extracted/isolated from cellulose, receiving tremendous attention from researchers across the various fields, owing to their exceptional properties. CNCs are needle-shaped or rodlike nanostructures referred to as cellulose nanowhiskers (CNWs) [1]. The primary cellulose sources like hardwood pulp, softwood pulp, microcrystalline cellulose, sisal, cotton, wheat straw, rice straw bacterial cellulose, algae, banana fibers, sugar, etc. are used for the extraction of CNCs. CNCs are extracted by top-down approaches using physical, chemical, and enzymatic processes [2]. The surface functionalization of CNCs broadens the scope of their applications. CNCs are easier to functionalize, and various techniques and protocols are established for the same. CNCs are known for their exceptional properties like high surface area, mechanical strength, thermal stability, and optical and rheological properties involving liquid crystalline nature [3]. The self-assembly property and alignment of nanofibers in a helical manner mimicking the lobster cuticle arrangement are a few of the unique characteristics of CNCs [4]. The characteristic Bouligand arcs, the helical structure found when dried, enhance the mechanical and optical properties of CNCs [5, 6]. The crystalline nanostructures possess and impart various biophysical characteristics such as biocompatibility, biodegradability, adaptable surface chemistry, tunable functionality, lightweight, high mechanical strength, improved thermal properties, etc., which makes them greatly interesting. Functional materials are in great demand as they enable the development of novel materials with enhanced properties for synergistic benefits. CNCs are functional materials of natural origin that can be functionalized to tune their applications in various fields. Over the past few years, researchers have extensively focused on developing techniques for the extraction and functionalization of CNCs, resulting in the development of advanced and novel nanocomposites and hybrid materials for applications in the fields of energy, electronics, sensing, catalysis, drug delivery, biomedical engineering, etc. [7]. This book chapter comprehensively discusses the sources and synthesis techniques of CNCs. CNCs can be extracted using physical, chemical, or biological processes. In this chapter, various steps involved in the synthesis and one of each process have been discussed in detail, emphasizing on the size, morphology, yield, and crystallinity of CNCs extracted using different techniques. Functionalization of CNCs and the three possible routes of surface modification/functionalization, i.e., via synthesis, adsorption, and chemical modification, are discussed in detail. The confirmation of the functionalization and its effect on the different properties of CNCs is discussed in detail. The properties of CNCs are classified as functional and biological properties basing on their application. The functional properties of CNCs discussed in this chapter include the mechanical, thermal, optical, and rheological
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properties, while biological properties include biocompatibility, immune response, genotoxicity, and biodegradability. The CNCs developed using different methods with unique properties were explored for their application in a variety of fields. The last section of this chapter emphasizes the applications of the CNCs and composite materials in drug delivery, food packaging, tissue engineering, liquid crystalline devices, etc. The application of CNCs as bio-ink for 3D printing has also been discussed. Other applications include catalysis, sensing, and antimicrobial activity. This book chapter introduces the cellulose nanocrystals, various sources from which CNCs can be extracted, and different processes to isolate them. The different approaches and their effect on the size and morphology of CNCs, varying with the type of application, give the reader an insight into the available techniques and their suitability for the application. The different types of functionalization techniques of CNCs, both simpler and complex, show the possibility of achieving the desired functionalization for respective applications. The properties of CNCs and their application in different fields show the potential of CNCs, which can be harnessed by the processing of precursor materials abundant in nature. This chapter will serve as a beginner’s guide to explore the possibility of applying CNCs in diverse fields.
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Structure, Morphology, and Properties of Cellulose Nanocrystals
Cellulose nanocrystals are the crystalline structures extracted from cellulose, obtained from various natural sources. CNCs are usually rodlike or whisker-shaped structures with various unique properties like high tensile strength, high stiffness, thermal stability, liquid crystalline behavior, etc. The structure, different morphologies, and properties of CNCs are discussed in this chapter.
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Structure and Morphology of CNCs
The structure and morphology of CNC depend on various factors such as the cellulose sources and their synthesis procedures and surface functionalization [8–10]. The effect of each of these parameters on the morphologies of CNCs is discussed below. The structure and morphology of the CNCs play a crucial role in determining the properties and applications of CNCs. Hence it is important to understand the structure and morphology of CNCs and the various parameters that affect them.
2.1.1
Effect of Sources and Processing Techniques on Structure and Morphology of CNCs A significant variation in morphology of CNCs could be attributed to the cellulose sources and processing techniques [11]. The differences in the size and shape of CNCs obtained from a) different sources using a single isolation technique and b) a single source by different extraction procedures are discussed below. The size and aspect ratio strongly depends on the cellulose source and the processing
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technique as a combination of each source/process results in CNCs with distinct characteristics. The cellulose source is one of the major factors deciding the morphology and size of the nanocrystals. The various sources (bacteria, tunicates, and wood) were subjected to acid hydrolysis using sulfuric acid, and the structural differences in the CNCs were understood by transmission electron microscopy (TEM) [9]. The CNCs obtained from bacteria, tunicate, and wood are shown in Fig. 1a (i), (ii), and (iii), respectively. The CNCs extracted from bacteria, tunicate, and wood show pronounced morphological differences. The bacterial CNCs (Fig. 1a (i)) seem to be bundled or aggregated, while the CNCs extracted from tunicates appear more individualized. The bundling of the bacterial CNCs could be attributed to the electrostatic attraction of the nanofibers. Close packing or bundling was also observed with the wood-derived CNCs. The effect of the isolation/extraction technique on the morphology of CNCs was also studied using wood pulp as a cellulose source. Wood pulp was processed by enzymatic hydrolysis, mechanical refinement, sulfuric acid hydrolysis, and TEMPO-mediated oxidation. AFM imaging was employed to observe the range of morphologies of CNCs. Wood pulp subjected to enzyme hydrolysis resulted in a network of nanofibrils (Fig. 1b (i)). At the same time, mechanical refinement yielded the largest nanofibers of all the compared cellulose samples (Fig. 1b (ii)). Sulfuric acid hydrolysis produced short rodlike bundled CNCs (Fig. 1b (iii)), while TEMPO-mediated oxidation resulted in thin nanofibers (Fig. 1b (iv)) [9]. The source of cellulose and the isolation/extraction technique significantly impact the structure and morphology of CNCs. Acid hydrolysis is one of the most common procedures used for the isolation of CNCs. The effect of hydrolysis time is another important parameter whose effect on the structure and morphology of CNCs is discussed below.
a
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Fig. 1 A. TEM imaging of CNCs extracted from different sources: (i) bacteria, (ii) tunicate, and (iii) wood using acid hydrolysis. B. AFM topography imaging of CNCs extracted from wood by different methods: (i) enzymatic, (ii) mechanical refinement, (iii) acid hydrolysis, and (iv) TEMPO oxidation. Reprinted with permission from ACS publications (Sauci et al.) Ref [9]
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2.1.2 Effect of Hydrolysis Time on Structure and Morphology of CNCs The morphology of CNCs is also affected by the type of acid used for hydrolysis and reaction time. The strength of the acid used and medium’s ionic strength also influence the morphology of CNCs formed [8]. Kassab et al. reported that hydrolysis time has a direct effect on the geometric dimensions of CNCs. The structure and morphology of CNCs extracted by subjecting sunflower oil cake to acid hydrolysis for 15 and 30 min were observed by TEM imaging. The CNCs showed needlelike morphology with average dimensions (length/width) of 9 3/354 101 and 5 2/ 329 98 nm for CNCs extracted at 15 min and 30 min, respectively [12]. The TEM micrographs of CNCs extracted by subjecting microfibrillated cellulose to acid hydrolysis for 1, 2, and 4 h were studied by Li et al. The CNCs were needlelike structures, and the average dimensions (length/width) of the CNCs obtained after acid hydrolysis for 1, 2, and 4 h were 471.25 150.12/ 8.56 6.44, 346.51 90.64/7.08 5.21, and 228.36 63.78/6.05 3.53 nm, respectively. The aspect ratios of CNCs were 55.05 20.37, 48.94 17.52, and 37.75 15.17, respectively, indicating a decreasing trend with an increase in the hydrolysis time from 1 to 4 h. In addition to the width and lengths of CNCs, the polydispersity has also reduced with the hydrolysis time achieving a more uniform dimension with hydrolysis time [13]. The hydrolysis time decides the dimensions of the CNCs, affecting their aspect ratio and polydispersity. In addition to the hydrolysis time, the functionalization of CNCs is another factor that can affect the structure of CNCs. 2.1.3
Effect of Surface Functionalization on Structure and Morphology of CNCs Pourmoazzen et al. reported the subsequent changes in CNC fiber morphology following the surface functionalization with cholesterol [14]. The SEM and TEM imaging of unmodified and modified CNCs (by cholesterol) showed a difference in their assembly due to hydrophobicity which further affects the properties of CNCs. The unmodified CNCs were rodlike structures that tended to self-assemble exhibiting a broad size distribution similar to spherical CNC structures with a fiber-like structure. Meanwhile, the modified CNCs partially attached to each other, self-organized into a fluffy foam, and exhibited a porous network structure. Surface modification with cholesterol was also reported to prevent particle aggregation significantly. Lin et al. investigated the effect of the sulfation (surface functionalization by sulfating agent) on morphology, dimensions, and physical properties of CNC samples. The unmodified CNCs were rodlike or needlelike structures, with a length ranging between 100 and 300 nm and width ranging between 10 and 30 nm. The modified CNCs were observed to be more homogeneous, due to the enhanced electrostatic repulsion in aqueous suspension [15]. The various parameters affecting the structure and morphology of CNCs have been discussed in detail in the above sections. CNCs extracted from multiple sources are usually rod-shaped with dimensions varying with respect to sources and experimental conditions. The following section discusses the other possible morphologies of CNCs in addition to their rodlike structures.
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2.1.4
Various Morphologies of CNCs: Rods, Spheres, Network, and Core-Shell Structures Cellulose nanocrystals extracted from cotton cellulose by acid hydrolysis followed by freeze-drying showed different morphologies: rods, spheres, and gel networks [16]. Acid hydrolysis of cellulose at 45oC resulted in crystalline cellulose products in three different morphologies: rods (Fig. 2a), spheres (Fig. 2b), and porous network (Fig. 2c and d). The spherical structures were most abundant, while the porous network was in the least quantity compared to others. These structures could not be separated using centrifugation or filtration. The dimensions of rodlike crystalline structures observed from TEM images were width of 1000
shows the sources of some different nanocelluloses with their properties and specific dimension ranges [13]. According to microscopic studies, the elementary fibrils fundamentally form the basic structure of plant cellulosic material. Fibrils produce hierarchical microfibrils which are arranged in the plants’ cell wall structure. Wood microfibrils have a crystalline and noncrystalline area that, under harsh acidic treatment, the amorphous region is solved or destroyed and CNF is released. Mechanical fibrillation as an industrial approach for CNF separation has multisteps such as homogenization, microfluidization, or ultrafine grinding. In addition, based on the cellulosic biomass sources, different pretreatments like biological treatment (enzymes) and chemical and mechanical treatment are applied. Pretreatment processes normally decrease energy consumption and enhance CNF quality [8].
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Different Techniques for CNF Synthesis
According to the production of the nanomaterials, nanocellulose is produced in two different methods. Spherical cellulose nanoparticles (SCNPs), nanocellulose fibers (CNFs), and nanocellulose crystals (CNCs) were provided in bottom-up approach, and bacterial nanocellulose (BNC) was made by top-down way through microorganism synthesis. Some bacteria like Acetobacter xylinum are able to consume culture medium nutrition and secrete ribbonlike fibrils that have nanometer diameter and specific crystalline structure in the medium [15]. The production routes for several nanocellulose types (CNF and CNC) are schematically shown in Fig. 2. In essence, CNFs contain separated microfibrils from the plant cell wall. Their preparation involves breaking down the complex fiber matrix by chemical and mechanical treatments. If true individualization results, the width of CNFs depends on the botanical source and corresponds to the width of the microfibril in the original plant. As such, the cellulose nanofibers (CNFs) with appropriate length, flexible structure, nanosize width (less than 100 nm), high surface area, thermal dimension stability, and good mechanical properties have been applied in several industrial usages. Wood-based CNFs have a typical diameter of 10 nm to 30 nm. CNFs have both a crystalline and an amorphous region. Each
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Fig. 2 Overview for processing routes for several nanocellulose morphologies, including cellulose nanofibrils (CNFs), cellulose nanocrystals (CNCs), and bacterial cellulose (BC) [8]
microfibril consists of a crystalline domain intermixed with disordered amorphous regions [5, 6]. The acid treatment of CNF causes the hydrolysis of wood amorphous regions due to a lower amount of microfibrils and orientation. Acid mixing affected the wood structure through dissolution of the noncrystalline parts, and after centrifugation and ultrasonication, a rodlike shape material was obtained. In this way, these cellulosic fibers lose their amorphous parts in contact with sulfuric acid and hydrochloric acid. These rodlike crystals have a low aspect ratio and are generally referred to as cellulose nanowhiskers (CNW) or cellulose nanocrystals (CNC) [16]. CNCs are rod-shaped crystals and have less flexibility than nanofibers. The properties of nanocrystals are governed by the type of acid used and protected the temperature and the time of hydrolysis. The CNC is usually produced with a diameter of less than 50 nm and a length of 200–500 nm [18]. In addition, the kind of acid affects surface
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Table 2 The effect of carboxyl concentration introduced by TEMPO-oxidation as a pretreatment during mechanical production of CNF [20]
Sample CNF-2 CNF-3 CNF-4 CNF-5 CNF-6 CNF-8 CNF-10 CNF-15
Yield of fibrillation (%) 90.02 0.3 91.27 0.5 92.53 0.3 93.01 0.2 94.87 0.4 97.03 0.3 97.69 0.1 98.88 0.4
Transmittance at 600 nm (%) 59 66 68 70 76 78 80 83
Water retention value (g/g) 3.9 0.3 4.8 0.5 6.8 0.2 8.2 0.3 8.4 0.1 9.3 0.4 10.8 0.2 11.4 0.4
Specific surface (m2/g) 172.4 149.5 180.2 172.4 220.6 231.3 285.9 317.0
Diameter (nm) 14.50 16.72 13.87 14.50 11.33 10.81 8.75 7.89
functionality, and it is possible to make some functional groups on the nanocrystal surface through acid treatment. For instance, sulfuric acid provides a sulfate group, and clorhidric acid creates a single bond hydroxyl group on cellulose nanocrystal surface [17]. For the first time, CNF was discovered by Turbak et al. in 1983 who made nanocellulose through homogenizing of soft wood past. Due to the presence of high tension in this method, obtained CNFs had lower thermal stability and mechanical strength rather than the new methods [19]. Recently several preparation methods have been tested for increasing the efficiency of nanocellulose production from fibers. For this matter, fibers in two ways (soluble or commercial pulp) were prepared, and through the specific mechanical treatments, special nanocellulose fibers with width range around 80–90 nm were obtained. Other than the kind of mechanical processes and types of raw materials, the carbohydrate structure has a significant effect on nanocellulose size variation [19]. As a pretreatment for mechanical fibrillation, Serra investigated the effect of the catalyst amount in TEMPO-oxidized CNF on properties. Table 2 shows the relation between carboxyl content and physical properties. As it can be seen, increasing the carboxyl groups enhances the fibrillation, water retention, and specific surface in CNF [20].
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Processes for CNF Extraction from Plant Resources
Plants are made of cellulose, lignin, pectin, hemicellulose, pigments, or other extra materials. Cellulose chains are arranged in microfibrils or bundles of polysaccharides that are arranged in fibrils (bundles of microfibrils), which in turn make up the plant cell wall. This arrangement not only aids in the stability of plant structures but also suggests that cellulose is a biomaterial with high strength and other superior mechanical properties. The wood microfibrils have a crystalline and noncrystalline
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area, where under the harsh acidic treatment, the amorphous region is dissolved or destroyed and CNF is released. The extraction process of CNF nanocellulose has generally three steps consisting of pretreatment, extraction, and purification [21]. Mechanical fibrillation as an industrial approach for CNF separation can be performed according to different techniques such as homogenization, microfluidization, or ultrafine grinding [22]. In addition, based on the cellulosic biomass sources, different pretreatment like biological treatment (enzymes) and chemical and mechanical treatment is applied [22]. Pretreatment processes normally decrease energy consumption and enhance CNF quality [8].
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Alkali and Acid-Chlorite Pretreatment of Cellulose Extraction
Pretreatment is one of the most important parts of CNF extraction as it facilitates the other steps of the process. Nanocellulose extraction is a multistep process which depending on the methods, resulted in different types of CNFs. Lignocellulosic biomass is composed of other extra materials like lignin and hemicellulose, and the removal of these components is necessary for obtaining high-quality CNFs. So normally through one of the alkali or acid-chlorite treatments, cellulose macromolecule is separated from other ingredients [21]. Besides, one of the most important raw material which applies to CNF separation is the agricultural waste and residues that are cheaper and more economical than other resources [24]. Preliminary alkaline treatment using NaOH or KOH is typically used to remove extra components such as lignin. Alkaline pretreatment helps solubilize and extract lignin from the lignocellulosic materials by affecting the acetyl group in hemicellulose and linkages of lignin-carbohydrate ester. This treatment does not disturb the lignin aromatic structure significantly [7, 8]. Then neutralization and separation of pure cellulose were completed by filtration and rinsing. For instance, rice straw waste has suitable potential for CNF production by this method. Rice straw waste is treated with caustic soda in different conditions (concentration, 8–16%; temperature, 90–160 C; time, 1–2 h) to eliminate extra components, and the raw material is prepared for cellulose separation [25]. The separation of pure cellulose from other components through the acid-chlorite treatment is called bleaching or delignification which is not similar to the normal bleaching process for cellulosic textiles. To obtain a suitable result, lignocellulosic biomaterial was added to a mixture of glacial acetic acid, hot distilled water, and sodium chlorite stirring for 4 h [26]. After reaching pH ¼ 7 and removing lignin, rinsing with distilled water is necessary. Also for “holocellulose” production, whitecolored residues should be dried at ambient or higher temperatures [27]. Recently, Wengang Yang and coworkers prepared CNFs with an average diameter of 8 nm isolated from corncobs using a stepwise method that included steam-explosion pretreatment, alkaline treatment, sodium hypochlorite bleaching, high-speed blending, and ultrasonic treatment. The alkaline treatment and hypochlorite bleaching were used to remove noncellulosic components in particular lignin.
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Micro- and Nanofibrillation of Cellulose
Plant celluloses have a specific internal matrix that is made of cellulose fibers and several components like lignin and hemicellulose in which the outer layer of cellulose fibers contains cellulosic microfibrils. The MFC can be extracted from the fibers using different treatments to create a weblike structure called micro- or nanofibrillated cellulose (MFC/NFC). MFC is a type of hydrophilic cellulose that has a high water-holding capacity and produces gel by forming hydrogen bonds. Although the hydrophilic property is one of the significant advantages of MFC in some applications such as paper production, it is a disadvantage in other usages [28]. The MFCs normally are generated using various methods such as mechanical, chemical, and biological methods, and sometimes the combination of these approaches is applied. Nowadays, the main source of MFCs is wood pulp, and also other sources such as non-wood plants and bacterial cellulose are studied by researchers [29]. Several morphologies of the CNF compared to cellulose microfibers (pulp fibers) and other types of nanocelluloses (cellulose nanocrystals and bacterial cellulose) are shown in Fig. 3. Mechanical fibrillation equipment can be used by applying mechanical pressure and creating pure shear force such as mill, homogenizer, and microfluidizer [33]. Owing to high-energy consumption and other limitations of mechanical methods [34], chemical and biological methods like enzymatic hydrolysis have been used to produce cellulose nanofibers [35]. Due to the adverse effects of chemical methods on the production system, biological treatment is considered to achieve the goal. Low enzyme consumption, the high selectivity of enzymes, and the existence of the green process for nanofiber extraction provide the enzymatic approaches more practical methods [36]. Recently, several types of enzymatic pretreatments were applied to improve the performance of cellulose nanofiber extraction. According to the advantages of enzymatic treatment, several types of these biological materials have been investigated for nanocellulose production [37]. Some enzymes like endoglucanase (EG) can act on the amorphous area of carbohydrate networks and disrupt the communication of β-1,4 cells. Other enzyme types such as hemicellulose, lacquer, and lytic polysaccharide monooxygenase (LPMO) with different performance selectively remove hemicellulose and lignin from the plant cellulose to provide pure cellulose for medical and biomedical application [38]. Also, it was reported that the blend of cellulases and xylanases has a synergistic effect on the reserve of the crystalline structure of cellulose in the purification process [39] or the use of endoglucanase decreases the fiber diameter and produces finer fibers [40]. Through mechanically processing cellulose fibers, nanocellulosic fiber can be isolated through various mechanical approaches like ball milling, ultrasonication, as well as high-pressure homogenization, which is the most represented in the studies. Nevertheless, such processes have the main drawbacks of requiring high-energy inputs. Thus, it is incorporated normally with some primary pretreating processes to reduce energy consumption [41].
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Fig. 3 Various shapes of nanocellulose fiber. (a) SEM of CNFs [30], (b) TEM of CNCs [31], and (c) SEM of BC [32]
The approaches of nanocellulose extraction include the increasing research concerns regarding several laboratory-scale investigations reported in the last 10 years. There are also some pilot-scale reports at the industrial level for producing nanocellulose. Inventia, Sweden, in 2011 set up the first pilot plant for producing nanocellulose; however, its production units are oriented by the United States, Europe, Canada, and Asia such as Japan, China, India, and Iran. Mechanical process and acid hydrolysis are, respectively, the most adopted approaches in industries for isolating nanocellulose fibers and nanocellulose crystals. These extraction methods were successfully practiced in the lab for several decades before commercializing the production of nanocellulose on an industrial scale. However, the main concerns include the high cost of chemicals and products, the maintenance costs of tools acted in acidic situations, environmental administration of acid wastewater effluent created from the procedures like acid hydrolysis technique, as well as high-energy use for the mechanical treatment procedures [42].
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Acid Hydrolysis Synthesis
The nanocrystalline cellulose or cellulose nanocrystals (NCC or CNCs) are extracted by removing the noncrystalline sections involved between amorphous areas in cellulosic microfibrils via acid hydrolysis. Different types of acids such as sulfuric acid, hydrochloric acid, formic acid, acetic acid, and phosphoric acid were used to disperse nanocrystalline cellulose, and among the acids, sulfuric acid is the most popular chemical for this purpose. After acid treatment and crushing, posttreatments like centrifugation and neutralization with alkaline chemicals were applied to separate crystalline cellulose. Then rinsing with distilled water is necessary to remove extra chemicals and remain pure nanocrystalline cellulose suspension. Based on the research, reaction time, temperature, and amount of acid are the most important factors that affect the extracted nanocellulose properties [43]. Although this method is a routine approach to obtain nanocrystalline cellulose, there is some consideration for environmental pollution with acidic wastewater. CNFs can be obtained by acid hydrolysis of sugarcane by 60% sulfuric acid at 40 C for 10 min. The exact size, dimensions, and crystallinity of these nanofibers are dependent upon the acid hydrolysis conditions and source of cellulose employed.
3.5
Enzymatic Hydrolysis
One of the most important techniques for cellulose modification is enzymatic treatment. This biological approach through a complicated process can digest cellulosic fibrils and produce a soft surface for cellulosic materials. Among the different kinds of enzymes, cellulase, endoglucanase, and cellobiohydrolase are the most applicable enzyme for washed cellulose [44]. During the enzymatic hydrolysis, the enzymes cleave the glycosidic chains in cellulose, diminishing fiber size without modifying the crystalline structure of the polysaccharide. Obtained results from different researches showed that cellulases and hemicellulases have a synergic effect on lignocellulosic material hydrolysis and perform under the mild conditions against the acid hydrolysis method [45]. Besides, it was reported that the pretreatment of wood chips with ionic liquid and the use of laccase for enzymatic hydrolysis provide specific nanocellulose that has higher crystallinity and thermal stability in comparison with nanocellulose extracted from native wood [45]. Figure 4 shows different steps of enzymatic hydrolysis for nanocellulose and nanocrystalline cellulose production.
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Electrospinning of Cellulose Nanofibers
Electrospinning is a multipurpose method with simple equipment for nanofiber production, and the fiber diameter can be controlled by adjusting the parameters affecting the process. It is worth noting that electrospun fibers are long, continuous, and very uniform [47]. To produce electrospun cellulose nanofibers (ECNF), the
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Hemicellulose Cellulose Lignocellulosic Biomass Lignin (A) Pretreatments
Secondary cell wall
(cellulose extraction)
amorphous region
Cellulose molecules
Nanofibrils crystalline region (B) Controlled enzymatic hydrolysis Microfibrils
(mainly endoglucanases)
Cellulose fibril
(C) Mechanical treatment Cellulose nanofibers
D: 8000), high crystallinity (80–90%), excellent tensile strength (2 GPa), greater Young’s modulus degree (138 GPa), high water-holding capacity, ultrafine network structure, thermal resistance, durability, stability, nontoxicity, hydrophilicity, biodegradability, and rheological properties [9]. Gluconacetobacter xylinus is the most studied bacteria due to its high ability to produce many BC under optimized conditions [10]. Moreover, the metabolic pathway of bacterial cellulose nanofibers is related to the cell growth and the genomic expression, involving multiple activator and regulator enzymes; it has been shown that bacterial cellulose is synthesized in the cytoplasm of the cell and then spun out via membrane pore to crystallize into nanofibers [11]. The production process was explained by the cell’s need to protect itself from external agents, like toxins, pathogenic bacteria, molds, and ultraviolet radiation [12]. However, BC presents as a material to maintain the cell in the liquid-air interface while storing and adsorbing nutrients [13]. So far, bacterial cellulose undergoes several functional methods such as mechanical, chemical, or biosynthetic processes to enhance their properties for industrial and medical applications [11]. Therefore, BC nanofibers’ active functional hydroxyl groups make them very biocompatible for healthy interactions with different materials [14]. This knowledge may lead to high productivity and low-cost fabrication. Due to the impressive properties like high functionalization capacity and high surface area, BC was successfully used as an excellent adsorbent or membrane biosorbent in wastewater/water treatment. The modified BC revealed high efficiency in heavy metals, dye, organic pollutants, and numerous other contaminants treatment [15]. More researchers recently investigated the application of BC in the biomedical field as an alternative to classic biomaterials. Its biocompatibility, biodegradability, nanoscale 3D network, and strength properties demonstrated promising results in tissue engineering and natural scaffold by enhancing cellular adhesion and proliferation [16]. It also exhibits a better wound healing ability, skin care, vascular grafts, and dental implants by maintaining a moist environment and protecting from inflammations [17]. However, drug delivery, immobilization enzymes, and bioactive compounds are also applied either by coating or by impregnating bacterial cellulose nanofibers [18]. Furthermore, BC demonstrates new features as antimicrobial and antioxidant material, highly used in food storage and packaging industries [19]. In addition, BC are mainly reviewed as electromagnetic sensor devices due to their optical, electrical, and magnetic properties [20, 21]. Many more studies have investigated the implication of nanostructured material to explore the feasibility of reinforced green nanomaterials. Thus, this chapter aims to describe the importance of bacterial cellulose nanofibers by discussing the biosynthetic pathway, properties, and optimized production and providing an overview of its current applications.
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Structure and Unique Properties
Adrian Brown was the first to describe a jelly mass covering the fermented medium’s surface, which was later identified as cellulose produced by Acetobacter xylinum [1, 4]. Later studies have identified several other strains capable of producing BC, such as Acetobacter pasteurianum, Acetobacter rancens, Acetobacter hansenii, Agrobacterium, Alcaligenes, Aerobacter, Achromobacter, Azotobacter, Bacterium xylinoides, Enterobacter, Escherichia, Klebsiella, Pseudomonas, Rhizobium, Salmonella, and Sarcina ventriculi (Fig. 1) [3, 22]. These microorganisms belonging to Gram-negative or Gram-positive bacteria are recognized as aerobic, rod-shaped, and nonspore-forming and characterized by lack of flagellation [22]. Agrobacterium tumefaciens and Rhizobium using saccharides as carbon source showed an intrinsic
a
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Fig. 1 Celluloses joined by (1–4) glycosidic connections, with β-D glucopyranose units. Different bacterial genus’s generated microbial cellulose as depicted from the scanning electron micrograph (SEM) of S. enterica (a and b), G. xylinus (c and d), and D. dadantii (e and f). The lower panel depicts the six-membered cyclical structures with minimal conforming and reactive roles as primary and secondary alcohol are the main chemical features for this structure and an acetal group. Copyright 2011. Microbiology Society [26]
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production of cellulose nanofibers with a diameter of 5 nm. However, the production of cellulose nanofibers is insufficient and restricted on low volume [5]. Currently, the Acetobacter sp., specifically Gluconacetobacter xylinus (Komagataeibacter xylinus), has been known as one of the most efficient cellulose nanofiber producers [23]. This aerobic alpha-proteobacteria strain is a member of the acetic acid bacteria, with fascinating properties like non-photosynthetic features that can oxidize sugars and ethanol to cellulose and acetic acid. Therefore, G. xylinus has a genome consisting of 3193 genes without gaps; four genes are responsible for bacterial cellulose synthesis and genes for pentose phosphate, glycolytic, and other metabolic pathways [11]. It was demonstrated that the production of cellulose nanofibers by G. xylinus is enhanced through the following conditions: pH (5–6.5), temperature (25–30 C), aeration and agitation, and carbon and nitrogen sources. G. xylinus cells produced extracellular cellulose nanofibers perpendicularly to the bacterial axis with high density and a standard width of 24 nm [24]. Most frequently, the production of BC was assumed as an alternative way of biofilm to protect G. xylinus against radiations and toxic compounds [10, 25]. Like G. xylinus, new bacteria were found to be promising for cellulose nanofiber production, such as Asaia bogorensis, Enterobacter CJF, and Dickeya dadantii 3937. The nanofiber morphology of the synthesized cellulose from Dickeya dadantii 3937 is homolog in diameter, branching pattern, and bead-like structures to accumulate secondary metabolites [26]. As shown in Fig. 1, significant differences in cellulose structure exists among three bacterial species: (Fig. 1a, b) S. enterica formed a highly branched cellulose matrix where it is completely trapped within it, (Fig. 1c, d) G. xylinus dispersed within thick fibers of produced cellulose, and (Fig. 1e, f) D. dadantii had same thick fibers as G. xylinus with fewer branch strands. The BC consists of high homopolymerization with 4000 to 10,000 glucose units bonded through (β-1!4) glycosidic linkages [27]. The thickness and the waterholding capacity of BC are a hundred times thinner and more water-retaining than the regular cellulose [17]. The shape, the high crystallinity (80–90%), and the development of numerous inter-/intramolecular hydrogen bonds of BC give better mechanical and interfacial properties [28]. However, the BC is pure (without hemicellulose and lignin) and more stable than plant cellulose [3]. Its mechanical strength also characterizes its high tensile strength, high crystallinity, and remarkable durability [29]. It also presents a high dynamic fiber-forming, high lightweight, selective porosity, resistance to thermal degradation, small size, and the capability to control physical properties during modifications [27]. Along with these properties, Table 1 shows the excellent biological affinity, biocompatibility, and biodegradability offered by BC.
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Biosynthesis Mechanism
It is costly to manufacture BC in synthetic media with various carbon sources and increasing factors that are typically added to yeast extract and peptone. The researchers are, therefore, finding cheap high-sugar raw materials as substrates for
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Table 1 Summary of the unique properties of BC and their biomedical applications, utilizing BC’s unique properties BC’s unique properties Biodegradability
Biocompatibility in contact with living tissues Ease functionalization with different polymers
High chemical stability
High mechanical strength
High stability against gamma radiations and steam Hight wet strength
Applications Biomedical applications of BC as scaffolds would degrade to safe components in the human body after the construction of an extracellular matrix reached Properties suited for the processing of wound implants, face shields, cellulose-based diapers, wound dressings, and drug delivery systems Improve barrier properties, mechanical character, moisture absorption, oil absorption, and antimicrobial characteristics with BNC working which is easily achievable for different applications Biopharmaceutical packaging materials. It is also the wrapping that avoids any chemical reaction between the paper and the substance BC is extremely highly mechanical for several load-bearing components, such as bone tissue implants, for different applications Effective gamma sterilization or steam; helpful for sterile equipment packaging Especially for the marking of labels on clinical samples, including blood, that has to remain active because samples are often injected into deep freezers at low temperatures
Copyright 2019. Elsevier BV [29]
the processing of BC. In this context, many raw materials for BC processing have been studied such as coffee remnant, extracted from fruit peeling and tobacco surplus, sugar beet molasses, whey protein mediums, industrial distillation waste, maize profound alcohol, fruit juice, maize stems, litchi, maize acid hydrolysate, and waste brew fermentation [30–37]. The method allows the use of raw material for BC processing of surplus in beverage, biorefinery, fiber, olive, and biomass factories. The findings revealed that the carbon source used affects BC characteristics: water retention efficiency (67–96%), the crystallite size (5.7–6.4 nm), and inherent viscosity, oxygen, and water vapor diffusion concentrations [38]. Various technical methods can be used to increase BC production and manufacture cellulose with desirable characteristics (Table 2).
3.1
Factors Affecting the BC Biosynthesis Process
We need a significant and stable bacterial strain with insufficient growing requirements and a capacity to easily be scaled to industrial settings to manufacture efficient bacterial cellulose (BC). Generally, the cellulose generated is readily extracted by using various methods for different medically essential applications. All these aspects (Fig. 2) will be discussed in this chapter. A typical culture medium consists of balanced components to ensure optimal strain growth with high-value products.
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Table 2 Major characteristics of bacterial cellulose (BC) produced under different technological approaches Method for BC production Static production
Production in shaking culture
Production in an airlift bioreactor Production in rotating disc bioreactors Production in trickling bed reactor
Procedure characteristics The process is used most extensively in the laboratory. The step involves up to 2 weeks to complete. The hydrogel layer is formed from cellulose Increased supply of bacteria with oxygen. It could contribute to lower bacterial genetic stability and lower development of BC. Cellulose production of various particle sizes and types (mainly of spherical structure). Convenient for development on economic size Low power supply with an adequate supply of oxygen. The pellet contains cellulose Homogeneous cellulose development. The yield of cellulose is compared to static The concentration of oxygen and reduced shear strength are high. Manufacture BC as odd sheets
References [39]
[22, 40]
[22, 41] [42] [43]
Copyright 2019. MDPI [38]
Fig. 2 Schematic representation of BC’s vital aspects and its potential use in the biomedical field. The bacterial cellulose production depending on the used strain, different carbon sources, static or agitated conditions, and versatile in situ and ex situ methods applied in BC modification. Copyright 2019. MDPI [38]
The bioprocess parameters for BC’s fermentative production depend mainly on the selected bacteria, carbon source, temperature, reactor design, pH, static or agitated systems, and O2 and CO2 availability [44]. As mentioned above, Gluconacetobacter xylinus is recognized as the perfect suitable bacteria for CNF production. This strain revealed high stability in largescale production and fascinating productivity of cellulose nanofibers (Fig. 3)
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Fig. 3 Key factors in the development of bacterial cellulose: (a) the species of bacteria, (b) the source of carbon, (c) different medium conditions, and (d) other medium conditions for culture. The fermentation is static and active in order to achieve different 3D forms. Copyright 2020. Springer [50]
[45]. The production of cellulose nanofibers by G. xylinus is highly influenced by the pH, temperature, and source of carbon. Studies on the buffering system showed that the optimal pH for cellulose nanofiber production ranges from 5 to 7 [46]. During cell growth, significant amounts of organic acid are released, leading to the medium’s acidification (pH ¼ 4), which inhibits the metabolic pathway of cellulose nanofiber formation [38]. The pH shifting to the range of cellulose nanofiber productivity has been proved its efficiency by having an optimum productivity at five [47]. However, the carbon source is considered a potent factor for cellulose nanofiber production. Results showed that the use of glucose gives 100% productivity of cellulose nanofibers. However, high amounts of gluconic acid were obtained, which restricts the bioprocess [27]. Also, fructose and glycerol were potent in nanofiber synthesis, with 92% and 93% productivity, respectively [48]. Other organic compounds such as galactose, sucrose, citrate, maltose, ethanol, succinate, and starch showed productivity ranging from 10 to 33% [45, 48]. Consequently, many different media, such as Hestrin-Schramm, Yamanaka, Hassid-Barker, acetate buffered, CSL-fructose, Zhou, etc., revealed high, green, and low-cost cellulose nanofiber productivity (Table 3) [49]. The vitamin C supplement on HS-ascorbic acid medium proved to enhance the BC yield due to its antioxidant activity. The addition of ethanol super optimal broth with catabolite repression (SON) proved to inhibit the G. xylinus growth and BC production. Furthermore, the Hestrin-Schramm
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Table 3 Different chemical medium composition for bacterial cellulose nanofibers production Types of medium HS HAS HB Yamanaka Zhou SONa
Park M1A05P5 SOC5.5 CSL-Frub FM YPD GYB AB MHS Joseph fru-CSS AHS
Composition Citric acid (1.115 g/L), glucose (20 g/L), yeast extract (5 g/L), Na2HPO4 (2.7 g/L) The citric acid (1.115 g/L), vitamin C (5 g/L), glucose (20 g/L), yeast extract (5 g/L) CaSO4 (2 g/l), CaSO4 (2.5 g/l) (2.2 g/l), saccharide (100 g/L), yeast extract (2.5 g/L) Yeast extract (5 g/L), (NH4)2SO4 (5 g/L), KH2PO4 (3 g/L), MgSO47H2O, (0.04 g/L) (0.06 g/L) Glucose (18 g/L), sucrose (21 g/L), (NH4) 2SO4 4 g/L), steep corn liquor (20 g/L) Glucose (15 g/L), ethanol (6 ml/L), (NH4)2SO4 (2.0 g/L), Na2HPO412H2O (3 g/L), MgSO47H2O (0.8 g/L), nicotinamide (0.0005 g/L), glucose (15 g/L), glucose (3 g/L) CH3COOH (10 g/L), glucose (10 g/L), yeast extract (7 g/L), peptone (10 g/L) CH3COOH (1.5 mL/L), ethanol (1.5 ml/L), glucose extract (10 g/L), CH3COOH (1.5 ml/L) NaCL (0.5 g/L), KCL (0.18 g/L), MgCl2 (2.5 g/L), MgSO4 (2.5 g/L), glucose (3.6 g/L), LB (20 g/L) Sweet fructose (40 gL), MgSO4.7H2O (0.25 g/L), FeSO47H2O (0.0026 g/L) CaCl22H2O (14.7 mg/L), fructose (40 g) Meat extract (3 g/L), glucose (15 g/L), NaCl (5 g/L), peptograph (5 g/L) Yeast extract (5 g/L), glucose (20 g/L), peptone (5 g/L) Yeast extract (5 g/L), glucose (20 g/L) yeast Glucose (20–60 g/L), CH3COOH (1.778 g/L), C2H3NaO2 (5.772 g/L), glucose extract (5 g/L), peptone (5 g/L) Citric acid (1.5 g/L), glucose maize (20 g/L), corn steep liquor (10 g/L) MgSO47H2O (0.25 g/L) polyacrylamide co-acrylic acid (10 g/L), fructose (20 g/L), corn steep liquor, NH4/2SO4 (3.3 g/L), KH2PO4 (1 g/L) Citric acid (1.6 g/L), Na3C6H5O72H2O (2.4 g/L), KH2PO4 (1 g/l), Na3C6H5O72H2O (2.5 g/l), Na3C6H5O72H2O (2.4 g/l) Yeast extract (4 g/L), glucose (50 g/L), ethanol (20 g/L), KH2PO4 (2 g/L), MgSO47H2O (0.73 g/L), glucose (50 g/L)
Copyright 2019. Springer [49] Hestrin and Schramm (HS); HS-ascorbic acid (HAS); Hassid-Barker (HB); super optimal broth with catabolite repression (SOC); CSL-fructose (CSL-Fru); fermentation medium (FM); yeast extract-peptone-dextrose (YPD), acetate buffered medium (AB); modified-HS (MHS); fructosecorn steep solid solution (fru-CSS); altered HS (AHS); glucose yeast extract broth (GYB) a Nicotinamide (.00005 g/L), FeSO47H2O (0.005 g/L), H3BO3 (0.003 g/L) b CaCl2 2H2O 14.7 mg, NaMoO4 2H2O, 2.42 mg, ZnSO4 7H2O 1.73 mg, MnSO4 5H2O 1.39 mg, CuSO4 5H2O, 0.05 mg, inositol 2 mg, nicotinic acid 0.4 mg, pyridoxine hydrochloride 0.4 mg, thiamine hydrochloride 0.4 mg, D-pantothenic acid calcium 0.2 mg, riboflavin 0.2 mg, p-aminobenzoic acid 0.2 mg, folic acid 0.2 mg and D-biotin 2 mg
is found to be the most optimized medium for cellulose nanofiber production composed of 2% (w/v) glucose, 0.5% (w/v) peptone, 0.5% (w/v) yeast extract, 0.27% (w/v) Na2HPO4, and 1.15 g/L citric acid. The Hestrin-Schramm medium’s pH was optimum for cellulose nanofiber production by G. xylinus, which formed
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crystalline and nanofibril cellulose [13]. Recently, agro-industrial waste such as molasses-corn steep liquor medium as a source for BC production is considered economical, environmentally friendly, and productive. Moreover, complex nitrogen and vitamin sources play a crucial role in BC’s cellular growth and production. The C/N ratio should be carefully maintained during the process [51]. Studies showed that the replacement of yeast extract and peptones by low-cost by-products like steep corn liquor that contains proteins (45%), lactic acid (26%), and minerals (3%) like Ca2+ activates the BC formation [52]. However, the temperature is one of the critical factors for G. xylinus growth and its metabolic production. The variation of temperature affects the cellulose nanofibers’ structure and properties, where researchers agreed that the optimum temperature ranges between 28 C and 30 C [53, 54]. G. xylinus is also strictly aerobic as oxygen is a crucial factor for forming cellulose nanofibers [55]. Studies have confirmed that high aeration influences the shape and the ramifications of the formed nanofibers, where the best oxygen tension was 10%, without affecting cell growth [56]. However, it has been reported that the presence of carbon dioxide pressure reduced the nanofiber production, cell growth, and metabolic pathways of the G. xylinus [17]. Furthermore, the static and agitated processes also affect the production of cellulose nanofibers. Ruka et al. [13] studied the effect of static and agitated fermentation on the cellulose nanofiber production and cell growth of G. xylinus growing on the Hestrin-Schramm medium. Generally, the agitation showed an increase in bacterial growth compared to the static process. However, the nanofiber’s production decreased due to reducing the need for nanofibers to stabilize cells and favoring microbial growth [13]. Consequently, they reported a structural disorder, low crystallinity, higher water holding, and genetic mutation appearance [56]. In stirred aerated bioreactors, the main problem reported is cellulose nanofibers’ adhesion on walls causing the reduction of nanofiber production [57]. Scientists have designed various processes to optimize BCNF production in static and agitated conditions (Fig. 4). Static conditions have been largely used due to their good maintenance of the morphology and the shape of the BC, while agitated conditions, such as horizontal rotating disc bioreactor [58], bioreactor with spin filters [59], bioreactor with plastic composite supports [60], airlift bioreactor [61], and aerosol bioreactor [62], can form multi-shaped BC with high large-scale productivity and collection. However, it has been shown that immobilizing G. xylinus enhances the nanofiber production 2.5-fold more significantly than the free cells [63]. These methods seem to be suitable for industrial applications in different fields.
3.2
Synthetic Pathway
In G. xylinus, the enzyme cellulose synthase is encoded by the gene “Bcs” operon, containing four subunits: BcsA is recognized as the identifier of cellulose producer
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Fig. 4 Different bioreactor processes for the bacterial cellulose nanofibers production showing the various approaches utilized for the synthesis of nanomaterials from horizontal lift reactor, aerosol bioreactors, and rotary disc reactor with the corresponding generated various nanomaterials geometries. Copyright 2014. Elsevier BV [64]
and responsible for the polymerization of uridine diphosphate glucose (UDPGlc), BcsB is the activator of cellulose synthase via binding with the cyclic di-guanosine monophosphate (c-di-GMP), BcsC controls the formation of cell membrane pore, and BcsD plays the role of crystallization of cellulose into nanofibers the formed cellulose [25]. The bacteria can biosynthesize 50% of cellulose from hexoses, glycerol, dihydroxyacetone, pyruvate, and dicarboxylic acids [37]. As Fig. 5 reveals, 4, glucose-6-phosphate is the primary cellulose biosynthesis medium with phosphoglucomutase isomerized to glucose-1-phosphate [28]. UTP (uridin triphosphate) previous reactions were formed by uridine-50 -phosphate-α-D glucose (UDPGlc) in uridine glucose pyrophosphorylase action [28]. The UDPGlc is the precursor in cellulose formation, which polymerizes into1,4-β-glucan chains and a nascent chain-forming cellulose chain. Finally, the BC form between the cell’s outer and cytoplasmic membranes forming nanofibers shapes with a diameter (2–4 nm) [5]. The cellulose production can be accelerated by inhibiting glucose6-phosphate dehydrogenase through ethanol and acetate additions, while the biosynthesis is controlled by c-di-GMP and signaling molecules of the QS system [11].
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Surface Functionalization
Studies on functionalization or BC modifications have mainly been employed via chemical or mechanical methods, making it more valuable [66]. The mechanical methods are used to elevate the agglomeration of dried cellulose nanofibers by suspending them in an aqueous solution (100 MPa) on bacterial nanocellulose gives excellent nanofibers without chemical treatment and reasonable use in food, pharmacy, and cosmetic industries [68, 69]. Grinding and refining techniques also perform better dispersion of cellulose nanofibers in the paper industry [70]. On the other hand, several chemical methods have been reported to have a low impact on the morphology of BCNFs and the crystal structure, and they are as follows: esterification, oxidation, salinization, and etherification (Fig. 6) [71]. In the meantime, researchers have been established to manufacture usable BC fibers with fluorescence properties by using 6-carboxyfluorescein-modified glucose as a substratum (Fig. 5) [65]. Moreover, the electrospinning method applied high voltage through nanofibers to overcome the surface tension and form a jet solution [72]. Ardila et al. [73] functionalized BC directly blended with chitosan by using electrospinning. The approach leads to fabricate nonwoven mats for wound healing with high antimicrobial activity. In addition, Martínez-Sanz et al. [74] evaluated BC’s preincorporation as a nanocomposite within polyhydroxyalkanoates by electrospinning. The content
Fig. 5 Schematic illustration of the glucose (Glc) labeling with 6CF for the formation of the 6CF-Glc using a microbial in situ fermentation process of carbohydrate modified with a carbon source (6CF) fermented as such ferment. (a) Clusters of Glc and 6CF-Glc moieties, (b) fermentation of the microbe, (c) formation of the 6CF-BC fibers by K. sucrofermentans, (d) 6CF-BC microstructure, (e) 6CF-BC micro-fermented pellicles. Copyright 2019. Nature Communications. [65]
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Fig. 6 General description of the BC chemical changes made by organic and mineral reagent therapy, including oxidation, silanization, esterification, and etherification. Copyright 2017. Elsevier BV. [71]
has high barrier characteristics for applications in food packaging. Moreover, the mechanical and antibacterial properties of BC polycaprolactone/propolis have been strengthened by electrospinning [75]. As the demand for cost-effective techniques, ultrasonication procedure has gained attention because of its alternating low- and high-pressure waves, leading to better fibrillation [69]. The BC was mixed with polyvinyl alcohol gel via ultrasonication, resulting in a biocomposite film with high tensile strength, water impermeability, thermal resistance, and antimicrobial activity [76, 77]. The biocomposites proved their ability to be used in food packaging [77]. The cryo-crushing and steam explosion techniques were also applied to better dispersion and functionalize BC [70, 78]. Furthermore, green nanotechnology has received crucial attention by providing green nanomaterials, which can be used in various fields [79]. The functionalization of BC by cadmium sulfate nanoparticles has been shown the excellent performance as a photocatalyst, novel luminescence, and photoelectron transfer devices [80]. Arias et al. [81] functionalized BC by dispersing iron oxide nanoparticles. The obtained nanocomposite proved to enhance the magnetic properties, leading to fair use in rapid cell recruitment and drug delivery agents. The fabricated BC-based hybrids for nanocomposites revealed an enhancement in mechanical and tensile properties due to higher bond strength [82]. Moreover, Parnsubsakul et al. [83] developed eco-friendly BC functionalized by silver nanoparticles to detect pesticides on fruit surfaces. On the other hand, the modification of BC nanofibers using chimeric proteins containing adhesion peptides has been well studied on human microvascular endothelial cells, where it showed enhancement in their adhesion properties and
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biological activities [84]. Also, enzymatic treatment such as endoglucanases, exoglucanases, cellobiases, etc. has been used to obtain functionalized BC [85, 86]. Chemical pretreatment has shown excellent functionalization via cationization, carboxymethylation, and acidic or basic treatments [87]. Recent studies revealed that carboxymethylation enhances the viscosity and the electrostatic repulsion of BC, resulting in high use as sensor material, surfactant, and packaging films [88, 89]. Moreover, some emerging and posttreatment techniques are also being carried out to functionalize the BC but are limited to organic solvents [53]. BC can act as a stabilizing or reducing agent for the synthesis of nanoparticles. Incorporating BC during nanoparticle synthesis protocols has broadened the possible technical solution to solve many medical and environmental challenging issues. Ifuku et al. [90] synthesized silver nanoparticles on BC’s surface using an ion-exchange reaction, producing silver nanoparticles with controlled size. Similarly, a facile method for synthesizing cobalt ferrite nanotubes with a 9–15 nm diameter uses BC as a reducing agent [91]. Moreover, Arias et al. [81] used BC to synthesize iron oxide nanoparticles with ammonium hydroxide as a catalyst, and the obtained nanoparticles were gathered in the porous sites onto the BC and were measured (20–30 nm). The porous structure of BC makes it useful for the immobilization of enzymes and bioactive compounds. Immobilized urease on BC is highly recommended in several applications [92]. The maximum urease adsorption capacity was determined to be 240 mg g1 at pH 6, while the immobilized urease’s desorption rate was found to be 98.9% without loss of enzyme activity. Another urease immobilization study showed an excellent immobilization at pH 6.5 with high enzyme activity after immobilization (81%) [93]. Moreover, Bayazidi et al. [94] immobilized lysozyme onto BC by using a physical absorption method where it was found that lysosomal activity decreased by about 12% after immobilization. On the other hand, the immobilization of proteins via BC gained attention due to its excellent properties. Heme proteins, such as horseradish peroxidase, hemoglobin, and myoglobin, have been immobilized on the BC nano-refined gold [95]. The nanocomposites showed high biocatalytic activity and biostability of the immobilized proteins. Zheng et al. [96] developed a new material that consists of collagen immobilized within BC, while covalent bonds were enhanced using dialdehyde. Results showed that the composite was bioactive for cell adhesion.
5
Biomedical Applications
Over the past few years, both academia and industry have been drawn by BC scaffolds, and substantial exploration has been underway. BC scaffolds have been reported to be useful in applying wound healing, tissue engineering, medication delivery, reconstruction of artificial blood vessels, etc. Recently, several examination papers have summarized the use of BC scaffolds in biomedicine. However, complex summaries focusing exclusively on recent BC-based composite scaffolding techniques are still restricted for biomedical applications. BC was regarded as a reliable
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Fig. 7 Several BC applications in the biomedical field highlight the major aspects in wound healing and tissue engineering, lens production, tubular implants, and blood vesicle stents. Copyright 2016. Elsevier BV [97]
contender for several medicinal applications for nontoxicity, high purity, and biocompatibility. Many promising biomedical products are recently developed for BC-based composite scaffolds, compounded by other ingredients like nanoparticles or polymers. BC-derived nanomaterials in a range of polymer scaffolds for biomedical applications have also proved promising reinforcing agents. The BC is considered an attractive material for biomedical applications due to its noncytotoxic, non-genotoxic, highest strength, and biocompatibility. Some medical features of BC, including wound healing, drug delivery, bone and cartilage regeneration, etc., are illustrated in Fig. 7, which will be discussed in the following sections.
5.1
Wound Healing
Recently, because of its nanostructure, the potential for water absorption, strong permeability, nontoxicity, structural stability, nanoporous construction, and moist setting, BC has been commonly used in skin regenerative and wound-treated medicines [98]. However, they do not have antibacterial or antioxidant activities. Thus, the in situ synthesis of an antimicrobial film based on BC/polyvinyl alcohol filled with silver nanoparticles, enhanced their antibacterial activity and the ability to use in wound dressing [99]. Similarly, the directly blended chitosan with BC leads to fabricate nonwoven mats for wound healing with high antimicrobial activity [73]. The ε-polylysine on the BCNF surface has been immobilized as a crosslinker with procyanidins, which shows intense antibacterial activity with active nanohybrid against Escherichia coli and Staphylococcus aureus, in order to increase antimicrobial activity [100]. Other studies have incorporated metal oxide nanoparticles, such as silver oxide nanoparticles [101], silicon dioxide coated with copper nanoparticles [102], and copper sulfate nanoparticles [103], onto BC to enhance their
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Table 4 Products based on bacterial cellulose available in the market Product BIOFILL ®
Application Ulcers, burns/artificial skin
BIONEXT ®
Ulcers, burns, lacerations/wound dressing
MEMBRACEL ®
Ulcers, burns/temporary skin substitute Venous ulcers/wound dressing
XCELL ®
DERMAFILL ® BIOPROCESS ®
Burns/wound dressing Ulcers, burns/artificial skin
GENGIFLEX ®
Recovery of periodontal tissues/dental implants, the grafting material Tendon repair/tissue reinforcement matrix
SECURIAN ®
Effects Reduced injuries and illness discomfort, quicker recovery, etc. Reduced pain and inflammation of wounds, more straightforward cure, etc. Fast skin regeneration Pressure reduction, reduced illness, quicker cure, etc. Quicker healing Reduced pain and inflammation of wounds, more painless cure, etc. Lower inflammation and fewer operational measures Exhibited good cell adhesion, proliferation
Company Robin Goad
Bionext Produtos Biotecnológicos Ltda Laboratorio Celina XCELL Biologix™ Fibrocel Biofill Produtos Biotechnologicos Biofill Produtos Biotechnologicos Xylos Corporation
Copyright 2020. Springer [98]
antimicrobial activity and reduce inflammation in wound dressing applications. Furthermore, Table 4 listed the BC that has been approved by the FDA and has been commercially used for various wound dressing. The BC showed an efficient activity for skin disease treatment, where a combination with nanoemulsions of Boswellia Serrata extracts revealed anti-inflammatory dressing on the chick area without any toxicity [104]. In a related study, Ataide et al. [105] set up a nanofiber tissue from bromelain and BC for enhanced antiinflammatory and antimicrobial properties against external actions. The dressing material formed of BC-based polyhexamethylene biguanide and sericin showed a fair use for cell proliferation and collagen production (65%) [106]. The development of natural facial masks has received increasing interest. Aramwit et al. [107] developed BC gel adsorbing antioxidant silk sericin on its surface. The tests demonstrated that the obtained gel exhibited excellent biocompatibility without subcutaneous irritation and noncytotoxic. Being biocompatible, noncytotoxic, and noncarcinogenic, BC is a great material for cosmetic surgery and the cosmetic industry with low cost and multifunctional properties. Thus, according to Jun et al. [108], a chemical reaction was used to create a distributed BC with 2,2,6,6-tetramethyl-1-piperidine-N-oxy radical as a catalyst; the modified nanofibers obtained presented a high tensile strength while gelatin improved skin adhesion and prevented harmfully impaired substances. Furthermore, Chantereau et al. [109] developed patches composed of BC and vitamin B-based
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ionic liquids for the use in skin care products. Consequently, results showed high thermal stability, no cytotoxicity to human keratinocyte cell lines, and significant antioxidant activity. Moreover, innovative microneedle patches of BC loaded with hyaluronic acid have been designed to overcome invasive skin penetration issues in dermo-cosmetic applications, where they showed an active delivery and release of the molecule to the skin [110].
5.2
Biomedical Scaffolds
In this application, BC’s nanofibrous form offers a promising material with high surface area, pore interconnectivity, and supported cell proliferation and differentiation. However, BC showed potential uses in the regeneration of bone, cartilage, and blood vessels. As stated by Georgieva and Hribernik [111], BC bio-based composite membranes with arrangements for nanofibers and gelatin were established by successive periodic oxidation procedure and freezing/carbodiimide cross-linking. The membrane did not evoke cytotoxicity toward MRC-5 human cells while supporting the gelatin sites’ attachment (Fig. 8). Therefore, a novel synthetic cell carrier formed of Caco-2 models of the human intestine-based BC exhibits an excellent scaffold material with high cellular compatibility, good protein expression, and potent tight epithelial barrier [112]. Similarly, a bilayer nanofibrous material consisting of muscle cells cultured on the surface of BC-potato starch used for hollow organ reconstruction [113]. The BC scaffold
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Fig. 8 (a) Fluorescent microscopic images of BC-gelatin composite membranes on top, bottom, and cross-section aspect; (b) their kinetic degradation; (c) MRC-5 cell barrier effect. Copyright 2019. Nanomaterials. [111]
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demonstrated high mechanical characteristics with the improvement of urinary tract reconstruction engineering. In reality, the BC was studied for cartilage, cardiovascular stent, and soft tissue engineering as biocompatible material. The 2-hydroxyethyl methacrylate monomer impregnated in BC showed high performing uses in mouse mesenchymal stem cells [114]. BC’s high aspect ratio leads to a wide surface area that has established a new heparin bowl to imitate natural extracellular matrix and facilitate blood compatibility [115]. A novel film based on BC-reduced graphene oxide composite was synthesized using the bacterial reduction method while maintaining good hydrophilicity and electrical properties. The new function increased human marrow mesenchymal stem cell adhesion and proliferation [116]. Müller et al. [117] prepared independent films of in situ oxidative chemical polymerization for BC and multipurpose composites for broad applications, including sensors and tissue engineering scaffolds. In an attempt to treat corneal trauma and ulcerations, the active biomaterial BC showed higher stability, mechanical resistance, and conformability to ocular globe surface [118]. Butchosa et al. [119] immobilized chitin nanocrystals inside the BC, where the composite demonstrated high antibacterial activity. Moreover, due to its extensive use in tissue engineering scaffold, gelatin was immobilized through BC via crosslinking by procyanidin, which revealed that 0.25% wt. of gelatin was the better concentration in order to maintain its bioactivity and supported cell growth [120]. Furthermore, the phospholipid lecithin has also been immobilized on BC’s surface by using chemical cross-linking with proanthocyanidin. Results showed that the immobilization of lecithin decreased the thermal resistance and hydrophilicity of BC but at the same time demonstrated the promising ability for tissue engineering [121].
5.3
Drug Delivery
BC is an ideal biopolymer for drug delivery material due to its swelling capacity and biodegradability. Tsai et al. [122] studied BC’s ability to hold the silymarin and zein nanoparticles, showing excellent drug release properties with effective antioxidant and antibacterial activities. Moreover, studies developed in situ drug carrier systems based on gentamicin microparticles incorporated on BC's surface [123]. Results revealed that gentamicin’s release could be significantly adjusted in strong bonds and promising a system for drug carriers. As shown in Fig. 9, the spray dry technique has successfully released BC containing mannitol. The drug system showed a pH-dependent drug release, gastro resistance, and potential carrier for lipophilic drugs [124]. As a model medication for ibuprofen dual-stimulus-sensitive release mechanism, hybrid hydrogels made of BC and sodium alginate have been developed. Therefore, in alkaline environments, ibuprofen’s release is pH-dependent, regulated by calcium alginate deprotonation or protonation in hydrogels [125]. Recently, Song et al. [126] produced an efficient transdermal medicament supply without loading medication by dramatically oxidized BC (TMPOs) 2,2,6,6-
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Fig. 9 Spray dried of drug system formed of bacterial cellulose nanofibers coating mannitol microparticles for oral delivery. Copyright 2020. Elsevier BV [124].
tetramethyl-1-piperidine-N-oxide. The obtained semi-dissolving microneedle patches could deliver a large number of drugs to the skin.
5.4
Lenses
Another exciting application of BC nanofiber is adapted to conform contact lenses for cornea regeneration. Cavicchioli et al. [127] formulated ciprofloxacin impregnated in the BC membrane to improve the healing of eye burns as the capacity for contact lens regeneration and protect it against bacterial infection. Recently, Coelho et al. [128] produced based material of BC, ciprofloxacin and sodium, combination compound lenses, glycidoxypropyltrimethoxysilane or chitosan nanoparticles. This therapy contact lens research revealed a positive finding of functioning BC without cytotoxicity or genotoxicity effects for all lenses checked.
6
Environmental Protection and Improvement
In the world, more than 942 km3 of municipal and industrial wastewater are released annually into the environment; they are often highly contaminated with heavy metals and organic pollutants, representing a severe environmental impact on air, soil, and aquatic systems [129]. Hence, the scientific community is continuously looking for new sustainable and advanced water resource treatments [130]. BC’s use as combined filtering and adsorbing membranes has received attention due to its renewability, hydrophilicity, and cost-effectiveness on a large scale.
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Fig. 10 Schematic illustration of bio-based multifunctional air filters absorbed by highly active fiber surfaces and different contaminants (particulates, chemicals, medical, and others). Copyright 2017. Elsevier BV [132]
6.1
Air Filtration
Recently, the primary source of air pollution is particulate matter and toxic gases such as sulfur dioxide (SO2) and nitrogen oxides (NOx), carbon monoxide (CO), ozone (O3), and many organic compounds (VOCs). Air filtration membranes based on BC have recently attracted attention due to its low-cost production, highefficiency multifunctional air filters, and low airflow resistance [131]. Liu et al. [132] synthesized a 3D nano-network of BC and modified soy protein to remove particulate matter. It was found that the natural filter highly removed the particulate matter and developed a promising bio-based material for air filtration (Fig. 10).
6.2
Heavy Metal and Dye Wastewater Reduction
Pigments, dyes, and toxic metals constitute a widespread and harmful source of pollution, liberated from dye production, textile products, the pulp and paper processing sectors, rubber, battery, and other industries in vast quantities. Thanks to their increased environmental effect, their elimination attracted a lot of public and scholarly attention. The standard procedures for removing dye and heavy metals are costly, have reasonable efficiencies, and involve a systematic process. Another treatment method, including precipitation exchange, convection, reverse osmosis, and direct precipitation, was recommended for their improved efficiency. The photocatalyst is the most sustainable material for the degradation of pollutants such as metals and dyes. Chen et al. [133] designed BC with aminophtalocyanine tetracobalt where the nanocomposite matter demonstrated an effective catalytic operation for rhodamine B dye wastewater discoloration. Similarly, Gholami et al. [134] demonstrated that BC grafted with polydopamine particles could remove heavy metals, such as cadmium and lead, as well as organic contaminants such as methylene blue, methyl orange, and rhodamine 6G from aqueous
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Fig. 11 The effective adsorbent for heavy metal ions and thinning treatment is bacterial cells/ magnetic attapulgite-chitosan composites. Copyright 2020. Elsevier BV [136]
media. Recently, a simple network loading process has been developed for the removal of the aqueous medium malachite green (MG) by an advanced 3D magnet polymer hydrogel with BCNF, graph oxide nanosheet(s), iron oxide nanoparticles, and polyvinyl alcohol [135]. The adsorbent showed high MG removal with a capacity of 270.27 mg g1 at room temperature and superparamagnetic property to be easily collected from aqueous solution by a small magnet. Chen et al. [136] crafted a BCNF-mixed magnetic attapulgite/chitosan, which showed effective adsorption to various metal ions, such as Pb2+, Cu2+, and Cr6+, and anionic organic dyes, including Congo red (Fig. 11). The BC-coated polyethyleneimine membranes synthesized by a flush-coating and post-cross-linking method presented potent adsorption for copper and lead ions from aqueous solutions [137]. However, a novel membrane-based on BCNF with polydopamine particles and palladium nanoparticles has demonstrated success in the removal of cationic, anionic, and neutral pH dye (3–9) (99%) [138]. In an attempt to remove mercury from wastewater, Tamahkar et al. [139] synthesized modified bacterial cellulose nanofibers by using Cibacron Blue F3GA. Results showed the successive mercury adsorption with efficiently repeated workability of the modified nanofibers.
6.2.1 Organic Pollutant Removal From Wastewater Some wastewater’s complexity due to many contaminants (organic and inorganic pollutants) needs their treatment by adsorption or oxidation through physicochemical or biological means. In most cases, the oxidation process can transform organic contaminants into lower toxicity compounds or higher biodegradability. Derazshamshir et al. [140] studied the effect of BC on removing phenol compounds and showed excellent phenol adsorption (97%) concerning pH, temperature, ionic strength, and specific binding cavities. Moreover, the modified BC/carboxymethyl
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Fig. 12 E. coli filtration of BC membrane suspension: (a) pre-filtration BC membrane, (b) E. coli suspension before and after filtration, (c) filtration BC membrane. Copyright 2020. Springer. [146]
cellulose stabilized with copper nanoparticles using microwave heating method has been used for organic pollutant removal [141]. The modified nanofibers exhibited a potent degradation of methylene blue dye and 4-nitrophenol while presenting significant recyclability, while the incorporation of titanium oxide nanoparticles into BC successfully reduced methanol and methylene blue from aqueous solution [142]. Another study has shown the efficiency of hybrid nanofibers based on BC and cadmium sulfate nanoparticles in removing methyl orange (82%) at visible light [143]. Chen et al. [144] crafted a novel, gold nanoparticle deposition-formed nanohybrid catalytic in 4-aminophenol to 4-aminophenol reduction 2.0,6,6-tetramethylpiperidine-1-oxyl-oxidized BC.
6.3
Disinfection of Wastewater
On the other hand, 1D hybrid nanofibers by incorporated palladium-copper nanoparticles in BC have been synthesized by in situ liquid-phase reduction [145]. The hybrid nanofibers demonstrated high catalytic activity for water denitrification. The development of suitable membranes for the disinfection of contaminated water from pathogenic microorganisms remains very challenging. Alves et al. [146] showed the potent efficiency of BC membrane to remove E. coli from industrial effluent compared to the commercial membrane (Fig. 12).
6.4
Water Desalination
The increasing global demand for drinking water has become essential to search for alternative methods. Nowadays, seawater distillation is considered an essential solution to solve the potable water scarcity. Seawater desalination uses reverse osmosis (RO) membranes, which are becoming a common commodity to extract freshwater from saline feedwater (Fig. 13). The feedwater is forced onto the surface of a membrane, which selectively passes water and retains salts, at comparatively
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Fig. 13 Schematic of the RO process [151]
high pressures. However, RO is limited to a high-cost installation and high-energy pressure of 50 to 80 for seawater desalination, which hinders the long-term performance of the membrane [147]. Moreover, water distillation through solar energy steam generation is presented as a sustainable and environmentally accepted process. Technically, solar water desalination proves its efficiency to purify water, but it is restricted to the heat loss during heating the bulk water, causing a limitation of solar desalination stand-alone [148]. However, BC is gained much interest as a cheap and green carbon source for the production of carbon-based materials dealing with deionization and water desalination. Belaustegui et al. [149] used BC to design designed the 3D nanostructured hierarchically porous membranes in aim to remove salt. Results showed unprecedented desalination capacities (55–79 mg g1 of salt at an initial concentration of 585 mg L–1). Forward, Alberto et al. [150] fabricated an RO membrane from BC that used to remove NaCl. Membranes’ performance exhibited high thickness, strength, and porosity with a potential NaCl removal (97.9%). Various techniques are used to extract potential contaminants from the water, such as sediment deposition, filtration, distillation, reverse osmosis, and UV treatment. A significant number of hydroxyl groups are present in nanocellulose frameworks, which promote various chemical changes to its structure. Nanocellulose is a great, robust substance that can be customized to eliminate particular toxins from the water. Numerous pollutants can be eliminated from the water, including microbes, viruses, and heavy metals, by implementing different chemical functions through electrostatic attraction. Different methods, like adsorption of chemicals and
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membrane isolation, are being utilized to remove such contaminants using different options, adsorption of which is the most powerful and successful for eliminating contaminants. Adsorption implies an association by electrostatic attraction or by chemical bonds with contaminants, such as heavy metal ions, dyes, etc., on the surface of a solid substance. A high SSA allowing access to usable classes on the surface is essential to a practical implementation. Adsorption of aqueous solution cationic heavy metal ion species like Cu(II) and Ag(I) could be accomplished by using various techniques to introduce negatively charged functional groups mostly on surfaces of cellulose
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Energy Applications
Nanocelluloses are shown as interesting materials for energy applications due to their low cost, versatile chemical modifications, high aspect ratio, thermal stability, mechanical strength, and flexibility. In photovoltaic modules, various materials (semiconductor silicon and group III–V elements) were used to transform solar energy effectively. Nevertheless, solar cells with inorganic materials are challenging and expensive for processing. Nanomaterials are currently being explored in solar cells as they are sustainable, clean, and affordable. BC is highly optical and is highly suited to use in high-performance conversion systems. The CNCs are significantly optical and suitable to be used in increased applications for energy conversion. NC does have high resistance, module, and presence ratio. It is stable in certain solvents and has broad electrochemical windows for stabilization. It can also be used as a separator and electrolyte. Since it includes highly responsive –OH surface groups, it is simple for the surface to be chemically modified. The materials’ nanocomposite properties can be optimized to enhance electrochemical efficiency for a particular purpose, thereby rendering them an effective candidate for electrode usage. As shown in Fig. 14, Rajla et al. [152] fabricated self-standing films (45 μm thick) of CNFs coated on polyethylene terephthalate for their piezoelectric response by monitoring the respective ferroelectric hysteresis. These cellulose nanomaterials can play pragmatic effects in the electronics’ performance by using conductive composites, proton exchange membranes (PEMs), electrochromics, energy storage devices, and piezoelectric sensors. In addition, their high surface modification allows offering high compatibility with nonpolar polymers, giving an eco-friendly energy devices [153]. In light of its fascinating properties such as the large surfaces, strong electric conductivity, and high mechanical power, BC proves to be an exciting use in solar panels, fuel cells, battery systems, energy collection, or cleaner storage. In the solar cells, Jiang et al. [154] designed an interface for solar steam generators based on BC and polydopamine. The biodegradable interface demonstrated exceptional optical absorption, photothermal transition, water transport performance, stabilization, and efficient solar power generation (78%). Furthermore, by self-assembling TEMPOoxidized BC, Wu and Cheng [155] formed reliable, thermal, and transparent films displayed for solar cell flexibility. The combination of polyaniline and BC networks
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a
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Fig. 14 (a) Photographs of a self-standing and bendable CNF film, (b and c) schematic side view of sensor assembly comprising of CNF layer sandwiched between a double layer of PET and Cu, (d) a photograph of assembled sensor. Ferroelectric hysteresis based on voltage curves for the CNF film at (e) 40–50 V.μm1 and (f) 5–15 V.μm1 electric fields under room temperature. Copyright 2016. American Chemical Society. [152]
formed a suitable composite material for dielectric solar devices [156]. BC demonstrated exemplary performance in the fuel cells as a membrane and electrode materials for the microbial fuel cell. Mashkour et al. [157] showed that unmodified nanofibrous BC by polypyrrole played an effective role as hydrogel bioanode for microbial fuel cells due to their high conductive surface. Different from the conventional fibrous membranes, a novel bioanode separator was made up of nanofibrous cross-linked BC and polyaniline using the same researchers’ vacuum filtering method. As shown in Fig. 15, the bacteria colonization on the anodes’ surface increases the charge transfer resistance of BC-CNT-PANI twice higher than BC-CNT, and the anodic biofilm formation gave a higher polarization, conductivity, and redox activity of BC-CNT-PANI, which attributed to a good adhesion of bacterial cells to the nanofibrous membrane [158]. For batteries, BC nanofibers attract significant attention as separators (membrane) for lithium (Li) ion batteries. Jiang et al. [159] reported the potent ability of BC as a promising material for the application in high-performance LIB separators due to their unique fibrous cross-linked 3D network, thermal stability, ionic conductivity, electrochemical stability, and battery charge/discharge capacities. At the same time, Xu et al. [160] prepared BC using a fast-freeze-drying method, which showed an excellent lithium-ion conductivity and an exceptional Li-ion transference with a reversible capacity after 150 cycles. A recent investigation revealed that a 3D carbonaceous BC aerogel loaded with amorphous iron oxide F2O3 showed an enhancement in capacitieslike lithium storage and the flexible structure of the active materials free BC [161].
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Fig. 15 Modified conductive bacterial cellulose electropolymerized polyaniline. Microbial fuel cell super capacitive anode. Bio-anodes based on BC-CNT and electropolymerized BC-CNT-PANI for anodic biofilm effect. Copyright 2020. Elsevier BV [158]
An extended application of BC where Sano et al. [162] developed electromagnetically controlled BC with high electrolysis property in micro-and macro-environments for divers biological applications. Another enhanced study has successfully produced flexible hybrid electrodes of BC conjugated to tin oxide nanoparticles and graphene oxide and coated with an organic thermoelectric polymer. The versatile electrodes displayed an excellent efficiency in long-term stability (the capacitance stayed 84.1% after 2500 loading/unloading cycles) [163]. Recently, Abraham et al. [164] fabricated a flexible catalytic electrode for hydrogen evolution reaction, formed of BC. The resulting electrode showed a satisfying performance and withstood prolonged electrolysis (48 h) in an alkaline medium.
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Packing Applications
Innovative techniques conjugating BC to other polymers or nanoparticles generate materials that exhibit enhanced properties with exciting applications in various fields, for example, the combined BC with polypyrrole and zinc oxide nanoparticles by soft polymerization method, leading to electrical resistance and promise use in antioxidative food and smart packaging (Fig. 16) [165]. The freshly produced BC with nanoparticles of zinc oxides show a high level of antioxidants’ photocatalytic activity through a strong interaction between hydroxyl and amino groups [166]. In another study, the BC has been investigated as a potential ingredient in food products, such as
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Fig. 16 Route options of film use of bacterial cellulose: (a) impregnation with other film components, (b) physical and/or chemical disintegration of BC membranes through a BCNF or BCNC processing environment, (c) insertion of a second biopolymer into the growth media for nanocomposites constructed at the ground stage. Copyright 2017. Elsevier BV [171]
corn oil containers sealed with BC and polyvinyl alcohol films, which demonstrated significantly lower levels of lipid peroxidation. The adding of BC did not affect the product yield, but it increased dough elasticity, loaf specific volume, crumb moisture, softness, and porosity [167]. Similarly, Marchetti et al. [168] examined the potential rheological improvements of BC on the gluten-free muffin batter that showed firmness, viscosity, and consistency indexes increased with the increase of nanofibers levels. Simultaneously, the same team suggested that BC could also be used as a food additive to improve the fatty acid profile of meat emulsions without any adverse effect on the quality of meat sausages [169]. Besides, Zhai et al. [170] showed that BC have potential properties of coating fresh-cut apples.
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Future Directions
The excellent properties of BC and their useful applications offer diver fields the possibility to substitute their green technology materials. It is essential to highlight the promising continuous studies on electronic and spintronic devices. For example, bacterial cellulose nanocomposites have been recently investigated as friction layers for triboelectric nanogenerator, which have full use for self-powered implantable,
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transient electronics, and wearable electronics [172]. Conjugating BC has enhanced this application with magnetic nanocomposites for better energy production [173]. Overall, BC has a high purity of cellulose that can be utilized with active materials or be a source of carbon to develop flexible energy storage materials [174]. Therefore, BC has been exposed to metal-organic frameworks to fabricate reticulated nanofiber composites for efficient oxygen reduction reaction and sodiumion storage, and results revealed the high-performance and cost-effective use of BC [175]. The application of BC in bone tissue engineering has gained attention in the past few years. The BC loaded with hydroxyapatite nanocomposites has been found to improve better adhesion, proliferation, and differentiation of human bone marrow stromal cells [176]. The BC could also impregnate with collagen and growth factor for potential bone reparation and regeneration processes [177]. However, more studies are needed to be established on the crucial role of BC in cartilage tissue engineering, including their functionalization and long-term stability. Furthermore, a recent study demonstrated the possible in situ self-assembly of BC onto electrospun nanofibers, which exhibited an excellent hydrophobicity and high crystallinity and gave a promising approach for other functional properties of BC [178]. Moreover, a natural renewable polymer that consists of BC coated with synthetic polymers demonstrated to be a promising alternative for biomedical material applications, such as gloves and elastic dentistry [179].
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Conclusion
BC offers an excellent platform for various applications in different fields due to their green synthesis, biocompatibility, ease to formulate, stability, biodegradability, nontoxicity, and different mechanical properties. Many studies have optimized the suitable medium for the biosynthesis, where the Hestrin-Schramm presents the most productive conditions. The high purity can be used in specific industries, such as cosmetics, food, and pharmaceutical. However, its large-scale production appears promising to use in textile and wastewater treatment, but it required further biochemical studies. This chapter reports the most advanced method for functionalizing bacterial cellulose nanofibers that can be used, such as mechanical and chemical pretreatment. The authors believe that combined BC with green nanomaterials provides a wide range of application areas. Moreover, BC showed impressive applications in tissue engineering scaffolds, dermal disease, biosensors, and drug delivery that provide a multifunctional material at a low cost. Therefore, searching for an optimal way to use BC remains essential to utilize their outstanding properties.
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Emerging Application of Nanocelluloses for Microneedle Devices
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Monika Dwivedi, Jyotsana Dwivedi, Shuwei Shen, Pankaj Dwivedi, Liu Guangli, and Xu Xiarong
Contents 1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1 Insight to Categories and Characteristics of Nanocellulose . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Preparation of Nanocellulose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1 Conversion of Cellulose to Nanocellulose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2 Nanocellulose Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3 Production of Nanocellulose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4 Pretreatment Techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5 Extraction Techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Emergence of Nanocellulose for Microneedle (MN) Fabrication . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1 Microneedle Device and their Categories . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2 Fabrication Technologies and Characterization of Microneedle . . . . . . . . . . . . . . . . . . . . . 3.3 Application of Microneedle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4 Advantage of Microneedle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5 Limitation of Microneedle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Nanocellulose for Microneedle Fabrication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1 Effect of Nanocellulose Combination on Microneedle Fabrication . . . . . . . . . . . . . . . . . . 4.2 Limitation of Nano Cellulose Combination on Microneedle Fabrication . . . . . . . . . . . 5 Conclusion and Future Aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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M. Dwivedi (*) · S. Shen · P. Dwivedi · X. Xiarong (*) Lab for Multimolar Biomedical Imaging and Therapy, University of Science and Technology of China, Hefei, China e-mail: [email protected] J. Dwivedi Department of Pharmacy, Pranveer Singh Institute of Technology (PSIT), Kanpur, India L. Guangli Anhui Medical University, Hefei, China © Springer Nature Switzerland AG 2022 A. Barhoum (ed.), Handbook of Nanocelluloses, https://doi.org/10.1007/978-3-030-89621-8_33
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Abstract
In quest of an efficient delivery system and for accurate delivery of drug to the ailment site, various researchers focused on development of a versatile delivery system. In progression, investigations on novel materials gained spotlight to add new dimension in the delivery devices to provide a more compatible and innovative platform for drug delivery. For innovative delivery systems, biomaterials like nanocelluloses were exploited for designing various scaffolds and delivery devices like microneedles. Microneedle devices are current trends of drug delivery where nanocellulose has evolved as protagonist for delivery aspects and strengthen the structural integrity of device. Nanocelluloses provided a wide choice for polymers to design biodegradable microneedle device. Nanocellulose also offers wide scope in surface engineering to upsurge the applicability of polymer for desired functionality of microneedle device. This chapter detailed the advances in microneedle exploiting nanocellulose or their combinations as well as it also illuminates current research efforts focusing on production of nanocelluloses and application for microneedle devices and their anticipated prospects. Keywords
Fabrication · Processing parameters · Drug delivery systems · Biomaterials · Biomedical scaffolds · Biodegradable polymers Abbreviations
2-[HEA]- [HSO4] AmimCl BC BM BmimCl BmimHSO4 BmimOAc BNC CMC CMF CNF Co2+ Co(NO3)2 Cr(NO3)3 d DMAc DP Fe3+ Fe(NO3)3 H3O+
2-hydroxyethylammonium hydrogen sulfate 1-allyl-3 methylimidazolium chloride Bacterial Cellulose Bone marrow 1-butyl- 3 methylimidazolium chloride 1-butyl-3-methylimidazolium hydrogen sulfate 1-allyl-3 methylimidazolium chloride Bacterial Nanocellulose Carboxymethyl cellulose Cellulose microfibrils Cellulose nanofibrils Cobaltous cation Cobalt nitrate Chromium(III) nitrate Particle size Dimethyl sulfoxide Degree of Polymerization Ferric ion ferric nitrate Hydronium ion
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HBr HCl HPH H3PO4 H2SO4 HS ILs IPN KGy MCC MimHSO4 MN MPa MTS NaBr NaClO NaClO2 NaOH NCC NFC Ni2+ nm Ni(NO3)2 OP OPi P PFI PVA PVP rpm SF TBAA TEMPO UV ZP γ
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Hydrogen bromide Hydrochloric acid High Pressure Homogenization Phosphoric acid Sulphuric acid Hestrin-Schramm Ionic liquids Interpenetrating network Kilogray Microcrystalline cellulose 1-butyl-3 methylimidazolium hydrogen sulfate Microneedle Megapascal Microstructured transdermal system Sodium Bromide Sodium hypochlorite Sodium chlorite Sodium hydroxide Nanocrystalline Cellulose Nanofibtillar cellulose. Nickelous ion nanometer Nickel nitrate Organophosphate Opioid Pressure of homogenizer Papirindustriens Forsknings institutt Poly vinyl alcohol Poly vinylpyrrolidone Revolutions per minute Silk fibroin Tetrabutylammonium acetate 2,2,6,6 tetramethylpiperidine-1-oxyl Ultra-violet Zosano Pharma Gamma
Introduction
Nanocellulose is one of the leading biodegradable and sustainable nanomaterial found in nature. Derived from native cellulose present in plant cells, nanocellulose is generally nanometer-scale material. Derived from cell wall, nanocellulose is related to lignocellulose that contains cellulose, hemicellulose, and lignin. Being both crystalline and amorphous, it is very hard to break the crystalline part of the
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cellulose due to the presence of strong hydrogen bonds (▶ Chap. 25, “Nanocelluloses in Sensing Technology”). Cellulose is passed through different sequential treatments to convert into crystalline nanocellulose and nanocellulose fibers. Three basic techniques for producing nanocellulose from cellulose are chemical, mechanical, and biological (▶ Chap. 29, “Nanocelluloses for Removal of Heavy Metals from Wastewater”). In Mechanical techniques, mechanical forces are applied to create a critical tension center in fibrous material and defibrillate the cellulose. In chemical techniques, degradation of cellulose takes place by the addition of active chemicals like acid hydrolysis, ionic liquids, TEMPO-mediated oxidation, and metals salts. Biological Techniques include biological reactions that result in the degradation of cellulose. Combinations of these techniques are also applied for the optimization of the production process as well as to characterize the final product [1]. Nanocellulose benefits in recycling, reproducibility, surface tunable chemistry, and biocompatibility. Cellulose nanofibrils (CNF) are very thin fibrils (around 5–20 nm) having a large surface area. These are the chain of cellulose crystals connected along with the microfibril axis disordered amorphous domains. It makes gel-like material that can be used for developing biodegradables combined with ecofriendly, safe, uniform and dense films for numerous functions, especially for biomedical purposes [2]. They can be extracted from sugar, hemp, banana, coir, softwood, or wood pulps. All the microbes such as algae, tunicate including some other plants contain cellulose synthesis protein that further catalyzes the glucan chain polymerization. In present days, it is commonly obtained from a vast variety of vegetation, crops, plants, bacteria as well as animals [3].
1.1
Insight to Categories and Characteristics of Nanocellulose
The cellulose is thoroughly characterized depending upon its origin and shape, size as well as geometrical configuration. The nanocellulose can be isolated from wood, aquatic animals, plants(algae), and some bacterias. Nanocellulose varies in shape, size, and geometry depending on it, nanocellulose can be nanocrystalline, amorphous and some other form like nanoyarns. The range of the crops, plants, and vegetables have been studied concerning the variety of the cellulose/ nanocellulose which includes hemp, rice, timber, kenaf, flax, sisal, and husk (▶ Chap. 1, “Nanocelluloses: Sources, Types, Unique Properties, Market, and Regulations”). Being abundantly available, wood is an elegant starting material for cellulose and nanocellulose isolation. It is a natural composite material with a graded structure consisting of cellulose, lignin as well as hemicellulose. Wood consists of an anisotropic arrangement that displays an amazing combination of outstanding strength, rigidity, resilience, as well as lesser density. Different multistage processes undergo several chemical and mechanical treatments in the production of nanocellulose from wood [4]. The other natural source, tunicates are aquatic invertebrate animals, mostly, members of the subphylum Tunicata. Most sea squirts belong to the family Ascidiacea have been studied in a particular category, which is the breed of aquatic invertebrate filter feeders. Researchers are also working on various dissimilar species like Halocynthia papillosa, Halocynthia roretzi, and Metandroxarpa uedai. The
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cellulose gets synthesized in the external tissue of the tunicates known as tunic, from there a distinguished cellulose portion mentioned as tunicin is obtained. Tunicate cellulose comprises almost fresh cellulose of CIb allomorph form with significant crystallinity. The nano/microfibrils of tunicate cellulose hold a large ratio and excellent specific surface area [5]. Algae are also considered a great source of cellulose and nanocellulose. It is of different varieties like red, brown, and green like Boergesenia, Micrasterias denticulate, Valonia, Cladophora. The cell wall of algae is also a source of microfibrils, extracted via mechanical refining or acid hydrolysis from the cell wall of algae. The architectural arrangements of CMFs vary with different algae. To exemplify, Valonia microfibrils have a square cross-sectional area (nm2) because they consist of Ia crystalline form. Conversely, Micrasterias denticulate microfibrils hold a rectangular cross-sectional area (nm2) as they are mostly of the CIb crystalline form. Bacterial cellulose (BC) is also obtained by metabolic operations of a specific variety of bacteria. Gluconacetobacter xylinus is one of the most renowned breeds of BC-producing bacterial microfibrils. Such bacteria create dense gel containing microfibrils with 97.99% water under a particular culturing environment. Bacteria cellulose crystallites are usually having CIa crystalline form alongside the degree of polymerization (DP) of bacterial cellulose (1000–6000). They benefitted in adapting the culturing environment to adjust crystallization and configuration. The additional big role of bacterial cellulose is its purity which discriminates it with plant cellulose that is related to hemicellulose or lignin. Otherwise, plant cellulose and bacterial cellulose possess identical molecular arrangements [6]. Based on dimension, shape, generation strategy the nanocellulose is further characterized into a subcategory that depends upon the resource along with processing methods [7]. The severe issue that needs to be removed for the efficient commercialization of cellulose nanofibrils is the huge amount of energy utilized in the mechanical disintegration of preliminary microfibril to nanofibrils. Owing to a few negative characteristics, the use of nanofibrils is limited in various industries such as the paper industry due to sluggish watering. Altogether, attributable to insufficient compatibility of hydrophilic reinforces with hydrophobic polymers in polymer composites. Therefore, chemical modification is required for cellulose nanofibrils to reduce the quantity of hydrophilic hydroxyl active groups [8]. Cellulose nanocrystals possess a rod-like shape and have partial flexibility in contrast to cellulose nanofibrils because of their higher crystallinity. They are also known as nanorods, nanowhiskers, and rod-like cellulose crystals. The geometrical shape and size of cellulose nanocrystals range from 5 to 50 nm in diameter as well as range of 100–500 nm in length. The dimension of nanocellulose largely depends upon the cellulose resource and the extraction process. The nanocrystals from bacteria and tunicates are larger than those received from cotton and wood [9]. The Theoretical Young’s modulus of cellulose nanocrystal alongside with chain axis is anticipated to be 1675 GPa which is like the modulus of Kevlar and greater than the modulus of steel. The young’s modulus of cotton cellulose nanocrystals is 105 GPa while the tunicate cellulose nanocrystal is 143 GPa.
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Table 1 Geometrical characteristics of nanocrystals from different cellulose sources Cellulose Source Wood Cotton Algae (Valonia) Bacterial cellulose Tunicate cellulose Sisal Ramie
Length, L (nm) [6] 100–300 100–150 1000–2000 100–1000
Cross section, D (nm) 3–5 5–10 10–20 10–50
Axial ratio, L/D 20–100 10–30 50–200 2–100
Reference [8] [9] [10] [11]
>1000
10–20
~100
[12]
100–300 70–220
3–5 5–15
~60 ~12
[13] [14]
Amorphous nanocellulose is obtained by acid hydrolysis of cellulose followed by ultrasound disintegration. They are generally elliptical with a diameter range of 50–200 nm. Due to its amorphous nature, it is beneficial in having higher functional groups, noteworthy availability, enhanced sorption, improved thickening potential. However, their specific mechanical properties limit their use as reinforcing nanofillers. They have a significant role as a carrier for bioactive ingredients and thickening agents in the various aqueous systems. Cellulose Nanoyarn is another emerging category of nanocellulose, obtained by electrospinning of cellulose or its derivatives solution [10]. Table 1 represents the geometry of nanocrystals depending on their source:
2
Preparation of Nanocellulose
The primary structure of the cellulose fiber gets transformed into nanofibrils (CNF) or microfibril bundles (CMF) having a diameter 10-100 nm, when the plant cell wall is exposed to the influential mechanical disintegration. Various feedstocks is processed by mechanical method to obtain cellulose nanofibrils or cellulose microfibril such as ultrasonication, grinding, microfluidization, homogenization ae well as cryocrushing. Different mechanical and chemical treatments were allocated towards restructuring the orientation of microfibril in original cellulose. Individual step, as well as the length of de-naturing, describes the particular property and the nature of the obtained nanocellulose. Firstly, different chemical alkali or enzymatic hydrolyses were applied to attain hydroxyl active moiety that improvises inner surface, crystallinity, break hydrogen bond, and overall leads to the reactivity of fiber. Secondly, mechanical treatment is applied like high-pressure harmonization, grinding, cryocrushing with liquid nitrogen, and so on [11].
2.1
Conversion of Cellulose to Nanocellulose
In 1838, Cellulose was first purified by a French scientist. The amount of cellulose depends upon its source. It is made up of β-Dglucopyranose rings. The two rotating rings are called units that create the cellulose network. The total number of rings
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varies from 100-300 for cellulose powder or 26,500 to 44,000 for Valonia. In a few works of literature, it is mentioned that it is insoluble in water due to the presence of strong hydrogen bonding that needs to be broken carefully. Though, Lindman reported that it shows amphiphilicity which makes it water-soluble [5, 12].
2.2
Nanocellulose Properties
The properties of nanocellulose like other natural fibers rest on various factors like chemical configuration, interfibrillar arrangement, cell dimensions, microfibril angle, and defects according to a different part of plant species. The mechanical properties are also significant for pharmaceutical use such as in drug coating procedures or preparation of nanocomposite-based drug delivery systems. Microcrystalline cellulose could be used as a basis for producing nanocellulose. Figure 1 detailed the characterization technique used for nanocellulose [5, 13].
Surface Charge/ Colloidal Stability (Zeta potenal, DLS)
Morphology
Crystallinity
(AFM, TEM)
(XRD, NMR)
NANOCELLULOSE CHARACTERISTICS Sulfate half ester content
Parcle Size (DLS, AFM/TEM)
(Conductometric traons) Thermal properes (Thermogravimetri c, DSC)
Fig. 1 Different techniques of characterizing nanocellulose
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Production of Nanocellulose
The initial step is to select the appropriate source, as the constituents varies according to the different resources of nanocellulose. This may perhaps result in the different yield as well as properties of nanocellulose produced. For instance, Chen and Lee described different crystallinity index by varying the source (cotton cloth led to the highest crystallinity (83.6%), while Panax ginseng led to the least crystallinity (62.2%). This variance was credited to the less amorphous ingredient with a highly ordered structure in cotton and more hydrogen-bonding interactions. Correspondingly, the fibril widths and the yield of production also varied in a wide range (from 15.6 to 46.2 nm and from 24.6% to 69.3%, respectively). Consequently, picking a proper source (usually having high cellulose content and fewer impurities) is an important aspect of nanocellulose production [14].
2.4
Pretreatment Techniques
Afterward choosing an appropriate source, pretreatments are desirable to eliminate the impurities (such as hemicellulose, lignin, wax), such impurities like lignin act as a physical barrier for processing. Pretreatments break the cellulosic structure surrounded by impurities allowing the cellulose to become available for processing. This also decreases the energy consumption during the mechanical disintegration of cellulose. Usually, pretreatments are physicochemical, biological, chemical, and physical (Fig. 2). For example, in chemical techniques, delignification takes place in the presence of an organic or aqueous solvent that extracts lignin from lignocellulose. Alkaline and bleaching treatments are also a good example of the same techniques. Generally, two major problems that occur during the fibrillation process are (i) Fibril accumulation (ii) the high amount of energy required for fibril delamination.
Fig. 2 Diagrammatic representation of different techniques used in nanocellulose production
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2.4.1 Alkaline Pretreatment Alkaline pretreatment is generally executed using diluted solutions of NaOH or KOH. In this technique, H+ is switched in the fiber network with alkali metal in the solution allowing detachment of interfibrillar regions from cellulose fibers. Such pretreatment needs a detailed control to avoid the microfibrillar morphology loss and unwanted reactions that branch cellulose chains dropping the aspect ratio of nanofibers. With such a method, surface tension could be compact along with improving the adhesion between the cellulose fibers and polymer matrix; though, it is ineffectual in changing the crystallinity of cellulose fibers. Prominently, this technique may be inadequate for the elimination of impurities from cellulose in some cases; researchers have coupled alkaline pretreatment with different techniques to develop the removal process [15]. 2.4.2 Bleaching Pretreatment Bleaching pretreatment breakdowns phenolic constituents or molecules having chromophore present in lignin and eliminates the byproducts of this breakdown. This pretreatment is characteristically performed with NaClO2 in which the duration of the process defines by cellulose source. As a result, the lignin reacts with NaClO2 and dissolves out as lignin chloride. Furthermore, researchers have used acetate buffer (solution of NaOH and glacial acetate acid) as well as the combination of sodium chlorite and glacial acetic acid as the agents for the bleaching treatment. As in the alkaline pretreatment, the bleaching pretreatment is also unsuccessful in altering the crystallinity of cellulose fibers [16].
2.5
Extraction Techniques
Like the pretreatment techniques and sources, extraction techniques also affect the characteristics of nanocellulose such as the crystallinity, aspect ratio, dispersion stability, thermal stability. These techniques are usually classified into three major categories: chemical, biological, and mechanical [17].
2.5.1 Chemical Techniques of Nanocellulose Production Chemical techniques include chemical agents that damage cellulose resulting production of nanocellulose. It may be achieved by acid hydrolysis, metal salts, ionic liquids (ILs), and TEMPO mediated oxidation. (i). Acid Hydrolysis This technique was used for production of NCC by many researchers. In this, mineralacids like HCl, H2SO4, HBr, and H3PO4 defibrillate cellulose. Accordingly, acid hydrolysis affects both crystallinity (high order) and amorphous (low order) regions of cellulose; it mainly eliminates the amorphous region, while it approximately retains the crystalline region ending up with NCC production. Remarkably, some acids like H2SO4 could form negatively charged nanocellulose fibers; sulfate ions esterify hydroxyl groups of cellulose. Nevertheless, nanocellulose produced by HCl is not charged. The main disadvantages of hydrolysis with strong acids include a
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high risk of corrosion, a low recovery rate, and acid wastewater production. The last one comes from the washing process used for neutralizing the nanocellulose suspension. In acid hydrolysis, the reaction duration and temperature, as well as the acid type and its concentration control the morphology and size of nanocellulose. Various studies had revealed the effect of hydrolysis duration and HBr concentration on the production yield of nanocellulose [20]. The production yield of nanocellulose is directly proportional to acid concentration (Table 2). (ii). Metal Salts Transition metal salts are used alone or as co-catalysts for production of nanocellulose. Metal salts are normally classified on basis of their valence state: monovalent, divalent, and trivalent. The valence state of metal salt co-catalysts affects the rate of the acid hydrolysis reaction. This technique has benefits in being less corrosive to equipment and more environmentally friendly as compared to inorganic one. This is extremely favorable for industrial application. Chen and Lee effectively prepared nanocellulose using a Cr(NO3)3 solution as the co-catalyst of acid hydrolysis (H2SO4 at 82 C for 1 h) from 4 kinds of municipal solid wastes. Chen et al. [21] linked different transition metal salts (Fe(NO3)3, Co(NO3)2, and Ni(NO3)2) as co-catalysts of acid hydrolysis (H2SO4 at 80 C for 45 min) in producing nanocellulose. Such studies proved that these salts selectively degraded the cellulose amorphous structure resulting in enhancing the crystallinity index (from 41.7% to 65%-70%). Also, the Fe3+ cation hydrolyzed the feedstock more successfully than Co2+ and Ni2+ cations (due to producing more H3O+ and, therefore, an increase rate of hydrolysis). Stimulatingly, in 2017, Chen et al. [21] produced nanocellulose using Cr(NO3)3 in the absence of mineral acids and/or mechanical treatments for the first time. By altering temperature, duration, and Cr(NO3)3 concentration, they create the optimum conditions: 70.6 C temperature, 1.48 h duration, and 0.48 M Cr(NO3)3 concentration. In such conditions, the production yield, crystallinity, and average width of nanocellulose were 87%, 75.3%, and 31.2 54.2% nm, respectively [22]. (iii). Ionic Liquids (ILs) Ionic liquids (ILs) mention to liquids containing ions, molten or fused salts. Certainly, ILs are a different class of salts having liquid at ambient temperature. Such as which can dissolve cellulose contain tetrabutylammonium acetate (TBAA), 1-butyl- 3 methylimidazolium chloride (BmimCl),1-allyl-3 methylimidazolium chloride (AmimCl), 1-butyl-3 methylimidazolium acetate (BmimOAc), 1-butyl-3 methylimidazolium hydrogen sulfate (BmimHSO4) 2-hydroxyethylammonium hydrogen sulfate ([2-HEA]- [HSO4]). ILs features two interactions in the dissolution mechanism of cellulose. Particularly, major two benefits of this contain dealing with environmentally friendly solvents and biorenewable feed stocks. In a study by Miao et al. [22] they formed NCC (20–30 nm in width) at 65 C from wood pulp board using tetrabutylammonium acetate (TBAA). By using an aprotic co-solvent, dimethyl sulfoxide (DMAc), they assisted in breaking down the ionic association of the IL with cellulose. In another study, Tan et al. [23] investigated the effect of temperature on the crystallinity index of nanocellulose using 1-butyl-3-methylimidazolium hydrogen sulfate (BmimHSO4). They reported that with increase in temperature crystallinity of
Alpha Cellulose
Alpha Cellulose
Kenaf pulp
Source Cotton linter
Different metal salt catalysts + acid hydrolysis
Acid hydrolysis + Ultrasonication Metal salt (Cr (III)catalyzed hydrolysis)
Production technique Enzymatic hydrolysis + acid hydrolysis
86 87.5
77.2 91
31.2 46% (optimum)
18.4 33% 31.6 46%
Chemical
Chemical
20 25
Yield (%) 82
10 28
Fiber size (nm) 200
Chemical + mechanical
Category Biological + chemical
Table 2 Nanocellulose Production from Other Sources
62.6 88.9
73.9 74.8
75.4
Crl (%)
Highlight Optimum acid hydrolysis conditions: 62% wt. H2SO4, 25 min at 47 C Optimum enzymatic hydrolysis conditions: a dose of 20 U g1 odp in 2 h Industrial feasibility (a small enzyme dose and hydrolysis duration) Optimum conditions: 43% sulfuric acid at 60 C for 90 min hydrolysis and 60 min ultrasonication Maximum production yield of 87% at optimum process conditions: 70.6 C, 1.48 h, and 0.48 M Cr(NO3)3 Simplicity in the operation (and equipment) plus dealing with less corrosive chemicals Optimized operational conditions: 82 C, 0.22 M Cr3+, 0.80 M H2SO4, and 1 h duration Catalysts greatly increased the hydrolysis efficiency Synergistic effect of H3O+ (from H2SO4) and Cr3+ cations increased the crystallinity index (compared with using dilute acid or metal salt alone)
(▶ Chap. 18, “Nanocelluloses as a Novel Vehicle for Controlled Drug Delivery”)
(▶ Chap. 11, “Bacterial Cellulose Nanofibers”) [19]
Ref [28]
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NCC get increased. Remarkably, Chen et al. [21] suggested that increased crystallinity is due to the elimination of hemicellulose and lignin found in amorphous regions. (iv). TEMPO Oxidation The TEMPO-mediated oxidation includes a TEMPO/NaBr/NaClO solution (or other similar solution such as TEMPO/NaClO2/NaClO) in water. TEMPO (2,2,6,6 tetramethylpiperidine-1-oxyl) and NaBr dissolve in water, and then, the oxidation starts by adding NaClO as a primary oxidant. Acts as a catalyst for proceeding reaction, the TEMPO reagent is changed to an N-oxoammonium salt (R1R2N+¼O) under certain conditions. Then, sodium hypochlorite and sodium bromide restore the catalyst to the TEMPO form again. In such treatment, the surface hydroxyl groups (the hydroxyl groups on C6 that show greater reactivity than C2 and C3) are selectively converted into carboxylate groups. This reaction takes place on the surface of cellulose fibers in amorphous regions (leaving the crystalline structure almost intact) that leads to negatively charged surface nanocellulose. Sodium chloride is the byproduct of this procedure. Remarkably, the reaction takes place in acidic and basic conditions both. For example, of an acidic pH condition, Hirota et al. [24] investigated a 4-acetamide-TEMPO/NaClO/NaClO2 oxidation system on never-dried mercerized wood cellulose at 60 C and pH 4.8 for 1–5 days. As a result, they produced NCC (4–7 nm in width and 100-200 nm in length) with 67%-77% production yield after performing mechanical treatment on the oxidized product. In another study conducted in a basic pH condition, Liu et al. [25] compared the characteristic of nanocellulose produced via acid hydrolysis and TEMPO-mediated oxidation (TEMPO/NaBr/NaClO at pH 10.5 and ambient temperature) from corncob residue. Their result showed that TEMPO-mediated oxidation led to the finest diameter (2.1 52% nm in width) and the lowest crystallinity (50%) with the highest yield (78%). The decrease in crystallinity (12%) indicated that the crystalline region of corncob residue was sensitive to the TEMPO mediated oxidation [5].
2.5.2 Biological Techniques In this, a biological reaction takes place utilizing microorganisms (like fungi and bacteria) or directly with a cellulose enzyme which destroys lignin and hemicelluloses while maintaining the cellulose materials. Enzymes that especially damage cellulose are ligninases, cellulases, and xylanases. Mainly fungi produce cellulases, whereas some bacteria and actinomycetes could also yield cellulase activity. Biological production of nanocellulose is an environmentally sustainable course accomplished in the deficiency of corrosive chemicals. Consequently, such treatment is not only less corrosive compared to chemical treatments but also produces less hazardous waste. Interestingly, this process can be used for producing BNC, NCC, and NFC (▶ Chap. 9, “Cellulose Nanofibers”). As described in the literature, two major biotechnology-based techniques exist for BNC production using microorganisms as static and agitated cultures. In static culture, the medium is commonly kept at 28–30 C in which bacterial cellulose
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accumulates as a white pellicle on the surface as shown elsewhere; however, an agitated culture forms dispersed BNC. As an example, one traditional culture medium for BNC production (regardless of using static or agitated culture) that was first introduced in 1954 includes the following compositions: 2% glucose, 0.5% peptone, 0.27% of anhydrous disodium phosphate, 0.15% citric acid monohydrate and 0.5% yeast extract. This composition of media is recognized as the HestrinSchramm (HS) culture medium, and it is still in use for culture medium practice. Optimizing productivity is the main challenge in the BNC production, yield, and quality of BNC while controlling the formation of byproducts. Hence, factors controlling these procedures concern strain selection and cultivation conditions (e.g., medium pH, static or agitated cultivation) [5].
2.5.3 Mechanical Techniques Mechanical treatments can produce NFC with diameters ranging from 50 to 1000 nm. Normally, mechanical forces exhibit a breaking phenomenon which forms critical tension centers in the fibrous material. It starts mechanical-assisted chemical reaction, leads to primary transformations which finally end up with the production of nanocellulose. Nevertheless, researchers have coupled mechanical techniques with other techniques to reduce energy consumption of the mechanical disintegration or to decrease the fiber length. Mechanical techniques mainly include high pressure homogenization (HPH), microfluidization, refining, ultrasonication, crushing, and radiation [26]. (i). High-Pressure Homogenization (HPH) It is one of the conventional mechanical techniques in which cellulose slurry is inserted into a container with the help of a small nozzle at high pressure. Interestingly, Wang et al. [27] detected that on increasing the pressure or the number of cycles the average particle sizes of nanocellulose decreased. It increases the magnitude of the disruptive forces in the homogenization equipment. Remarkably, particle size (d) and the pressure of homogenizer (P) have the following relationship: d α P-0.6 (0.25 < P < 40.5 MPa). Its benefits are high efficiency and simplicity in the deficiency of organic solvents. Though, the disadvantage is an undesired condition in which blockage may occur which makes cleaning the equipment tedious. Several researchers have produced nanocellulose via the HPH process alone or coupled with other techniques: ionic liquids, alkaline treatment, acid hydrolysis, enzymatic hydrolysis, ultrasonication, bleaching, steam explosion, milling, and grinding [28]. (ii). Microfluidization Microfluidization is an additional conventional mechanical technique for producing NFC; investigators have it alone or coupled with other techniques. The microfluidizer uses an intensifier pump for increasing the pressure. Then, it splits the pressure stream into two flows, transfers each flow through a fine orifice, and smashes them together in the center of the microfluidizer. Shear and impact forces defibrillate the fibers. These forces originate from the colliding streams, channel walls, and cavitation fields leading to reducing the size of fibers to form nanocellulose. The microfluidizer may produce a narrower distribution of particle size compared to HPH as it could break the intermolecular hydrogen bonds of the cellulose easier. Interestingly, higher pressures (more than 124 MPa) or more cycles
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(more than two) increase the mean particle size of nanocellulose due to droplet coalescence. Furthermore, the crystallinity index of nanocelluloses produced by microfluidization could be higher than HPH since less degraded cellulose entered the clay galleries, resulting in a less amorphous ingredient [29]. (iii). Refining The most promising mechanical technique for nanocellulose production is conventional refining. Researchers have used various devices to refine cellulose pulp and produce NFC such as a disk refiner, PFI mill, Valley beater, and grinder. Mostly, refining results in reduction of size therefore increases the fiber specific surface area and volume (due to thecutting effect and superficial fibrillation). For this process, disk refiners are oppressed, and fiber slurry is relocated between stator and rotor disks via inbuilt gap. Grooves and bars which have covered the surfaces of these disks subject pulps to repeating stresses leading to nanocellulose production. Likewise, during the operation of a PFI mill, the head containing the bars is pushed to one side of the casing. Fibers in a PFI mill are centrifuged between the inner roll and outer bedplate that rotate in the same direction but with dissimilar speeds which cause mechanical shearing forces. Also, rotating bars impart a higher impact force on fibers and results in internal and external fibrillation and, consequently, fiber size reduction. Nanofibers produced by PFI mill or a Valley beater contain significant moisture in it. Subsequently, higher moisture content leads to storage and handling problem resulting increased bulk volume and possibility contamination. Similar to PFI mills, in grinders, cellulose slurry is passed between the static and rotatory grindstones revolving at approximately 1500 rpm that subjects the fibers to shearing stresses. These forces rupture the cell wall and break down the hydrogen bonds to form nanocellulose [5, 30]. However, many passes may be required in the fibrillation process. Notably, the energy consumption of a PFI mill and Valley beater could increase the cost of NFC production. Also, Lee and Mani estimated that 20,000 revolutions in a PFI mill consume 3.5 mWh/ton energy. However, straightening fibers in a Valley beater seems to be more energy-efficient compared to a grinder. Improved straightened fibers generated in a valley beater are attributed to intermittent compression forces. This also resulted in low energy consumption by disk refiners than the homogenizer and microfluidizer. This implies that energy consumption in mechanical technique is an important factor to consider for reducing the cost of production [31]. (iv). Ultrasonication Ultrasonication is another mechanical technique that researchers have used alone or coupled with other techniques to produce nanocellulose such as alkaline treatment, grinding, microfluidization, biological treatment, homogenization, acid hydrolysis, steam explosion, ionic liquids, and TEMPO-mediated oxidation. This process has the advantage of ultrasound hydrodynamic forces that form microscopic gas bubbles (cavitation) leading to the generation of mechanical oscillating power. In consequence of the power generated by the interaction force, cellulose fibers finally break down into nanocellulose. Due to a large amount of heat generation during this process, it is usually performed in a water pool to control then heat transfer. In a study by Chen et al. [32] they reported that ultrasonication results in definitive structural changes in cellulose fibers leading to nanocellulose production without influencing the chemical composition, crystal structure, and thermostability of cellulose.
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Thus, ultrasonication technique had offered new directions for extraction and formulation processes for biomedical and pharmaceutical applications. Controlling factors in this technique are mainly the cellulose concentration, duration, and power of ultrasonication. For instance, Chen et al. [32] observed that increasing cellulose concentration in the suspension formed finer nanofibers with a higher crystallinity index. (v). Cryocrushing Cryocrushing is an advanced mechanical technique employing modified crushing for nanocellulose production. This technique exploits liquid nitrogen to freezes the fibers and high shear forces are applied on freeze fibers to crush them. Due to high mechanical impact, freeze crystals exert tremendous pressure on the cellulose cell walls resulting in the formation of NFCs. Use of cryocrushing process alone is limited due to large fiber size ranging from 1 μm to 100 nm [33]. (vi). Radiation Radiation (microwave, UV, gamma, electron beam irradiation) is an assistant technique in the process of nanocellulose production. At high doses (200-300 kGy), radiation treatment could produce nanocellulose by the degradation of large fragments of macromolecules. However, the production yield is very low (1.0%) indicating that the radiation treatment alone is insufficient for this purpose. Therefore, researchers have coupled this technique with other mechanical or chemical techniques. For instance, Kuzina et al. [34] increased the yield of nanocellulose production in an acid hydrolysis treatment from 34% to 75% by taking advantage of radiation techniques (at a dose of 200 kGy). Their finding also indicated that γ radiation penetrates the bulk material, while the interaction of UV light with cellulose is more selective. UV at a wavelength of 253.7 nm has sufficient energy to break any chemical bond in cellulose, although its energy (112 kcal/mol) is several orders of magnitude below that of γ rays. Besides, their investigation disclosed that UV light can only capable of penetrating only amorphous regions of cellulose surface. Also, Kim et al. [35] proved that electron beam irradiation could control the molecular weight and crystallinity of nanocellulose during the production process. As an outcome, this technique affects the elimination of the amorphous region of cellulose assisted with the acid hydrolysis resulting in narrowing of the nanocellulose particle size distribution [36]. (vii). Other Mechanical Techniques Some other mechanical techniques are also in use for production of NCC, such as, steam explosion, ball milling, extrusion, blending, and aqueous counter collision [5].
3
Emergence of Nanocellulose for Microneedle (MN) Fabrication
3.1
Microneedle Device and their Categories
As a “protective umbrella” of skin, the stratum corneum protects skin tissues from infection and dehydration, however, it also impeded drugs (especially macromolecules) diffusion into human body naturally [37]. Studies revealed micron-sized needles-based patch can increase the diffusion efficiency of the drug in several
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magnitudes, and henceforth, various microneedles have been developed based on different materials since 1990s. As shown in Fig. 3, the microneedles can be divided into solid microneedles, hollow microneedles, drug-coated microneedles, dissolvable microneedles, hydrogel-forming microneedles, and separable arrowhead microneedles. Solid microneedles are applied to the skin to create transient aqueous microchannels in the stratum corneum. Subsequently, a conventional drug formulation (transdermal patch, solution, cream, or gel) is applied, creating an external drug reservoir (Fig. 3a). Previous studies have proved that solid microneedles significantly increase the transdermal delivery efficiency of vaccines and some macromolecular drugs. Also, other reports revealed that microneedle structure has a conjoint influence on permeation efficiency of device. Owing to advancement in microneedle technology, hollow microneedle were designed as painless injections to deliver particular medication into the skin (Fig. 3d) that added a great value to improve the transdermal delivery [38]. Such MNs can deliver larger amounts of drug substances by combing with diffusion or pressure or electrically driven flow devices.
Fig. 3 Different types of microneedles for facilitating drug delivery transdermally. (a) Solid microneedles. (b) Coated microneedles. (c) Dissolvable microneedles. (d) Hollow microneedles. (e) Hydrogel-forming microneedles. (f) Separable arrowhead microneedles. (The image was reproduced with permission from reference [46])
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The coated microneedles are prepared by coating solid microneedle with a drug formulation, and the coated drug formulation will be dissolved and deposited after being inserted into the skin (Fig. 3b), for example, coated microneedles have been applied to treat subcutaneous tumors. A dissolving microneedle can achieve higher drug loading as they are usually fabricated by mixing a degradable polymer with a drug through casting it in a mold. A dissolving microneedle can achieve higher drug loading and they are usually fabricated by mixing a degradable material with a drug followed by casting it in a mold [39]. In dissolving drug containing array, MNs tips dissolve by dissolution upon contact with skin interstitial fluid (Fig. 3c). Whereas, as sown in Fig. 3f separable arrowhead MNs when inserted into the skin, the sharp tips mounted on blunt shafts encapsulating the drug separate from their metal shafts and remain embedded in the skin for subsequent drug release. These unique microneedles combine the mechanical strength of metal microneedles and eliminate biohazardous sharp waste by using a water-soluble and pyramid-shaped polymer “arrowhead.” Hydrogel-forming matrices based MNs are relatively safe and new type of MN arrays that are more favourable for drug delivery. The needle tips will rapidly take up interstitial fluid from the tissue after the insertion, thus inducing diffusion of the drug from the patch through the swollen microprojections (Fig. 3e). In addition, hydrogel-forming MNs are removed intact from skin, leaving no measurable polymer residue behind [40].
3.2
Fabrication Technologies and Characterization of Microneedle
MN devices can be developed by chemical etching, chemical vapour deposition, laser cutting, injection moulding, Hot embossing, drawing lithography, casting with mould, laser cutting, laser-drilling, 3D printing, ceramic micromolding and sintering. The microneedle fabrication process depends on the needle material and geometry. The silicon microneedle is fabricated by coating silicon wafer with a nitride and oxide layer using a low-pressure chemical vapour deposition, and then lithographically patterned using plasma etching also, silicon microneedle can be fabricated using etching process based on reactive ion etching with a chromium mask, as well as isotropic etching in an inductively coupled plasma etcher [41]. Anisotropic wet etching of crystalline silicon using an alkaline solution has also been utilized to obtain solid microneedles. As an additional approach, microneedles have been fabricated to serve as neural probes by dicing a silicon substrate to create a grid pattern of deep grooves and then acid etching the resulting pillars to create sharpened probe tips. Ceramic microneedles could be made lithographically using a two-photon-induced polymerization, where a focused laser was scanned to induce polymerization of photosensitive polymer–ceramic hybrid resin in the shape of the microneedles. Solid ceramic microneedles also could be prepared by micromolding an alumina slurry using a PDMS microneedle mold and ceramic sintering. As for metal microneedles, they can be prepared by laser cutting, three-dimensional laser ablation, and metal electroplating methods. Two-dimensional metal microneedles
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have also been prepared by electroplating or electroless-plating of metal onto positive or negative microneedle molds [42]. Drawing lithography is a unique additive process to fabricate MNs. This method produces 3D polymeric structures extended directly from 2D viscous polymeric materials. The polymer is cooled down until it becomes a viscous glassy liquid. After contact of the drawing pillars on a coated glassy liquid surface by plate moving, 3D structures are selectively elongated from the 2D glassy liquid-plate viz. finally isolated and produce hollow microneedle. Polymeric MNs have been produced by wide variety of mould-based techniques. Some examples of these techniques are: hot embossing, injection moulding, casting, investment moulding, and X-ray methods. On the other hand, 3D printing is also capable to customize microneedle by simplifying the fabrication of 3D models to stack layer by layer. With similar techniques, different types of microneedles can be produced to improve tissue adhesion and hydrogel microneedles [43]. A crucial step in the development of successful MN devices is mechanical characterisation. MNs normally experience a wide range of stresses, including those experienced during insertion or removal. Therefore, such devices must possess inherent strength to avoid failures, including MN bending, buckling and base-plate fracturing. Mechanical tests involve applying a perpendicular force and a transverse force (applied normal to the MN y-axis) is applied at a defined point on the MN shaft until the MN fractures. This type of test normally needs the use of a mechanical test station, which records both displacement and force, when MN fracture occurs, a sudden decrease can be observed in the force-displacement curves generated. The maximum force exerted immediately before this drop is normally taken as the MN failure force. The above tests are focused on mechanical testing of the needles. The base-plates need to be flexible enough to confirm the topography of the skin without fracturing. For this purpose, a three points bending test has been use. A maximum peak observed in the force-distance curve represented the force required to break the base plate. Additionally, the baseplate bending upon fracture was calculated to evaluate the flexibility of the base-plate, the release kinetics of the microneedle can be determined spectroscopically by loading pigments or substances capable of changing color in reaction with enzymes as a reference [44].
3.3
Application of Microneedle
The advantage of improving drug delivery efficiency has promoted the applications of microneedle in different biomedical fields. For example, MN can be used for cosmetic applications, mainly for treatment of skin blemishes and the delivery of active cosmetic ingredients. Kumar et al. [45] demonstrated enhanced localized delivery of eflornithine for reducing facial hirsutism via microneedle delivery system. MN technology can be used to treat different types of scars by piercing the skin multiple times to induce collagen growth. With the microneedles as delivery tool, 40 μg of teriparatide was capable of increasing bone mass equivalent to 20 μg s.c injection daily. A microneedle device
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integrated with mesenchymal stem cell-derived exosomes and a small molecular drug(UK5099), could enhance the treatment efficiency at a reduced dosage, leading to promoted pigmentation and hair regrowth, showing augmented efficacy compared to the subcutaneous injection. MN technology can also used for biocompatible resin for the fabrication of 3D printed microneedle arrays via transdermal mode for insulin delivery. Further, in vivo animal trials showed appreciable reduction of glucose levels within 60 min, altogether, attained steady-state plasma glucose over 4 h. Drug delivery through microneedles had forecast various opportunities at commercial level. Figure 4 demonstrates several under development devices based on microneedles for commercial purpose. 3 M™ has developed a hollow microstructured transdermal system (sMTS™) (Fig. 4a) that offers reproducible intradermal delivery, and a patient-friendly design. Zhang et al. [46] developed a lidocainesMTS product with rapid onset, prolonged local analgesic action, and minimal tissue reaction and characterized it in vivo in a swine animal model. The use of microneedles led to rapid insulin absorption and a reduction in glucose levels. In second phase, on consuming standardized meal microneedle devices found to be more efficient in dropping postprandial glucose levels comparative to bolus insulin delivery. Clinical trials involving the use of microneedles for the delivery of insulin, doxorubicin, and aminolevulinic acid have also been reported. Zosano Pharma Corporation has developed ZP-PTH (Fig. 4c), which is a transdermal MN formulation of parathyroid hormone 1-34 (PTH) [47]. Another type of MN-based device that has been developed are Micro-injection systems like MicronJet ®, Intanza ®, Dr.pen, and various other intradermal delivery MN devices of drugs, proteins, and vaccines have been reported for effective clinical use(Fig. 4g–k). A dissolving cosmetic MN
Fig. 4 Different types of microneedles used to facilitate drug delivery transdermally. (a) Microstructured Transdermal System, (b) Microinfusor, (c) Macroflux ®, (d) MTS Roller™, (e) Microtrans™, (f) h-patch™, (g) MicronJet, (h) Intanza ®, (i) Dr.pen, (j) Endymed, (k) Dermapenworld, (l) Skyn. (Images(a–h) was reproduced with permission from reference [18])
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product containing hydrolyzed hyaluronic acid is also commercially available from Skyn. The fractional radiofrequency MN system (Fig. 4j, l) works by creating radiofrequency-induced thermal zones without epidermal injury was introduced for facial rejuvenation.
3.4
Advantage of Microneedle
Commonly systemic administrations like oral, subcutaneous injection, intravenous injection showed complications of liver damaging. While the transdermal administration has significant advantages like delivering drug directly into the blood or lymph circulation as well as reducing patient variability which occurs due to GI factors on drug absorption. Not only, it is capable to release constant rate of drug for a longer time but also avoid the Peak-to-trough Fluctuation of drug in Plasma. As, skin is also one of the most accessible tissues for enhancing the portability of the administration. The transdermal administration can easily controlled by the patient/ adminstrarer that makes it very friendly for infants, elderly or patients. However, the passive diffusion by traditional transdermal is limited. In contrast, the microneedle strongly improves drug delivery efficiency. Clinical applications also showed that it barely stimulates pain-related nerves, nor does it causes infections and allergic reactions. The increase in local drug concentration also improves systemic drug absorption efficiency and bioavailability. The release kinetics of the drug depends upon the constituent polymers’ dissolution rate, controlled drug delivery is thereby achievable by adjusting the polymeric composition of the MN array, or by modification of the MN fabrication process. The principal benefit for solid, hollow and coated microneedle is the mature processing technology, the reproducibility of application, and no residue. The principal benefit for dissolving and separable arrowhead MNs is easy and low cost scale up due to polymeric materials viz. cost effective and easy micro molding fabrication process. Various materials, including poly(vinyl alcohol) (PVA), poly (vinyl pyrrolidone) (PVP), dextran, carboxy methyl cellulose (CMC), chondroitin sulfate and sugars have all been used to produce this type of MN array. Notably, water-soluble biodegradable polymers reduce probability of skin biohazards. Moreover, safe MN disposal is facilitated, since the MN are, by definition, self-disabling. As for hydrogel-forming MNs, they offer a simplified one-step application process, can be withdrawn intact, leaving no polymeric residues behind, and would not be blocked by compressed dermal tissue upon application [48].
3.5
Limitation of Microneedle
There is immense potential for the use of micron-sized needles for transdermal drug delivery enhancement; nevertheless several concerns have also been raised regarding their use. Solid MN are applied to the skin and then removed, and the requirement for a two-step application process may lead to practicality issues for patients. The
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materials used to produce solid MN are typically silicon metals and polymers. However, those fabricated from silicon and some polymers may not have the adequate mechanical strength to pierce the skin. The coated microneedle allows a simple one-step application process, but even materials such as alginic acid have been applied to increase the thickness of the coating layer, the amount drug coated on microneedle is still difficult to exceed 1 mg. The main limitations of hollow MNs are the potential for clogging of the needle openings with tissue during skin insertion and the flow resistance, due to dense dermal tissue compressed around the MN tips during insertion. The use of Hollow MNs also requires the cooperation of a syringe or a micro-flow pump, and the liquid drug formulations should in suitable viscosity. However, in case of the dissolving MNs main limitation is the deposition of polymer in skin, that mark them as undesirable systems for some specific delivery pupose. Such MN typically requires high temperatures during manufacture, which may damage biomolecular cargoes. Hydrogel-forming MNs could overcome some of the limitations typically associated with coated MNs, such as extremely reduced MN loading capacity, difficulty in achieving accurate drug coating, and controlling rate and extent of drug release [49]. The clinical treatment of skin diseases must be done according to patient variability. Microneedle can be adjusted by changing the structure design or microneedle mold as per the patients need. However, the fabrication of microneedle depends upon micro-manufacturing technologies, such as ultraviolet radiation, ion etching, and laser micro-cutting. These technologies require costly equipment. Another valid concerns are to create microscopic pores into the skin which can lead to bacterial and fungal infections. Also, increase of allergens can result in hypersensitivity reactions. In addition, there are potentials for misuse and abuse of microneedles. More importantly, the use of microneedles does not always result in the achievement of therapeutic drug concentration.
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Nanocellulose for Microneedle Fabrication
4.1
Effect of Nanocellulose Combination on Microneedle Fabrication
There is a tremendous amount of research being carried out to study the influence of MN on transdermal drug delivery. However, to find widespread clinical applications for these microneedles, several challenges need to be addressed, including the concern that some MN may not have the adequate mechanical strength to pierce the skin. The ideal scenario is to fabricate MN with a low insertion force and a high fracture force. For example, the biopolymers such as gelatin, collagen, and starch are of the tendency to absorb water, which will decrease their mechanical stability post processing. To overcome this limitation, cellulose nanoparticles have been applied to impart high mechanical strength to membranes, and they also have biocompatible properties and have been used in biomedical applications such as drug delivery and
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scaffolds [50]. Including cellulose nanoparticles in minimal amount in the composite improve the mechanical strength by reinforcing the bonding between the fiber and matrix, or modifying the cellulose fibers to be more hydrophobic. As a result, addition of nanocellulose into microneedle composite reduce its elongation and improve tensile stress [51].
4.2
Limitation of Nano Cellulose Combination on Microneedle Fabrication
As a hydrophilic fiber, cellulose exhibit strong tendency to absorb water and this results in the weakening of the composite. After producing nanocellulose, modification of its surface according to the desired application may be needed, otherwise the abundance of hydroxyl groups existing could lead to aggregation in many nonpolar solvents [52]. Also, the hydrophilic surface may cause incompatibility with hydrophobic polymers and drugs. With the modifications, nanocellulose could increase the compatibility, dispersibility, and overall performance of the nanocellulose-based composites system. Although, nanocellulose generally shows very low toxicity, however, in some cases it could cause considerable toxic outcomes. Therefore, we should pay more attention on applying nanocellulose in microneedle system, as size, morphology, degree of crystallinity, surface chemistry, colloidal stability, extraction techniques, as well as cellulose sources may affect the toxicity [53].
5
Conclusion and Future Aspects
This chapter describe characteristics of the nanocellulose depending on the process condition, the technique applied and advances in nanocellulose based microneedles. This compilation also discuss combined techniques to optimize the production procedure for nanocellulose. The selection of the best combination depends on the source and preferred characteristic. Also, the availability of production amenities is important to take into account. Based on the presented compiled data, the following general points for nanocellulose production could be concluded: A source comprising greater amounts of cellulose and lesser impurities (hemicellulose, lignin, silica, wax, oil) is better that results in the best choice for the production process. Biological treatment in combination with mechanical or chemical techniques could be best for producing nanocellulose with a satisfactory production yield. Furthermore, Ionic liquids type defines the effects of increasing temperature, time, crystallinity index, and concentration on fiber sizes [5, 6, 13–16]. Combination of hydrolysis and ultrasonication produces nanocellulose having a particle size less than 20 nm from this source. The refining technique has the caliber to produce NFC with a great production yield. This technique is endorsed in the case of making a large bulk of nanocellulose alone. Mechanical, biological, metal salts and ionic liquids (ILs) techniques are most exploited in nanocellulose production
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due to their environmental-friendly characteristics. Nanocellulose production by using metal salts or acid hydrolysis normally results in NCC, whereas mechanical techniques or TEMPO mediated oxidation mainly forms NFC [5]. Nanocellulose emerged as a biocompatible alternate for synthetic polymers with a variety of desired ranges to bring forward a natural way for control drug delivery. Being a versatile natural polymer, they are excellent biopolymers for MN patch [51]. Nanocellulose not only opened a new avenue for commercial products based on microneedles in a safe and eco-friendly mode but they also put forth cost-productive materials with desired morphology and properties. Along with drug delivery through the skin for skin diseases, cancers, and other medical applications, nanocellulose based microneedle device are the future of cell and tissue regeneration. They will lead the market of local delivery devices owing to their cytocompatible, biodegradable nature and invivo safety. Moreover, chemical tailoring of nanocellulose is the recent approach that imparts different functionality in nanocellulose to meet the requirement of delivery for therapy and diagnosis.
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Part III Processing
Nanocellulose for Antibacterial, Anti-biofouling Applications: To Antiviral Development in the Future
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Hideyuki Kanematsu, Dana M. Barry, Ryo Satoh, Risa Kawai, and Paul McGrath
Contents 1 2 3 4
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Classification of Nanocellulose, Structures, and Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . Biofouling and Microorganisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Application Cases from the Viewpoint of Fouling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1 Membranes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2 Medical Application . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Antiviral Characteristics: Future Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Conclusion and Future Prospects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Abstract
Nanocellulose is produced from natural resources, such as plants and bacteria, by using artificial mechanical and chemical processes. Since it is made from natural resources, nanocellulose is environmentally friendly, biocompatible, and biodegradable and has low toxicity. In addition, it has high mechanical strength and elasticity and many other attractive properties for a variety of applications. H. Kanematsu (*) · R. Kawai Department Material Science and Engineering, National Institute of Technology (KOSEN), Suzuka College, Suzuka Mie, Japan e-mail: [email protected] D. M. Barry Department of Electrical & Computer Engineering, Clarkson University, Potsdam, NY, USA Science/Math Tutoring Center, The State University of New York at Canton, Canton, NY, USA R. Satoh Department Creative Engineering, National Institute of Technology (KOSEN), Tsuruoka College, Yamagata, Japan P. McGrath Department of Electrical & Computer Engineering, Clarkson University, Potsdam, NY, USA © Springer Nature Switzerland AG 2022 A. Barhoum (ed.), Handbook of Nanocelluloses, https://doi.org/10.1007/978-3-030-89621-8_20
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However, it doesn’t have inherent antifouling properties. In this chapter, we analyze nanocellulose materials from the viewpoint of antifouling properties. We discuss the fundamental aspects needed for the analyses and introduce the concepts of antibacterial and antifouling properties. Then, some specific cases are provided. Finally, the antiviral property for nanocellulose materials is proposed for future investigations.
1
Introduction
Cellulose is a type of polysaccharide. A polysaccharide is a long chain of polymeric carbohydrates composed of monosaccharide units bound together by glycosidic bonds. Examples of polysaccharides include starch, agarose, glycogen, pectin, etc. in addition to cellulose. Commercial products, often used in our daily lives, are composed of polysaccharides [1–3]. These products have some common characteristics. One of these is thickening, the function of polymers that makes liquid thick and increases viscosity. Another one is gelatification, which is the formation of gelatin. Stabilization is also an important characteristic. Dressings and other foods, with dispersed substances in matrices, are often stabilized by the existence of polysaccharides. Not only foods but also cosmetics, coatings, adhesives, inks, and cleaning agents benefit from polysaccharides. The polysaccharide cellulose is composed of a combination of β-glucose units [4,5]. Therefore, it is different from starch, which is composed of a combination of α-glucoses. Cellulose is hydrolyzed to glucose by water molecules. However, it is generally chemically stable. It is a structural component of the primary cell wall of green plants, etc. Also, it is secreted by some bacteria. Nanocellulose, a product obtained through artificial treatments, has many industrial applications. In this chapter, we focus on nanocellulose from the viewpoint of biofouling and describe its characteristics and applications.
2
The Classification of Nanocellulose, Structures, and Properties
Cellulose is one of the main components for plants as well as bacteria, as already mentioned. It is basically the polymeric substance composed of glucose unit (β-1,4-anhydro-D-glucopyranose units). Figure 1 shows the basic structure of cellulose.
Fig. 1 The basic unit structure of cellulose
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Nanocellulose is formed by some artificial processes [6–9]. It is basically defined as cellulose that has structures designed and adjusted on the nanoscale. Concretely, nanocellulose indicates three kinds of cellulose materials (Fig. 2): cellulose nanocrystals (CNC), cellulose nanofibrils (CNF), and bacterial cellulose (BC). Just like many other polysaccharides, cellulose is obtained from natural resources such as bacteria, plants, algae, and animals. Generally, wooden pulp has been used as raw material in most cases other than BC. The production process has been investigated in various ways. Usually, CNC is produced through hydrolysis processes in acid environments, while CNF is obtained through mechanical processes in addition to hydrolysis. On the other hand, BC is produced from biosynthesis processes [10]. The processes used to make nanocellulose produce small and fine cellulose networks on the nanoscale. The representative characteristics of nanocellulose [11–13] are mechanical properties, including high mechanical strength, stiffness, low density, biocompatibility, biodegradability, non-toxicity, and high surface activities (Fig. 3). Fig. 2 Classification of nanocellulose
Fig. 3 Characteristics of Nano-cellulose and biofouling
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As for mechanical properties, the high mechanical strength together with stiffness and low density are the most important for application purposes. The strength of cellulose is about five times higher than that of regular steel while its density is five times lower. Therefore, nanocellulose has a high strength-to-weight ratio. Its coefficient of thermal expansion is also low as compared to that of glass. In addition, the elasticity of nanocellulose is always constant in a broad temperature range from -200 C to 200 C. These characteristics may lead to many practical applications in the near future. From the viewpoint of biofouling there are four major characteristics. The first characteristic of importance is the surface activity of nanocellulose. From the structural viewpoint of nanocellulose, many hydroxyl groups exist on the material surface. This means that the surface tends to be electrostatically negative and hydrophilic. These properties promote the attachment of bacteria to the material. Usually, bacterial surfaces are negative, even though positive parts exist at the same time. This is also true for material surfaces. Therefore, surface sections that have opposite electrical signs would be successfully attracted to each other. This is not restricted only to the force between materials’ surfaces and bacteria, but also that between materials’ surfaces and EPS (extracellular polymeric substances) derived from bacteria. As for hydrophilicity, such a surface is surrounded by a film of water. In this case, bacteria will not have the opportunity to approach the surface. Therefore, hydrophilic surfaces generally avoid bacterial attachments. However, other factors must be considered. For example, electrostatic forces may play a role in the attachment process. There are many factors involved in the attachment process of bacteria, so the analysis for the attachment mechanism is not simple. However, hydrophilicity is one of the important factors to analyze it (Fig. 4).
Fig. 4 Hydrophilic surfaces and biofouling
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The high surface activity due to the existence of hydroxy groups on surfaces could lead to the possibility of surface modification. Many other functional groups may be designed. From this viewpoint, antibacterial nanocellulose with antibacterial organics could be developed and produced. Such a high reactivity is attributed to nanocellulose’s highly specific surface area. This is related to the fouling properties of nanocellulose. A second important characteristic of nanocellulose for biofouling is biocompatibility. Since nanocellulose is basically produced from natural resources, its biocompatibility is basically high. However, human beings do not have the appropriate enzymes to decompose cellulose. In the light of this, nanocellulose is stable in human bodies, and its biocompatibility may have to be evaluated as relatively high or moderate. The third important characteristic of nanocellulose regarding biofouling is biodegradability. Even though human beings lack the enzymes to decompose it, there are many organisms, including bacteria and algae, that can. Plastics and polymers found in marine environments cause pollution due to a lack of necessary regulations [14–16]. Increasing applications and reuse of these items by industry and individuals could improve the situation worldwide. The final important characteristic of nanocellulose is its low toxicity. This is related to the biocompatibility and biodegradability properties. It links to biocompatibility because it has low toxicity and is basically derived from natural resources. This characteristic gives nanocellulose potential medical use. There are some reports of harmful nanocellulose effects involving experiments using mice [17–19]. However, nanocellulose is not seriously toxic to cells or DNA. Considering the aforementioned characteristics of nanocellulose, some biofouling properties are presented and discussed in the following sections.
3
Biofouling and Microorganisms
Biofouling is the accumulation of microorganisms, plants, crustacea, etc. on surfaces where it is unwanted [20]. It is classified into two types, mainly from the viewpoint of attachment size: microfouling and macrofouling [21]. For the former, the attached organism is mainly bacteria, while larger organisms, such as barnacles, oysters, etc., attach to materials in the latter case. In this chapter, we focus on microfouling by bacteria. Bacteria generally seek nutrients, particularly in oligotrophic environments, to survive. Since the material surfaces are generally unstable in terms of energy balance, carbon compounds, which serve as nutrients for bacteria, adsorb to the surface to compensate the energy balance and form a very thin inhomogeneous film. It is generally called “conditioning film.” Due to the existence of this film, bacteria tend to move toward the material surface. Such a movement of bacteria driven by the existence of nutrients is called “chemotaxis.” Then, bacteria can continually move and attach to the material surface. However, there is a high potential barrier for bacteria to approach the surface and to attach. Also, the bonding
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may not be strong for some bacteria. As a result, we can presume that some of the attached bacteria may soon detach. Such a repeated attachment and detachment process might continue over an extended period of time. However, the number of attached bacteria will continue to increase. When the bacteria count reaches a certain threshold value, then a signal deduction process from outside to the inside of the bacteria and their DNA occurs and brings about the simultaneous excretion of polysaccharides. This phenomenon is called quorum sensing [21]. As described above, quorum sensing (QS) is actually one of the signal deduction processes. Generally, bacteria excrete many kinds of signal matters around them. The signal matter for QS is called an “autoinducer” (AI). Many kinds of AI have been investigated and are already well-known. For example, the gram-negative bacteria AI is N-acylhomoserine lactones (AHL) in many cases, while gram-positive bacteria is autoinducing peptide (AIP). The high density of bacterial cells in a local area increases with the signal. When the concentration of signal matter reaches a threshold value, it enters bacterial cells and stimulates a part of the bacterial DNA that relates to the excretion of polysaccharides. As a result, bacteria in biofilms excrete polysaccharides simultaneously, and the material surfaces become surrounded by sticky matter. Biofilms form at this point [21]. The schematic process is shown in Fig. 5. The above statement suggests that biofilms would be affected by the number of bacteria on material surfaces. Therefore, the chemical interaction between the substrate and bacteria, with excreted matter, is important. The surface morphology is also a key factor for the attachment of bacteria. When bacteria approach a material surface, they need to overcome a relatively high potential barrier to get through it. Bacteria have many pili at their cell surfaces.
Fig. 5 Schematic illustration for biofilm formation
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The smaller parts could go through the potential barrier and attach to the surface. There are many types of pili, and each has a certain function for bacteria. For example, the fourth pili are often mentioned as functions to twitch, glide, and provide other surface movements. The first fimbriae are well- known as a factor for bacteria to firmly attach to a surface. Therefore, the surface morphology and topography are very important for bacteria to attach to surfaces and to increase their numbers. Such a mechanical factor differs from the physical-chemical processes recognized in various fields. For example, shark’s skin, the lotus leaf, and some other special surfaces could avoid fouling. This is called the lotus effect. In this case, a certain special topographical shape of a surface leads to water-repellent or oil-repellent effects due to features on the nano-meter scale. Other than that, we can imagine very easily that bacteria could grip markedly uneven surfaces with their fimbriae. The authors can confirm that more uneven surfaces could increase bacterial attachment in biofilms. As described above, the main cause for fouling is bacteria attaching to material surfaces, and the local aggregates of bacteria to form biofilms. The process is called biofouling, and the potential formability of biofilms depends on physical-chemical interactions between bacteria and material surfaces and on surface topographical characteristics. From this viewpoint, we will examine and discuss nanocellulose materials.
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Application Cases from the Viewpoint of Fouling
4.1
Membranes
Membranes are specific examples where fouling problems exist. We frequently encounter membranes. Human beings and other organisms have cell membranes. Inside the membranes, various chemical reactions occur. Reactants and products move through membranes. In addition to those biological membranes, there are various artificial membranes for industrial applications and for use in our daily lives. Basically, membranes eliminate pollutants, including bacteria, fungi, and viruses, by virtue of their small pore size. Table 1 shows the types of membranes, their pore sizes, and purity [12]. Microfiltration’s pore size is generally from 100 nm to 10 μm and could catch solids and bacteria. Ultrafiltration membrane pore sizes are approximately 2 nm to 100 nm and filter viruses, proteins, and large macromolecules. Nanofiltration membranes have pore sizes of 1–2 nm and eliminate monovalent ions. Table 1 Comparison of structural characteristics among three kinds of nanocellulose
Category CNC CNF BC
Size 50–500 nm 4–100 nm 20–100 nm
Purity High Low High
Crystalline nature High Low High
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Regarding pore sizes, viruses could be captured and eliminated, using nanocellulose membranes. The pore size of nanocellulose membranes depends on the original source and production methods. However, the diameter of nanocellulose could be downsized to around several nanometers. In fact, a new type of nanocellulose membranes has been developed to eliminate COVID-19 and other viruses [23]. The addition of antifouling effects to nanocellulose membranes is very important as fouling can lead to clogging problems. Thus, the filtration capability would be decreased. As described in Sect. 3, biofouling can be driven not only by chemical interactions between membrane surfaces and bacteria-related matter but also by the smoothness of membrane surfaces. Nanocellulose materials generally have very smooth surfaces. Therefore, it would be hard for biofouling to occur on them. In addition to downsizing pore spaces, chemical modification of nanocellulose surfaces must be available to capture and eliminate microbes. As described in Sect. 4.2, silver nanoparticles (AgNPs) could be added to the surface of nanocellulose chemically. Since AgNPs could show antiviral effects, the chemical surface modification of nanocellulose membrane components might work well. Not only bacteria but also viruses could be eliminated by chemical surface modification. However, the evaluation technique is not currently universal for viruses. Therefore, the investigation and confirmation of the effect should be one of the future tasks. This topic will be discussed in Sect. 5. However, bacteria can be captured and controlled by the addition of the antifouling effect through chemical modification.
4.2
Medical Application
Nanocellulose has been developed for medical applications. Some of the products are still at the investigation stage, while others have already been put to practical use. However, the market of medical nanocellulose for the near future would be 97 billion US dollars as of 2017 [24]. Therefore, the development of nanocellulose materials and their application to the medical field are expected to be rapidly accelerated. The most promising field in medical and life science is the application to drug delivery systems [25–28]. They have been investigated to apply to suitable tablets or co-stabilizers. Nanocellulose-based drug carriers are divided into three categories – microparticles, hydrogels, and membrane films. Using the unique characteristics of nanocellulose appropriate and successful drug delivery systems have been realized. Since nanocellulose has excellent mechanical properties and good biocompatibility, it has been investigated for the application to tissue bio-scaffolds. Due to the same characteristics, nanocellulose has been studied for use in medical biomaterials. For those applications, most are still at the research stage. The most advanced applicability belongs to the replacement of blood vessels which has already been confirmed in animal trials. Antifouling properties of nanocellulose are related to the work described above. As already mentioned, nanocellulose itself does not have a strong antibacterial effect since it has affinity to organisms and does not have high toxicity since it is derived from natural resources. However, antibacterial matter could be incorporated into
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nanocellulose in various ways. Nanocellulose is basically and originally a porous material made up of networks of cellulose fibers. Even though the pore sizes might be at the molecular level, it means that antibacterial matters could be penetrated into micro- or nano-pores successfully. Antibacterial nano-inorganic particles could mechanically enter the pores. Using such a concept, many kinds of antibacterial inorganic materials were investigated. The most promising one was silver nanoparticles (AgNPs) [29, 30]. AgNPs are very well-known for the high antibacterial effect. In addition to the effect, they show antifungal and antiviral effects. Therefore, AgNPs are expected to be used for broad anti-infection purposes. Mechanical and direct mixing are seen as the simplest methods. However, the most investigated way for the hybridization was not by mechanical mixing but by using chemical processes. In fact, when considering the application to membranes, such a mechanical mixing and penetration into pores might be a cause for serious clogging. Furthermore, the homogeneous distribution of nanoparticles through direct mechanical mixing is generally very difficult. Usually, nanocellulose membranes are immersed into a AgNO3 solution with strong reducing agents. Then, silver nitrate is chemically attached well and effectively to the edge of side chains. In the same way, many oxides have been investigated to add antibacterial effects to nanocellulose. AgNPs have been applied to all types of nanocellulose: BC, CNF, and CNC. Other than AgNPs, some oxides have been investigated. For example, ZnO, TiO2, and Ag2O were applied to CNC as films [31–33]. ZnO, TiO2, and CuO were also applied to CNF as nanocomposites, nanofibrils, and paper sheets. ZnO was hybridized to BC as films and sheets [34, 35]. MgO was also hybridized to BC as membranes [36]. All of them were confirmed for their antibacterial effect for E. coli, S. aureus, K. pneumoniae, etc. Organic compounds were also hybridized to nanocellulose. Representative organic compounds were benzalkonium chloride (BZC), polyhexamethylene biguanide (PHMB), and povidone-iodine (PI) [37–39]. Recently, chitosan made from chitin, a natural antimicrobial agent, has attracted researchers’ attention for the purpose [40, 41]. Even though original nanocellulose does not have serious toxicity, the hybridization of organic compounds to nanocellulose might increase toxicity as a result in some cases. Toxicity is basically an amount-depending property. Therefore, appropriate design for those hybridizations will be needed regarding quantity. When an antibacterial effect is added to nanocellulose, the number of pathogenic bacteria, fungi, and even viruses attached to the surface of nanocellulose can be expected to decrease. Then, biofilms would be controlled and as a result, infection would be reduced. Therefore, such an antibacterial nanocellulose would work well for medical applications in addition to their inherent excellent properties. Strictly speaking, the antibacterial effect and anti-biofilm characteristics should be differentiated. Even though a material might have high antibacterial effect, it does not always have a high anti-biofilm property. The concept of biofilms is much broader, and the antibacterial effect is only one step of biofilm formation and growth processes. Many other factors would be involved for biofilm formation and growth in a longer period. However, the concept of antibacterial effect is included in the biofilm-related factors
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and would affect their formation and growth. It should be mentioned that the addition of the antibacterial effect to material surfaces is meaningful and important to control infections.
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Antiviral Characteristics: Future Problems
Nowadays, the pandemic caused by COVID-19 has been issued and drastically changed our world and daily lives. Therefore, people are concerned about how long viruses could remain active on various materials. From this viewpoint, the virus activity on cellulose and particularly nanocellulose is still unknown, and there is insufficient scientific data at this point. However, there are some tips and findings at the cradle stage. Membranes catching viruses mechanically have been developed. Usually, the pore size of membranes is critical to eliminate viruses, as already described. Principally, viruses can be eliminated by membranes. As for the antiviral characteristics of nanocellulose itself, it is not yet clear. This concept includes the process of attachment of viruses and also the keeping capability of viral activities on nanocellulose. As for the evaluation of antiviral properties of materials themselves, the international standard was established by a Japanese noncommercial organization, called SIAA (the Society of International Sustaining Growth for Antimicrobial Articles), a couple of years ago. It is defined as ISO 21702. Originally, SIAA made contributions to make the standard for the evaluation of the antibacterial effect of materials as ISO 22196:2007 (Fig. 6) [42]. In the standard, the concept of a film-covering method was created. On the material surface, a bacterial solution is placed with parts of the material surface covered with polymer films. Then, after a certain incubation time, the films and materials are washed to obtain bacteria in the petri dishes. After a certain time, the solution with viruses is applied to a solid culture media. Then, the colony number on the culture is counted, with the number corresponding to the antibacterial effect of materials. As for antiviral evaluation, a similar film-covering process can be applied. However, it is impossible for us to count the viral activity on culture media by using the naked eye. Therefore, the viral solution washed down to the petri dish is applied to a particular cell in this case. The cell has died due to the active viruses. As a result, one can observe macroscopic circle areas on the culture with cells. It is called “plaque,” and the number of plaque corresponds to the viral activity. This film-covering viral evaluation for material surfaces will make it possible for us to evaluate how long various viruses can remain active (Fig. 7) [43]. Since COVID-19 brought about a pandemic, people often say that COVID-19 could keep active on stainless steel for 7 days and only 2 days on materials made of wood. The tendency would depend on the type of viruses present. Also, the experimental conditions (temperatures, humidity, surface conditions of materials, etc.)
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Fig. 6 Measurement method for antibacterial effect of materials (ISO 22196)
Fig. 7 The plaque assay for antiviral measurement of materials (ISO 21702)
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would affect the results. The authors are now going to apply the standard test to various materials. Nanocellulose is one of our important targets. Incorporating such an experiment would lead to a better understanding of the antiviral properties of nanocellulose.
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Conclusion and Future Prospects
In this chapter, we described the antibacterial, anti-biofilm, and antiviral aspects of nanocellulose. At this point, the differences among those so-called anti-infectious capabilities of materials might be ambiguous. For example, what should we differentiate clearly between antibacterial and anti-biofilm characteristics? Both are related to bacterial activities and they are correlated to some extent. In most cases, the antibacterial effect of materials would also be applied to the antiviral one. Even though the resemblance is reasonable in the light of the similar outer structures for bacteria and viruses, we might get a chance to improve the effect of countermeasures much more by focusing on the differences and utilizing them. Now we are still suffering from the COVID-19 pandemic. Therefore, the market for antibacterial, anti-biofilm, and antiviral technologies is expanding drastically. According to a market forecast, the current size of 30 billion US dollars will be increasing at the pace of 7–8% every year for the next 10 years. Then the detailed analyses and technological examinations mentioned above will be required. Nanocellulose must play an important role in our future markets. Acknowledgment A part of this work was supported by GEAR 5.0 Project of National Institute of Technology (KOSEN) in Japan.
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Contents 1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1 Organic Nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2 Inorganic Nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3 Carbon-Based Nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Nanocellulose for Flexible Energy and Electronic Device . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Nanocellulose for Wound Healing Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 3-D Bio-Printed Nanocellulose for Tissue Engineering . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Nanocellulose for Food Packaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Nanocellulose for Water Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Abstract
Cellulose, one of the most widely used polymeric materials, contains β-1,4-linked glucopyranose units with each glucopyranose unit having three hydroxyl groups. The hydroxyl groups confer high hydrophilicity and biodegradability to cellulose and their ability to form strong hydrogen bonds provides cellulose with high strength and insolubility in water and usual solvents. Nanocellulose is either isolated from plants or synthesized by bacteria and possess unique properties of high strength, low density, high crystallinity along with biodegradability and biocompatibility. Nanocellulose does not have some features of electrical, magnetic, and antibacterial properties that limit its utility in some biomedical applications. This is overcome by decorating nanocellulose with nanoparticles depending on the desired end-use of the system. Metal oxide nanoparticles decoration confers special optical, electronic, magnetic, and antibacterial T. Khan (*) · J. Shaikh Department Pharmaceutical Chemistry, SVKM’s Dr. Bhanuben, Nanavati College of Pharmacy, Mumbai, Maharashtra, India e-mail: [email protected] © Springer Nature Switzerland AG 2022 A. Barhoum (ed.), Handbook of Nanocelluloses, https://doi.org/10.1007/978-3-030-89621-8_22
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properties to the system and have been developed with appealing outcomes. Nanocellulose/metal oxides hybrids demonstrate significant antibacterial, magnetic, sensing properties, improved absorption as required in packaging, wound healing, magnetic resonance imaging, drug delivery, bioseparation, and water purification applications. This review is an effort to highlight the applications of nanoparticle decorated nanocellulose for improved performance across diverse utility sectors. Keywords
Nanocellulose · Nanoparticles · Tissue engineering · Water treatment · Food packaging Abbreviations
Ag AgNPs Al Al2O3 Al2O3 Au BB BC BCF BCM BCP BNC C.F CA CBNs Cd CeO2 CNCs CNF CNFs CNFs CNT Co Cu CV DAPT DH DI E. coli ECHs EDS
Silver Silver nanoparticles Aluminum Aluminium oxide Aluminum oxide Gold Bambusa bamboos Bacterial cellulose Bacterial cellulose fibrils Bacterial cellulose membranes Bacterial cellulose pellicle Bacterial nanocellulose Citrobacter freundii Cellulose acetate Carbon-based nanoparticles Cadmium Cerium oxide Cellulose nanocrystals Cellulose nanofibrils Cellulose nanofibers Cellulose nanofibrils Carbon nanotubes Cobalt Copper Cyclic voltammetry 4,6-diamino-2-pyrimidinethiol Dendrocalamus hamiltonii deionized Escherichia coli Electro conductive hydrogel Energy dispersive spectroscopy
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Fe Fe2O3 FO FTIR GCD GO HA HAF hMSCs HRTEM HUVEC LBNPs LIB LSPR LVP LVP MFC MO NaOH NC NCC NFC NPs nZnO ONC PANI Pb Pd PE PHBV PPy PSF Pt PVA RGO S.E SEM SiO2 SiO2 TEA TEM TEMPO TGA TGF-β1 TiO2
Iron Iron oxide Forward osmosis Fourier Transform Infrared Spectroscopy Galvanostatic charge/discharge Graphene oxide Hydroxyapatite Human fibroblast Human mesenchymal stem cells High-resolution transmission electron microscopy Human umbilical vascular endothelial Lipid-based nanoparticles Li-on batteries Localized surface plasmon resonance Lithium vanadium phosphate Lithium vanadium phosphates Micro-fibrillated cellulose Methylene orange Sodium hydroxide Nanocellulose Nanocrystalline cellulose Nano-fibrillated cellulose Nanoparticles Nano zinc oxide Oxidized nanocellulose Polyaniline Lead palladium Polyester Poly 3-hydroxybutyrate-co-3-hydroxyvalerate Polypyrrole Polysulfone platinum Polyvinyl alcohol Reduced graphene oxide Staphylococcus epidermis Scanning electron microscope Silica oxide Silicon dioxide Triethanolamine Transmission electron microscopy Tetramethylpiperidine-1-oxyl Thermogravimetric analysis Transforming growth factor beta-1 Titanium oxide
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TOBC TOC TOCNFs TPP XPS XPS XRD Zn ZnO ZrO2
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Tempo-oxidized bacterial cellulose Total organic count Cellulose nanofibers Sodium tripolyphosphate X-ray Photoelectron Spectroscopy X-ray photoelectron spectroscopy X-ray diffraction Zinc Zinc oxide Zirconia
Introduction
Biodegradable and/or bio-based polymers are increasingly being used to replace synthetic polymers [1]. Anhydroglucose units are glucose molecules joined together by 1,4-glucosidic linkages to produce cellulose polymer strands. Anhydrocellobiose is made up of two anhydroglucose units. Nanocellulose is generally extracted from cellulose which generally has a size range of less than 100 nm in diameter and length in several micrometers with a density of 1.6 g/cm3 [2]. Based upon the differences in their structures and morphologies, nanocelluloses classified as nanocrystalline cellulose (NCC) are also called cellulose nanocrystals/cellulose microcrystals/cellulose nano-whiskers; bacterial cellulose (BC) also called microbial cellulose [3], nanofibrillated cellulose (NFC) also known as cellulose nanofibrils (CNFs)/cellulose nanofibers (CNFs)/micro-fibrillated cellulose (MFC) [4]. Various types of nanomaterials have been produced at nanoscale using nanotechnology. Nanoparticles (NPs) are a broad category of materials that comprise particulate compounds with a minimum diameter of 100 nm [5]. A variety of techniques can be used to create nanoparticles. They are commonly dispersed in a wide range of hosts, such as glass or a liquid solvent, but they can also be prepared in the gas phase to form an aerosol. Solution-phase syntheses have proven to be the most practical and adaptable, with majority of current research focus on colloidal approaches employing polar and nonpolar solvents as the reaction media [6]. NC has been utilized to generate functional nanocelluloses as well as to improve mechanical properties by combining nanocelluloses with antibacterial agents and metal/metal oxide NPs such as Ag-NP, ZnO-NP, CuO-NP, and Fe3O4-NP [7]. In the last several years, several book chapters, review articles, and research papers have been published on the application of nanocellulose decorated with nanoparticles as reinforcing agents in diverse areas ranging from biosensors to energy storage devices [8], flexible electronics [9], enzyme immobilization, wound healing [10], biodegradable packaging, oxygen barrier [11], CO2 absorbent materials, water purification [12], and oil recovery illustrating the evolving landscape of nanocellulose-based materials across a diverse range of applications [13]. Various applications of nanocellulose in wound healing are achieved through chemical modification of NC, cellulose nanocomposites, NC decorated with
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nanoparticles, NC functionalized with antibacterial agents, and 3-D printed NC materials for wound healing [14]. Nanoparticle decorated NC has been utilized in food packaging applications as the most important function of food packaging is to keep food items fresh and safe throughout storage and transit. As a result, it is critical to protect food from spoiling caused by microbes and chemical pollutants, as well as absorption of water vapor, oxygen, carbon dioxide, volatile chemicals, and moisture, as well as exposure to light and external physical forces. Packaging materials comprising of NPs decorated NC offer attractive features of physical protection and generate appropriate physicochemical conditions, thereby ensuring the quality of food [1].
2
Nanoparticles
Nanoparticles (NPs) are a broad class of materials that comprise particulate compounds with a minimum size of 100 nm. These materials are not simple molecules and therefore they can be 0D, 1D, 2D, or 3D depending on the overall shape [5]. They are composed of three layers: (A) the surface layer that can be functionalized using a range of diverse small molecules, surfactants, metal ions, and polymer; (B) the shell layer, that is chemically and physically distinct from the core; (C) the core, that is the NPs central part and generally referred to as nanoparticles itself [15]. NPs are classified into several types based on their shape, size, and chemical characteristics. Some of the most well-known classes of NPs are listed below, based on their physical and chemical properties.
2.1
Organic Nanoparticles
Organic NPs or polymers are also known as dendrimers, polymeric micelles, liposomes, and ferritin nanoparticles. They are biodegradable, non-toxic, and some include a hollow core, such as micelles and liposomes also known as nanocapsules. They are sensitive to thermal and electromagnetic radiation such as heat and light. Apart from their common characteristics such as size, composition, surface shape, they also determine the drug carrying capacity, stability, and delivery systems, apart from drug entrapped or adsorbed drug system, affect their area of applications and efficiency [16].
2.1.1 Polymeric Nanoparticles Polymers are macromolecules made up of a high number of repeating units arranged in a chain-like molecular structure that can have a wide range of compositions, structures, and characteristics [17]. Polymeric nanoparticles are organic based that have small particles with a diameter of 1–1000 nm that can be loaded with active compounds within or surface-adsorbed to the polymeric core [18]. The former are matrix particles with a solid overall mass, whereas the latter are adsorbed with other
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molecules at the outer border of the spherical surface [19]. Polymeric nanoparticles are mostly employed in the delivery of drugs and also used in bioimaging and biosensing assays [20]. In a recent study, Huang et al. compared the effects of BC membranes for delivering berberine hydrochloride and berberine sulfate to commercial tablets. BC has been identified as a potential drug carrier for greatly extending the duration of model drug release [21].
2.1.2 Liposomes Nanoparticles Liposomes are lipid-based vesicles that have been intensively studied as unique and targeted drug delivery nanocarriers [22]. They are made by substituting the liquid lipid in an emulsion with solid lipid that is solid at room and body temperatures. Drug molecules can be encapsulated in a number of places inside lipid-based nanoparticles (LBNPs). Lipophilic drugs are distributed throughout the lipid matrix, whereas hydrophilic drugs separate to the exterior of lipid matrix [23]. Clinical studies on anticancer, antibiotics, antifungal, and gene-delivery for liposomal nanoparticles have taken place. The anticancer drugs cytosine arabinoside was utilized in some of the early experiments to increase in vivo activity of liposome-entrapped medicines in animal models, mice with L1210 leukemia [24].
2.2
Inorganic Nanoparticles
Nanoparticles that are not composed of carbon are known as inorganic nanoparticles and inorganic nanoparticles are made up of metal and metal oxide nanoparticles.
2.2.1 Metal-Based Nanoparticles They are purely made and synthesized from metals to nanometric sizes using destructive or constructive techniques. Most of the metals can be transformed into nanoparticles. Aluminum (Al), cadmium (Cd), cobalt (Co), copper (Cu), gold (Au), iron (Fe), lead (Pb), silver (Ag), and zinc (Zn) are the widely utilized metals for nanoparticles synthesis [23]. These NPs have unique optoelectrical properties due to their well-known localized surface plasmon resonance (LSPR) characteristics. Metal NPs are used in a variety of scientific fields due to their superior optical characteristics. Gold NPs coating is commonly used for SEM sampling to improve the electronic stream, which aids in the acquisition of high-quality SEM pictures [25]. 2.2.2 Metal Oxides-Based Nanoparticles Metal-based nanoparticles are synthesized to amend their properties to form metal oxide-based nanoparticles. For example, The reactivity of iron NPs is increased in the presence of oxygen at room temperature to form iron oxide (Fe2O3) nanoparticles [26]. Aluminum oxide (Al2O3), cerium oxide (CeO2), iron oxide (Fe2O3), magnetite (Fe3O4), silicon dioxide (SiO2), titanium oxide (TiO2), and zinc oxide (ZnO) are the widely synthesized nanoparticles and exhibit unique characteristics in comparison to their metal counterparts like copper, iron, gold, and silver [27].
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2.2.3 Ceramic Nanoparticles Ceramic NPs are nonmetallic inorganic solids that are made by heating and cooling methods. They are amorphous, polycrystalline, dense, porous, and in hollow shapes [28]. New synthetic approaches were used to enhance the physical-chemical characteristics of nanoscale ceramics such as hydroxyapatite (HA), zirconia (ZrO2), silica (SiO2), titanium oxide (TiO2), and alumina (Al2O3) in order to minimize their cytotoxicity in biological systems [20]. However, the usage of novel ceramic materials elicited negative reactions from the host (in a variety of tissues, including immune system). In terms of ceramic nanoparticle use in biomedicine, regulated drug release is one of the most explored fields [29].
2.3
Carbon-Based Nanoparticles
Carbon-based nanoparticles (CBNs) are composed entirely of carbon. Fullerenes, graphene, carbon nanotubes (CNT), carbon nanofibers, carbon black, and occasionally activated carbon of nano size are examples of carbon-based NPs [16]. Carbonbased materials offer a good surface-to-volume ratio, thermal conductivity, stiff structural characteristics that can be modified post-chemically, and good biocompatibility [30]. As a result, CBNs are used in a variety of biological applications, including drug delivery applications, tissue scaffold repairs, and cellular biosensors [31]. Examples of nanoparticles with nanocellulose hybrids in various fields for improved performance is illustrated in Table 1. Nanoparticles Decorated Nanocellulose Nanocellulose reinforced with nanoparticles composites have been studied in many fields. Although the study focus, methodology, and outcomes of these studies differ, they all have the same end goal: to build functional materials with high performance and added value by utilizing nanocellulose advantages of lightweight, high strength, cheap cost, and renewable sources [45]. In the framework of sustainable nanotechnology, diverse types of NCs have already drawn substantial attention, thus functionalization and mass manufacturing are two issues that need to be addressed in order to boost its industrial application and utilization. We discuss here the diverse and evolving applications of NPs decorated NC in electronic and energy devices, wound healing, drug delivery strategies, tissue engineering, food packaging, and water treatment. A schematic illustration of application of nanocellulose with nanoparticles is presented in Table 2. Table 1 Examples of nanoparticles decorated with nanocellulose hybrids Sr. No. 1. 2. 3.
Nanoparticles Organic nanoparticles Inorganic nanoparticles Carbon-based nanoparticles
Applications Wound healing, food packaging, electronic devices Food packaging, wastewater treatment, electronic devices, wound healing Wastewater treatment, 3-D inks
Reference [32, 33] [34–41] [42–44]
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Table 2 Summary of application of nanocellulose with nanoparticles Sr. No 1.
Nanocellulose Cellulose nanofibrils
Modified nanocellulose with nanoparticles Cellulose nanofibrils decorated with reduced graphene oxide and carbon nanotubes showed a great potential as flexible electronic device. Cellulose nanofibrils with graphene oxide and polypyrrole form a film by chemical reduction process. They showed a great potential for portable energy storage device. Cellulose nanofibrils with carbon nanotubes and polyaniline form a hydrogel by in situ oxidative polymerization. They showed great potential for wearable electronic devices. Cellulose nanofibrils and carbon dots were prepared using ultrasonic treatment. They exhibit a promising hybrid film for photoluminescent. Cellulose nanofibrils and silver nanoparticles were prepared via in situ reduction. The hydrogel form showed a great potential for wound dressing material. Cellulose nanofibrils and carbon nanotubes showed a great potential for electronic devices in treatment of arrhythmia. Cellulose acetate nanofibrils with graphene oxide prepared via electrospinning technique showed a great potential for bone damage repair and tissue engineering. Cellulose nanofibrils with dextran coated silver nanoparticles showed a great potential for food packaging material. Cellulose acetate nanofibrils with hydroxyapatite prepared via ultrasonicassisted mixing method resulted as a potential material for water purification membrane. Nanocellulose with silver and platinum nanoparticles prepared via in situ chemical reduction showed to have great potential for forward osmosis membrane.
Reference Zheng
Hou
Wang
Jiang
Shin
Pedrotty
Liu
Lazic
Pandele
Tato
(continued)
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Table 2 (continued) Sr. No
Nanocellulose
2.
Bacterial cellulose
Modified nanocellulose with nanoparticles Cellulose acetate with activated carbon prepared via thermal-induced phase separation showed utility in waste water treatment. Bacterial cellulose fabricated with silver nanoparticles on reducing with silver nitrate showed a strong antibacterial activity and good biocompatibility for wound dressing material. Bacterial cellulose-silver nanoparticles prepared via in situ process from hydrolytic decomposition showed strong antimicrobial activity. Bacterial cellulose synthesized via in situ process of SiO2 coated with Cu nanoparticles showed good antibacterial property. Bacterial cellulose and casein impregnated with iron nanoparticle showed good antibacterial property for wound healing applications. Bacterial cellulose pellicle with silver nanoparticles results in 100% antibacterial activity with high biocompatibility for wound healing. Bacterial cellulose with nano zinc oxide modified via in situ synthesis process showed good potential for antibacterial wound healing applications. Bacterial cellulose with DAPTmodified gold nanoparticles prepared via impregnation that result in good antibacterial property. Bacterial cellulose pellicles with silver nanoparticles prepared after impregnation results to promote a good wound healing property. Bacterial cellulose with reduced graphene oxide prepared via freezedrying process results exhibit a great potential for medical devices and biosensors. Bacterial cellulose with palladium and graphene oxide prepared by in situ process resulted to form a potential membrane for ultrafiltration.
Reference Bai
Tabaii
Barud
Ma
Patwa
Wu
Luo
Li
Pal
Jin
Xu
(continued)
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Table 2 (continued) Sr. No
3.
3
Nanocellulose
Cellulose nanocrystals
Modified nanocellulose with nanoparticles Bacterial cellulose with activated carbon and lead showed a great potential as bioadsorbent materials. Bacterial cellulose with ferric oxide prepared via pH-controlling embedding process showed a great potential as adsorption membrane for heavy metal ions. Cellulose nanocrystals with silver nanoparticles synthesized via peroxidate oxidation showed a good antibacterial property against wound healing. Cellulose nanocrystals with silver nanoparticles synthesized via in situ process showed strong water absorption capacity and antibacterial property. Cellulose nanocrystals with silver nanoparticles and PHBV prepared via solution casting method results exhibit a promising material for food packaging materials. Cellulose nanocrystals with silver nanoparticles and PHBV matrix prepared by one-pot green synthesis. The results exhibit a promising domain for disposable overwrap films. Cellulose nanocrystals with graphene oxide and PHBV matrix prepared by solution casting method. The results showed as a promising tool for food packaging material.
Reference Huang
Zhu
Drogat
Singla
Zhang
Yu
Li
Nanocellulose for Flexible Energy and Electronic Device
Zheng et al. prepared a solid-state supercapacitor aerogel electrode from cellulose nanofibrils (CNF)/ reduced graphene oxide (RGO)/ carbon nanotubes (CNT). The SEM image of CNF/RGO/CNT aerogel film with a thickness of about 200 μm showed an electrical conductivity of 12 S m1, equivalent to activated carbon. Although, the size reduced to the nanoscale showed the highly porous microstructure of the aerogel preserved in the compressed CNF/RGO/CNT aerogel film. The X-ray diffraction (XRD) pattern of aerogel film showed a strong diffraction peak of CNF/RGO/CNT aerogel at 2θ ¼ 10.8 , corresponding to the (002) lattice planes of the graphene oxide nanosheets. Cyclic voltammetry (CV) and galvanostatic charge/
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discharge (GCD) tests have been used to evaluate the electrochemical performance of the electrode made from the CNF/RGO/CNT aerogel films. Specific capacitance, energy density, and power density of all-solid-state flexible supercapacitors of compressed CNF/RGO/CNT aerogel film as electrode were found to be 252 F g1, 8.1 mW h g1, and 2.7 W g1, respectively. Furthermore, the supercapacitors demonstrated outstanding cyclic stability, with over 99.5% specific capacitance remained after 1000 charge/discharge cycles. The CNF/RGO/CNT aerogel film may be a potential electrode material for producing lightweight, flexible, low-cost, and rechargeable energy-storage devices due to its high electrochemical performance, great process scalability, cheap cost, and environmentally friendly. Figure 1 represents the synthesis process of CNF/RGO/CNT aerogel film [46]. Hou et al. prepared a novel film for supercapacitor electrode from CNF, reduced graphene oxide (RGO), and polypyrrole (PPy). The resultant sandwich-like film had the bulk PPy encased in RGO/CNF framework, resulting in a free-standing and extremely flexible supercapacitor electrode. The S-PRC film shows strong electrostatic and π-π interactions between RGO and PPy-based composite (PPyc) caused the RGO/CNF and PPyc layers to cling and stack together tightly. The electrochemical performance of sandwich-like film electrode has a high specific capacitance of 304 F g1 and good cycling performance, retaining 81.8% of capacitance after 1000 cycles. Based on the obtained films, a solid-state symmetric supercapacitor showed a high specific capacitance of 625.6 F g1 at 0.22 A g1, a maximum volumetric energy density of 21.7 Wh kg1 at a power density of 0.11 kW kg1, and capacitance retention of 75.4% after 5000 cycles was successfully fabricated. These
Fig. 1 Synthesis process of fabrication of CNF/RGO/CNT aerogel film as a supercapacitor electrode
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findings showed that the sandwich-like film electrode provided was a potential alternative technique for the development of future portable energy storage devices that are lightweight and flexible [37]. Wang et al. have developed an electroconductive hydrogel (ECHs) as a potable energy-storage devices through in situ oxidative polymerization process to form the “core –shell.” In this study, carbon nanotubes (CNT), polyaniline (PANI) were used as an electrode and 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO)-cellulose nanofibers (TOCNFs) were used as a bio-dispersant. The UV-visible spectroscopy shows the transition between the inter-band and the polaron band of PANI produced two peaks of TOCNF-CNT@PANI-2 at 285 and 475 nm, respectively. Because of the cross-linking of polymer chains, the end band (800 nm) of the TOCNFCNT@PANI-2 complexes was smooth, indicating that it was successful in doping PANI into the conductive state. The XRD diffraction revealed that peaks of CNFs at 2θ ¼ 15 has vanished with the addition of PVA hydrogel, and a broad new peak at 2θ ¼ 22.2 arose, containing the diffraction peaks at 2θ ¼ 19.4 which correspond to the orthogonal lattice from PVA with a semi-crystalline structure. All of this demonstrated significant contacts between PVA, borax, and TOCNF-CNT@PANI-2 nanocomposite in the composite hydrogels, forming a 3-D network. The ECH has excellent mechanical toughness (σs ¼ 128 kPa cm3 g1 and Ee ¼ 61 kPa), strong viscoelastic properties (G’1 ¼ 18.2 kPa and G’max ¼ 7.6 kPa), and excellent electroconductivity (upto 15.3 S m1). At a current density of 0.4 A g1, the TOCNF-CNT@PANI/PVA-2 hydrogel electrode had a specific capacitance of 226.8 F g1. Due to the reversible and dynamic borate-associated network, the ECHs displayed quick self-healing within 20 s at room temperature and exceptional flexible performance. The overall studies exhibit that ECHs provide a new platform for personal wearable electronic devices. Illustration of synthesis process of TOCNF-CNT hybrids film PVA and PANI (Fig. 2) [47]. Jiang et al. have developed a photoluminescent hybrid film from TEMPOoxidized nanocellulose and carbon dots (ONC). According to a covalent crosslinking between carboxyl groups of ONC and amino groups of freshly generated CDs, transparent CDs/ONC hybrid films exhibiting blue luminescence following UV illumination at 365 nm were successfully achieved. The ONC has a size of 1–2 μm in length and around 30 nm in breadth, according to the TME image. The DLS measurement of the CD size distribution corresponds to the HRTEM results, suggesting that the particle size spans mostly between 6 and 11 nm. CD clearly conjoin ONC nanofibrils, showing that CDs have effectively adhered to the ONC surface. Using quinine sulfate as a reference, the quantum yield of CDs terminated with amino groups was found to be 10.27%. The XRD diffraction pattern for NC, ONC, and CD/ONC hybrid film were found to be 14.70, 16.50, 22.70, and 35.00. They were assigned at the 101, 101, 200, and 040 reflections of cellulose I. The hybrid film photoluminescent (PL) intensity, after 2000 cycles of bending, shows a negligible drop of less than 5%. Further stating that this hybrid film can be used to synthesize photoluminescent CD [43]. Zhang et al. prepared Li-on batteries (LIB) through lithium vanadium phosphate (LVP) and nanofiber carbon (NC) multi-structure self-assembly framework. The
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Fig. 2 Schematic representation of fabrication of TOCNF-CNT@PANI/PVA composites hydrogel
synthesized nanofiber exhibited short-rod like structure with a diameter of 20–50 nm and length of 100–300 nm. The initial specific capacity of LIB cathode is 131.6 mA h/g that is close to the theoretical value of 133 mA h/g. Even when the temperature rises to 30 C, it can still indicate 109 mA h/g as specific capacity. The composites also have a good long-cycle performance. After 1000 cycles at a temperature of 10 C, it retains 90% of its capacity. These bead-like LVP-NC composites have good application value, simple and low-cost synthesis approach can be employed to manufacture high-performance cathode materials in the future [48]. Thus, we can state that functional nanocellulose will provide new possibilities for the design of flexible energy and electrical materials, which is crucial in the development of the next generation of green materials.
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Nanocellulose for Wound Healing Applications
Wound healing has been extensively researched in an attempt to establish an “optimal” approach for achieving rapid recovery while reducing scarring and maintaining function. A wound is a breakdown in the skin epithelial cells and that can be followed by damage to the structure and function of normal tissue surrounding it [49]. Wound healing is a complex and biological process that results in repair and regeneration of the damaged skin tissue [50]. The purpose of wound healing is to
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restore epithelial cells and the function, integrity, and strength of the skin [51]. Hemostasis, inflammation, proliferation, and remodeling with tissue formation are the four stages involved in wound healing [52]. Tabaii et al. developed an antimicrobial membrane composed of silver nanoparticles (AgNPs) and bacterial cellulose (BC). AgNPs/BC membranes have been formed using sodium tripolyphosphate (TPP) and sodium hydroxide (NaOH) by reducing silver nitrate as a substrate and permeated into bacterial cellulose membranes. The analysis of both the membrane one treated with TPP and NaOH has been done by SEM, UV-Visible spectroscopy, and X-ray diffraction. The results indicated showed that the water holding capacity was found to be 164. The AgNPs/BC membranes exhibit inhibition of E. coli and S. aureus with 100% and 99.99%, respectively. Thus, both nanocomposite membranes indicated strong antibacterial activity, good biocompatibility, and no cytotoxicity has a promising material for wound healing [53]. Wu et al. studied bacterial cellulose pellicle (BCP) with AgNPS for wound healing activity. The BCP was TEMPO-mediated oxidated using TEMPO/ NaClO/NaBr at pH -10 to form TEMPO-oxidized BCP (TOBCP). Subsequently, TOBCP was ion-exchanged in AgNO3 solution to form TOBCP/Ag+ and thermal reduction on TOBC nanofiber by AgNPs with a diameter of ~16.5 nm has been synthesized to form TOBCP/AgNPs. Analysis of TOBCP/AgNPs was confirmed by techniques such as SEM, X-ray diffraction, TGA, and FTIR. The SEM results showed a 3-D network of BC nanofibers on the surface of TOBCP indicating successful synthesis of nanofibers. TOBCP/AgNPs have shown significant effects for antibacterial activity to inhibit E. coli and S. aureus. The prepared TOBCP/AgNPs have good biocompatibility, thus can be used for wound healing application and illustration of tempo-oxidized bacterial cellulose (TOBC) nanofibers (Fig. 3) [54]. Drogat et al. have developed wound-healing gels from cellulose nanocrystals and AgNPs. Cellulose nanocrystals are oxidized to generate aldehyde function, by periodate oxidation to reduce Ag+ into Ag0. Transmission electron microscopy results showed spherical silver nanoparticles with a diameter of 20–45 nm and ultraviolet-visible absorption spectroscopy showed the absorbance at 425 nm was
Fig. 3 Tempo-oxidized bacterial cellulose (TOBC) nanofibers
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used to characterize the nanoparticles. The spherical shape of AgNPs has been found to be 20–45 nm from the microscope studies (TEM). Thus the studies state that AgNPs colloidal suspension was found to be a promising candidate for wound healing [55]. Barud et al. developed a nanocomposite membrane from bacterial cellulose and silver nanoparticles composites for wound healing. Composites were prepared by hydrolytic decomposition of AgNO3 solution using triethanolamine (TEA) as a reducing and complexing agent by in situ preparation of Ag nanoparticles. The SEM images of BC-Ag-TEA showed spherical silver particles attached to BC membranes and UV-absorption of nanoparticle was found to be 427 nm. The mechanical strength of the bacterial cellulose was found to be 11 GPa and tensile strength as 98 MPa with 1.2% elongation. The antimicrobial activity against S.aureus and E.coli was found to have a zone of inhibition of 2 cm and was effective for the treatment of wound healing [56]. Ma et al. synthesized an antibacterial membrane for wound healing. The bacterial cellulose (BC) was synthesized by in situ process with SiO2 coated Cu nanoparticles. Characterization of Cu-SiO2/BC membranes via XRD has shown board reflection peak at 220 and X-ray photoelectron spectroscopy (XPS) is used to determine their chemical properties and morphologies of (CuSiO2/BC) membrane. The antimicrobial activity against S. aureus and E. coli was found at 3 mm and 4 mm, respectively, could be a suitable biofilm for wound healing treatment [57]. Patwa et al. developed injectable hydrogels from casein, alginate, and iron nanoparticles loaded on bacterial cellulose (BCF). An amide and ionic crosslinking of alginate-casein with the incorporation of BCF was found to have supramolecular interaction. According to morphological analysis, iron-oxide nanoparticles were impregnated within the bacterial cellulose network with a loading of 20 wt.% and the swelling studies revealed that water uptake of hydrogels was around 4000%, making them good wound dressing materials. The porous internal structure facilitated cell viability, which was confirmed by the fibroblast MTT assay. The overall results state that alginate-casein hydrogels loaded with BCF could be a promising approach for wound healing treatment [58]. Singla et al. designed a nano bio-composites in the form of film and ointment from cellulose nanocrystals (CNCs) and silver nanoparticles (AgNPs). By the process of in situ synthesized, the AgNPs were impregnated into the cellulose nanocrystal matrix. The film and ointment were characterized by using techniques such as SEM image that revealed the smooth, porous, and ribbon shape of chemically treated fibers as compared to raw fibers. The TEM micrographs showed uniforms sized of DH-CNCs as 18 0.5 nm and 272 52 nm while BB-CNCs as 20 1 nm and 385 97 nm. The cellulose nanocrystals obtained from Dendrocalamus hamiltonii (DH) and Bambusa bamboos (BB) were used and examined for tensile strength obtained of DH/CNC/Ag as 0.024 0.005 MPa and BB/CNC/Ag as 0.032 0.008 MPa. Both the composites have shown good water uptake capacity and antibacterial activity against Staphylococcus epidermis (S.E) and Citrobacter freundii (C.F). Thus, the dual properties of both composites make it a versatile material for wound healing [59].
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Wu et al. developed a composite film from bacterial cellulose (BC) and silver nanoparticles (AgNPs). For the controlled release of Ag+ and to reduce the toxicity, the silver nanoparticles were synthesized through in situ process with bacterial cellulose as a template. A controlled release of Ag+ with no toxicity of nanoparticles were observed. Antibacterial activity against E. coli, P. aeruginosa, and S. aureus was examined that showed a good antimicrobial activity of AgNP-BC. Characterizations of AgNP-BC through SEM result in 3-D porous structure with pore size of 100 s nanometer between the BC nanofibers and AgNPs. The study revealed that AgNP-BC could decrease inflammation and facilitate the healing of wounds [60]. Moniri et al. developed nanocomposite films from bacterial nanocellulose and silver nanoparticles (AgNPs). Within the BNC structure, spherical AgNPs with particle sizes ranging from 20 to 50 nm have been synthesized and impregnated. The antibacterial activity against S. aureus, S. epidermis, and P. aeruginosa with inhibition ranges from 7 0.25 to 16.24 0.09 mm was seen by the resulting nanocomposites. The genes TGF-β1, MMP2, MMP9, CTNNB1, Wnt4, hsa-miR29b-3p, and hsa-miR-29c-3p play a significant role in wound healing based on bioinformatics databases. Thus, the results state that BNC/Ag has potential activity against wound healing [61]. Luo et al. prepared a flexible wound dressing materials with nano zinc oxide (nZnO) and bacterial cellulose membranes (BCM). The bacterial cellulose membrane was modified via chemical crosslinking (in situ synthesis) with a pore size of 20–90 μm. The enhancements of the moist environment of nZnO/BCM have shown an average water vapor transmission of 2856.60 g/m2/day. The 5 wt.% nZnO/BCM was found to show good antibacterial activity against S. aureus and E. coli that has demonstrated through bacterial suspension assay and plate count methods, while MTT assays revealed no detectable cytotoxicity in mammalian cells. As a result, the developed nZnO/BCM offers a lot of potential in biomedical applications as an antibacterial wound dressing material [40]. Shin et al. prepared antibacterial hydrogel of TEMPO-oxidized cellulose nanofibers (CNFs) with silver nanoparticles (AgNPs) via in situ reduction of silver ions and were embedded on alginate hydrogels. The antibacterial activity through bacterial cells and disk diffusion test with E. coli was assessed by confocal microscopy which showed higher intensities of red fluorescence for AgNPs/TCNF and Ag+/ TCNF. The results for both the hydrogels estimated the release amount of silver to be 11.4 g and 15.4 g, with an inhibition of bacterial growth for 24 hours. The cytotoxicity assay against NIH3T3 cells was performed which showed a minimum cytotoxicity at a concentration of 1–10 μg/ml for AgNPs/TCNF, while Ag+/TCNF showed major cytotoxicity at a concentration of 5–10 μg/ml and no cytotoxicity at a concentration of 1 μg/ml. As a result, the AgNPs/TCNF hydrogel should be a better choice for wound dressings with long-term antibacterial action [62]. Li et al. developed nanocomposites dressing for wound healing with impregnation method by using bacterial cellulose and 4,6-diamino-2-pyrimidinethiol (DAPT)-modified gold nanoparticles (Au-DAPT NPs). The field emission transmission electron microscope (FE-TEM) analysis of the BC-Au-DAPT nanocomposites fiber showed good uniformity and dispersity of Au-DAPT NPs. The antibacterial
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activities of Au-DAPT NPs against four bacteria that include E. coli, P. aeruginosa, MDR E. coli, and MDR P. aeruginosa. The results revealed that P. aeruginosa and MDR P. aeruginosa were suppressed by Au-DAPT NPs at minimal inhibition concentration (MIC) of 8 and 16 μg mL1, respectively. The MTT cytotoxicity assay on human fibroblast (HAF) cells and human umbilical vascular endothelial (HUVEC) cells. The Au-DAPT NPs only influenced the proliferation of the HAF cells and HUVEC cells at extremely high concentrations (128 μg mL1), although the cell survival rate was still as high as 91.1% and 94.7% for the HAF cells and HUVEC cells, respectively. The water uptake ability of BC-Au-DAPT nanocomposites at 1440 min for different concentration is as follows 16 > 8 > 32 > 64 > 0 > 128 μg mL1. The BC-Au-DAPT nanocomposites showed low inflammatory reactivity against in vivo experiment against rat wound models. Thus, overall studies revealed that BC-Au-DAPT nanocomposites as a new material for treating MDR bacteria-infected wounds. The representation of the synthesis process of BC-Au-DAPT nanocomposites (Fig. 4) [63]. Pal et al. designed an antibacterial membrane using bacterial cellulose pellicles and silver nanoparticles. After impregnation, Ag+ ions linked to BC fibers and turned into Ag nanoparticles when exposed to UV light, as shown by the composite color shift from colorless to amber. The reflections of the face-centered cubic metallic silver (JCPDS #76–1393) in the Ag/BC nanocomposite produce well-defined additional diffraction peaks at 38.1, 44.2, 64.4, and 76.7 , respectively, confirming the presence of silver nanoparticles in the Ag/BC nanocomposite. Individual particles, measuring around 5–12 nm in diameter were adhered to the surface of the cellulose
Fig. 4 Schematic illustration of the fabrication process of BC-Au-DAPT nanocomposites
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nanofiber, were clearly visible (indicated with red circles) using energy dispersive spectroscopy (EDS) elemental mapping. Antibacterial activity of composites, such as pellicles, as measured by disc diffusion and growth dynamics techniques against Gram-negative bacteria (Escherichia coli) exhibited high bacteria-killing ability. Even after a long soaking time, no substantial silver release was seen from the Ag/BC pellicles. Because composite pellicles are retained in a moist environment that also promotes wound healing, the material might be effective in wound-healing therapy [41]. A wide range of materials has been employed as a composite in the future to treat wound healing. Thus, it can be new promising materials in research that show a lot of promise, so there is a hope for new therapeutic solutions in the near future.
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3-D Bio-Printed Nanocellulose for Tissue Engineering
Liu et al. prepared a hybrid nanofiber scaffold for bone tissue engineering via using graphene oxide (GO) incorporated cellulose acetate (CA) nanofibers for improved biomineralization and osteogenic differentiation of human mesenchymal stem cells (hMSCs). Tensile stress and Young’s modulus were 2.7 and 7.2 times greater in the 1.0 GO-CA nanofibrous mats than in the CA nanofibrous mats, respectively. SEM was used to examine the surface morphology and fiber diameter of electrospun CA nanofibers with and without GO inclusion. The hMSC adhesion and proliferation property of GO-CA nanofibers against the control group (TCP substrate) indicated that the addition of 1% addition of GO in CA nanofibers has improved significantly. The calcium phosphate deposition increased as the amount of GO in CA nanofiber increased, suggesting that doped-GO aided in the biomineralization of nanofibrous scaffolds. The XRD spectroscopy revealed the crystals included the components P, O, and Ca, indicating that the crystals detected by SEM were calcium phosphate. The osteogenic differentiation study result showed that the increase in calcium phosphate nanocrystals increased the ALP activity of hMSCs cultivated on GO-CA nanofibrous mats, indicating a greater level of osteogenic differentiation. The current findings show that GO-doped CA nanofibrous scaffolds enable biomineralization and create a biomimetic environment for hMSC osteogenesis, suggesting that they might be useful in bone damage repair and other regenerative medical fields [64]. Jin et al. prepared a composite film via using bacterial cellulose (BC) nanofibers and reduced graphene oxide (RGO) for tissue engineering. The fabrication of BC-RGO film was done in three steps as follows: (1) intermedius BC-41 culture, (2) self-assemble, and (3) free-drying. The schematic representation of fabrication of BC-RGO film (Fig. 5) [65]. The SEM image of the BC-RGO film revealed interconnected network between the G. intermedius BC-41 and RGO through layer-by-layer stacking. The Raman spectra, shows that the D peak clearly increases and the G band of BC-RGO film is seen at 1595 cm-1, due to the bacterial reduction of GO sheets. These BC-RGO films were identical to those seen in pristine graphite 47, indicating that the BC-RGO film was successfully reduced by using the G. intermedius BC-41. The tensile strength of
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Fig. 5 Schematic illustration of the fabrication process of BC-RGO film by (1) intermedius BC-41 culture (2) self-assemble and (3) freeze-drying
BG-RGO film was found to be 1.32 0.1 MPa, and ultimate elongation of 4.23 0.16%, respectively. The water contact angles of BC-RGO film and RGO film revealed a good hydrophilicity (14.31.3 ) of BC-RGO film compared to high hydrophobicity (92.943.2 ) of RGO film, because of high density of bacterial cellulose nanofibers embedded in it. In vitro studies show that the BC-RGO film may successfully improve hMSC adhesion, growth, and proliferation. Furthermore, as compared to RGO film, BC-RGO film has been found to be highly supportive for interaction of cells and surface of film and has a significantly superior cellular response. Thus, the overall results revealed that BG-RGO film could be a potential substrate for application in tissue engineering, medical devices, and biosensors [65]. Kuzmenko et al. developed a 3-D scaffold for tissue engineering via using CNF/CNT composite conductive ink. The single fibrils diameter was found to be 10–20 nm. The homogeneous dispersion of 20 wt.% of CNTs inside CNF hydrogel has the electrical conductivity of 3.8 101 S cm1. Assume that SWCNTs and CNFs have bulk densities of 1.35 g cm3 and 1.50 g cm3, respectively. The SH-SY5Y cell lines were used for the cell study of CNF/CNT, scaffolds showed neural tissue development with good electrical conductivity. Thus, the overall studies showed that 3-D printed inks exhibit an excellent scaffold for tissue engineering [44]. Pedrotty et al. prepared 3-D ink patch via using CNT and NFC for arrhythmia treatment. The dynamic yield stress for both the NFC and SWCNT were found to be 217 and 106 Pa, respectively. The atomic force microscopy of the NFCs and SWCNTs were found to have low surface roughness of 3.4 1.3 nm with electrical conductivity of 4.3 101 Scm1. During epicardial, ventricular pacing and mapping were performed for thoracotomy on six canines that demonstrated conduction in all six canines after activation on mapping. The patches resulted in restored
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conduction and velocities in all six canines. Thus, the study demonstrated that cardiac conduction can be improved through electrically conductive carbon nanotubes after surgically disrupted epicardial myocardium in canines [66]. The NC-based scaffolds were demonstrated to be attractive materials for regeneration of different tissue engineering and organs due to their remarkable features.
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Nanocellulose for Food Packaging
Zhang et al. prepared ternary nanocomposites film for food packaging by using cellulose nanocrystals/silver nanohybrids (CNC-Ag) and biodegradable poly (3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV). The FE-SEM microscopic showed all the nanocomposites containing 10% nanofillers had smooth fragmented surfaces with no microscopic aggregation, indicating excellent nanohybrid dispersion within the PHBV matrix. TGA and DTG were used to investigate the thermal stability of clean PHBV and PHBV nanocomposites. It is possible that the low amount of AgNPs destroys the hydrogen bonding connections between PHBV and CNCs, resulting in low thermal stability. AgNPs, on the other hand, worked as nucleating agents, increasing the crystallinity of PHBV nanocomposites and thereby promoting their thermal stability, when more Ag nanoparticles are present. The antibacterial ratio of PHBV and PHBV/CNC was negligible, but the antibacterial ratio of ternary nanocomposites was 98.9–100%, indicating that ternary nanocomposites had greater antimicrobial activity for both E. coli and S. aureus than neat PHBV and binary nanocomposite with only CNCs addition. Thus, the overall properties of these ternary nanocomposites have shown considerable promise as food contact packaging materials [67]. Yu et al. prepared a biodegradable nanocomposite film from poly(3-hydrxybutyrate-co-3-hydroxyvalerate) (PHBV) and cellulose nanocrystals/silver (CNC-Ag) nanohybrids. It is a one-pot green synthesis consisting of Fischer esterification and redox reaction that may successfully create corn-like CNC-Ag nanohybrids with great thermal stability and, because of its hydrophobic ester groups, may have good miscibility with the PHBV matrix. The representation of synthesis process of CNC-Ag nano-hybrids with inclusion in PHBV (Fig. 6) [68]. The FE-SEM micrograph showed nanoparticles with sizes of around 20–40 nm were evenly formed on the CNC surface. Furthermore, the crystallinity derived from DSC curves (XDSC) showed that when the CNC-Ag concentrations rose, to 53.7% for the nanocomposite with 10 wt.% CNC-Ag, then decreased to 50.0% for the nanocomposite with 15 wt.% CNC-Ag. The nanocomposites containing 10 wt.% CNC-Ag have a 140% increase in tensile strength and a 200% increase in Young’s modulus when compared to pure PHBV. Thermal analysis of nanocomposites was found as T0, T5%, Tmax, and Tf values rose by 23.7, 20.7, 34.2, and 27.8 degrees Celsius, respectively. Furthermore, increasing CNC-Ag concentration resulted in significant decreases in water absorption and WVP values. The antibacterial activity of nanocomposites revealed a good antibacterial activity against E. coli and S. aureus. According to the findings, high-performance nanocomposites have a lot
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Fig. 6 Schematic representation of synthesis of CNC-Ag nanohybrids and inclusion into PHBV
of promise in the domains of food, beverage packaging, and disposable overwrap films [68]. Li et al. prepared a novel composite using cellulose nanocrystals (CNC), graphene oxide (GO), and poly (3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) for food packaging through a simple solution casting method. The SEM image of PHBV matrix incorporated with CNC in concentrations range of 1–3 wt.% was found to have smooth fractured morphology. Covalently bonded 1 wt.% CNC-GO showed a 170.2% increase in tensile strength, a 137.5% rise in Young’s modulus, and a 52.1% improvement in elongation to break when compared to neat PHBV. The Tmax was increased by 26.3 C for the ternary nanocomposite with covalent CNC-GO, and this ternary nanocomposite exhibited robust barrier properties, good excellent crystallization ability, good antibacterial activity, and lower migration levels. As green, high-performance food packaging materials, these new nanocomposites have a lot of promise. The schematic illustration of CNC-GO nanocomposite film (Fig. 7) [69]. Lazic et al. prepared a dextran-coated silver nanoparticle with CNF-based nanohybrid film for food packaging. The TEM image of nanohybrid film showed an average size of 12.0 1.9 nm. The oxygen barrier property of the film was found to be 0–0.42 wt%. The wetting behavior of nanohybrid CNF films with varied amounts of dextran-coated AgNPs was examined using macroscopic contact angle (CA) in physical contact with various liquids, exhibit hydrophilicity from 20.8 to 52.4 for milliQ water, and from 35–37 for 3% acetic acid and 62–74 for 0.9% NaCl solutions. The oxygen transmission rates (OTR) was found to be 2.07 for pristine CNFs. The OTR values of films containing dextran-coated Ag NPs (from 1-dex to 3-dex) were found to reduce with an increase in the content of the dextran-coated Ag NPs from 1.40 to 0.78 cm3 m2 d1., possibly due to the Ag NPs blocking majority of the hydroxyl groups of dextran, and, consequently, making them not available for interaction with those from CNFs. This results in an increase in the diffusion path for
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Fig. 7 CNC-GO nanocomposite film (Covalent and non-covalent bond) and its application in food packaging
molecular permeation through these films, diminishing the oxygen transmission through such a matrix. The antimicrobial activity in E. coli after five repeated cycles of 24 h exposure to 0.9% NaCl solution resulted in 99.9% inhibition of the bacteria. The performance of CNF matrix in biodegradable and eco-friendly food packaging applications, is improved by utilization of thin layer dextran-coated Ag NPs as an effective barrier, with useful antibacterial properties [33].
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Nanocellulose for Water Treatment
Pandele et al. used immersion precipitation to make cellulose acetate (CA)/hydroxyapatite (HA) membranes. Scanning electron microscope (SEM) shows surface aspect alterations and the development of hydroxyapatite crystals in the composite membranes, both on the active and porous surfaces. With the continuous addition of hydroxyapatite particles inside the membrane structure, water flows increased, ranging from 8.29 L/m2h for the CA membrane to 20.96, 23.25, or 26.73 L/m2h for the composite membranes with 1, 2, and 4 wt.% HA. Particle agglomeration was prevented through high-performance ultrafiltration membranes based on cellulose acetate and nano hydroxyapatite were produced utilizing the surfactant-assisted phase inversion technique. Overall, adding an amphiphilic surfactant to the membrane preparation process prevented hydroxyapatite particle agglomeration and enabled a high filler percentage in the organic matrix to be effectively incorporated. In comparison to earlier published research, the membranes produced using this
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technique had improved water flow values (34.96 L/m2 h bar) and fouling resistance [70]. Tato et al. prepared water purification membranes by using nanocellulose (NC)-based composites with silver (Ag) and platinum (Pt) nanoparticles to fabricate the support layer of thin-film composite (TFC) membrane. The nanocellulose surface was modified to include amino silane functionalities and by in situ chemical reduction the metal nanoparticles were deposited on NC-NH2. Through phase-inversion method polyester (PE) mesh and porous mid-layer made of polysulfone (PSF) were used to incorporate NC-composites. The amino-silane group was successfully incorporated to the NC surface, according to FTIR and XPS results. The thermogravimetric analysis showed the metal loading of 12% Ag and 20% Pt on the NC membrane. The antimicrobial properties were evaluated via Kirby-diffusion test that showed the biocidal potential of NC-NH2Ag. The forward osmosis (FO) process was performed using various feed solutions such as raw wastewater, urea aqueous solution, and deionized (DI) water. The total organic count (TOC) was performed on commercial membranes, NC, and PSF membranes showing the rejection values as 96.9%, 94.6%, and 90.3%. Whereas, the inclusion of metal nanoparticles to NC membranes appears to have an opposite tendency in TOC rejection, with AgNP (92.4%) < PtNP (94.0%). Overall results suggest that the formation of biofilm from metalized nanocellulose (MNC)-TFC membranes has higher water fluxes and solute rejection using wastewater samples. The representation of FO membrane process for water treatment (Fig. 8) [71].
Fig. 8 Schematic representation of FO membrane process using semi-permeable membrane
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Xu et al. prepared a novel membrane for wastewater treatment with bacterial nanocellulose (BNC) loaded with palladium (Pd) and graphene oxide (GO). During the development of BNC membrane, the GO flakes were incorporated on the matrix followed by PdNPs via in situ process. The Pd/GO/BNC film’s cross-sectional SEM image depicts a laminated structure with a thickness of 7 m, resulting from the packing of GO flakes within the BNC fibers. The in situ synthesis process used here resulted in a uniform distribution of Pd nanoparticles over the GO sheets, as seen in this transmission electron microscopy (TEM) image of Pd/GO/BNC membrane. PdNPs on GO/BNC display lattice fringes with a lattice spacing of 0.23 nm, similar to Pd planes in high-resolution TEM (HRTEM) images. The researchers selected the degradation of methylene orange (MO) in the presence of NaBH4 as a model catalytic reaction of organic dye molecules to evaluate the catalytic activity of the Pd/GO/BNC membrane. The result showed that Pd/GO/BNC retained 94.7% of its catalytic activity even after ten cycles, which demonstrates the excellent catalytic stability of the Pd/GO/BNC membrane. The water flux and particle rejection capacity of the potential Pd/GO/BNC membrane was examined using a benchtop cross-flow system for large-scale water treatment. After stabilization under positive pressure of 58 psi (4 bar), the Pd/GO/BNC membrane showed stable water flux (33.1 L m2 h1) over a 6-h flux test, which is 2.3 and 2.8 times higher than the flux performances of commercial ultrafiltration color reduction membrane (YMGESP3001, pore size 1000 Da) with a MO rejection rate of 95.2% (14.5 L m2 h1 under 58 psi) and commercial nanofiltration membrane (YMDKSP300). The foregoing findings showed that the Pd/GO/BNC membrane has the potential to be used in a large-scale ultrafiltration process [72]. Huang et al. prepared bio-adsorbent composite from amino-functionalized magnetic bacterial cellulose/ activated carbon for removal of methylene orange (MO) and Pb2+ from aqueous solution. The SEM images of AMBCAC were distinct from those of raw BC, revealing an uneven surface. Whereas the raw BC showed a smooth and homogenous nanofibrils with fibrils diameter in the range of 10–50 nm. Clearly, the uneven surface of AMBCAC increased adsorption active sites and created a suitable environment for drawing additional target pollutants near adsorption active sites. Simultaneous adsorption studies were carried out in aqueous solutions of Pb2+ and MO with the same starting concentration of 30 mg L1 and pH values ranging from 2.0 to 6.0. The optimum pH for Pb2+ and MO adsorption was 5.0 and 3.0, respectively, while the absorption studies of AMBCAC were 161.78 mg g1 for Pb2+ and 83.26 mg g1 for MO under the ideal condition. The findings of the adsorption kinetics and isotherm analyses show that the Pb2+ and MO adsorption processes are well-fitting with the pseudo-second order kinetic model and the Langmuir model, respectively. Because of the effective and quick adsorption of both heavy metal ions and dye, as well as the easy and convenient magnetic separation, the AMBCAC can be used as a potential environmentally friendly bio-adsorbent for water purifications [42]. Bai et al. prepared a bio-adsorbent for removal of dyes such as methylene blue (MB) and rhodamine (RhB) from wastewater via using cellulose acetate (CA) and activated carbon (AC) composite monolith. The novel adsorbent was prepared by
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thermal-induced phase separation method. The AC with the irregular sheet-like structure was loaded in the pore structure of the CA/AC composite monolith, indicating that the composite material was successfully prepared, according to SEM images. The adsorption of the dye on the cellulose acetate and activated carbon revealed abundant space on the composite monolith. Under the same initial concentration, the adsorption of MB and RhB on the cellulose/AC composite monolith had higher equilibrium adsorption capacities of 26.7 mg g1 and 13.0 mg g1, respectively. The adsorption followed pseudo-second-order kinetics and the Freundlich isotherm model, respectively, according to the kinetics and isotherm studies. The cellulose/AC monolith’s recyclability was tested by repeating the adsorptiondesorption process eight times. For the first-three times, none of the color adsorption capacity changed much. When compared to the original adsorption capacity, the adsorption ratio for MB remained 89% and 93% for RhB after eight cycles. The adsorption capacity of MB declined from 53.4 to 46.2 mg g1, and RhB dropped from 26.3 to 23.6 mg g1. These results demonstrate that the existing material has a remarkable potential to regenerate. Thus the composites monoliths can be used as a potential candidate for wastewater treatment [73]. Zhu et al. prepared a nanocomposite as adsorbents for heavy metal ions. To biosynthesize spherical Fe3O4/BC nanocomposites, a pH-controlling embedding process was used as a novel method. During fermentation, XRD and SEM images revealed that Fe3O4 nanoparticles with an average diameter of 15 nm were dispersed evenly in BC. The X-ray diffraction patterns of spherical Fe3O4/BC nanocomposites, revealed a characteristics diffraction peak of 14.560, 16.600, and 22.640 represent a typical (Iα) crystalline of cellulose, demonstrating the successful fabrication of Fe3O4 nanoparticles. The saturation magnetization (s) of the spherical Fe3O4/BC nanocomposites with 33 wt% ferrous loading was 41 emu/g, and the related coercivity was 27 Oe. At identical ion concentrations, the adsorption capacity of these three ions is quite different and in the order of Pb2+ > Mn2+ > Cr3+, while the elution capacity is ranked as Mn2+ > Pb2+ > Cr3+. Thus, the overall results revealed that nanocomposites have high elution and adsorption capacity for heavy metal ions [74].
8
Conclusion
Nanoparticle decorated nanocellulose-based materials hold immense potential across diverse applications in several industry sectors ranging from energy storage devices, electronics, wound healing, biodegradable packaging, CO2 absorbent materials, water purification, and oil recovery. The existence of surface functional groups on nanocellulose, such as carboxyl, hydroxyl, amino, and thiol make it amenable to versatile functionalization for specific applications. Metal oxide NPs, metal NPs, and magnetic NPs offer significantly better antibacterial and magnetic functions to bacterial cellulose and cellulose nanofibrils, wherein NC serves as a support material, providing flexibility and a high surface area for impregnation of NPs. Magnetic iron oxide NPs demonstrate superior efficiency in drug delivery, imaging, bio-separation, catalysis, and wastewater cleaning. Nanoparticle decorated
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nanocellulose is an emerging technology platform with a potential to significantly improve the performance attributes across diverse industries and will continue to fuel interest in new research with different metal and metal oxides along with more studies on their metabolic fate and toxicity, especially in theranostic applications.
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Nanocellulose as Reinforcement Materials for Polymer Matrix Composites
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Himani Punia, Jayanti Tokas, Surina Bhadu, Anju Rani, Sonali Sangwan, Aarti Kamboj, Shikha Yashveer, and Satpal Baloda
Contents 1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Nanocellulose: Accessibility and its Characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1 Cellulose Nanocrystal (CNC) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2 Cellulose Nanofiber (CNF) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3 Bacterial Cellulose Nanofibers (BCs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4 Cellulose Nanogels (CNGs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5 Spherical Cellulose Nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Reinforcement of Interactions between Polymer and Nanocomposites . . . . . . . . . . . . . . . . . . . . 3.1 Tensile Properties of Nanocellulose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2 Different Kinds of Covalent Interaction for the Preparation of Polymers and Nanocomposites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Processing Methods of Polymer Nanocomposites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1 Hot-Melt Processing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2 Wet Processing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 In Situ Polymerization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1 In Situ–Formed Bacterial Cellulose (BC) Nanocomposites . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2 In Situ Polymerization of Monomer in the Presence of Bacterial Cellulose . . . . . . . . 5.3 In Situ Growth of Bacterial Cellulose in the Presence of a Polymer . . . . . . . . . . . . . . . . 5.4 In Situ Growth of Bacterial Cellulose in the Presence of a Nanofillers . . . . . . . . . . . . . 5.5 In Situ-Formed Plant Cellulose (NC) Nanocomposites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Conclusion and Future Prospective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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H. Punia (*) · J. Tokas · S. Bhadu · A. Rani Department of Biochemistry, College of Basic Sciences & Humanities, CCS Haryana Agricultural University, Hisar, Haryana, India S. Sangwan · A. Kamboj · S. Yashveer Department of Molecular Biology, Biotechnology & Bioinformatics, College of Basic Sciences & Humanities, CCS Haryana Agricultural University, Hisar, Haryana, India S. Baloda Department of Horticulture, College of Agriculture, CCS Haryana Agricultural University, Hisar, Haryana, India © Springer Nature Switzerland AG 2022 A. Barhoum (ed.), Handbook of Nanocelluloses, https://doi.org/10.1007/978-3-030-89621-8_25
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Abstract
Cellulose is one of the most desirable materials with no exceptions. In recent years, considerable work on nanocellulose-based polymer composites has played a significant role in the production of sustainable and efficient materials. Different kinds of nanocelluloses, derived from bottom-up strategy (bacterial celluloses) to top-down strategy (cellulose nanofiber and nanocrystal), are probably suitable for a wide range of industrial applications. The form of a nanomaterial, as well as the choice of the polymer matrix, is indeed crucial for producing well-defined nanocomposites from a polymer-fill-compatible viewpoint for the desirable reinforcement and precise application. Cellulose nanofiber (CNF) and cellulose nanocrystal (CNC) are some of the nanocellulosic materials to produce the polymer-based nanocomposites. Because of several important properties such as biocompatibility, CNCs have attracted great attention from polymer researchers as strengtheners of nanocomposite fillers. Their preparation is quite challenging because of its extensive formulation, which may lack in compatibility with the polymer. This problem might be averted via several covalent and noncovalent interactions. The main focus is on melting processes and a brief discussion on their synthesis and properties that have not yet been accurately processed and continued to be a challenge. This chapter will provide a general guide for the design and use of nanocellulose properties and the development of functional polymers for polymer/nanocellulose compounds to pave the way for different interactions between polymer and fillers via different processing methods. Keywords
Cellulose · Covalent interactions · Nanocomposite · Nanofibers · Nanocrystals
1
Introduction
The production of high-performance and/or practical polymer materials utilizing nanoparticles or nanofillers has now become a significant field of current research in both academia and industry [1]. The selection of nanofillers for the preparation of nanocomposites has raised environmental issues during this decade. In order to introduce renewable and biodegradable nanofillers, an overwhelming need is felt. A great deal of research has been conducted on cellulosic nanomaterials in this respect due to their abundant availability and biodegradability and many other significant inherent characteristics that contribute to the expression of versatility and improvement of performance as materials [2]. Due to their specific characteristics, such as various surface OH groups and their related ease of surface alteration, high power, (potentially) low costs, and renewability, the development of polymer nanocomposites by means of the nanocelluloses has also been of growing importance. These nanomaterials still have some drawbacks, including hydrophobial polymer matrix-based heavy moisture adsorption and low compatibility. In order
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to achieve the desired efficiency and functionality, it was important to incorporate some kind of contact, whether covalent or not, between the polymer and nanocellulose. The nature and scope of the interactions are the key considerations for the nanocellulose dispensability in the polymer matrix and overall characteristics of the nanocomposite. Nanotechnology has become one of the driving forces behind a new industrial revolution in several fields, ranging from bio-nanocomposites and biofuels, passing through medical or even sensing and biosensing applications [3–5]. Nanocelluloses and their nanocomposites have been emerging since the past decade, providing advanced solutions to several key challenges in the modern society [6]. Broadly, nanocellulose can be categorized into nanostructured materials and nanofibers. The first category includes microcrystalline cellulose and cellulose microfibrils, whereas the second one comprises cellulose nanocrystals, cellulose nanofibrils, and bacterial cellulose. Cellulose nanocrystals (CNCs), usually produced by acid hydrolysis, consist of cylindrical, elongated, less flexible, and rodlike nanoparticles with 4–70 nm in width; 100–6000 nm in length; and 54–88% crystallinity index [7]. However, in the last few years, the nomenclature has progressively converged to cellulose whiskers; cellulose nanowhiskers; and, more recently, cellulose nanocrystals and nanocrystalline cellulose [8]. Nanofibrillated cellulose (CNF), commonly obtained by mechanical treatment, presents an entangled network structure with flexible, longer, and wide nanofibers (20–100 nm in width and > 10,000 nm in length) and lower crystallinity with respect to CNCs. On the other hand, bacterial nanocellulose, also known as microbial nanocellulose, is considered as a promising and costeffective natural nanomaterial for biomedical uses [9]. The amorphous nanocellulose (ANC) is another class of nanocellulose of spherical to elliptical shape with a diameter ranging from 80 to 120 nm. Cellulose nanoyarn (CNY), one of the less investigated nanocellulose with diameters of 100–1000 nm, is often obtained by electrospinning of solutions containing cellulose or its derivatives. More recently, cellulose nanoplatelets (CNP), which are formed by entangled cellulose nanofibrils of 3 nm in diameter, have been prepared through oxidation under mild conditions. The thickness of such CNP is around 80 nm [10]. The emphasis of the following sections of this chapter will be placed on one type of nanocellulose, i.e., cellulose nanocrystals, where the preparation methods, properties, surface modification, and the recent applications of these nanomaterials will be treated. The initial areas of specialization of nanocellulose researchers are wide ranging: physical chemistry including colloids, interface structures, wood science, mechanical engineering, plant biology, etc. A description of the structure and properties of cellulosic nanomaterials [11] and their surface modification [12–14] can be found in literature from the past few decades. Their colloidal activity has also been based on in terms of the function of nanocellulose [15]. Meanwhile, the course of their compounding with synthetic polymers is feasible for the practical use of nanocelluloses. Since the late 1980s, research on molecular composite materials of cellulose and its derivatives with polymers has made substantial advancement prior to nanocellulosic polymer composites [16]. It should be remembered that the researchers seeking to enter the area of nanocellulose are strongly predictive of such
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Fig. 1 Different techniques of nanocelluloses to act as polymer nanocomposites. Adopted from [20]
results. Different techniques have been discussed to cooperate nanocelluloses in polymer nanocomposites such as acidic hydrolysis, controlled hydrolysis, enzymatic hydrolysis, chemical and mechanical disintegration, and liquid crystallinity based on their thermal, mechanical, optical, and rheological properties [17] (Fig. 1). There are also a few articles summarizing the developments in nanocellulose-enhanced polymer nanocomposites, as well. These articles concentrate solely on cellulosic bio-nanocomposite preparation and properties [18], achieved mechanical characteristics [19], comparison of mechanical strengthening of nanocellulose form and content [20], and treatment of nanocellulose composites. However, the reviews did not demonstrate the existence of polymer nanocellulose interactions resulting in the desired strengthening. Taking account of the recent literature on polymers, this chapter aims at defining and classifying the potential modes of interaction, such as covalent or non-covalent interaction between polymers and nanocellulose.
2
Nanocellulose: Accessibility and its Characteristics
The cellulose consists of 1–4-bound anhydrous D-glucose groups and a normal high-molecular-weight homopolymer. Given that cellulose does not act as a molecule perpendicular to a molecular chain, it crystallizes in intermolecular hydrogen bonding to form microfibrils. The natural crystal system is cellulose I [13]. Through defibrillation and/or chemical preparation, highly crystalline nanocelluloses are generated as a minimum unit. As long as extreme degradation of the chemical composition is not involved, in theory, the nanocelluloses will no longer be loosened. Nanocelluloses have been gaining interest since the end of the twentieth
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century when successful approaches have been re-evaluated to be collected as, or from, microfibrils. From the perspective of biosynthesis, the structure of the cellulose synthase in the plasma membrane defines the unit of a package of cellulose molecular chains that comprise microfibrils. The polymerized cellulose shall be extruded from terminal enzyme complexes (TC) where the amount of cellulose chains found within a microfibril is determined from the number of synthetic sites of each site that make up TC and synthetic proteins [11]. The number of synthetic sites and their structure differ according to the organisms. With regard to wood, the hypothesis has been recognized that 6 6 cellulose molecular chains are clustered, although there are recent studies that higher plants are initially containing 18 cellulose microfibrils [21]. As the sequence of reports is very recent, the researchers stop going into depth here, but in the future, the debate will deepen further. Crystalline regions and regions without a long-range order (amorphous) occur along the microfibrils in higher plants when viewed in the direction of the fiber. This periodic structure is consistent with what has long been known as the levelling-off degree of polymerization (LODP) [22]. LODP manifests as very crystalline particles with a residue of 200–300 formed by the beating and treatment of pulp or enzymes. Different ideas have been suggested regarding the amorphous portion, but studies continue to explain the exact structure. The cellulosic nanomaterial family consists of the acidic controlled hydrolysis of cellulose nanocrystal, CNF (controlled acidic hydrolysis), CNF (chemical and mechanical disintegration), and Acetobacter bacterial celluloses [23] (CNF). They often rely, according to their form and the conditions of extraction, on the type of cellulosic source [23]. In this study, the authors address the promising industrial materials CNC and CNF with industry reporting. Incidentally, many testing firms supply CNC [24], while CNFC supplies CNF [24]. Manufacturing and distribution were carried out by firms in the paper, machinery, and chemical industries [25]. Aggregation is a common problem in utilizing CNF and CNC [11, 13, 26]. The authors have indeed stated that molecules of cellulose appear to accumulate by hydrogen bonds, leading to crystallization, but even on the nanocellulose scale, the simplicity of aggregation is noteworthy. Nanocellulose, normally given as an amorphous state, should not be dried unintentionally in order to prevent aggregation. There is a question about aggregation, even though nanocelluloses are freeze-dried. However, if water is supplemented with tert-butanol and lyophilized in the aqueous dispersion, agglomeration is, to a certain degree, suppressed.
2.1
Cellulose Nanocrystal (CNC)
Cellulose nanocrystals (CNCs) are derived from natural polymer, cellulose. Being unique nanomaterials, they have gained significant interest owing to their different chemical, mechanical, optical, and rheological properties. As nanocrystals are obtained from most abundant and naturally occurring fibers, therefore, they are renewable and biodegradable in nature. Thus, for most applications, they assist as
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a sustainable and environmental-friendly material. When surface functionalized using hydrophobic polymer matrices, they can be converted into high-performance nanocomposites (as they are naturally hydrophilic in nature) that are capable to meet various challenging requirements. Bulk cellulose consists of microfibrils, which in the presence of combination of mechanical, chemical, and enzyme treatment yields the highly crystalline regions of cellulose microfibrils. These cellulose microfibrils are then subjected to mechanical and chemical treatments (the latter being better) to convert them into stiff rodlike CNCs. CNCs are the most widely accepted nomenclature; however they are also referred to as nanofibers, whiskers, microcrystallites, nanoparticles, etc. [27]. They consist of cellulose chain segments and exhibit properties like high surface area, high specific strength, and modulus. In addition to it, they also have unique liquid crystalline property as the cellulose chain segment is nearly a perfect crystalline structure.
2.1.1 Potential Sources of Cellulose Nanocrystals CNCs with variable structure, properties, and applications could be synthesized based on different sources from which they can be obtained (Table 1). Plant cell walls, microcrystalline cellulose, cotton, algae, bacteria, and animals can serve as potential source. Wood as a source material is very popular because of its availability and well-established existing infrastructure for harvesting and post-harvesting handling procedures. It is purified to remove lignin, hemicellulose, and impurities [28, 29]. Plants are also a fascinating option as a source because of their abundance and well-established infrastructure of textile industries. Plant materials like hemp [30], cotton [31], wheat straw [32], ramie [33], pineapple leaf [34], potato and sugar beet [35, 36], and banana rachis [37] are some of the examples. Algae are also capable to produce cellulose microfibrils in their cell walls. They possess unique cellulose microfibril structure as different algal species have difference in biosynthesis process. Various green algae species like Micrasterias denticulata, Valonia, and Boergesenia are most frequently studied for cellulose microfibril research [38]. In animals, tunicates are the only one known to have cellulose microfibrils. They have a thick leathery mantle in mature phase that is formed of cellulose microfibrils embedded in a protein matrix. They produce cellulose by using enzyme complexes existing in epidermal membrane, and the properties of cellulose vary Table 1 Geometrical properties of nanocrystals from different cellulose sources. Adopted from [46] Source Bacterial cellulose Cotton Wheat straw Tunicate cellulose Sugar beet pulp Wood Algae (Valonia)
Cross section (nm) 5–10 7–15 5 10–20 5 3–5 10–20
Length (nm) 100 nm to μm 100–400 220 100 nm to μm 210 100–300 100 nm to μm
Axial ratio N/A 10–20 45 67 40 30–70 N/A
References [40] [40–42] [42] [40, 42, 43] [42] [40, 44] [40, 45]
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from species to species. Bacterial species like Gluconacetobacter xylinus is most widely studied that secrete cellulose under special culturing conditions in response to stimulus like ultraviolet light. A thick gel known as pellicle appears on the surface of the liquid medium that is composed of cellulose microfibrils and 97% water. The opportunity to adjust the culturing conditions to achieve altered microfibril formation and crystallization makes use of bacterial-derived cellulose as a popular approach [39].
2.1.2 Methods Applied for CNC Preparation CNC is referred to any one dimensionality of cellulose of size 100 nm [47]. Therefore, the process of mechanical, chemical, and biological hydrolysis and the combined methods are the processes of reducing the size of natural cellulose to finally obtain CNCs (Fig. 2).
Mechanical Process Mechanical processes are physical methods to extract cellulose microfibrils. The processes include high-pressure homogenizers, micro-fluidization, fine grinding by grinder/refiners, high-intensity ultrasonic treatments, and freezing smashing [48]. These processes exert enough shear forces that can help to extract cellulose microfibrils as the cellulose fibers split apart along the longitudinal axis during the procedure. These extracted cellulose microfibrils do not possess any chain folding and are just a string of cellulose crystals that are linked with disordered or paracrystalline regions [49].
Fig. 2 Hypothetical schematic of dilute acid pretreatment process to extract the crystalline regions of cellulose from amorphous domains. In the middle, the configuration of cellulose repeating unit with the β-1,4 glycosidic linkage under the effect of intra/intermolecular hydrogen bonding is denoted. Adopted from [51]
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Chemical Process The chemical process came into focus as all abovementioned mechanical processes demand great energy consumption. The chemical-based hydrolysis is an effective way to treat natural cellulose and partially break the glycosidic bonds present among the glucose units of cellulose [50]. In addition to less energy consumption, the process also yields rodlike short nanocrystals with improved crystallinity. The processes alkali hydrolysis, acid hydrolysis, and TEMPO hydrolysis (that requires development of TEMPO reaction system) are some of the chemical processes approached (Fig. 2). Acid hydrolysis is the most widely applied out of all as it is a simple process that makes use of strong acids (such as sulfuric, nitric, or hydrochloric acid) that can remove amorphous domains leaving the crystalline regions unaffected. Strong acids are preferred as they can easily penetrate the amorphous regions that are regularly distributed along the microfibrils. Biological Source The pollution-causing effect of wasted solutions of acid or alkali is evident despite the low cost and convenience associated with the chemical process. Therefore, focus has been deviated toward the noncomplicated, pollution-free, and efficient preparation methods. In this direction, the bacterial nanocellulose (BNC) from bacterial cellulose such as Acetobacter, Azotobacter, Achromobacter, and Aerobacter came out to rescue [52]. The bacterial cellulose was even reported to be better than plant cellulose as they had higher crystallinity (over 60%), purity, degree of polymerization (between 2000 and 6000), and tensile strength [53]. The nanocrystals obtained also possess better mechanical and thermal properties when compared to sulfuric acid hydrolysis [54]. However, each BNC has its own merits on the basis of difference in the bacterium type and its culture conditions. Combined Method The energy-extensive mechanical processes, environment-degrading chemical processes, and underactivity of biological processes are some of the cons that result to adoption of new innovative approach. This approach relies on combination of all these methodologies to set an irresistible trend in CNC preparation. Alemdar and Sain [55] synthesized microfibrillar cellulose (MFC) of 10–80 nm diameter. Meanwhile, the MFC obtained from the preoxidized pulp had 5.51 nm and 4.7 nm of average diameter by rotation and ultrasound, respectively [56].
2.1.3 Properties of Cellulose Nanocrystals It is crucial to consider these factors when comparing reported properties of a given particle type. CNCs possess unique physicochemical and mechanical properties such as high surface area (250 mg/g), high tensile strength (7500 MPa), high stiffness (Young’s modulus up to 140 GPa), and an abundance of surface hydroxyl groups. These hydroxyl groups impart hydrophilic characteristics to pristine CNCs, which may improve their dispersibility within polymer matrices. Various factors such as size, shape, dispersity, charge, electrolyte, and external stimuli can affect the liquid crystallinity, pitch, domain size, ordering, and other properties (Table 2):
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Table 2 Different properties of cellulose nanocrystals (CNCs) and coated films. Adopted from [57] Property of CNCs Hydrodynamic diameter (nm) Average dimensions (length, L) from TEM measures Average dimensions (diameter, D) from TEM measures Aspect ratio (L/D) Zeta potential (mV) Conductivity (mS cm 1) Polydispersity index Aw after freeze-drying Property of CNC-coated PET film Aw after coating and drying Thickness of PET film (μm) Thickness of CNCs coating (nm) Transparency (T% at 550 nm) Haze (%) Optical contact angle (water) at 57% RH Optical contact angle (water) at 81% RH Optical contact angle (water) at 97% RH
Values 101.15 3.65 139 33 16 5 94 44.40 4.12 0.095 0.024 22.95 0.63 0.26 0.01 0.46 0.05 12.0 1 756.3 22.3 85.67 0.3 1.89 0.1 11.23 0.41 9.33 0.56 8.05 0.31
1. Mechanical properties: Quantitative mechanical property’s measurement is extremely challenging owing to small particle size and restricted metrology techniques available to characterize CNCs along multiple axes. Several factors like percent crystallinity, crystal structure (Ia, Ib, and II), defects, anisotropy, and the property measurement techniques contribute to the wide distribution in reported values of different and given particle type. 2. Thermal properties: Thermal chemical degradation and coefficient of thermal expansion (CTE) are some of the thermal properties discussed in CNCs. Thermogravimetric analysis (TGA) is used to measure thermal chemical degradation of CNCs (usually occurs between 200 C and 300 C) in terms of weight loss as a function of temperature at a given heating rate. The heating rate, type of surface modification, and particle type are the factors on which thermal chemical degradation depends. 3. Liquid crystallinity (LC): Liquid crystallinity and the bi-refrainment nature of CNC’s suspension impart interesting optical phenomena to the CNCs. A simple settling of the crystals can separate into two phases; one is chiral nematic phase and the other isotropic phase with the longer crystals exhibiting anisotropy. Major factor in determination of LC is aspect ratio of the particles. At lower concentrations, higher aspect ratio symbolizes more anisotropy that drives transition to the liquid crystal phase, whereas under certain conditions, it is also known to exhibit nematic behavior where CNCs align as rigid rods due to their stiffness and aspect ratios. Fascinatingly, sulfuric acid–based and phosphoric acid–based crystals have chiral nematic structures, whereas hydrochloric acid–based crystals have a bi-refrainment glassy phase with crosshatch pattern.
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4. Rheological properties: Rheological characterization is done by studying the gelation (viscometric measurements), liquid crystallinity, and ordering properties. LC transitions of CNC suspension under shear show concentration-dependent flow rate, and such behavior is due to CNCs alignment that eases the flow of these rodlike structures. In addition, the time constant of relaxation is also dependent upon aspect ratio. 5. Optical properties: CNCs exhibit interesting optical phenomenon owing to LC coupled to bi-refrainment nature of the particles. This optical phenomenon can emerge at times of LC formation, as nanoparticles can form tactoid assemblies in dilute solution that also show birefringence.
2.1.4 Applications of CNC 1. CNC reinforcement composites. 2. Barrier films. 3. Biomaterials. 4. Other applications. 5. Drug delivery applications. 6. Biosensors application. 7. Water purification. 8. Food packaging application.
2.2
Cellulose Nanofiber (CNF)
Cellulose nanofibers (CNFs) have various attractive properties like biocompatibility, high hydrophilicity, and biodegradability, which make them suitable for using in several biomedical applications like bioimaging, tissue engineering, drug delivery, and biosensing. This property is useful for environmental applications as well [58], as the cellulose nanofibers are used as membranes in water purification and in filtration systems, so they should not degrade and liberate toxic substances in water, making it unfit for human consumption. Various properties of cellulose nanofibers have intense effects on the environmental applications. With the increase in the purity of cellulose nanofibers, their thermal stability also increases. This property plays an important role in the applications like sensor fabrication and decomposition of numerous pollutants catalytically during the remediation of wastewater. The high purity of CNFs also enhances the crystallinity of the nanofibers, which further improves the compactness of the structure of CNF and hence maintains their integrity. The stability of CNF structure increases with increase in crystallinity. This high crystallinity also increases the sorption properties of the CNFs toward various volatile compounds from air and water. Thus, the adsorbents based on the CNFs can be used for the remediation of the polluted water and air. The sorption ability of CNFs has numerous applications such as in catalysis, sensors, and compound separation applications at molecular level. CNFs are alluring for use in several applications because of their thermostability, high purity, mechanical stability, high crystallinity (70%–80%), low density, high
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Nanocellulose as Reinforcement Materials for Polymer Matrix Composites OH
OH
OH O
HO
O OH
O O
HO
NaIO4
OH O
O
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O OH
O O
O
OH
OH
Nanocellulose
Dialdehyde nanocellulose (DAC)
CNF
NaIO4
DCNF
PVA/CNF
PVA/DCNF PVA
NaIO4 CNC
DCNC Crosslinking bond
PVA/CNC
PVA/DCNC
Fig. 3 Schematic illustration of physicochemical structures of CNC and CNF composite films. Adopted from [60]
purity, excellent permeability, high specific surface area, high water content, high porosity, and biocompatibility. In comparison with the nanocellulose derived from lignocellulose, the nanocellulose derived from the bacterial cellulose is beneficial for hybridization due to their high purity, high specific surface area, and high crystallinity which results in magnificent thermal and mechanical properties of the nanocomposites. However, the flaws in it include high hydrophilicity (causing cellular adherence and proliferation to be lesser than the other protein-based materials) and low compatibility with the other hydrophobic polymers. Although bacterial cellulose has been studied for examining its industrial availability, its use in various applications including bioengineered tissue/organ, modern food, health industry, drug delivery, and renewable materials is expected in the coming years, along with the current and future science and technology progresses. A significance has been observed between CNCs and CNFs (Fig. 3). The properties of films and the chemical and mechanical features of the different nanoparticles are summarized in Table 3. This includes both types of nanocellulose, CNF and CNC; before and after TEMPO-oxidized treatment (CNF-T and CNC-T); and the reference montmorillonite (MMT).
2.3
Bacterial Cellulose Nanofibers (BCs)
Cellulose is a linear macromolecule consisting of repeat units comprising two D-anhydroglucose rings linked to one another by β-(1 4) glycosidic bonds. Cellulose has innumerable industrial applications in the cosmetic and pharmaceutical industries [61] and paper industry [62] and also to produce the “green” (nano) composite matter [63]. The research area concerned with the development of composites and
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Table 3 Physical and chemical properties of nanocellulose and nanoclay. Adopted from [59] Nanocellulose
Nanoclay
Morphology Shape Length (nm) Thickness (nm) Aspect ratio Chemical properties Crystallinity index (%) Surface charge (lmol/g) Zeta potential (mV) Thermal properties Onset temperature of thermal degradation ( C)
CNF Fibrillar
CNC Rodlike
CNF-T Fibrillar
CNC-T Rodlike
MMT Plateletlike 532 (125) 3 (1) 177 (72)
652 (292) 14 (5) 47 (27)
174 (83) 8 (3) 22 (13)
532 (145) 8 (3) 67 (31)
173 (55) 6 (3) 29 (17)
77 (1) 101 (13) 18 (3)
86 (1) 159 (26) 30 (2)
81 (1) 1563 (42) 47 (2)
85 (1) 727 (105) 44 (3)
– 943
289 (13)
241 (7)
223 (13)
223 (5)
305 (5)
40 (1)
bio-based materials through the modification of cellulose has gained much more attention recently [64]. Along with the plant sources, cellulose can also be acquired from the bacteria, e.g., Acetobacter xylinum [65], and it is considered as a promising and sustainable nanofibrous material. The in situ approach of self-assembly fabrication is the facile and pioneering way of producing the BC-based nanocomposites and fibrous hybrid structures. The A. xylinum strain grows preferably over the surface of some natural fibers and polymers, when present in the culture medium rather than growing freely in the pure medium. Hence, the nanocomposites and hybrid structures based on BC can be formed through the process of fermentation in the presence of natural polymers or fibers. The diameters of bacterial cellulose (BC) fibers range from 55 to 60 nanometers and possess many distinctive characters like high water-holding capacity [67] and purity [68]. Their stiffness, strength, and thermal stability are also high as compared to the conventional cellulose fibers derived from plants [69]. The cellulose has been used to convert into numerous nanostructures such as nanofibers [70], aerogels [71], nanocrystals [40], hydrogels [72], films and nanoparticles [11], and nanowhiskers [73] (Fig. 4). Of all the nanostructures that are derived from cellulose, wide investigations are being carried out on cellulosic nanofibers because of their excellent flexibility, biodegradability, mechanical strength, chirality, thermostability, possibility of functionalization, and low thermal expansion.
2.3.1 Methods of BC Nanofication Three main methods are involved in the nanofication process of bacterial cellulose [74]. Each of them involves a purification step along with the treatment and posttreatment procedure. The processes involved are shown in Table 4.
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Fig. 4 Bacterial cellulose nanofibers either nanocomposites or hydrogels with nanofiber network structures. Adopted from [66]
Table 4 Nanofication process of bacterial cellulose Methods Purification
Treatment procedure
Posttreatment procedure
2.4
Acid hydrolysis Washing, homogenization, drying, and grinding With mixture of H2SO4/HCl at 45 C
Centrifugation, dialysis, and ultrasonication
Enzymatic hydrolysis Mechanical defibrillation
Ionic liquid 48 h of freeze-drying
With buffer solution of cellulase and citrate at 50 C with shaking till colloidal suspension formed
Water traces removal at 90 C under vacuum using 1-ethyl-3methylimidazolium acetate (EMIMAc) Centrifugation
Centrifugation and dialysis
Cellulose Nanogels (CNGs)
Nanogels can be characterized as strongly cross-linked, copolymerized nano-sized hydrogel systems or monomers that can be ionic or nonionic [74]. The size of nanogels ranges from 20 to 200 nm [75]. Nanogels are hydrophilic three-dimensional networks of patterns with a tendency to imbibe water or physiological fluid which should be immersed in vast volumes without modifying the structure of the internal network. Cellulose nanowhiskers/nanofibrils maintaining the native crystallinity, cellulose can be shaped as regenerated hydrogel via coagulation and dissolution. In fact, the
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newly found aqueous alkali hydroxide-urea solvent is suitable for gel preparation; it has been shown that the resulting cellulose aerogels have remarkable mechanical efficiency, high light transmittance, and high nanometer order porosity [76]. It has also been shown to be useful for physically robust, foldable, and translucent bioplastics of cellulose [76]. Owning to the ease of preparation and processing, in situ polymerization of synthetic polymers in three-dimensionally nanoporous cellulose gels (NCG) is used to produce cellulose-polymer hybridization. Nanogels provide more surface energy than macro-sized hydrogels, thereby improving the ease of usage and efficient length of agrochemicals and ensuring that transporters conform to plants to release in vivo agrochemicals.
2.5
Spherical Cellulose Nanoparticles
Cellulose is the amplest biopolymer in the world. It has gained much research interest due to its chemistry, biosynthesis, and ultrastructure [27, 77–79]. Several efficient systems have been developed by the researchers for the recycling and utilization of cellulose waste in food, textile, chemical, cosmetic, and polymer industries for dealing with the respective economic and environmental concerns [80–84]. Several methods are there for utilizing, recycling, and degrading the cellulose waste, which include the ultrasonic and enzymatic degradation. Out of these, the enzyme application has received significant attention for the production of useful products and the development of new processes [79, 80, 85]. Cellulases act as catalysts in the hydrolysis of cellulose. These days, waste cotton fiber has become one of the cellulosic wastes which is used in the reuse and recycling procedures. Cotton has the maximum proportion of cellulose, i.e., more than 95% among the other cellulosic sources, and it occupies around one-third of the global market of the textile fibers with a yearly output of more than 23 million tons per year [84, 86, 87]. There have been various reports on the characterization and preparation of cellulose nanoparticles in various forms such as whiskers, nanospheres, nanocrystals, nanofibrils, nanowhiskers, nanopowders, microfibrils, and nanofibers, which are prepared from different cellulosic sources [78]. The cellulose nanoparticles have various advantages like low cost, non-toxicity, higher availability, low density, and high specific strength along with modulus [77, 86, 88–90]. So, they are of great use in various areas such as tissue engineering scaffolds, nanocomposites, health and cosmetic, pharmaceutical, filtration media, and food and automotive industries [91]. Many studies have suggested that the developed cellulose nanoparticles are rod-shaped whiskers [13, 87, 90, 92, 93]. However, there are a few studies with regard to the preparation of spherical cellulose nanoparticles [78, 94, 95]. Spherical cellulose nanoparticle production used to be carried out by acid hydrolysis, which is a non-eco-friendly process. Meyabadi et al. [96] reported a versatile and simple approach for the preparation of spherical nanoparticles using the waste cotton fibers employing the enzymatic treatment coupled with ultrasonication. Generating the uniform spherical nanoparticles is problematic through chemical, ionic liquid, or mechanical approaches. Hakkak et al. [97] reported a novel
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facile method for creating and isolating spherical cellulose nanoparticles from the ionic liquid using acetonitrile nonsolvent addition. This novel method of regenerating the spherical nanoparticles is a simple procedure which produces the spherical cellulose nanoparticles of the size range 100–400 nm with high uniformity. In this, solvent exchange drying method was used to minimize the moisture content for the formation of discrete nanoparticles. The applications of these materials involve uses in the bioplastics, implant materials, polymer composites, biodegradable tissue scaffolds, films and foams, and membrane preparation through surface modifications. Chemically, these spherical cellulose nanoparticles have high-amorphous cellulose content. The range of particle sizes which are obtained by solvent exchange drying and acetonitrile non-solvent fractionation informs about the size, and the uniformity in the nanoparticle distributions suggests the weight fractions of the fractionated cellulose. This ionic liquid technique is energy efficient and simple and probably has suitability with other biopolymers as well as has the potential in preparing the spherical cellulose nanoparticles with surface functionalization. A comparison between the spherical cellulose particles and the natural cellulose spectra discloses the absence of any novel bands, which confirms that there is no chemical modification to cellulose, whereas the CH2 bending absorption is observed to decrease, which suggests that there is a reduction in the extent of crystallinity of the sample. Also, the stretching band of C-O-C is intense in the particles as compared to the natural cellulose which suggests that the amorphous cellulose content is higher in the cellulose particles as compared to the starting material. Li et al. [94] exhibited the possibility of preparing the nanospherical cellulose structures using short staple cotton through pre-swelling of the fibers preceding the acid hydrolysis. It is a direct means of production of spherical cellulose nanoparticles having controlled sizes, ranging from 60 to 570 nm in diameter. This demonstrates that these nanoscale particles can be synthesized using the cellulosic fibers by a refined procedure. Through this method also, there is a possibility of the cellulose crystallinity index to increase as the particle size becomes smaller. Beaumont et al. [98] devised a method for developing spherical nanoparticles through carboxymethylation and successive homogenization. After the complete formation, the particles can be redispersed in water, thus having a property which makes them different from most of the other alternative cellulosic nanomaterials. Although several methods have been proposed for the formation of spherical cellulose nanoparticles, still, an effortless and “green” route for spherical and functional cellulose nanoparticles still remains a challenge.
3
Reinforcement of Interactions between Polymer and Nanocomposites
For polymer matrix composites, a strong interaction is necessary with the adjacent surface to be impactful on the object with their maximum beneficial property. A strong interaction is necessitated between polymer and nanocomposites to augment
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Fig. 5 The reinforcement mechanisms of nanocellulose polymer composites. Adopted from [101]
the mechanical strength, biodegradability, and biocompatibility to improve their performance [27, 42]. The use of CNC is exigent in preparation of nanocomposite as its compatibility is very less with the polymer. To avoid this inconvenience, different types of covalent and non-covalent interaction are introduced to attain the perfect attachment between CNF and polymer (Fig. 5). The mechanical properties improve due to crystalline structure of CNF. The hydrogen bonds within structure are directly proportional to the polymer stiffness, whereas the hydrogen bonds with any other molecules help in forming polymer sheet. Multiple hydrogen bonds and crystalline structure restrict the solubility in water [99]. The adhesion is strong enough in CNF as the hydrogen bond is formed between the adjacent surfaces by using the hydroxyl groups [100]. The irreversible binding (hornification phenomenon) among cellulosic materials makes the CNF very valuable at the industrial level [39]. Nanocellulose materials have the strong natural adhesion property which assists in the binding role with the adjacent surfaces.
3.1
Tensile Properties of Nanocellulose
The nanocellulose (both BNC and NFC) valuable characteristic is strong mechanical properties like extortionate tensile strength, flexibility, and stiffness which help during packing in biocomposites [38]. Among the essential properties of nanocellulose is to enhance the strength along with stiffness of cellulose crystals as the tensile strength of a single cellulose crystal (range 1.6 and 3.0 GPa) is very less as comparative to cellulose with the extended chains by the hydrogen bonds [102]. Nanocrystalline Cellulose (NCC), as one of the strongest natural materials
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with high tensile strength, high hardness, and convertible surface properties by the presence of hydroxyl groups. The tensile strength is measured by using the Raman scattering, X-ray diffraction, and atomic force microscopy (AFM) (Table 5). Table 5 Examples of biodegradable polymer-CNF nanocomposites and their mechanical properties with CNF content. Adopted from [103]
Matrix Poly (ethylene oxide)
Poly(vinyl alcohol)
Chitosan Poly(lactic acid)
Soy protein
Starch
a
Content 20
Tensile strength (MPa) 8.5
Young’s modulus (GPa) 0.055649
1 4 7 7 5
3.2 2.1 17.5 21.6 ~80a
0.074 0.052 0.840 1.654 ~1.5a
5 5
33.07 ~80a
0.536 ~4a
60 3
55.6 46
1.022 2.940
10
~160a
7.99
5 10 2–5
58.36 98.6 19–30
1.598 2.894 1.4–2.0
CNF (pulp) MCC (pulp)
5 22
70.6 37.9
32.0 4.8
MCC CNF (pulp) BC CNF (bamboo) CNF
2 10 2 2
70 74.8 56.8 52.6
25.9 4.8 2.2 2.2
31
60
1.789
CNF (soy chaff) CNF (cotton) CNC (kneaf) CNC (rice straw)
5
11
0.174
22
31.0
1.036
6
8
0.330
10
26
0.901
Cellulose (resource) CNC (MCC) CNC CNF CNC CNF CNF (curava) CNF (flax) CNF (MCC) CNF (pulp) CNF (banana) CNF (aloe vera) CNC CNF CNF (flax)
Process Electrospinning
Solution casting Solution casting
Solution casting Solution casting Extrusion Solution casting Extrusion
Solution casting Hot solution casting Solution casting Solution casting
CNF cellulose nanofiber, CNC cellulose nanocrystal, MCC microcrystalline cellulose, BC bacterial cellulose
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Table 6 Tensile properties of different nanocomposites. Adopted from [107] Nanomaterial NCC NFC NCC NFC NCC NCC NFC/NCC NFC NFC NFC/NCC NFC/NCC NFC
Source Bacteria Soy hulls Tunicate Rutabaga MCC Cotton Sugar beet Potato pulp Hemp Wood pulp Flax Wheat straw
Polymer matrix Cellulose acetate (0–15% filters) – Waterborne epoxy (0.1% filters), butyl acrylate (6% filters) Polyvinyl alcohol (10% filters) Polylactic acid (5% filters) Polyvinyl alcohol (0–12% filters) Butyl/styrene acrylate (6% filters) Glycerol/starch (0–45% filters) Polyvinyl alcohol (10% filters)/polylactic acid (5% filters) Polyvinyl alcohol (0–12% filters) Waterborne polyurethanes (0–31% filters) –
Nanocomposites also possess high tensile strength and flexibility (Table 6). Leitner et al. [104] reported nanocomposite based on nanofibril from sugar beet cellulose and PVA by solution casting and showed improved tensile strength as the nanofibril content increased. Zimmermann et al. [105] observed the significant reinforcing effect of nano-sized cellulose fibrils isolated by mechanical treatment of sulfite pulp for PVAbased nanocomposite. Sriupayo et al. [106] prepared and characterized a chitin whisker-reinforced PVA nanocomposite with or without heat treatment. They showed improved thermal stability, tensile strength, and water resistance.
3.2
Different Kinds of Covalent Interaction for the Preparation of Polymers and Nanocomposites
The strong attachment between the nanocellulose and polymer is required to toughen the mechanical strength up to ten- to hundredfold [18]. The interaction via covalent bonding provides the strong attachment of polymer on nanocomposites. The polymer attachment can be classified into “grafting to” and “grafting from.” Under the “grafting to” approach, the polymer reactive functional group creates steric hindrance during attachment process with nanocomposites as already other polymer chains are present. This steric hindrance in “grafting to” approach resulted in highdensity graft. On the other side, “grafting from” approach engrosses in the polymer chain expansion on the nanocomposite surface. In “grafting from” approach, highdensity graft can be prepared as the polymerization initiation takes place on surface of nanocomposites. The medium for the interaction must be suitable for the appropriate attachment of polymer, and to avoid any interference, mostly water is replaced by the organic solvent; for instance, whenever the interaction takes place in hydrophobic reaction reagents, the water medium is exchanged by acetone. Different types of modification
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are introduced on the surface of nanocomposites to enhance the binding position as well as mechanical strength to synthesize the highly dense graft. For instance, in the toluene medium, –OH groups are reacted with isocyanate to produce the dense assembly via the “grafting to” approach [108].
3.2.1 Reaction between Hydroxyl Group and Epoxides The hydroxyl group of CNC can act as a nucleophile in the presence of epoxides under alkaline conditions to form a covalent interaction via ether linkage. The alkaline condition eliminates the steric hindrance trouble by activating CNC hydroxyl group to participate in etherification process. Generally, the concentration for alkaline condition, i.e., 0.37 M NaOH, is suitable for the high-density graft as the surface of CNC has multiple hydroxyl groups. During covalent interaction via etherification process, epoxides are most suitable for the nucleophilic reaction as they are flexible to form C-O-C linkages with CNC [109].
3.2.2 Reaction between Hydroxyl Group and Isocyanate The hydroxyl group is able to produce the urethane linkage by reacting with isocyanate (–NCO), and the nanocomposites having urethane linkages are considered stable for the use as fabricate polymer [110]. Commonly, polyethylene glycol (PEG) is used for the urethane linkage as they contain the –NCO group as terminal units. The nanocellulose is formed by using “grafting to” approach in the presence of PCL- or PEG-terminated isocyanate react with the hydroxyl group of the CNC present in the toluene (most suitable) medium. This kind of modification improved the mechanical properties like stiffness and ductility, including the thermal stability. An approach is adopted to utilize –NCO groups of isophorone diisocyanate to interact with hydroxyl group of CNC to synthesize polyurethane-CNC nanocomposite, and the tensile strength increases approximately by 1.6-fold in polyurethane-CNC nanocomposite as compared to pristine polyurethane [111].
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3.2.3 Reaction between Hydroxyl Group and Peptide The amide bond is also favorable in the preparation of stable nanocomposites. For the formation of amide linkage, there is requirement of –COOH functional group and the polymer with the –NH2 end group. To synthesize nanocellulose, hydroxyl group TEMPO-oxidized CNC contains reacts with NH2-terminated Jeffamine (a copolymer of ethylene oxide and propylene oxide) to form covalent interaction that provides steric stabilization and thermostability in the polymer [112]. 3.2.4 Reaction between Hydroxyl Group and Silane The CNC –OH groups are reactive to the methoxy or ethoxy group of silanes via a covalent interaction. The polymerization takes place at styrene (St) and 2-ethylhexyl acrylate (EHA) by using methacryloxypropyltrimethoxysilane (MPMS) as coupling agent in the presence of CNC for preparing the polymerCNC nanocomposites [113].
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Processing Methods of Polymer Nanocomposites
Nanocomposites are substances with at least one phase with constituents of 1–100 nm size. Commonly used material for nanocomposites synthesis are nanosilica, TiO2, SiO2, Al2O3, polyhedral oligomeric silsesquioxanes (POSS), carbon nanofiber (CNF), multi-walled carbon nanotubes (MWCNT), double-walled carbon nanotube (DWCNT), single-walled carbon nanotubes (SWCNT), montmorillonite (MMT), graphite nanoplatelet (GNP), and nanoclay. Nanocomposites are characterized by lower part warpage, better electric conductivity, improved mechanical properties, smooth surface finish, and enhanced flame retardancy (Fig. 6). For nanocomposite formation, nanoparticles are locked in the polymatrix (Fig. 7). Synthesis of nanocomposites depends on functionalization, alignment, and dispersion of nanoparticles in polymatrix. There are various techniques of nanocomposite processing like solution processing, melt mixing, and in situ polymerization (Fig. 6).
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Evaporation
Casting Nanocellulose as reinforcement
Liquid or solution
Impermeable substrate
Evaporation
Nanocellulose as reinforcement or the film
Liquid or solution
Absorption
Permeable substrate
Papermaking Nanocellulose as film structure
Coating
Extrusion Evaporation
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Blend of matrix polymer & reinforcement
Film Nanopaper Drainage
Screw feed
Heating
Fig. 6 Schematic illustration of primary means of preparation in films which contain nanocelluloses. Adopted from [26]
4.1
Hot-Melt Processing
This method of processing is used for nanocomposites where polymer matrix is insoluble; here matrix is heated at high temperature for melting purpose as the name of this processing technology infers. This is used in case of thermoplastic polymers like polystyrene, HDPE, polypropylene, polyamide 6, and polycarbonate. Here high volume of nanoparticles could be dissolved in matrix. In addition to this, thermoplastic polymer properties remain the same when cooled down and during heating get melted and form nanocomposite films easily. Semicrystalline polymers and amorphous polymers are processed at above melting temperature and glass transition temperature, respectively. In this process, a viscous liquid is formed on melting polymer pellets. Then, nanoparticles are mixed into the liquid using an extruder or a high-shear mixer. The extrusion, compression molding, or injection molding is used for preparing bulk nanocomposite solution. In this process, addition of nanoparticles to the melting polymer can distort polymer structure under large shear conditions; therefore, optimization of conditions is required for complete range of polymer/ nanoparticle ratios [114]. This processing technology is employed at large scale in industries due to this method’s speed and simplicity.
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a Processing
Monomers
Nanocellulose
Nanocellulose reinforced polymer composite
b
Initiator Polymerization Monomer Nanocellulose
c
Nanocellulose reinforced polymer composite
Swelling
Organic filler (nanocellulose)
Solvent
Solublization Polymer
Intercalated platelets
Solvent
Fig. 7 Polymerization techniques of cellulose nanofibers and reinforcement into polymer nanocomposites. Adopted from [124]
Petrovic et al. [115] synthesized nanocomposites of silica-polyurethane by combining polyol with silica. This mixture was cured using diisocyanate along with 0.1% catalyst at 100 C for 16 h. the resultant particles are of 12 nm size and range between 10 and 20 nm. Using melt mix method, nanocomposites of polypropylene (PP) matrix and calcium carbonate (CaCO3) were synthesized using Haake mixer and result into highly dispersed nanocomposite samples using lesser filler volume amount of 9.2% and 4.8% wherein aggregation happened at high-volume amount of 12% [116]. Dispersion of nanoparticles usually creates issue in nanocomposite formation. Rong et al. [117] show that grafting of monomers made of styrene to surround silica nanoparticles yields good dispersion. The silica nanoparticles are first heated to remove water from surface, and afterward monomer is poured along with solvent; then the solution is irradiated for solvent extraction and finally nanocomposite if silica is prepared by mixing polypropylene using tumbling mixer, extruding, and compounding. In this method, polymer particle mixing showed the improved interaction [117].
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Wet Processing
In wet processing techniques, solutions or suspensions are used for the formation of thin-layer films, resulting in either stand-alone films (casting) or coatings on different substrates. Drying techniques vary from ambient conditions drying to conventional hot air drying and infrared to microwave energy drying, while each method influences the film or coating properties. Compared to extruded coatings, the applicable coating weight can be much lower, maintaining the desired barrier properties. The use of nanoparticles in coating dispersions can bring many advantages to the resulting coating properties. Compared to multilayer films, nanocoatings demand lower material usage, being both an economic and ecological advantage. Additionally, surface coatings can be used for modulating repellent properties on various surfaces, e.g., for water-repellent paper-based packaging or easy-to-empty features. In this method of processing, nanoparticles are mixed in a solvent or polymer solution. Dispersion is facilitated by use of energetic agitation like high-shear mixing, magnetic stirring, sonication, or reflux which facilitate better dispersion at high speed. The sonicators used are categorized into mild sonicators with a water bath, and high-power sonicators having a tip or horn are used. Nanoparticles are not easily dissolvable as nanoparticles have very high aspect ratio. To boost nanoparticle dispersion in the polymer matrix solution, usually a surfactant is added [114]. The resultant solution is put into a mold; then solvent is vaporized, and a sheet or film remains after complete evaporation [118]. Solvents are chosen based on the solubility of polymers. Nanocomposites of polymethylmethacrylate (PMMA) and alumina nanoparticles were produced using wet processing methods by mixing alumina nanoparticles and methyl methacrylate (MMA) monomer using sonication at lesser viscosity. Later on an initiator is added, and then, the resulting solution is polymerized using nitrogen and then desiccated to remove solvent [119, 120]. Jin et al. [121] showed higher dispersion of MWCNTs in the polymer solution using solution processing. Here, MWCNTs were dissolved in chloroform. Then, polyhydroxyaminoether (PHAE) was added to the prepared MWCNT-chloroform solution during sonication process. Then it was dried, and this resulted into nanocomposite formation with 50% MWCNT concentration [121]. Similarly, using magnetic stirrer, expanded graphite (EG) and hardener of epoxy resin (DGEBA) were mixed, and then epoxy resin was poured in the EG/hardener solution, and the resultant solution was stirred [122].
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In Situ Polymerization
Researchers have been urged to invent effective methods and procedures in order to take better advantage of renewable nanoscopic materials [123]. One such approach is in situ cellulose nanocomposite processing, where the uniform dispersion of the nanocellulose in polymer matrices is obtained and the filler/matrix relation is strengthened. Cellulose nanocomposites can be treated in situ in several ways, viz.:
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• Uniform cellulose nanoparticles dispersal that decreases aggregation and improves interactions with increasing polymer molecules. • Adequate cellulose surface treatment can form strong bonds to the growing polymer molecules. • Solid bonding (between nanocellulose and polymer matrix) may be used to change the biodegrading activity of the compost environment in a synthetic, nondegradable substrate. • Moisture absorption is reduced when nanocellulose is encapsulated and less exposed to the air by the growing polymer molecules. While the in situ process provides certain benefits, certain drawbacks are still present. This method can only be applied when polymerization takes place in the fluid phase, and the polymerization medium can disperse nanocellulose. The consistency of nanocellulose with matrices is another significant concern. With high hydrophobicity in hydrophobic monomers, for example, acrylics, it is difficult to dislocate nanocellulose, which contributes even to poorly interfaced hydrophobial matrices. Chemical compatibility is needed in order to overcome this challenge. The most efficient form of compatibilization is the use of the extremely reactive and functional surface with excessive hydroxyl groups to bind the appropriate binding agent to the nanocomposite surface. The compatibilizer increases the dispersion of nanocellulose into hydrophobic matrices and gives the filler/matrix interface high connectivity. Several researchers attempted various compatibilizers, viz., 1-azido-2,3-epoxypropane [125], amine functionality [126], and GTMA [127], to reduce this problem. In situ processing of cellulose nanocomposites with bacterial cellulose or microbial cellulose (BC) and wood nanocellulose (NC) is as follows.
5.1
In Situ–Formed Bacterial Cellulose (BC) Nanocomposites
There are two basic synthesis approaches that are adopted for creating BC nanocomposites, in situ and ex situ. For the in situ method: (i) Another component such as a monomer is impregnated into the BC network which is polymerized in situ. (ii) At the beginning of biosynthesis, a water-soluble polymer is also added in the BC culture media. (iii) At the onset of bacterial synthesis, nanofillers are inserted in the BC culture medium, where BC behaves as the matrix. The structure and characteristics of BC nanocomposites can be conveniently modified using these in situ deposition techniques [128–130]. Composites of such BC are found for antibacterial, optical, electric, and magnetic uses as well as for catalytic and biomedical operations [128].
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In Situ Polymerization of Monomer in the Presence of Bacterial Cellulose
In situ polymerization of monomer in the presence of bacterial cellulose can be achieved via BC/polylactic acid (PLA) [131], BC/polystyrene (PS) [132], BC/ 2-aminoethyl methacrylate (PAEM) [133], BC/polyacrylamide (PAM) [134], and BC/polypyrrole (PPy) [135]. A successful BC network impregnation with an in situ low-viscosity monomer may therefore give the cellulose nanocomposites superior properties and clearly demonstrate the benefit of the in situ method that gives new blueprint for diverse biomedical applications the opportunity for synthesis.
5.3
In Situ Growth of Bacterial Cellulose in the Presence of a Polymer
Various substances were incorporated directly into the culture medium which resulted in BC/polymer nanocomposites growing in situ. The water soluble nature, strong mechanical characteristics, and biocompatibility of polyvinyl alcohol (PVA) attracted many attention [90, 136]. The presence of PVA was found to influence the in situ growth of BC through the formation of spherulites [137]. Several authors have worked in this area [138, 139].
5.4
In Situ Growth of Bacterial Cellulose in the Presence of a Nanofillers
In situ synthesis of BC with a nanofiller will ensure that the nanofiller is dispersed equally in a BC matrix and that the advantageous 3-D BC structure is preserved. The nanofillers are nanoparticles, nanoplatelets, nanotubes, nanorods, etc., and dangerous interactions between the BC network synthesized locally, and nanofillers are likely to occur. Researchers have prepared in situ biosynthesis nanocomposite hydrogels with BC and graphene (GE) [140], graphene oxide (GO)/BC nanocomposites [141] using environmentally friendly one-step in situ biosynthesis process, BC-nanoclay (NC), BC-xGnP, and BC-CNF nanomaterials [128].
5.5
In Situ-Formed Plant Cellulose (NC) Nanocomposites
Ex situ techniques are quite popular for preparing plant cellulose (NC)-based nanocomposites. However, there are very few reports on in situ-formed NC-based nanocomposites which include NC/polyfurfuryl alcohol [142] with a potential for diverse applications; NC/polyacrylamide [143]; NC/polyaniline (PANi) [144] with applications as flexible electrodes, sensors, and electrically conductive and flexible films and papers; NC/polyurethane (PU) [145] with improved properties that have widespread applications in a range of commodity products such as elastomers,
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foams, paints, and adhesives and also useful for biomedical applications; NC/ polyacrylate [146, 147] which can lead to the development of novel materials for new applications with easier processability; and NC/polymethylmethacrylate (PMMA) [148] which can be explored for surface coating or structural applications where transparency will be retained with the benefits of enhanced mechanical strength and improved moisture resistance property. To conclude, techniques like in situ processing of cellulose nanocomposites may soon emerge as an important manufacturing route.
6
Conclusion and Future Prospective
Composites packed with natural fillers (natural fibers, NCs, and nanofibrillar cellulose), owing to the need for sustainable, friendly fabrics with better properties, have become strongly focused on researchers and companies’ investments. Many natural fibers were used to create composites, which include coconut (Cocos nucifera), sisal curaua (Ananas erectifolius), and jute (Agave sisalana) (Corchorus capsularis). Cellulose nanocrystals and nanofibrillated cellulose which are crystalline were also commonly used to achieve cellulose portions. These natural fillers were commonly used in the matrices and matrices of polymers. Improvements were found in its thermal and mechanical properties. Composites reinforced with enhanced performance natural fillers are a strong choice to acquire lightweight and more environmentally conscious car industry components. From a technological standpoint, however, the wider use of these materials is only accomplished if manufacturing costs and mechanical and thermal efficiency correlate with the commonly used materials. Furthermore, other factors should be considered, such as reproductive stage and long-life cycles. In general, the prospects are positive; the use in automotive industries of polymer composites improved by natural fillers possesses the strong ability to reduce the high volume and lead to a more stable society with non-biodegradable waste in waste dumps. In automotive applications, polymer composites enhanced with natural fillers were used. However, there are still some thresholds to the widespread use of such composite materials, especially with regard to their manufacturing cost, shorter life cycle, and the inability to monitor microstructures that led to limited commercial success. The efficiency and environmental attractiveness in combination with the use of composites of 20% natural material will reverse this pattern. For example, the influence of nonbiodegradable polymers in the natural environment is reduced by at least 20% by fillers. To sum up, the multi-billion-dollar industry of polymer composites fortified with natural fillers in the automotive field still searches for innovative products to make more attractive materials, thus raising its profit margin. In brief, functionalization and mass manufacturing are the two paths for the growth of nanocellulose-reinforced polymer composites, which basically meet the need for safer, heavier, cheaper, and more diverse materials. In fact, the growth potential of this sector is reflected by many of the current challenges. Every minor advance will push the entire industry into a significant landmark, independent of
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theory, technology, and practice. In the following uses: engineering plastics, practical films, bio-scaffolds, catalysts, drug carriers, adsorption materials, and lightweight electronic parts, nanocellulose-reinforced polymer composites are playing an increasingly important role, with further future applications under review. Nanocellulose-reinforced composite materials are thus predicted to be the most important composite material in the coming era with more study.
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Synthesis and Applications of Organic Framework-Based Cellulosic Nanocomposites
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Vasanthakumar Arumugam and Yanan Gao
Contents 1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Classification of Plant Nanocellulose and Their Structural Characteristics . . . . . . . . . . . . . . . . 3 Synthesis of Various Organic Framework Cellulosic Nanocomposites . . . . . . . . . . . . . . . . . . . . 3.1 Fabrication of CF composites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2 Synthesis of Nanoparticle Immobilized Cellulose Fiber Composites . . . . . . . . . . . . . . 3.3 Immobilizing MOFs into a Cellulosic Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4 Synthesis of COF-Grafted Cotton Fiber . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5 Synthesis of MOF/Cellulose Composite . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6 Fabrication of Hybrid Films via an In Situ Synthetic Method . . . . . . . . . . . . . . . . . . . . . 3.7 Preparation of MOF Containing Cellulose Paper Composites . . . . . . . . . . . . . . . . . . . . . 3.8 Synthesis of MOF-Incorporated CNF Composites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.9 Fabrication of MOF-Based CNF Nanopapers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.10 Fabrication of MOF-CNF Papers by Direct Mixing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Characterization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1 Adsorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2 Gas Adsorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3 Detection of Metal Ions` . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4 Iodine Capture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.5 Extraction of Organics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.6 Separation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.7 Wastewater Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Bio-application . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1 Antibacterial Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2 Drug Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Future Perspective and Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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V. Arumugam · Y. Gao (*) Key Laboratory of Ministry of Education for Advanced Materials in Tropical Island, Resources, Hainan University, Haikou, China e-mail: [email protected] © Springer Nature Switzerland AG 2022 A. Barhoum (ed.), Handbook of Nanocelluloses, https://doi.org/10.1007/978-3-030-89621-8_26
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Abstract
Generally, organic frameworks are an emerging class of crystalline frameworks with regular porosity and a complex molecular structure with active functional groups. Covalent organic frameworks and metal-organic frameworks are the most popular in framework material chemistry. Due to their fascinating physical and chemical properties, they have been used in a wide range of applications including adsorption, separation, catalysis, membranes, energy storage devices, and pharmaceuticals. The foregoing makes developing nanocomposites based on these organic frameworks with diverse supporting elements such as nanoparticles, graphene, carbon nanotubes, cellulose, and other components more appealing. Among them, cellulose-based nanocarrier materials are more interesting, due to their cost-effectiveness and abundant availability. Therefore, in this chapter, we focus on composites which were made by the combinations of organic frameworks with cellulosic materials. The reasons for developing these kinds of composites are to improve the stability of organic frameworks and reduce cost for wide range of industrial applications. Since, COFs and MOFs are relatively less stable, their crystallinity and molecular structures would be readily lost in harsh conditions as well as expensive. Therefore, the stable supporting materials are required to enhance their stability for a long time to sustain in harsh circumstance while doing different applications. Particularly, in this chapter, we are going to discuss much more about the synthesis of various COF-/MOF-based cellulosic composites and their wide range of applications. Compared with COFs, MOF-based cellulosic composites have been reported more in recent years. Generally, MOFs have effective interactions with cellulose molecules due to their metal coordination and, also, they have shown excellent performance in their applications. Particularly, these classes of composites were used as a membrane for nanofiltration, adsorbent in wastewater treatment, extraction and removal of toxic ions, biomedical and metal applications. Keywords
Covalent organic frameworks · Metal-organic frameworks · Cellulose nanocrystals · Cellulose fibrils · Nanofiltration · Bridging organic linkers
1
Introduction
Cellulose is one of the major components present in plants which is photosynthesized from CO2 and water. In the last century, researchers began to focus on the preparation of bio-based nanomaterials from natural fibers of plant celluloses. Compared with existing petrochemical products and inorganic nanomaterials, nanocellulose exhibits unique morphology, physical characteristics, and functions and high stability. Therefore, they can be used in a wide range of applications [1]. Furthermore, there is a possibility to produce abundant nanocelluloses from sustainable
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resources of biomass. Also, the advantages of cellulose fibers are inexpensive, renewable, biodegradable, flexible, and abundant availability; these led to gaining more attention from researchers to consider this in material chemistry. Currently, we are facing many ecological and sustainable problems such as global heating, climate emergency, microplastics in the ocean, and non-biodegradable wastes, due to the drastic consumption of fossil fuels since the twentieth century, and greenhouse gases are one of the major reasons for those environmental issues. Therefore, it is necessary to control greenhouse gases especially CO2 for our modern society. Consequently, the development of CO2-accumulated nanocellulose to make modern nanoframework materials is one of the ways to control CO2 in a sustainable society [2]. Generally, cellulose-based materials are classified by their morphology and properties. There are several cellulosic materials available for various applications. Particularly, the hydrophilic surface and the porous structure of cellulose fibers (CFs) offer excellent properties for air permeance and sweat adsorption. Nevertheless, the nature of CF’s sweat-absorbing property provides a favorable atmosphere for microbes. Thus, there is a necessity to use several antibacterial chemicals, such as metal salts, halogen ion complexes, and other chemical agents with CFs. When used in large doses, these compounds may harmful to people, and the antibacterial efficacy of treated CFs can decline with time [3, 4]. The conversion of cellulose into soluble sugars by hydrolysis using cellulase is one of the important catalytic processes that is widely used in industrial applications including foodstuffs [5], agriculture, textile [6], pulp and paper [7], and bio-transformations [8]. In particular, cellulase plays a vital role in the biorefinery industry for the production of bioethanol from sugar bagasse by breaking down cellulose [9]. The content of cellulose may vary on account of the eco-factors and maturity of fibers. Researchers applied various chemical treatments including sulfonation, phosphorylation, nitration, etherification, oxidation, and esterification to cotton fibers for modifying the surface chemistry of the resulting cellulose [10–12]. Generally, organic frameworks are well-ordered crystalline porous materials, which offer a high surface area, chemical diversity, regular porosity, rigidity, and site-specific functional tunability [13]. Using organic frameworks in various fields makes them more attractive to researchers. The generation of these kinds of materials creates a new research platform for designing a broad range of materials with customized structure, size, dimension, porosity, and functionality [13, 14]. Some of the most common covalent organic frameworks (COFs) and metal-organic frameworks (MOFs) are mentioned in Fig. 1. Both COF and MOF have unique physical and chemical properties with a wide range of applications. Particularly, COF can be used in various applications including as catalyst [15, 16] and for charge and energy storage [17, 18], sensing [19], proton conduction [20], gas storage and separation [21], and energy production [22]. Conventionally, COFs have been constructed through the joining of covalent bond linkages such as boronic ester (B-O), imine (C¼N), hydrazine, azine, and so on [23], between organic building blocks. Among the above, imine-linked COFs are the most common and easier to synthesize from a wide library of covalent linkages.
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Fig. 1 Common MOFs and COFs [24, 25]
Generally, COFs composed of metal-free organic frameworks may be rendered into membranes and coatings in addition to their designable structures, whose chemical properties and nano-microstructure can be tuned [14, 16]. From these characteristics, one property that can be easily integrated into COFs is hydrophobicity. It is possible to control the surface characteristics such as hydrophilicity/ hydrophobicity at the atomic level [16]. Metal-organic frameworks (MOFs) are almost similar to covalent organic frameworks except the presence of metal coordination on it. Usually, metal ion-coordinated organic ligands or clusters and organic monomers are reacted together to form crystalline porous MOFs, which have extended structures in different dimensions (1D, 2D, and 3D) [26]. The uniqueness of MOF is its exact surface area with consists of tunable pores at the nanoscale level, the existence of unsaturated active metal functional sites and the ability to be chemically modified [27]. Due to these amazing properties, MOFs exhibit a great potential in different applications including gas storage and separation, catalysis, and chemical sensing [27]. However, they have quite commonly appeared as small powders because they were involved in their crystallization processes, which contributes to quick agglomeration and is not readily recyclable.
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da Silva Pinto M et al. recently reported the cotton functionalized MOFs that can be used to accomplish the targeted carboxymethylation by modifying the surface of the fibers using chloroacetate in alkali medium [28]. In this case, cellulose acetate is a substrate for MOFs, and that can be typically prepared through acetylation of cellulose using known reagents in the presence of a catalyst. Furthermore, this cellulose acetate is commonly used in various fields including membranes, plastics, fibers, photographic films, and lacquers [29, 30]. Therefore, these can be used to establish different hollow fibers with series of MOFs, namely, UiO-66 [31], ZIF-67 [32], MOF-199 [33], ZIF-8 [33], and Al-fumarate MOF [34], because cellulose acetate is readily electrospunable. In this chapter, we are going to discuss the COF- or MOF-incorporated cellulosic nanomaterial preparation and characterization and their various fields of applications including adsorption, separation, wastewater treatment, and biomedical applications.
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Classification of Plant Nanocellulose and Their Structural Characteristics
Generally, nanocelluloses are classified as fibers with widths of 500 nm with homogeneous width of ≈3 nm, and they can be separately distributed in water without the formation of fibril bundles. Mostly, CNCs exhibit spindle-like morphologies 2–30 nm in width nm and 95% of cellulose contents [36]. Cellulose is made up of units of D-glucopyranose bound by β-1,4-glycoside bonds as shown in Fig. 3. Therefore, a single unit of glucose contains three reactive hydroxyl groups, and these are responsible for the H-bonds that connect with other cellulose chains to form fibrils (see Fig. 3). And the resulting materials will be integrated by incorporating active functional groups, organic frameworks, or metals into hydroxyl groups through chemical modification. These changes may include (i) using a native fiber moiety that mimics the MOF complexing molecules, (ii) fiber modification by incorporation of organic ligands that mimic the MOF complexing moieties [29], (iii) inorganic oxides that are mixed into fiber surface to imitate an inorganic component of the MOFs [37]. During pretreatment for the preparation of CNFs with homogeneous width (≈3 nm), the surface of crystalline cellulose microfibril has been modified by the introduction of functional groups via suspension of charged group chemicals. The CNFs can be prepared via proposed chemical pretreatment such as carboxymethyl etherification, phosphorylation, esterification of phosphite, C6-carboxylation, esterification of sulfate, and plant cellulose fiber’s C2/C3-dicarboxylation [38]. The presence of water on the surface of pretreated cellulose microfibrils create strong anionic charges, electrostatic repulsions and osmotic effects that
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efficiently operate between celluloses. Consequently, in the original plant cellulose fibers, all the interfibrillar H-bonds between cellulose microfibrils are cleaved by gentle mechanical disintegration in water, yielding in the creation of completely individualized CNFs dispersed in water or partially fibrillated CNNeWs in hydrophobic polymer matrices. Therefore, chemical pretreatment and subsequent mechanical disintegration in water lead to reduce the widths of original plant cellulose from ≈30 μm to 3 nm. Positioning the charged groups selectively and densely on the surface of crystalline cellulose microfibril was successfully achieved during the chemical pretreatment processes of cellulose fibers. Consequently, the chemically pretreated cellulose preserves its original crystal structure of pristine cellulose.
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Synthesis of Various Organic Framework Cellulosic Nanocomposites
The traditional CNCs were prepared via acid hydrolysis of plant cellulose using H2SO4 (64%) at 70 oC for 30 min, which then successively disintegrates in water [39]. In experiments, the yield was decreased up to 40% because some portions of water-soluble crystalline regions were removed in raw plant cellulose as well as it contains disordered regions of low-molecular-weight compounds. These CNCs have been developed and are available as spray-dried CNCs in Canada, the USA, and Israel. The following methods such as prolonged sonication in water, esterification of sulfate and phosphorylation by sulfamic acid are the most recent processes that have been used to prepare CNC based composite from CNFs in ionic liquid medium [40].
3.1
Fabrication of CF composites
The desired quantity of pulp fibers was mixed with the required amount of Cu (OAc)2 H2O in a three-neck flask that would be fixed in a thermostat water bath. Then, water is used to make a homogeneous solution of the above mixture at the same flask. In addition, the above reaction system was stirred for some more time then added with a solution of H3BTC in ethanol while stirring at an ambient temperature. The color of the reaction mixture suddenly changes to deep turquoise from light blue; then, the reaction is further continued for several minutes at constant stirring. The general schematic diagram of composite (HKUST-1/CF) preparation is as shown in Fig. 4. A large amount of distilled water was used to remove the residual reactants from the final product. Afterwards, the ZCX-200 hand sheet former had been used to make a hand sheet of HKUST-1/CF composite manually. The final hand sheet was pressed for 5 min at 1MPa and then dried for 5 min at 105 oC. Until testing, the hand sheet was fixed at 23 oC for 24 h and 50% relative humidity [41].
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Synthesis of Nanoparticle Immobilized Cellulose Fiber Composites
Herewith AgNPs@HKUST-1@CNs composites have been taken as an example to expose the methodology of nanoparticle immobilized cellulose fiber’s composites. Figure 5 demonstrates the general synthetic methodology for nanoparticle organic frameworks with nanocellulose combined composites. In this case, in situ synthetic methodology has been used to immobilize HKUST-1 on CF surfaces. The desired amount (1g) of resulting HKUST-1@CFs was immersed in a mixture of ethanol/ water solution (50 mL) with required AgNO3 for 4 h at constant stirring. Next, microwave irradiation (800 W) has been applied to silver ions in the substrates of HKUST-1@CFs to synthesize the composite AgNPs@HKUST-1@CFs (see Fig. 5). The resulting composites of AgNPs@HKUST-1@CFs were repeatedly washed five times with deionized water and dried for 6 h in a vacuum oven at 50 oC to get the final pure targeted product [42].
3.3
Immobilizing MOFs into a Cellulosic Structure
The metal organic framework based cellulosic nanocomposite was synthesized through the following method. Initially, the desired quantity of UiO-66-NH2 MOF was suspended in acetate buffer pH 4.8 (5 mL) and add the required amount of
Fig. 4 Synthesis of cellulose fiber MOF nanocomposite
Fig. 5 Schematic illustration of the synthesis of Ag-MOFs@CNF@ZIF-8 composite filter [43]
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cellulase enzyme powder at constant stirring for 12h. In this case, various concentrations (5, 10, 15, 20, and 25 mg) of cellulase enzyme powder have been used for optimization for immobilization. The Bradford protein assay method can be used to determine the enzyme content, and bovine serum albumin (BSA) was used as a standard in the UV-Vis spectrophotometer [44].
3.4
Synthesis of COF-Grafted Cotton Fiber
COFs@cotton were synthesized using imine linked COFs and scandium (III) triflate catalyst via Schiff based reaction [45]. In this system, 1,3,5-tris(4-aminophenyl) benzene and 1,4-dioxane/mesitylene solution were charged in a 20 mL scintillation vial. The above mixture was sonicated at room temperature until a homogeneous solution of monomers is obtained. Next, the desired quantity of oxidized cotton fiber and scandium (III) triflate was added together and briefly ultra-sonicated. Afterwards, the cotton fibers were separated and put in another scintillation vial containing the required amount of terephthaldehyde and scandium (III) triflate. Then added a solution of 1,4-dioxane/mesitylene mixture to the above mixture and continue to sonicate for another 10 min. The yielding cotton fibers were purified by Soxhlet extraction for 24 h using methanol as solvent, and finally, the wet sample was further purified by washing with supercritical CO2. The final product was vacuum dried at 323 K for 12 h before testing [46].
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Synthesis of MOF/Cellulose Composite
The source of metal ion (Cu(NO3)2.3H2O and H3BTC) and organic ligands were required to generate MOF-199. The combined DMF/ethanol/water solvent was used to dissolve the abovementioned materials at constant stirring. Then, the solution of MCC in water was slowly added while stirring the reaction mixture. After this, a little amount of triethylamine (0.25 mL) was added to the above mixture at constant stirring, and the same was continued for the next 3 h to complete the reaction. Finally, the resulting material was washed with water and dried to get the targeted MCC/MOF-199 composite product [47].
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Fabrication of Hybrid Films via an In Situ Synthetic Method
The desired amount of transparent tempo oxidized cellulose nanofibril (TOCNF) was dissolved completely in water to make a homogeneous solution; then, the various quantities of EU(NO3)3 6H2O were applied separately into that suspension at constant stirring of 800 rpm at ambient temperature to generate a white homogeneous suspension. Following that, H4BTC was dissolved separately in ethanol and poured into the above-mentioned reaction system. The reaction system was heated to 60 oC for the formation of limpid from turbid then continue for the next 4 h. The
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obtained suspension was vacuum filtered using a PVDF membrane filter (diameter of 37 mm) with an average pore diameter of 0.22 μm and then cooled to room temperature. The final product was purified by washing with ethanol and distilled water. In the end, a pressing machine was used to press the film with 0.8 MPa pressure for 10 min and dried for 30 min at 60 oC [48].
3.7
Preparation of MOF Containing Cellulose Paper Composites
In this investigation, the author used MOF-5 which was reported previously and followed the same methodology [49, 50]. At room temperature, the desired quantity of 1,4-benzene dicarboxylic acid was dissolved in the required amount of DMF. Precipitated calcium carbonate-filled cellulose paper (PCCP) was applied to the solution by impregnation after dissolution. The samples of paper were completely impregnated in the solution and held at room temperature for 8 h. Subsequently, a certain amount of Zn(NO3)2 6H2O was dissolved in DMF separately; then, BDC and the impregnated cellulose paper were put together in a beaker and pipetted with the zinc nitrate/DMF mixture. Finally, the reaction mixture in the beaker was moved to a Teflon coated autoclave and heated to 120 oC for 24 h. The yielding product was cooled to room temperature, and DMF and absolute ethanol were in sequential order to wash the samples five times and air-dried at room temperature [51].
3.8
Synthesis of MOF-Incorporated CNF Composites
The CNF@Zn-MOF nanocomposite was synthesized using the following procedure: Initially, the desired quantity of 2,5-dihydroterephthalic acid was dissolved in a certain amount of NaOH solution. This solution was added to the ion-exchanged and surface-modified CNF suspension. A solution of Zn(NO3)2 6H2O in deionized water was then added dropwise into the suspension described above. This reaction mixture was constantly stirred for 8 h at 500 rpm. Afterwards, the clear yellow suspension was filtered and washed with deionized water several times. According to the TGA results, the final product was dried [52].
3.9
Fabrication of MOF-Based CNF Nanopapers
CNF@MOF nanopapers can be prepared on a wide scale. Polyvinylidene fluoride (PVDF) membrane filter has been used to vacuum filtered the clear suspension of CNF@MOF. Two metal molds were to clamp the filter cake and dried overnight in a vacuum oven at 70 oC. Afterwards, the paper was then pressed for 30 min by a home-designed mold pressing machine with pressure of 20 MPa. A versatile and highly transparent paper denoted as a CNF@MOF nanopaper was eventually obtained. The nanopaper thickness can be controlled by changing the volume and the CNF@MOF suspension concentration using the vacuum filtration process [52].
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3.10
Fabrication of MOF-CNF Papers by Direct Mixing
CNF-MOF papers can be prepared by direct mixing of CNFs and MOF powders. In general, the desired amount of MOF powder was dispersed in the required amount of water to make homogeneous solution by sonication. In the meantime, separately the CNF freeze-dried material was dispersed in water and homogenized with cooling water through sonication. Then, the suspensions of the MOF and CNF were mixed and sonicated for an extra 20 min. Subsequently, the MOF-CNF papers containing a certain percentage of MOFs were prepared using the same processes to produce CNF@MOF nanopapers [52].
4
Characterization
As synthesized organic framework based cellulose composite materials have to characterize with various advanced techniques to reveal their physical and chemical properties as well as get to know the overall nature of the material. Initially, FTIR and PXRD are most important techniques to confirm the linkage interactions and crystalline nature of the material. Following that, SEM and TEM analyses were carried out to expose the morphology of the composite material, which will be different from then pure individual material’s morphology (see Fig. 6). Furthermore, these images give an overall idea of how those individual materials are composed or
Fig. 6 TEM image of CAM nanofibers at different magnifications. High-resolution SEM image of the pure CNFs and the CAM nanofibers. SEM images of the CAM aerogel at different magnifications; the circled areas show the joints between the cross-linked nanofibers [53]
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bonded as composite, and from this we may assume the type of interactions and possibly the formed materials. Thermogravimetry analysis (TGA) was carried out in nitrogen flow thermogravimetric analyzer (60 mL/min) between 25 oC and 900 oC with a heating rate of 10 oC/min. Nitrogen sorption isotherms were measured at 77k in a surface area and pore size analyzer for micromeritics. Samples were degassed under a kinetic vacuum at 120–150 oC for 10 h. The software package of micromeritics has been used to determine the surface area and pore size in BrunauerEmmett-Teller (BET) method. In accordance with the standard test method of ASTM D-638, the mechanical properties of CNF@MOF nanopapers, MOF-CNF papers, and CNF papers were measured at room temperature using an Instron instrument at a crosshead speed of 2 mm/min. For the tensile strength testing, specimens with a dimension of 40 mm x 5 mm x 40 μm were prepared. For example, MCC@MOF-199 demonstrates the existence of a synergy between the two components, which leads to the development of a porous hybrid with an external connection like H-bonding between the functional groups of MOF-199 with the hydroxyl group of MCC [47]. Plenty of MCC hydroxyl groups serve as the dispersing agent in an aqueous sample of the MCC/ MOF-199 particles, and the structural supporting role is also played by the polymeric chains of MCC. It was observed that the nanofibers of CAM hybrid (~35 nm) which was derived from the incorporation of CNF into AI-MIL-53 have a larger diameter than the pure CNFs (~20 nm) (see Fig. 6). Figure 6 represents the classic single CAM nanofiber with core-shell structure; in this case, CNF was wrapped around by a nanolayer of AI-MIL-53. The high-resolution SEM images for nanofibers of CAM exhibit a smooth surface, which proved the continuous nucleation of AL-MIL-53 nanolayers onto the CNFs. The skeleton of the aerogel was developed by the interconnected cellular network with a pore diameter of ~10 μm (Fig. 7). This development of novel cellular architecture is obtained during the phase separation of interconnected CAM nanofibers and water through the freeze-drying process [54].
5
Applications
5.1
Adsorption
Chao Lei et al. developed a novel cellulose-based composite using cellulose aerogels and MOFs through in situ growth procedure of MOFs packing flexible cellulose aerogels at room temperature [51]. In this case, the author used UiO-66 and UiO-66NH2 MOFs to make cellulose-based composites. These composites were characterized by SEM, XRD, AAS, and TGA for revealing their physical and chemical properties. Furthermore, as-prepared composites were investigated for the adsorption of metal ions such as Pb2+ and Cu2+. The adsorbed quantity of metal ions by MOFs@cellulose aerogel composite is equivalent to the number of MOFs and cellulose aerogels, which suggests that MOFs are not blocked even after growing on surfaces of cellulose aerogel composite and still have significant adsorption
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Synthesis and Applications of Organic Framework-Based Cellulosic Nanocomposites 453
a
b
c
d
Fig. 7 (a) SEM of BC@ZIF-8. (b) TEM of BC@ZIF-8 nanofiber. (c) STEM image and EDX elemental mapping images of BC@ZIF-8 nanofiber. (d) XRD pattern of BC, ZIF-8 nanoparticles, BC@ZIF-8, and simulated ZIF-8 [55]
capacity. It was observed that the cleaning and recycling of composite materials of MOFs@cellulose aerogels are easy, and water can be used as a solvent for this process [51]. The resulting findings indicated that the adsorption time dependence was well suited to a pseudo-second-order kinetic model for Pd2+ adsorption with a rate constant of k2. And the adsorption of Cu2+ of UiO-66@CA and Ui-66NH2@CA shows that the second-order kinetics is reasonable and greater than the first-order kinetics. The adsorption of Pb2+ and Cu2+ by UiO-66@CA equilibrium adsorption capacity is greater than UiO-66 particles, which is significantly lower than the summation of the CA and UiO-66 equilibrium adsorption capacity alone. Large pores in the micron level of CA helps for the rapid adsorption of heavy metal ions. Simultaneously it would be playing a vital role in speeding up the interaction between MOF and metal ions. The resulting data revealed that the adsorption potential of UiO-66-NH2 and UiO-66-NH2@CA is greater than UiO-66 and UiO-66@CA for Pb2+ and Cu2+ adsorption. It is expected that great adsorption can be achieved by mixing various MOF and cellulose combinations in the future. MOFs which were used in the composite can be recyclable. The compressive stress increases by up to 50% and 60% by UiO-66@CA and UiO-66@CA-NH2, respectively, when compared to CA. The growth of MOF on cellulose leads to make its effective absorption properties. In this investigation,
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complicated filtration processes were not required for the separation of MOFs@CA composite, and it can be easily recyclable [56]. Even after repeated use, the CA material will remain dimensionally stable which means the structural internal network was not destroyed. The used MOF UiO-66-NH2 also exhibits great stability and preserves their original shape, and there were no significant crystalline changes observed after being reused more than five times. Thus, such outstanding reproducibility, reusability, and quick superstation process make these composite aerogels ideal materials for heavy decontamination.
5.2
Gas Adsorption
Recently several cellulose-based nanocomposites have been developed for the removal of various rare elements, organic pollutants, and toxic chemicals. Generally, several nanocarrier materials such as nanoparticles, nanotubes, organic frameworks, and magnetic materials are used to make composite materials for improving properties and enhancing their efficiencies. Organic frameworks, particularly MOF and COFs, have excellent adsorption properties, so they could be incorporated into cellulose to make more efficient outputs; at the same time, these materials are easily recyclable as well. Qiang Yang et al. [50] reported the cellulose paper@MOF-5 composite materials which were prepared by packing MOF-5 on the surfaces of precipitated calcium carbonate (PCC)-filled cellulose paper. The presence of PCC fillers on the cellulose paper significantly influence to reduce the formation of H-bonds among fibers of celluloses, thus, leads to make more hydroxyl groups of 1,4-benzendedicarboxylic acid (BDC) are available to react with the organic ligands to form MOF-5. Most of the MOF-5 crystals are small due to the increased number of crystal growing sites in the cellulose paper filled with PCC. Furthermore, the resulting composite material exhibits zeolite-like frameworks with a high surface area. This composite (paper@MOF-5) showed a superior capacity for nitrogen gas adsorption and also has a great potential to adsorb or store gaseous products like H2, CO2, CH4, etc. [51]. The presence of MOF-5 has been largely due to the excellent adsorption potential of the composite material PCCP@MOF-5. In this case, three active adsorption sites located near the metal center, therefore the adsorption of nitrogen molecules very began there even in low pressure; and later on nitrogen molecules fully adsorbed by other organic ligands while rising pressure to fill all the pores of the materials. Compared with the PCCP@MOF composite, the PCCP free material shows significantly less N2 adsorption. The small size of MOF particles on the cellulose surface leads to extend its surface area, that is the reason for its high capacity of adsorption [57]. From literature, it was found that the MOF@silk composite material was synthesized through layer-by-layer methodology, and this modified composite exhibits higher nitrogen adsorption capacity than the previously reported materials [58]. Moreover, the cellulose-modified MOF composite is a promising adsorption material that can adsorb various gases including CO2, H2, CH2O, and CH4. Another example of cellulose-based composites was reported by Uddin, M.K. et al. They
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Synthesis and Applications of Organic Framework-Based Cellulosic Nanocomposites 455
prepared zeolitic imidazolate framework (ZIF-L) cellulose hybrid composite at room temperature in an aqueous medium via straightforward synthetic methodology, and in this case zeolite frameworks look like lead structure [59]. The advantages of this process are its simplicity and being a fast method with an eco-friendly manner. In this investigation, the author applied a new strategy of multifunctional foam growth. The resulting foams have good mechanical properties with ultra-lightweight. They exhibit a strong high selective adsorption for CO2 with low ZIF-L loading.
5.3
Detection of Metal Ions`
Metal detection is important in many fields including food processing, pharmaceuticals, and foreign pollutants in recent years. Among various metals, Pb(II) can be used in a wide range of applications including catalysis, dyeing, pharmaceutical, and printing for different purposes [60–62]. Thus, exposure to Pb(II) ions in various places affects the human organ systems, especially the nervous, digestive, renal, cardiovascular, and endocrine systems [63, 64]. Therefore, contamination of the aqueous environment by lead makes serious problem; hence, advanced developments are needed in the field of adsorbents for the effective removal of Pb ions and toxic chemicals. So far, ion exchange, precipitation [65], adsorption [66], and biosorption [63] are the techniques that would be used for “Pb” ion remediation. Among them, adsorption is considered to be the most reliable, economical, and easiest way for the extraction of Pb(II) from water. And recently a variety of new materials such as nanostructured materials [67, 68] and microorganism-based [69] adsorbents have been developed for removing Pb and organics. Cellulose aerogels (CA) have great properties such as low cost, high strength, non-toxic, lightweight, water stability, durability, and excellent processability, which makes them a potential substrate for nanocomposites [70, 71]. The dispersion of MOF on the cellulose surfaces is a successful strategy to prepare a new functional composite material [72]. Zhu et al. [72] developed MOFs@cellulose nanocrystal composites for efficient water treatment. Maatar and Boufi’s [73] research group established polymer grafted nanofibrillated cellulose (NFC-MAA-MA) aerogels via radical polymerization using Fenton’s reagent in an aqueous medium. This has been used as an adsorbent to extract heavy metal ions from an aqueous medium. This composite can be used for adsorption of various metal ions including Pd2+, Cd2+, Zn2+, and Ni2+ ions due to its high adsorption capacity, and also it can be simply reusable with negligible loss of adsorption capacity. In this case, EDTA is used as a desorbing agent to extract more than 98% of the adsorbed metal ions [36]. Cellulose aerogels can be easily recyclable, and their porous structure and templating properties further enhance their adsorbing power in wastewater treatment [36]. It was observed that the adsorbing ability of pure cellulose aerogels is very low for heavy metal ions [39]. Literature shows that the ability of adsorption properties improved when CA is combined with nanoframeworks or when new active functional groups are introduced on the surface of CA [36].
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Nan Wang et al. synthesized Zn-BTC-coated MCNC composite material (MCNC@Zn-BTC) in the presence of Et3N under mild conditions [36]. The author used this novel material for extracting Pd(II) from water, and a series of systematic experiments was conducted for optimization. The Langmuir isotherm model confirms that the pseudo-second-order kinetics was observed for this adsorption investigation. Furthermore, this MCNC@Zn-BTC composite material’s preparation is easy, and it can act as an active adsorbent for the effective removal of Pd(II) ions in polluted water [74]. Haiping Wang et al. [47] successfully fabricated a fluorescent hybrid film (Eu-MOF@TOCNF) via in situ synthesis of Eu-MOF on the TOCNF surface in combined solvent media of ethanol/water. Compared to those previously reported in the literature, the presence of TOCNF led EU-MOF to have different morphologies. The resulting material shows that the coated Eu-MOF appeared in the form of film/nanoparticle on the surface of TOCNF. And this composite was highly stable in long pH ranges from 3 to 11. Therefore, it can be used in strong acid and alkali conditions as well as works well as a chemical sensor in a complex water system [48]. In addition, the sensing of Cu2+ could be successfully achieved via selfcalibrating luminescent of this material, due to great properties such as excellent selectivity, sensitivity, acid-base stability, and clarity. In particular, fluorescence intensity of the Eu-MOF@TOCNF film material decreases once the concentration of copper ions increases. The highlights of the above reveal that it would be a promising material for the detection of Cu+ in the water body [48].
5.4
Iodine Capture
Nuclear power is an important part of the energy system in the world due to its efficiency and stability, and overall, it is a clean energy [75]. However, the longstanding and high radiotoxicity produced by spent fuel containing radioactive elements and the dumping of spent nuclear fuel are the main downsides of nuclear energy [76]. The production of radioiodine (129I and 131I) in spent fuel reprocessing is highly harmful than other wastes containing radioactive elements such as 85Kr, 133 Xe, and 90Sr, due to its high volatility (131I) and long-range radioactive half-life (1.579107 years of 129I) [77]. Generally, the human body requires iodine, and therefore, it can easily absorb radioactive iodine from the circumstance via air circulation, food chains, and other sources. The thyroid gland selectively absorbs iodine which leads to hypothyroidism and even carcinogenesis [78]. Indeed, the Mayak nuclear spill research has shown a causal association between thyroid disease and radioiodine exposure [79]. Hence, the timely and efficient treatment for radioiodine is very essential, but it remains a challenging job. Ion exchange, evaporation and concentration, chemical precipitation, biological reaction, molecular adsorption, and membrane isolation are the latest methods that are used for the removal of radioiodine. In the view of the above methods, adsorption is the one technique that could be most commonly used, so several various adsorbents have been used including natural inorganic materials [80], activated carbon [81], ion exchange resin [82], nanomaterials [83], and porous organic polymers (POPs) [84]. Traditionally, both the vapor and liquid forms of iodine were successfully trapped using
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Synthesis and Applications of Organic Framework-Based Cellulosic Nanocomposites 457
organic amine-loaded porous materials, but it has some drawbacks too, such as easy sublimation of adsorbent, the low performance of adsorption, weak regeneration potential, and difficult reuses [84]. Modern material chemistry produces numerous active porous organic framework materials which are very useful for various applications including capturing of metal ions and iodine [15, 16]. Indeed, MOF has earned great interest in the field of iodine adsorption due to its amazing properties and stability [16]. The transition metals or cyanates of transition metal-containing Hofmann-type MOFs with the general molecular formula MII(pz)[NII(CN)4] (pz¼pyrazine, M ¼ Ni2+, Fe2+, Co2+; N ¼ Pt2+, Ni2+, Pd2+) – complexes having more number of cyanate groups – show effective adsorption among various MOFs [85]. The complex (NiII(pz)[NiII(CN)4]) exhibits a strong adsorption effect for iodine, and the adsorption potential is 1 mole of per mole of Hofmann-type structure [86]. Recently, two types of hybrid aerogels, namely, CoFe@CA-IS and Co@CA-D, were developed through in situ growth and doping techniques by using bimetallic Hofmann-type MOFs (Co-Fe)II(pz)[NiII(CN)4] and cellulose aerogels. These hydride aerogels exhibit outstanding performance for iodine adsorption. Furthermore, the addition of {(Co-Fe)II(pz)[NiII(CN)4]} into hybrid aerogel leads to an increase in its porosities. It was found that the porosities of these synthesized nanocomposites are significantly increased when compared to pure cellulose aerogels. In addition, the doping technique offers a significant improvement in its adsorption efficiency. Furthermore, the hybrid aerogels showed excellent equilibrium adsorption capacity even after being recycled more than five times. Results indicated that this MOF@cellulose hybrid aerogel has great potential in the treatment of iodine, and it could be used in a wide field [85]. Hybrid aerogels are a possible substitute material for iodine capture, and a technique for the preparation of effective and environmentally safe hybrid aerogels is given by the doping process [87]. The cellulose-based nanocomposite materials are a new class of advanced materials that accumulate pristine cellulose with functional materials for specific applications. A novel cotton fiber (CF) covalent organic framework (COF) hybrid monolith was prepared for the effective vapor and solution capture of iodine [42]. In this case, first, the cotton fiber was modified through silylation reaction with (3-aminopropyl) trimethoxysilane to generate amino functions on the fiber surface, and then the COFs were subsequently grafted. Notably, this iodine sorption was reversible on COF@cotton. After completing the adsorption process, I2COF@cotton was immersed in fresh ethanol to remove the encapsulated iodine from the framework. The COF@cotton’s adsorption capability almost remained constant after five uptake cycles, which suggests its strong reusability for iodine vapor capture [46].
5.5
Extraction of Organics
Due to the population, industrialization, and modern lifestyle, several new toxic organics have been used in our day-to-day life. Among them, chlorophenols (CPs) are organic toxic chemicals that have significant environmental issues due to their
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longevity in environmental matrices. CPs can be widely used in agriculture and industries as biocides, insecticides, disinfectants, wood preservatives, and intermediates [88]. Owing to these widespread applications of chlorophenols and their derivatives, they were found in many food samples including peach juice, tea, and honey. Furthermore, chlorophenols are also found in various naturals such as biological tissues, soil, air, wastewater, and some sediments [89, 90]. In addition, they can be produced as by-products of the chlorination of drinking water [91] and the chlorine bleaching of weed pulp [92, 93]. In this case, the author prepared a microcrystalline cellulose/MOF-199 hybrid (MCC/MOF-199) and used this as a sorbent for extraction of chlorophenols through the dispersive micro-solid phase extraction (D-μSPE) [47]. In the above investigation, the optimal conditions were optimized for each sorbent in the extraction of CPs. From the above, it was observed that the extraction efficacy of the MCC/MOF-199 hybrid is greater than the pure MCC and MOF-199. Furthermore, the high surface area and regular porosities are the advantages of cellulose-MOF hybrid. Additionally, cellulose offers additional features such as low density, hydrophilicity, and improved surface area, compared to pure MOF [47]. This material can be employed to detect various chlorophenols including 2-chlorophenol (2-CP), 4-chlorophenol (4-CP), 2,3-dichlorophenol (2,3-DCP), and 2,5-dichlorophenol (2,5-DCP) through D-μSPE methodology combined with high-performance liquid chromatography ultraviolet detection (HPLC-UV) in an aqueous medium. The key parameters of D-μSPE method such as the amount of sorbent, elution condition, duration of extraction, and pH significantly influenced the extraction, so these were investigated for optimization. In this investigation, a high sensitivity was observed with minimized time consumption due to the detection limit that is too low with less sample volume (200 μL). Moreover, the advantages of this method are novelty, fast with high sensitivity, wide linear range, much shorter extraction time, and insignificant matrix effect in target extraction. Finally, it is important to remember that the use of more sensitive detectors such as mass spectroscopy increases the accuracy and sensitivity of this technique which will enhance the quality and sensitivity of various fields in future [47].
5.6
Separation
The disposal of vast quantities of industrial wastes, including dyes and radioactive metal ions, is a serious water pollution problem since the revolution of industrial developments. Consequently, different techniques such as chemical precipitation [94], adsorption [95], ion exchange [96], and membrane separation [48] have been used for the removal of organic dyes and toxic metal ions from an aqueous solution. Among these, due to the easy operation and low cost, the adsorption technique is established to be an efficient and convenient process for water purification. However, complicated and tedious high-speed centrifugation or separation of the adsorbent has been achieved by filtration.
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a
b
Fig. 8 Schematic representation of filtration mechanism by Ag-MOFs@CNF@ZIF-8 filter. (Copyright 2018 Elsevier B.V. All rights reserved, reprinted with permission) [43]
It has been discussed previously that organic frameworks are porous crystalline materials that can be designed to serve as selective adsorbents. They may have high adsorption ability due to their high porosity and surface area. However, owing to the brittleness and cost of these crystalline materials, they wouldn’t be used alone for many industrial applications. Therefore, they can be converted into composite materials with other nanocarriers to be used for large-scale liquid stage separation processes. For this reason and because of its high flexibility and biocompatibility, nanocellulose would be considered as a promising supporting material as a nanocarrier for nanocomposites. A new flexible nanocellulose MOF composite material was synthesized in aqueous media by a straightforward in situ one-pot green method. The substance consisted of MOF particles of type MIL-100(Fe) which were immobilized on the nanofibers of bacterial cellulose (BC) (for an example see Fig. 8). This novel nanocomposite material was used to effectively isolate arsenic and Rhodamine B from an aqueous solution for achieving adsorption capacities of 4.81 and 2.77 mg, respectively. In this case, the nonlinear pseudo-second-order fitting could be a well model for this adsorption mechanism [6].
5.7
Wastewater Treatment
Nanocellulose is renewable and has great potential to be used as a support substrate, particularly in the form of cellulose aerogels or sponges [96]. So far, a few literature reported the combination of MOF with sponges or cellulose aerogels. Cranston et al. [97] developed a combined MOF immobilized cellulose nanocrystals through physical entanglement and van der Waals interactions between MOF particles and cellulose into a versatile and porous aerogel, thus making it suitable for water purification absorbents and other separation applications. The principles of H-bond and physical entanglements have been used to prepare shapeable fibrous aerogels of MOF templated nanocellulose by Li et al. [98] This material exhibited improved
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adsorption ability and rapid adsorption kinetics of Rhodamine B. Generally, many MOFs showed high catalytic efficiency for detoxifying chemical warfare agents (CWAs). In this case, the author loaded the MOF into the cellulose sponge to prepare a novel nanocomposite material for rapid degradation of CWA simulant [99– 101]. Particularly, on γ-glycidoxypropyltrimethoxysilane (GPTMS) modified cellulose sponge was achieved through in situ growth methodology. Large porosity, high specific surface area, and low density were obtained in this sponge. The functionalized cellulose sponge UiO-66-NH2 displayed excellent catalytic activity for 4-nitrophenyl phosphate (DMNP) detoxification, and its half-life was as low as 9 min [102]. In this case, the author used Rhodamine B as a model tracer to evaluate the adsorption potential kinetics via time-dependent UV-Vis spectroscopy method for adsorption on the MIL-100(Fe)@BC nanocomposite [6]. All adsorption experiments were conducted at room temperature. The capacity of adsorption for dye increases with increasing time and finally reaches equilibrium within a day to achieve a maximum percentage of removal. This nanocomposite’s high adsorption potential results from the hierarchical porosity, and tiny crystals of the nanocomposite were incorporated within the BC network, which gives a high number of adsorption external surface sites for the adsorption [6].
6
Bio-application
6.1
Antibacterial Activity
Literature reports only very few organic frameworks based on cellulose nanocomposites for antibacterial activity. Recently, a cellulose-based silver nanoparticles@HKUST-1@carboxymethlated nanocomposite was reported as antibacterial material [42]. These findings showed that due to the complexation between copper ions in HKUST-1 and carboxyl groups on the carboxymethylated fibers, the MOFs (HKUST-1) were uniformly anchored on the surfaces of the fiber (CFs). The silver nanoparticles were immobilized and well dispersed through in situ microwave reduction into the pores on the surfaces of HKUST-1 which resulted in the formation of novel composite Ag NPs@HKUST-1@CFs. The resulting antibacterial assays showed a far higher antibacterial activity of as-prepared composites than the samples of Ag NPs@CFs or HKUST-1@CFs.
6.2
Drug Delivery
More focus has recently been devoted to the development of modern approaches for designing new drug delivery systems with a regulated capacity to release drugs [100, 101]. Generally, the drug dosage in the blood begins to rise in the conventional drug delivery system and then decreases [102, 103]. An optimal system of drug delivery should convey a suitable drug concentration to the targeted sites while
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Fig. 9 Schematic diagram of the DOX@CS/Bio-MOF formation and its drug release behavior. (Copyright 2019 The American Chemical Society and Division of Chemical Education, Inc.) [107]
keeping other tissues secure [104]. In addition to the safety and easy preparation process, maintaining the drug dose at a certain necessary level for a long time to prevent burst release is important for an ideal drug release system [105]. Thus, finding a suitable carrier to achieve this target is one of the key challenges. The main advantages of controlled drug delivery systems are biocompatibility, inertness, strong mechanical strength, and the ability to achieve a high drug loading (see Fig. 9) [106]. Particularly, nanocarrier reduces the solubility of drugs which can effectively work with minimal side effects. To target cancer cells, an ideal nanocarrier for anticancer drugs should take a long time for circulation and have the potential to well deliver and release drugs into the cytoplasm. In general, the porous materials having a large pore volume and elevated surface area with tunable pore size have been more accepted candidates for biomedical applications [108]. Recently most of the researchers focusing on the combination of porous materials with nanoparticles or creation of new porous nanomaterials for wider applications of nanomaterial chemistry [109]. Among the porous materials, MOFs and COFs are the important materials which have unique intrinsic natures such as great biocompatibility, biodegradability, and loading ability of guests, thus making them great candidates as a drug carrier [110, 111]. Different interactions such as van der Waals forces, H-bonds, π-π interaction, coordination bonds, and anionscations electrostatic interaction could be observed between drugs and frameworks in
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MOF-based drug delivery system, whereas in the case of ionic drugs, the strong electrostatic forces between ionic drug molecules and ionic frameworks have a key role [110]. In any case, micro- or mesoporous MOFs are currently being used as biodegradable drug carriers [110, 112]. Therefore, nanoscaled MOFs are employed as biocompatible carriers, but they suffer from very rapid degradation in PBS which hampers controlled drug delivery applications [113]. Likewise, nanoscaled MOFs have also been well tolerated in vivo due to more progressive degradation and compatibility with biomedical applications [114]. The nanohybrid drugs have been produced by successful encapsulation of various drugs in nanoscaled MOFs [115]. Therefore, in a drug delivery system, the regulation of biocompatible nanoscaled MOF degradation is a great challenge [116]. In particular, scientists have applied three main strategies, namely, the “drug-matrixinteraction-controlled drug release,” “coating-controlled drug release,” and “cation-triggered controlled drug release,” to regulate the release of drugs from MOFs [110, 111, 117]. The pH-sensitive biopolymer coating was used to achieve controlled delivery of drugs in the Cu-MOF system [118]. Indeed, carboxymethylcellulose (CMC) is one of the cellulose-derived anionic water-soluble natural polymers [119]. Generally, the oral approach is one of the widely used techniques because of its noninvasive nature and because it also prevents patient pain and discomfort. Siamak Javanbakht et al. [120] developed a novel composite for an oral delivery system which is a Cu-based MOF encapsulated ibuprofen (IBU) drug nanohybrid (Cu-MOF@Drug) protected with pH-sensitive biopolymeric carboxymethylcellulose (CMC). It was observed from the results, the drug release studies have shown, that the CMC capsulated CU-MOF@IBU nanocomposite hydrogel bead (CMC/Cu-MOF@IBU) has stronger safety against stomach pH and has extended the stability of drug dosing providing a managed release under the conditions of the gastrointestinal tract [120]. The MTT test showed that the toxicity of the CMC/Cu-MOF@IBU against Caco-2 cells is low. Furthermore, the results also explain that the hydrogel bead may theoretically be used as an oral drug delivery system. Siamak Javanbakhta et al. developed a novel composite carboxymethyl/zincbased MOF/graphene oxide bio-nanocomposite (CMC/MOF-5/GO) material which was composed of graphene oxide (GO), carboxymethylcellulose (CMC), and zinc-based MOF-5 [120]. The purpose of this work is to enhance the solubility, surface charge, and drug loading capacity of graphene oxide. In this investigation, the author used a one-pot solvothermal technique to synthesize this composite, and it can be applied as a new drug delivery system. As-prepared nanocomposite CMC/MOF-5/GO was fully characterized and used as a carrier for encapsulation of anticancer drug doxorubicin (DOX). Furthermore, the examination of this drug delivery system showed that the DOX-loaded bio-nanocomposites enhance the efficiency of anticancer properties of the drug. The rate of DOX was significantly higher than that under physiological conditions at pH 7.4 under the tumour cell microenvironment at pH 5 [119]. Table 1 represents several cellulosic combined organic framework nanomaterials with their important characteristics and applications.
BC@Dopa-ZIF
Cellulose-MOF199
BC@ZIF-8 aerogel BC@UiO-66 aerogel ZIF@CA
ZIF-9@GEL; ZIF-12@GEL UiO-66@CA; UiO-66NH2@CA
PAF-1@CNF
ZIF-8@CNF@Cellulose foam
Zn2+
Cu2+
Zn2+ Zr4+ Zn2+
Co2+
Ni3+
Zn2+
Cellulose
Aerogels
Cellulose nanofibers
Bacterial cellulose (BC)
CFs@ZIF-8 filter
Zr4+
Co2+
Zn2+
Polysaccharide-MOF CP/CNF/ZIF-67
AgNps@CFs@HKUST1/CF ZIF-67@PAN
Metal ion Co2+
Cu2+
Cellulosic materials Cellulose
Gas and heavy metal adsorption
Separation of bisphenol A
Adsorption of heavy metals Organic pollutant degradation Heavy metal removal
Metal ion adsorption
Dye adsorption
Air filtration and formaldehyde adsorption Filtration and gas adsorption Iodine adsorption
Antibacterial
Application Antibacterial
p-Nitrophenol was 90% degraded and recyclable for three times UiO-66@CA and UiO-66-NH2@CA showed adsorption capacities of 40.1 mg g1 and 51.3 mg g1, respectively, for Pb2+ 1000 mg g1 adsorption capacity shown by composite aerogel with 77.93% removal of BPA within 10 s 30 times higher N2 gas adsorption capacity and 80 times higher compression strength than native cellulose foam
[109]
Maximum removal capacity of Cr4+ was 90.8%
(continued)
[111]
[110]
[51]
[71]
[107]
[106]
[55, 108]
[105]
[104]
[41]
References [103]
Nitrogen adsorption was 200 times higher than pure cellulose-based filters High iodine uptake capacity from vapor (1.87 0.18 g) and aqueous I2/KI solution (1.31 0.02 g) Methylene blue adsorption with maximum capacity of 1193 mg/g BC@ZIF-8 showed 81% of Pb+2 absorption
Remark CNF/ZIF-67 showed 11-fold increase in mechanical strength with higher antibacterial property against E. coli Composite was more effective against Gram-positive S. aureus Formaldehyde and PM 2.5 removal with efficiency of 87.2% and 84%, respectively
Table 1 Various types of cellulosic materials with different organic framework material nanocomposites and its important features and applications
16 Synthesis and Applications of Organic Framework-Based Cellulosic Nanocomposites 463
Cellulose paper
Cellulosic materials
Cu2+
Cu2+
Zn2+
Zr4+
Metal ion Cu2+
Table 1 (continued)
Cellulose paper@MOF-5
Polysaccharide-MOF CNF/HKUST-1 membrane Cellulose nanofibrils/ UiO-66-NH2 AgMOFs@CNF@ZIF-8 CNF@HKUST-1 nanopaper
Gas absorption
Filtration and antibacterial activity Air filtration
Gas absorption
Application Air purification
Due to high functionality and its light weight the hybrid nano paper have been shown excellent separation property in VOC separation over pure filter paper and pure CNF paper PCC fillers provided higher surface area for gas absorption
Remark Blocking efficiency is 95% of PM 2.5 with formaldehyde adsorption capacity of 47.71 mg Showed CO2 permeability of 139 Barrer with CO2/N2 selectivity ratio of 46 Filtration efficiency of 94.3% for PM 2.5
[50]
[115]
[114]
[113]
References [112]
464 V. Arumugam and Y. Gao
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Future Perspective and Conclusion
In the early twenty-first century, nanocellulose-based research was developed intensively and extensively by both industry and academia due to their high functionality, light weight, high modulus of cellulose microfibrils, and strong nanocellulose/ polymer composites. Nanocellulose/polymer composites are still promising materials for various application areas since the market size for polymer composites is sufficiently large. However, due to the extremely hydrophilic nature of nanocelluloses and their high costs (>100 USD per dry kg), the industrialization of nanocellulose/polymer development at low cost is very challenging. To date, only a few effective cases of nanocellulose/polymer composite commercialization have been published [121, 122]. Currently, the low production capacity (i.e., Pb(II) > Cu(II) and Cu(II) > Pb(II) > Pb (II) > Pb(II) > Fe(III) and therefore, consistently, with the order in which it was removed and regenerated cellulose from the three metallic ions. The sulfonic group has been reported to be ionized in a larger measure than other functional groups like hydroxy and carboxy groups, thus enhancing the sulfonic group’s electrostatic affinity with metal ions.
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Nanocelluloses in Drug Delivery System
Two essential factors must be integrated into the drug delivery mechanism during development and eventual release following administration since their effectiveness is primarily measured. The method of inserting the drug into a polymer matrix or capsule is the method to integrate. Reverse drug release mechanisms are used to liberate drug molecules from the solid and absorption and pharmacologic acts. Thus, the drug supply chain’s quality management can also be in vitro release, and knowledge about the carrier’s internal configuration, drug-transporter interaction, and in vivo behavior can also be used to predict. The amount of drugs and releases is associated, both because it depends on the matrix, the physical-chemical characteristics, and the relationship between the matrix, substance, and the cellular environment. While Ranby et al. developed nanocellulose in 1949 [40], its use in drug delivery has only increased in recent years. Researchers have widely examined different nanocellulose-based drug delivery systems, considering the myriad benefits of various types of nanocellulose (NCC, NFC, and BNC), including its nanodimensions, high surface area, recyclability, bioavailability, and surface-tuning chemistry. Popular types of medicinal carriers dependent on nanocellulose usually collapse into membranes, films, microparticles, gels, and hydrogels [41]. Besides, two primary types of drug administration dependent on nanocellulose are foreign and domestic. The internal route is mostly the oral route, while the external ways are mostly topical and transdermal – the territorial or structural impact of external and internal practices [42].
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Nanocellulose for Skincare Formulation
Transdermal therapeutic delivery refers to the route of administration through the skin. Transdermal drug delivery (TDDS) accounts for the therapeutic concentration through the skin into the systemic circulation. A transdermal system is often considered a controlled system for delivering drugs; some examples are listed in Table 3 [43]. The key benefit of TDDS is the clearance and management of the gastrointestinal tract and liver metabolism by oral doses. It would either minimize or remove side effects in the event of gastrointestinal complications [42]. However, the
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Table 3 Summary of the nanocellulose type with the dosage form and the mechanism of drug release Nanocellulose type CNC-chitosan CNC-alginate CNC-β-cyclodextrin CNF BC
Dosage form Microparticulates Hydro-microparticulates Hydrogel Tablets Hydrogel
Mechanism of drug release Normal or Fickian diffusion Diffusional passive transport Normal or Fickian diffusion Diffusion based release Mainly swelling, diffusion
Reference [45] [5] [46] [47] [48]
key downside of TDDS is its constraint in the use of comparatively large medicines; it can produce only small molecules that enter the skin. Indeed, the skin functions as a powerful medicinal buffer [44]. The mechanism of dermal uptake is illustrated in Fig. 3. The benefits of using cellulose-based products for this purpose have been assessed by Fu et al. [49]. They suggested that BNC also seemed to provide high therapeutic value due to its excellent biocompatibility in skin tissue repair and unique structural and mechanical properties compared with the higher plant cellulose. In a study by Silva et al. [49], BNC membrane TDDS (a traditional nonsteroidal anti-inflammatory drug) was tested for diclofenac sodium salt. Their results showed a permeation rate close to that of commercial patches for diclofenac in BNC membranes and lower than that of the gel. Via the benefit of easy application and planning, this technique has had a significant capacity to generate transdermal diclofenac along with a single layer structure that offers continued liberation. A hybrid model for transmission of antiseptic octenidine was also suggested by Alkhatib et al. [50]. Their reports showed an 8-day opioid release as a long-term dermal therapy ready-to-use device. Another example, Sarkar et al. [51] developed NFC/chitosan transdermal films to supply the NFC’s elegant carrier ketorolac tromethamine. Owing to the inclusion of 1 wt per unit NFC solution, their results showed continuous drug release profiles of matrices 40% of the medication was released at 10 h. The use of NFC as a matrix format substance for the continuous delivery of itraconazole, indomethacin, and beclomethasone in transdermal drug delivery was evaluated by Kolakovic et al. [52]. They developed film matrix systems with a prescription price between 20% and 40% with filtration technology. Their research results show that up to three drugs have been released NFC continuously demonstrating to be attractive to regulated releases of poorly water-soluble drugs for months. Furthermore, a significant return application in TDDS, for example, nanocellulose (GNP-NC) and NFC/hydroxypropyl methylcellulose nanocomposites, was also suggested by other nano-celluloid preparations [53]. Iontophoresis is indeed a viable alternative to the delivery of transdermal drugs that require electric current on the target membrane to be permeated by drugs. There is often a need for a drug storage tank in transdermal delivery, particularly if prolonged and lengthy drug releases are needed. A suitable material must also be chosen. Nanofibrillary cellulose that can produce hydrogels with such high moisture
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O O
R
CH2OCOR O
O Grafting O
Esterification
Click chemistry
O n
CNs
O
O OH O Polymerization H
O
O
P O
OH
TEMPO Oxidation / Carboxylation
O Phosphorylation
Fig. 3 Chemical modification to nanocellulose unit generates various functionalized surfaces, which would be valuable for the selective targeting of nanomaterials toward the diseased cells
content is one potential material. By pairing the delivery of iontophoretic pharmaceuticals with adequate hydrogel drug packaging, it will also be possible to accomplish more detailed tracking of the drug usage by regulating the amount of electric current used. Since the delivery of iontophoretic medicines provides improved skin diffusion of the drug molecule, it is essential that the storage mechanism is stable and does not cause abrupt releases of the medication into the reservoir because of the damage to the storage material. Several various drug routes use the skin as a place of assessment. Iontophoresis allows electricity to be applied to a given region of the skin in the transdermal medicine distribution, as illustrated in Fig. 4. The iontophoretic flow could be represented as the electricity and electroosmosis number. The ions pass through the electric field during electromigration. Thus, electroosmosis can be interpreted as charging flux through the skin. Some potential sites for delivering iontophoretic drugs include the oral mucosa in addition to the skin. The goal of iontophoresis is to increase the permeability of an ionized substance by the skin.
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Fig. 4 Schematic illustration of nanoparticle (NP) transdermal penetration pathways. Topically applied NPs can penetrate the skin with routes like (1) diffusion of NPs through the appendageal way, (2) NP internalization through the intracellular way, or (3) NP uptake through the intracellular way. The appendageal method involves NPs entering through the skin hair follicles, skin furrows, and sweat glands to carry the NPs to the dermis layer, which might be beneficial for slow drug release. The easiest way involves the intracellular route that involves a direct path through the cellular skin membrane through the epidermis’ multilayers. In contrast, the intracellular pathway involves a more tortuous path to pass between the stratum corneum cells and through the stratum basale cells to accumulate in the dermis layer. The image was generated using BioRender software (biorenerder.com)
There are several options for formulating the drug engine. It was demonstrated that peptides could be mounted onto nanogels, and iontophoresis can then be used for transdermal medication [54]. There are also approaches to the use of iontophoresis. For example, anode patches and cathode electrodes inserted into the patch may be used for iontophoretic skin patches. Moreover, it should not be overlooked that agents can be applied to boost permeability. It has been stated that the incorporation of oleic acid to the deposited-based propylene glycol or palmitoleic acid to the dispersal-hydrochloride salt propylene glycol vehicle will increase the permeability on hairless mouse skin under in vitro conditions without iontophoresis [55]. The iontophoretic transdermal drug delivery system is appropriate for treating chronic diseases in which the treatment balance is right, depending on illnesses or the patient’s condition and within a predetermined safe dose range. In particular, fentanyl and estradiol, lipophilic and powerful medicines with an Mw of less than § 400 Da, had a notable improvement in the delivery of transdermal drugs [43].
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Nanocelluloses for Oral Drug Delivery
Comprehensive research of various formulations of orally administered nanocellulose was published, with the general release principle illustrated in Fig. 5. Burt et al. used NCC as a transporter for cancer drug applications (docetaxel,
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Fig. 5 A schematic illustration of the stretchable drug delivery system
paclitaxel, and etoposide). They also improved the NCC surface by adding a cationic surfactant, CTAB, to increase the zeta potential of NCC by concentration. Their results then revealed a controlled substance release over a few days [56]. Furthermore, Mohanta et al. [45] have developed thin film, along with chitosan, as NCC drug carriers. Potentially, the chitosan amine groups can interact electrostatically with the NCC sulfonate groups. They were packaged in a combination of doxorubicin hydrochloride, and curcumin, both water-soluble and water-insolvable anticancer products. They reported why hydrogen bonding interactions (OHO and CHO) and van der Waals are its core relationships between doxorubicin and curcumin. Doxorubicin liberation (pH 6.4) was increased, as per the research, through protonation of its collective amines, which helped increase the solubility of the drug’s diffusion process. Notably, the cancerous cells’ extracellular pH is acidic (often 6.5– 6.9) may be desirable for cancer treatment [57]. To sum up, all water-soluble and water-insoluble medications have been consistently released from the drug carrier. Emara et al. [58] analyzed the impact of NCC and MCC carriers on the solubility of meloxicam, a poorly water-soluble medicinal substance. They developed strong dispersion in the presence of lactose through grinding and physical mixing techniques. According to their results, solubility increases by 33.72 1.4 percent to 55.97 + / 1.3 percent mg/100 mL by grinding MX powder (not including carriers). This illustrates how the SEM analysis reveals the impact of reducing the scale of such a mechanism. The findings show that the physical mixture of either MCC or NCC cannot increase MX solubility. Likewise, MCC grinds have not improved MX’s solubility than grounded powder MX (without carriers) as MX and lactose particles have become trapped in MCC particles and have produced a plastic-like mass that has hindered solubility. However, the solubility improved up to 20% compared with ground powder MX (in contrast to the original unground MX material), due primarily
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to its nano-dimension through co-grinding with NCC. It is noteworthy that increased NCC loading increases MX solubility and dissolution. This research, therefore, has shown that NCC is a suitable carrier for water-soluble drugs. To release metformin hydrochloride (MH), Guo et al. [59] formulate NFC/alginate and MCC/alginate beads. NFC was used to improve alginate beads’ floating and mechanical properties and enhance their drug release behavior. They demonstrated that MCC/alginate releases were combined by 56% in pH 7.4. In the first 60 min (0.3% MCC), a fast release resulted. Although the total liberation of NFC/alginate beads (0.3% NFC) was 10% higher at the onset than that of MCC/alginate, these beads demonstrated their durability in the next 240 min. They found that hydrophobic interactions (between NFC OH groups and alginate COOH groups) could enhance the biopolymer matrix’s stabilization and cohesion, contributing to continuous emergence. This avoided the fast release of 10% NFC over the first few minutes to facilitate monitoring of medication releases, as depicted in Fig. 5. Patil et al. [60] constructed a controllable release mechanism of nanocomposites by the combination of the active component NFC and dimethyl phthalate (DMP) with two biopolymers (gelatinized maize starch and urea-formaldehyde). As per its research results, the initial release of DMP was significantly hindered by the NFC while improving the total liberation and ensuring controlled release. Their hypothesis could be two fundamental choices: (1) liquid-uptake-induced diffusion and (2) NFC-related barrier effects. The high NFC surface presumably adequately filled the storm granules’ porous structure, which decreased the explosion significantly. They found that their networks within the starch matrix triggered a tortuous diffusion process for therapies (almost 80% of the medication was released within a week) and ended up prolonging the release. The drug delivery systems were prepared by Supramaniam et al. [61], with magnetic alginate nanocellulose beads (m-NCC). Indeed, they integrated m-NCC into the dots to improve ibuprofen’s mechanical power and release behavior. This addition could also contribute, by magnetic resonance imaging, to active detection and possible treatment of cancer tissue. Besides, due to their high physical presence, m-NCCs may restrict the ibuprofen movement during dissolution. Ultimately, their results revealed that the medication was regulated (and continued release between 30 and 330 min). In another study, Hivekhi et al. [62] developed and examined the liberating behavior of tetracycline hydrochloride, NCC-reinforced polycaprolactone (NCC-incorporated PCL). This resulted in the medicine’s controlled release, which slowed by an increase in NCC-incorporated PCL nanofibers (alternatively, 50% of the drug was released within 500 min from a PCL-NCC4 specimen). Hydrogels with activated bacterial cellulose-g-poly(acrylic acid) were tested as a possible oral protein supply system. These hydrogels lacking cross-connecting agents were produced by neutron radiation, removing any potentially harmful effects associated with cross-connectors. Bovine serum albumin was placed into hydrogels, a standard protein medication, and the discharge profile was examined in simulated gastrointestinal fluids. These hydrogels’ ability to preserve the BSA in acidic stomach environments was shown by the total emission of less than 10% in simulated gastric fluid (SGF) [63].
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Nanocelluloses in Tablet Formulations
The cellulose has an excellent compacting property and has a long history of use in the pharmaceutical industry, particularly drug-charged matrices for suitable oral tablets. Given an extensive history of tablet use, more study has been ongoing in advanced drug-loaded structures in which the risk of disintegration of the tablet as special excipients or prolonged drug release as modern drug carriers is still in place for different cellulose forms (nanocellulose) [7]. CNC can also be used as a co-stabilizer and its primary application as an excipient to improve polymer excipient physicochemical and fluid properties. A suitable excipient was proven to be acrylic beads prepared through emulsion polymerization using CNC as a co-stabilizer. The CNC presence has positively influenced the bead excipient scale and position, which, along with low flow rate and reduced angle cotangent, formed a stable structure [64]. In another study, CNF was better prepared than commercial microcrystalline cellulose to pack with lower powder porosity, showing a new, spray-dried CNF excipient for tablets’ manufacture. BC was film-coated on tablets using the same spray-drying technique and supplied with smooth, stable, and plied nanocellulose films with better mechanical characteristics than conventional Aquacoat ECD (polymers made up of aqueous ethylcellulose dispersion 30 wt percent) fabrics [65]. Cross-linking and/or surface changes are commonly concerned with contact with NFCs or CNCs. Cellulose, as a convenient oral tablet, is used in the drug-loaded matrices. Nanocellulose can regulate the release rate and provide the required dosage of drugs over time in all of these formulations [66]. Numerical simulations have been used for several years to deter medication releases and help optimum formulations and new structures [67]. Many of the current models rely on distribution, according to Fick’s rule of propagation. Since this method refers to drug transfer via thick pipes, funnel, and spheres, it is an essential release process that is very much based on the arrangement of matrices. The need for more sophisticated mathematical models becomes clear when accurate experimental data and observations are applied to diffusional models. Besides disperse releases, a range of other controlled release mechanisms include chemical regulation, osmotic control, and managed swelling and/or dissolution. More different kinds of sustained-release processes include the polymer’s morphology and the drug’s internal structure moving to the environment and specific features of the material chosen (i.e., polarity, crystallinity, solubility, the weight of the molecules, and preservatives) [68].
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Nanocelluloses in Cosmetics Formulations
Nanocellulose is a widely used nanomaterial due to its biocompatibility, high strength, low density, and superb mechanical properties. It is available in many forms, such as bacterial cellulose, nanocrystalline cellulose, and nanofiber cellulose [69]. Nanocellulose is employed to reinforce polymer matrices in many industries and fields such as medicine and healthcare, electronics, textile, 3D printing, and coating films, aerogels, and rheology modifiers [70].
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Fig. 6 Schematic illustration of the nanocellulose polymer’s dehydration on the polymer’s rearrangement releasing its therapeutic content
Many studies have shown the potential of using bacterial cellulose in the cosmetic field. It is used in facial masks to deliver active components and increase the skin’s hydration, as summarized in Fig. 6. Besides, it can be used as an emulsion stabilizer. In 2019, the highest number of articles was published about bacterial cellulose uses in cosmetics. Therefore, more studies are expected to be published in the forthcoming years [71]. Due to its high capacity to retain water and high permeability, bacterial cellulose is used to deliver hydrophilic agents such as anti-aging components and moisturizers. Besides, it was reported to be used as a whitening mask [72] [73]. Recently, facial masks are used to revitalize, heal, refresh, and even bring other beneficial facial skin results. Therefore, there is a big competition to prepare facial masks from natural components. It is well known that the gram-negative bacteria Acetobacter xylinum (Gluconacetobacter xylinus) can synthesize considerable amounts of cellulose, where these bacteria use glucose as the primary substrate. In this context, it is essential to find a good source of glucose. Coconut water derived from tropical coconut fruit is highly rich in nitrogen-containing compounds and sucrose. Thus, it can be used as a cost-effective substrate to produce bacterial nanocellulose [74]. In a study, bacterial nanocellulose gel was prepared at the surface of coconut water by Acetobacter xylinum at a pH of 4.5. Silk sericin was used to adsorb the bacterial nanocellulose gel to produce a bioactive facial mask. Silk sericin is known for its bioadhesiveness, antioxidant effect, and ability to activate collagen production. Besides, it increases the wound’s epithelialization. The results showed that silk sericin-releasing bacterial nanocellulose gel had enhanced mechanical characteristics and moisture absorption capacity compared to other facial masks available in the market. It was found that the gel releases silk sericin in a controlled release manner. The gel showed less facial adhesiveness, which indicates the facility of removing the mask without pain or irritation. It can be concluded that this bacterial nanocellulose gel which releases silk sericin can be used as a safe and effective mask to treat problems on facial skin [74] (Fig. 7). Pacheco et al. prepared masks by simply incorporating cosmetic ingredients into bacterial cellulose membranes. Bacterial cellulose was chosen because it is already
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Fig. 7 Implementations and relations with nanocellulose in cosmetics formulations and other topical applications. Hair and beauty products use nanomaterials to enhance the quality of life by providing innovation and enhancing the safety of sunscreen and antioxidants. Nanomaterials for some active medicinal ingredients are often used as a delivery system to treat various skin diseases
produced by microorganisms as a hydrogel membrane with high mechanical strength and biocompatibility, besides its high-water retention capacity due to its porous nanofibrillar structure incorporating and releasing agents rapidly. Therefore, bacterial cellulose is an excellent candidate to be used as a skincare mask. The prepared masks were tested on 69 volunteers for 2 months and were applied 3 times weekly. It was shown that these masks possess an appropriate skin adhesion and improved skin moisturization and hydration by 76% [73]. The cosmetic field has seen significant development over the years. It has widely helped people suffering from early aging signs, such as skin pigmentation and the appearance of fine lines and wrinkles. Almost 80% of facial aging is related to UV radiation due to sun exposure. Furthermore, UV radiation is responsible for other skin disorders such as photoaging, which is premature aging caused by unprotected repeated UV exposure; photo-carcinogenesis, which is a damage in DNA structure; and photo-immunosuppression which is known as suppression in the performance of the immunological system [75]. Therefore, to protect the skin from UV radiation, cosmetic products containing minerals known as metal oxide nanoparticles are prepared. These nano-systems possess an immense capacity to absorb the energy emitted from UV radiations and protect the skin from photodamage. Metal oxide nanoparticles act as free radical scavengers, and their incorporation in cosmetic preparations inhibits cell damage responsible for the appearance of fine lines and wrinkles [75]. Metal oxide nanoparticles can be replaced by nanocellulose due to their capacity to transform to
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different structures and morphologies by diverse methods. Thus, nanocellulose is incorporated in many cosmetic preparations as a UV absorber [76]. In a recent study, Bongao et al. have synthesized nanocellulose from waste pili pulp to use it as an alternative to cosmetic preparations’ mineral components. Waste pili pulp is produced during the extraction procedure of pili essential oils. Cellulose was isolated from hemicellulosic and lignocellulosic material by different traditional extraction procedures such as alkalization, boiling, and bleaching techniques. Then, nanocellulose was synthesized by acid hydrolysis using sulfuric acid, and the surface morphology analysis confirmed the nanostructure of the synthesized nanocellulose. Besides, the optical characteristics of the prepared cellulose suspensions were similar to that of the mineral nanoparticles used generally in cosmetics indicating the capacity of nanocellulose to replace these conventional mineral components [75].
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Nanocelluloses in Skincare Formulations
Nanocellulose is used in skin tissue engineering and wound healing in the form of scaffolds for cellular growth, to deliver cells into wounds, or as developed wound healing combined with the delivery of drugs. Skin tissue engineering is the reconstruction of the epidermis and dermis layers of the skin. The epidermis is the outermost layer of the skin composed of keratinocytes, whereas the dermis formed of fibroblasts is underneath the epidermis. Bacterial cellulose resembles natural soft tissues such as the skin; thus, it is more frequently used to reconstruct skin layers [77]. The utilization of bacterial cellulose in skin wound healing was reported for the first time in 1990, where bacterial cellulose was used as a temporary skin substitution to treat skin injuries such as ulcers, burns, and abrasions. It was found that the combination of bacterial cellulose with other bioactive molecules such as chitosan can improve the adhesion and the regrowth of human keratinocytes on bacterial cellulose [78]. Bacterial cellulose has been widely used in wound healing, such as to manage burns. It helps in temporary skin healing and constitutes an excellent physical barrier toward pathogens. Besides, it moisturizes the skin and can form a perfect environment to regenerate tissues. Bacterial cellulose is highly biocompatible due to its similarity in structure to cell-matrix components, especially collagen. It is used in many studies in bone tissue and cartilage implants to deliver active ingredients [71]. In a recent study, the preparation of new three-dimensional microporous scaffolds from bacterial nanocellulose using paraffin microspheres was highly useful in inducing the proliferation of embryonic fibroblasts in mice models. These results indicate the potential of using bacterial nanocellulose in soft tissue engineering [79]. Besides, bacterial nanocellulose is used in wound healing to regenerate the epidermis and dermis due to its suitable properties, such as high purity and its ability to absorb large amounts of water. After the creation of skin defects with a large area of almost 2 2 cm surgically on the back of the mouse model in vivo, the use of bacterial nanocellulose as a wound dressing has favored the healing of these skin
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defects without inflammatory syndromes compared to the control group of untreated mice [78]. Bacterial nanocellulose is widely used in wound dressing for skin transplantation due to its promising results. In one study, bacterial nanocellulose was biosynthesized by Gluconacetobacter xylinus and characterized in terms of morphology, surface area, and physicochemical properties. The evaluation of the in vitro cytotoxicity was then performed by studying the morphology, the viability, the adhesion, and the proliferation of NIH/3 T3 cells, which are Swiss mouse embryo fibroblasts. It was found the bacterial nanocellulose has relatively low cytotoxicity. The bonding and the expansion of NIH/3 T3 cells on bacterial nanocellulose were demonstrated by micrographs and were found suitable. Full-thickness large area skin defects were performed on the back of the C57BL/6 mice model by surgery. Then, the transplantation of wounds using bacterial nanocellulose was made, and the histology studies were achieved compared to a control group. It was found that the group treated with bacterial nanocellulose showed fast and good healing with low inflammation signs compared to the control group. These results demonstrated the effectiveness of bacterial nanocellulose as a wound dressing to promote epithelial tissue healing. Thus, bacterial nanocellulose can be considered a promising biomaterial for medicine as a wound dressing [80]. Recently, vitamin B-based ionic liquids were prepared and incorporated into bacterial cellulose membranes for skincare applications. B-complex vitamins are known for their antioxidant effects, thus preventing premature skin aging. However, their oral administration is accompanied by severe side effects. Therefore, B-complex vitamins are given topically. Ionic liquids are highly water-soluble and are used largely in cosmetic and pharmaceutical applications. The synthesized vitamin B-based ionic liquids were incorporated into bacterial cellulose membranes. Bacterial cellulose was used due to its nanofibrillar porous structure. Besides, it is a highly biocompatible pure component with high water retention capacity and high Young’s modulus. The results reveal that vitamin B-based ionic liquids incorporated into bacterial cellulose can be an excellent preparation to deliver B vitamins topically into the skin with no cytotoxicity for human dermal cells [81]. Recently, in another study, bacterial nanocellulose-hyaluronic acid microneedle patches were prepared for dermo-cosmetic uses. The patches were composed of soluble hyaluronic acid microneedles accompanied by bacterial nanocellulose as a back layer. In these patches, skin hydration, regeneration, and volumizing were ensured by employing hyaluronic acid. However, bacterial cellulose provides good support to incorporate rutin, a bioactive molecule with an antioxidant effect. The resultant microneedle arrays showed high homogeneity and regularity with 450 μm height, 500 μm tip-to-tip distance, and 200 μm base width. The prepared microneedles showed high mechanical strength to resist the insertion into the skin. The antioxidant effect of rutin was stable in these patches over 6 months at room temperature. In vivo experiments with human volunteers revealed the compatibility and the safety of the system on the skin, with no redness or alteration in the function of the skin barrier; these results confirmed the ability of bacterial cellulose to modify the release of biomolecules and its potential to be used in dermal and cosmetic preparations [82].
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Nanocellulose Membranes with Drug Delivery Function
Related mixtures may be differentiated by allowing some organisms to go through growth on selective media while others do not. The two main criteria for a membrane are longevity and selectivity. The high permeable and selective membrane production is often desired to make the membrane-based procedures more effective. Nanocellulose mats are highly successful in fostering auto-like deterioration and reducing discomfort as well as increasing granulation. These membranes may be produced in all shapes and lengths, useful for treating large areas of the body which are difficult to cover. For the first time, Helenius et al. [83] extensively researched nanocellulose in vivo biocompatibility. The nanocellulose membranes were then inserted for 1, 4, and 12 weeks into the rats’ subcutaneous area. The implants were examined with histology, immunohistochemistry, and electron microscopy in chronic inflammation, external body responder, cell growth, and angiogenesis. There have been no visible inflammatory symptoms of rooting, edema, or exudates around implants. No inflammatory signs (i.e., vast quantities of small cells surrounding implants or arteries) occurred. There were no fibrotic or giant cells. Fibroblasts invaded the nanocellulose that was well incorporated in the host’s tissue and did not cause a persistent inflammatory response, so the biocompatibility of nanocellulose is proven. Furthermore, Helenius et al. [83] also established further nanomaterial information and cell activity. Nanocellulose membranes were injected into the rats in their research, and biocompatibility was tested in vivo. Fibrosis or encapsulation did not induce external body reaction, and nanocelluloses were well incorporated in the rat conjunctival tissues. A few weeks after insertion, the rearrangement began, and fibroblast was wholly inserted into the structure, and collagen synthesis was first initiated. Silva had examined synthetic hydroxyapatite’s biological activity when inserted and protected by nanocellulose in the dental cavities (HAP-91). Silva [84] observed that nanocellulose combined with the HAP facilitates quicker bone recovery than the control unit. Membranes are formed as three triangles that filled the cavity that resists interaction with hydroxyapatite. Eight days after the operation and 30 days after treatment, tissues were the same after 50 days. Barud et al. [85] have produced a bacterial cellulose biological membrane and a consistent propolis isolate. Propolis has several physicochemical functions, such as anti-inflammatory and antimicrobial functions. Many of the above properties make the membranes of burns and severe wounds a successful therapy. The Gengiflex and Gore-Tex nanocellulose formula has been developed for dental implants. It is planned to help the regeneration of periodontal tissues [86]. Gengiflex bandage is made of two layers: the internal cellulose layer consists of microscopic cellulose, which gives the membrane power and chemically changes the exterior alkali cellulose sheet [87]. In the in vivo nonhealing bone defect model, Salata et al. [87] compared Gengiflex and Gore-Tex membranes’ biological efficiency. The findings show how Gore-Tex membranes (a hybrid of polytetrafluoroethylene, urethane, and nylon) had considerably decreased inflammation and the bone structure of both
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membranes encouraged during the same period. In Gore-Tex or microbial cellulose membrane bone defects, more bone formation was found relative to control sites. Tissue toleration of Gore-Tex are greater than Gengiflex [88]. On the other hand, different methods can be used to incorporate NCs in water treatment. The apparent use of NCs as adsorbing content is a simple solution. Adsorption is an alteration by electrostatic interaction or chemical interactions with contaminants such as heavy metal ions, dyes, etc. on a solid substance. A high SSA scheme that provides access to usable classes on the surface is key to effective implementation [89]. Furthermore, various contaminants, primarily cations and heavy metal ions, and negative molecules such as nitrates or phosphates may be eliminated from the water utilizing suitable alteration, e.g., ammonium groups, as well as organic contaminants, including drugs, dyes, fuels, and pesticides. While hydroxyl groups also attract heavy metal ions and thinning, changing OH groups in more affinity-related functional groups to loaded moistures increases adsorption capability by magnitude [90]. Metreveli et al. [91], Mautner et al. [92] initially developed cellulose Nanopapers with size exclusion and reported them parallel. Both groups have shown that virus pollutants in a random network, i.e., cellulose nanopaper, made from BC or plant CNFs, can be rejected up to the size of 10 nm. This method was then extended and further explored by other researchers [93, 94]. While the refusal of nanopaper membranes and filters had a great deal of promise, their permeability was the main downside. Whereas the exclusion efficiency was within the narrow range of UF, the permeability was in the opposite or better NF range.
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Nanocellulose Gels for Drug Delivery Applications
Various unique qualities of nanofibers (NFs), such as a high surface area per unit mass, large porosity, and versatile strength, have tremendous potential for managed drug delivery into biology and medicine. NFs have various uses, such as prescription stores, dental procedures, surgical devices for wound treatment, and tissue techniques [95]. Cellulose nanofibrillated hydrogel (NFC) has been extensively studied as a drug supplier, as a scaffold synthesis, as well as cell and drug transporters. Due to high water binding capability and biocompatibility, NFC hydrogels are particularly useful in wound healing applications. Besides, the NFC hydrogel can be dry freeze into stable aerogels that can be used to deliver medicine. For sorbents, intracellular pathogens, biomimetic substrates, and models for other usable products, aerogels can demonstrate well-defined pore morphologies or specific sorption properties. Nanocelluloses have the potential to achieve excellent interfacial chemical control with other aerogel blocks (essential for the selectivity of all sorbents), enhanced mechanical properties (currently, primary translational obstacles of other aerogels in applications with elevated pressure, for instance), and too high clear superficial areas (due to anisotropic structure). Hydrogels are typically formed by applying CNC/CNF to a precursor’s polymer solution, and by following free radical polymerization, the large nanocellulose portion is chemically cross-linked. In certain
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situations (e.g., supramolecular gels, chemical orthogonal precursors gels, CNF-based gels), mixed/homogenized precursor matter triggers freeze and contributes to hydrogels of interest, such as injectable and auto-healing properties. This section outlines advances and uses of nanocellulose hydrogels and aerogel materials with extensive literature revision. CNCs act as effective fillers for hydrogel nanocomposites due to their rigidity and mechanical strength. However, CNCs alone can be poorly adapted as single component gels due to their small enclosure capacity. CNC development has centered on the simple physical introduction of CNCs into polymer hydrogel networks as fillers/reinforcement substances. CNC hydrogels, including polyacrylamides (Pam), poly(meth)acrylates, poly(vinyl alcohol) (PEG), poly(ethylene glycol) (PEG) fabrics, and water-soluble polysaccharides, as well as other natural polymers like alginate and gelatin, are all common network polymers. The typical preparation methods include simple homogenization and physical interconnection between polymer networks, free polymerization of CNC suspension plants by radical polymerization, CNC cross-connection between UV and ion mediation, and cyclic freeze-thaw treatment. A bulk of research use 0.1–5% wt content based on the total weight of swelling gel, and such integration has resulted in up to 35-fold strengthening of the shear storage module (D0 up to 60 kPa) and absorption of up to 1500 times their dry mass in water. CNCs are typically mechanically integrated into hydrogels with low concentrations. Qinghua Xu and team [96] developed the nanocomposite hydrogel based on CNC and CS, the two most abundant natural polymers, and tested the composite’s drug liberation output in controlled theophylline delivery. Initially, the dialdehyde nanocellulose (DACC) was oxidized to CNC using a periodic treatment. To produce CNC/CS composites, chitosans were then cross-linked by DACNC (as well as a matrix and linker) in various weight ratios. Furthermore, the added value of DACNC is that glutaraldehyde is non-poisonous, widely used but not poisonous, and can also be used without difficulty for biomedical applications. They observed that a rise in the composite swelling ratio was possibly due to decreased interconnecting density. Furthermore, in the case of gastric pH of 1.5% and that in gastrointestinal liquids with a pH of 7.4, the pH-compatible hydrogel achieved different bioavailability with different pH levels the swelling rate of the drug-loaded hydrogels, which differed under different pH values [96]. Ahlen et al. [97] produced a new study that explores its potential for ODDS by using powered hydrogel contact lenses. By incorporating chitosan and poly(acrylic), they developed two alternative ODDS lens platforms nanostructures of acid (PVA) into polyvinyl and in situ lightened nanomaterials (CNC) through lenses of PVA (polyvinyl) nanostructures and cellulose (PVA). The nanoparticles disintegrated at a concentration of 0.2 mM of physiological lysozyme due to chitosan chain hydrolysis using lysozyme. Since nanoparticles have been integrated into the polymer lenses, drug release lasted more than 28 h. The study has shown that the nanoparticle-CNCPVA lenses have a much greater capacity for prolonged release of drugs due to the particulate matter that was leached from the inflationary PVA network. These researchers have noted that in situ freezing between the cellulose and nanoparticles prevents particle release by interlocking the CNC and allows them to become
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displaced in the PVA composites. They find that the material has demonstrated endless options in designing modern controlled drug release eye lenses and the potential for creating an enzyme-driven eye drug system [97]. McKee et al. [98] have demonstrated the most critical developments in self-healing hydrogels’ rigidity by using supramolecular connections powered by three-component identification. As a result of CNC generated from 0.1% to 0.2%, wt resulted in the gels’ storage made, which were the highest modulus throughout all PVA nanocomposites, from 3.8 to 14.3 kPa. Another research team [99] has shown that CNC changed with improved rheological and overall properties for chances is released continuously from poloxamer by pilocarpine hydrochloride (PL) in in vitro. The contributors reveal that both the PM and its nanostructured hydrogels have had an irregular distribution tendency when the essential gelation concentration of PM has decreased from 18% (w/v) to 16.6% (w/v), adding various percentages to the CNC (w/v). They also demonstrated from their study that the addition to PM for engineered nanocomposite hydrogels with different CNC percentages (w/w) resulted in the PL’s excellent continuing release for up to 20 h. They found the first-order eq. (R2 > 0.981) showed the highest linearity among all CNC nanocomposites and better described the in vitro medicine released [99]. CNC fillers have also been tested for the characteristic tempering-dependent swelling properties of the thermo-responsive poly-N-isopropylacrylamide (PNIPAM) polymer networks along with tunable mechanics. In most situations, small cross-linking molecules, such as methylene bis(acrylamide) (MBA), are used to construct a chemical cross-linking network using mechanically integrated CNCs [100, 101]. Furthermore, Yang et al. [102] showed how a higher surface charging intensity contributed to higher dispersibility, while a higher aspect ratio contributed to better mechanical properties in polyacrylamide hydrogels. To induce the desired improvements in gel properties, hydrogel and CNC phases are also controlled. CNC-enhanced interpenetration networks are implemented from the hydrogel viewpoint to leverage both the intrinsic reinforcing effect and the possible partition gain of CNC-composite gels. For instance, Wang et al. have demonstrated the development of an interpenetrating network of alginates and gelatin to promote cell migration and transport through an injectable hydrogel [103]. To induce the desired improvements in gel properties, hydrogel and CNC phases are also controlled. CNC-enhanced interpenetration networks are implemented from the hydrogel viewpoint to leverage both the intrinsic reinforcing effect and the possible partition gain of CNC-composite gels. For instance, Wang et al. have demonstrated the development of an interpenetrating network of alginates and gelatin to promote cell migration and transport through an injectable hydrogel. As proof of concept, Li et al. [104] loaded simple fibroblast growth factors into a biodegradable gelatin microsphere, which was then integrated into porous glutaraldehyde-cross-connected collagen/CNC skin tissue engineering applications to facilitate angiogenesis. Of note, hydrogels with 5 wt% of CNC, resulting from improved hydrophilicity of the gels, displayed a higher swelling rate than pure collagen gels. The gelatin microspheres lead to the long-term release of drugs and improved angiogenesis in Sprague-Dawley rats with subcutaneous implantation.
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Besides, Mauricio et al. formed an emulsion in 1 μm of vinyl-functional starch and CNC, undergoing free radical polymerization. Using 10 wt% of CNCs led to a more prolonged vitamin B12 release profile, around 2.9 times slower than starch-alone microgels [105]. Lauren et al. also illustrated a tool to map CNF polymer distribution and test drug distribution in vivo in a technetium-99 m manner. This also indicated that CNF hydrogels are suitable for a range of tissue-engineered implementations [106]. CNF polymer hydrogels have also been investigated for self-healing and drug delivery applications. These nanocomposite wetlands can demonstrate a reversible sol-gel transition through strain or temperature ramping due to ionic interactions between amine-terminated PEG and carboxylated CNFs [107]. In the early 1930s, Kistler [108] initially produced an aerogel, using supercritical drying, by separating the moisture from a wet glue. The complex multilevel mechanism, however, hampered the aerogel production. The dynamic multi-story method thus stopped aerogels from forming. Different forms of aircraft, including inorganic aerogels, have been found in recent decades (such as V2O5, SnO2, SiO2, Al2O3, and TiO2) [109]. Unique pore materials, including the low-density (0.003–0.500 gcm3), increased-porosity (80–99.8%), complete, precise surfaces (100–1600 m2/g), as well as enough chemical surface activities, are aerogels. Aerogel products that can be developed involve optoelectronics, adsorption catalysis, soundproofing, medical equipment, aviation components, and many more [110]. Korhonen et al. conducted radioactive deposition layers to deposit inorganic oxides on aerogels of the CNF and subsequently calcinated the structures, thus producing inorganically hollow aerogels of the nanotube with a substantial capacity as drug energy, catalysis, and filtration material [111].
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Nanocellulose Drug Delivery in Wound Healing Applications
The following section of such a review focuses rather explicitly on additional significant functions of nanocellulose in regenerative medicine, wound healing, and tissue repair. The prominent components for such techniques involve the development of arteries, neuromuscular junctions, and bone, cartilage, liver, and adipose tissues, the restoration of the urethra and solid mater, and the restoration of blood vessels and heart abnormalities at the core of materials development [112] as depicted in Fig. 8. Research by Bodin et al. was conducted in 2007 to produce nanofibrous cellulose bacterial scaffolds for cell adhesion-mediating GRGDS oligopeptides. The published work is centered on the use of nanocellulose in tissue engineering. Such constructs improved the in vitro adhesion of vascular human endothelial cells and were expected to generate complex vascular engineering [113]. An innovative tableting product, cellulose nanofibers have been studied but have also been suggested for the development of films for continuous intravenous drug delivery, e.g., analgesics, antiphlogistic, corticoids, and antihypertensives. Nanofibrillated polysaccharides were engineered in conjunction with silver nanoclusters as an innovative fluorescent polymer with an antimicrobial capacity of
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Fig. 8 Electrostatic adsorption of the desired molecules that are positively charged to the negatively charged polymer which will enhance its swelling properties which could be used to stop bleeding
alternative wound dressing materials [114]. Approximately the supporting silicone tubes made from bacterial cellulose (3 mm or 6 mm in diameter) were tested on the pig as a model. Bacterial cellulose and hydroxyapatite nanocomposites were developed with biocompatible mineralization in simulated body fluid to treat bone healing requirements [115]. The potential use of nanocellulose in neural tissue engineering was one of the first articles published in January 2013. Composite nanocellulose (BNC) and polypyrene (PPy) membranes have been used as a prototype in that same research to seed PC12 neuronal rat cells. The composite materials in BNC/PPy have valued and evolved considerably more than pure BNC. An electrically conductive PPy also allowed electrical cell stimulation that is regarded as beneficial to different cell functions [116]. The use of bacterial nanocellulose scaffolds and primary chondrocytes acquired via routine septorhinoplasty and autoplastic treatments were also investigated for reconstructing human auricular in vitro [117]. Furthermore, the nanocellulose wound dressings in large areas and full-thickness defects of the skin in the mouse in vivo were successfully applied [80]. Bacterial cellulose pellicles were introduced for “pro-temporary skin substitutes” to treat blackness, ulcers, abrasions, and other skin injuries as the first study on the use of bacterial cellulose in skin wound treatment emerged in 1990 [118].
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Nanocellulose Drug Delivery in Antimicrobial Materials
Since the antibiotic properties of silver are well documented in ancient times, the use of silver as an antibiotic (e.g., surgical sutures and wound dressings) has once again drawn interest because of more recent concerns associated with therapeutic resistant
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bacteria. Acticoat ® (Smith & Nephew) and Aquacel Ag ® (ConvaTec) are currently commercial examples. Many recent reports have investigated the antimicrobial impact of silver in nanoparticle material. The binding by silver nanoclusters (AgNC) to CNF was analyzed in this sense (Diez et al.). In this case, just a few silver atoms were nanoclusters, fewer than AgNPs. Silver nitrate and poly (methacrylic acid (PMAA) fluorescent solutions have been synthesized through a method defined in a previous article. Cai et al. [119] used aqueous alkaline hydroxide urea formulations for making cellulose gels than in situ shaped silver to form welldispersed AgNP cellulose gels, have previously noted a binding of silver as a nanoparticular to cellulose form. Gold or platinum was used to produce similar gels, and authors used aerogels produced by supercritical drying for electric, catalytic, or antimicrobial purposes. As a model for the in situ synthesis of AgNPs, cellulose fibers have been used, and the alteration of the process has proved to form platinum, porous or non-porous nanostructures. Cellulose sheets were first soaked in the solution of silver nitrate and then exposed to a sodium-borohydride solution in order to reduce the silver contamination after rinsing with ethanol. The resulting composite layer has been calcinated at a high temperature to burn off cellulose and create a film consisting of metallic silver nanofibers with the cellulose prototype structure [120]. The nanofiber structure was silver-dependent, and the AgNP community was inadequate to establish a nanofibrous morphology at low concentrations. Thanks to its exceptional physical properties, surface chemistry, and excellent biological properties, nanocellulose is valued for antibacterial application. Four different approaches are primarily used to create antimicrobial materials based on nanocellulose, comprising surface changes, antibiotic additions, nanomaterial mixture, and antibacterial polymer mix, as shown in Fig. 9. In the preparation of antibacterial substances, numerous quaternary ammonium compounds have been used, such as zwitterion betaines, essential for protein formation and DNA repair [121]. Nanoparticles such as metal or metal oxides, gold, silver, or copper are several strong contenders for antibacterial activity, such as zinc oxide, titanium dioxide, magnesium oxide nanoparticles, and titanium dioxide nanomaterials [9].
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Conclusion and Future Prospects
Nanocomposites are 3D polymer structures based on cellulose that can absorb and retain huge volumes of water. Their biomedical applications include drug carriers, biosensors, cloth, and wound dressings, which have their inherent appearance to the living material. They have a wide variety of applications. The recent performance of biomedical hydrogels has received immense attention from biodegradables and renewables of polymeric materials, particularly nanocellulose. Combined with innovations in nanomaterials visualization and therapeutics delivery systems, advancements advocate the perspective of optimizing multifunctional “intelligent” nanostructures, which can elicit individually tailored healthcare services. Several experiments are done to verify the aptitude of nanocellulose for combined in vivo application and treatment of cancer. Multipurpose nanoparticles can also be utilized.
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• Antibacterial materials
• Packaging Materials
• Wound dressings
Self-assembly
Surface modification
Combined materials
Nanocomposites
• Drug delivery systems
Fig. 9 Nanocellulose materials including NCC, NFC, EC, and ESC with their corresponding surface modification, self-assembly, combined nanomaterials, nanocomposites for packaging, drug delivery systems, wound dressings, and antibacterial materials
In the future, multiplex nanomaterials could also identify tumor cells (actively movement-focused). Imagine the release point (in vivo imaging), eliminating most cancerous cells with minimum side effects by sparing normal cells as well as tracking real-time development.
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Balaji Mahendiran, Shalini Muthusamy, Sowndarya Sampath, S. N. Jaisankar, and Gopal Shankar Krishnakumar
Contents 1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Tissue Engineering Process and Principles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Nanocelluloses for Tissue Engineering . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1 Cellulose Nanocrystals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2 Cellulose Nanofibrils . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3 Bacterial Cellulose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Nanocellulose Hydrogels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Nanocellulose Scaffolds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Nanocellulose 3D Printing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Conclusion and Future Prospects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Abstract
The most ubiquitous polymer that exists in nature is cellulose which occupies a predominant position in tissue engineering (TE) technologies mainly due to its beneficial properties such as renewability, non-toxicity, and biocompatibility. Nanostructured cellulose with size not exceeding 100 nm at least in one dimension is referred to as nanocellulose. In TE applications, nanocellulose-based scaffolds have created immense interest owing to its salient characteristic features such as water absorption, water retention, optical transparency, chemomechanical properties, special surface chemistry, and biocompatibility. In this chapter, we first provide a brief outline about how nanotechnology principles B. Mahendiran · S. Muthusamy · G. S. Krishnakumar (*) Applied Biomaterials Laboratory, Department of Biotechnology, PSG Institute of Advanced Studies, Coimbatore, Tamil Nadu, India e-mail: [email protected]; [email protected]; [email protected] S. Sampath · S. N. Jaisankar Department of Polymer Science and Technology, Council of Scientific and Industrial ResearchCentral Leather Research Institute, Chennai, Tamil Nadu, India e-mail: [email protected] © Springer Nature Switzerland AG 2022 A. Barhoum (ed.), Handbook of Nanocelluloses, https://doi.org/10.1007/978-3-030-89621-8_37
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have impacted TE process to develop functional biomaterials. Then we emphasize in summarizing the family of nanocellulose which includes cellulose nanocrystals (CNC), cellulose nanofibrils (CNF), and bacterial cellulose (BC) that are commonly employed in scaffold development for tissue-specific organ regeneration. A short overview of sources, methodology, physicochemical properties, and applications of different nanocellulose is discussed in depth. Additionally, we also discuss about the application of different nanocellulose-based hydrogels, three-dimensional (3D) scaffolds, and 3D printed constructs in a multitude of tissue engineering applications. Finally, the future challenges, opportunities, and potentials of nanocellulose are also discussed. Keywords
Nanocellulose · Cellulose nanocrystals · Cellulose nanofibrils · Bacterial cellulose · Tissue regeneration
1
Introduction
Nanotechnology applications have emerged successfully across all economic sectors allowing the expansion of new industrial revolution with broad spectrum of marketing potential. Nanotechnology has spurred new scientific advancements in manufacturing process in diverse fields spanning biomedicine, regenerative therapy, drug delivery systems, bioimaging, and biosensing [1]. Nanosize materials with size of about 1–100 nm, at least in one dimension, exhibit a unique physicochemical, optical, magnetic, and biological properties providing the opportunity to produce nanostructured materials with greater strength, better opacity, and improved electrical and biological performances when compared to bulk materials [2]. In this context, cellulose holds a great promise in several industrial uses as it is the most ubiquitous structural amphiphilic polymer resource with annual production of 7.5 1010 tons. Cellulose is the most abundant, green, renewable, and sustainable polymer that can be derived from an in exhaustive source of raw materials in the biosphere which includes plants, tunicates, algae, and bacteria [3]. Apart from renewability and availability, cellulose exerts certain benefits such as chemical inertness, excellent stiffness, great strength, low coefficient of thermal expansion, low density, dimensional stability, and ability to tailor its surface chemistry [4]. Over the past decades, cellulose in its newest form of “nanocellulose” has been proposed as a versatile biopolymer due to its attractive features such as biocompatibility, water absorption, water retention, optical transparency, and chemo-mechanical properties [5]. Nanotechnology interventions involving cellulosic substrates have created immense interest in developing nanostructured materials by various chemical, biochemical, and mechanical methods to modify cellulose for widespread advanced applications. The possibility to produce nanocellulose from multitudinous of unexplored biomass using various isolation and processing conditions, and pre- or post-treatment methods have provided an opportunity to
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fabricate 3D hierarchical structures at nanoscale for several emerging applications in biomedicine [6]. To this regard, the global market of nanocellulose is envisioned to surge up to USD 783 million by 2025. Therefore, the ever-growing demand of nanocellulose mainly owing to its environmental friendliness and natural origin has attracted both scientific and industrial attention in many interdisciplinary areas [7]. In this chapter, the contributions of nanocellulose in different forms devoted to TE applications are discussed. Firstly, the significance of TE is addressed with an overview on the principles to design 3D bio-artificial substitutes for tissue/organ regeneration with relevance to nanocellulose-based biomaterials. Secondly, the use of nanocellulose in different forms such as nanocrystals, nanofibers, hydrogels, and bacterial cellulose with regard to its properties, functionalization, advantages, and applicability is presented. Thirdly, the use of nanocellulose-based scaffolds in multitude of biomedical applications is highlighted by providing insights on development and potential applications. Fourthly, 3D printing of nanocellulose for tissue regenerative applications is outlined delineating the importance of selection of cellulosic materials, 3D printing technologies, and underlying applications. Finally, the future challenges, opportunities, and possible research outcomes of nanocellulose are also discussed.
2
Tissue Engineering Process and Principles
With the advent of tissue engineering and regenerative medicine (TERM), the field of biomedicine has seen rapid progression in creating novel therapies that can improve the healthcare of aging and diseased population which endures to be a global challenge. The field of TERM has grown exponentially in the past decades by combining multidisciplinary disciplines such as stem cell biology, functional scaffold material, nanotechnology, and 3D printing to create functional tissue-like-substitutes that can restore and repair organ damage [8]. TE involves the use of cells, scaffolds, and growth factors to regenerate impaired tissues/organs, whereas regenerative medicine integrates TE with other strategies such as cell/gene therapy and immunomodulation to improve in vivo tissue/organ reconstruction [9]. TERM holds a great promise in meeting the future demand of ailing patients, especially in organ transplantation where there is a significant shortage and enormous complications in organ donation. In the United States alone, there are more than 100,000 patients in waiting list as of 2019 for organ transplantation with substantial scarcity at its peak than ever before. TERM is recognized as the “holy grail” in modern medicine, where the feasibility to develop tailor-made, tissue-likesubstitutes is accomplishable in order to replace failed organs [10]. In comparison with conventional organ transplantation, TERM offers personalized development of whole or part of an organ with close biomimicry of the dynamic living tissues. The promise of regenerative medicine has manifested the potential possibility to regenerate a wide range of defective tissues/organs like the skin, bone, cartilage, nerves, kidney, heart, and liver [11].
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The primary purpose of TERM is to create a 3D cell/scaffold complex that has comparable functions to the native living tissue/organ which can be used to support cellular growth and proliferation at the damaged site. Generally, TERM employs the following three strategies for successful tissue regeneration: (i) cell/scaffold complex system, where cell-seeded biomaterials are implanted at the targeted site to induce repair and regeneration; (ii) cell systems, like stem cell transplantation; (iii) biomaterial system, to allow the process of tissue integration and subsequent regeneration. These three important strategies may be integrated to revitalize tissues/organs based on clinical needs. Ultimately these strategies assist in changing the tissue microenvironment with exogenous biomaterials and biological factors to improve the body’s healing process. Most often cell/scaffold complex system is commonly used in numerous applications, where 3D scaffolds allow appropriate cell growth and organize to form extracellular matrix (ECM) in the regenerative process. Accordingly, three key ingredients are essential for both morphogenesis and tissue regeneration to eventuate effectively such as (i) responding cells, (ii) inductive signals (regulatory biomolecules and growth factors), and (iii) ECM scaffolds as illustrated in Fig. 1 [12, 13]. Firstly, cell source is also an important parameter that needs careful consideration because cells populate the scaffold and produce matrix similar to the native tissue. Cells for regenerative therapy are either from autogenic (sample individual), allogenic (different individual), or xenogenic (different species) origin [14]. Predominately, autogenic isolation of primary cells from targeted tissues is widely used for tissue-specific regeneration. However, due to difficulties in cell collection and maintenance, the use of stem cells has gained popularity which includes embryonic stem (ES) cells, bone marrow mesenchymal stem cells (BMSCs), and umbilical cord-derived mesenchymal stem cells (UC-MSCs) [15]. Importantly, the
Fig. 1 Tissue engineering triad: combination of cells, scaffolds, and growth factors that synergistically recapitulate the desired defective tissues. (Reprinted with permission from Ref. [13], Copyright 2020, MDPI)
Scaffolds
Cells
Natural and synthetic polymers Composites
Mesenchymal stem cells (MSCs) Bioactive construct
Small molecules Proteins and peptides
Bioactive molecules
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Table 1 Advantages and disadvantages of natural and synthetic polymers used in tissue engineering applications Natural derived polymers
Synthetic polymers
Advantages Biodegradable & biocompatible Inherent presence of cell binding sites that supports cellular activities Non-immunogenic Native ECM-based tissue substitutes Processing versatility allows fine-tuning of scaffold properties Controlled degradation Inexpensive
Disadvantages Inadequate mechanical property Rapid biodegradation Lack of processing versatility Expensive Local toxicity due to degradation end products Lack of cell recognition sites Uncontrolled physical properties
combination of cell type and scaffolding should be done cautiously because the composition, topography, and the microarchitecture of the scaffolds have an impact on cellular behavior. The scaffold microarchitecture ranging from nano- to microscale topography has shown to affect cellular response by modifying cytoskeleton arrangements. Moreover, cell-material interactions are unique for diverse cell types, and material properties can also influence the extent of ECM production [16]. Secondly, growth factors are vital morphogenetic proteins that can guide tissue repair and renewal by instructing cell behavior. Tissue-specific growth factor receptor binding stimulates cellular signal transduction pathways that instigates cascade of events such as cell adhesion, migration, proliferation, and differentiation [17]. On the commercial scale, there are few clinically approved growth factors like human growth hormone, Humatrope ®; platelet-derived growth factor-BB, Regranex ®; bone morphogenetic factor-2 and 7, InFUSE™ Bone Graft/LT-Cage™; and OP-1 Putty used for various musculoskeletal disorders. These growth factors are often carried and delivered by bioinspired scaffolds for targeting tissue specificity [18]. Thirdly, 3D scaffolds serve as a template rendering the required physicochemical and structural support for the in vitro ECM formation, thereby ensuring slow degradation and resorption upon in vivo implantation [19]. Currently, in TERM there is a wide pallet of scaffolds derived from both natural and synthetic origin. Natural biomaterials such as proteins (collagen, gelatin, keratin, fibrinogen, elastin, and silk fibroin), polysaccharides (chitosan, chitin, alginate, gellan gum, starch, dextran, and cellulose), and glycosaminoglycans (hyaluronic acid) have been exploited for bioengineering functional tissue substitutes. Importantly, owing to their biological origin and similarity with native ECM, natural biomaterials are endowed with properties such as good bioactivity, controlled degradability, and favorable cellular response [20]. On the other hand, synthetic biomaterials cannot reiterate the whole spectrum of properties of the natural biomaterials, but they have certain advantages in processing characteristics in terms of molecular weight, degradation, and mechanical features with possibility to tailor the material property profile for tissue-specific applications. Synthetic biomaterials such as polyglycolide (PGA), polylactide (PLA), poly(lactide-co-glycolide) (PLGA), poly(D,L-lactic acid)
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Table 2 Diverse sources of cellulosic biomass commonly used in nanocellulose production [5] Source groups Hard wood: Eucalyptus, aspen, balsa, oak, elm, maple, birch Soft wood: Pine, juniper, spruce, hemlock, yew, larch, cedar Plants & agricultural wastes: Oil palm, hemp, jute, agave, sisal, triticale straw, soybean straw, alfalfa, kenaf, coconut husk, begasse, corn leaf, sunflower, bamboo canola, wheat, rice, pineapple leaf and coir, peanut shells, potato peel, tomato peel, garlic straw residues, mulberry fiber, mengkuang leaves Animal: Tunicates, Chordata, Styela clava, Halocynthia roretzi (Drasche) Bacteria: Gluconacetobacter, salmonella, Acetobacter, Azotobacter, agrobacterium, rhizobium, Alcaligenes, Aerobacter, Sarcina, pseudomonas, Rhodobacter Algae: Cladophora, Cystoseira myrica, Posidonia oceanica
(PDLLA), polyethylene glycol (PEG), and polycaprolactone (PCL) are used in scaffold designing mainly to fulfil the requirements of structural and mechanical properties [21]. The details in regard to advantages and disadvantages of both natural and synthetic polymers are discussed elaborately in Table 2. These apart, inorganic biomaterials such as metals (titanium and its alloy, stainless steel, and cobaltchromium alloys), ceramics (alumina, zirconia, hydroxyapatite, calcium phosphate cements and silicates), and their hybrid combinations are being largely perceived in numerous biomedical applications mainly owing to their biocompatibility, osteoconductivity, and osteogenic capacity [22]. Considering the above discussion about the key prerequisites in TERM, the importance of designing 3D porous scaffolds using appropriate strategies is of significant pertinence to its potential usage. The material properties such as porosity, pore size, pore connectivity, biocompatibility, safety, stability, and mechanical integrity are the key considerations which directly influence their functionality in regard to cellular activity and extent of ECM formation [23]. Traditional fabrication technologies such as foam replica method, particulate leaching, freeze-drying, gas foaming, and phase separation have been widely used to produce 3D scaffolds with a good degree of control over the optimization of physicochemical properties. Modern technologies like 3D printing, supercritical fluid technology, and microfluidics have emerged as promising tools to develop anatomically complex tissue structures with ameliorated structural, mechanical, and biological properties [24]. The rapid advancements in TERM in recent times have offered new pioneering technologies to develop patient-specific or tailor-made grafts with controlled healing and regeneration process. It is substantially evident that for a successful tissue repair to occur at the defective site, the function of scaffold is highly imperative because they essentially serve as a template trying to mimic the complexity of the nanoscale environment of the native tissue which is essential for tissue repair [25]. Among the plethora of biomaterials used in TERM, nanocellulose has been proposed as a versatile biopolymer due to its attractive chemo-mechanical and biological properties [26]. In the subsequent chapters, the contributions of nanocellulose in different forms dedicated to TE and 3D printing are addressed by highlighting the recent advances in nanocellulose preparation, modifications, and emerging applications.
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Nanocelluloses for Tissue Engineering
Biomaterials for TE based on nanocellulose extracted from native cellulose have triggered immense interest in tissue regeneration as result of its impressive physical properties, distinctive surface chemistry, and exceptional biological properties. Moreover, the β-(1–4) glucose linear polymeric chain of nanocellulose consists of three active hydroxyl groups which forms strong hydrogen bonds that attributes to excellent mechanical features, versatility in surface modifications, and superlative biocompatibility. These properties make nanocellulose as a potential candidate for various avenues in biomedical applications like regenerative medicine, drug delivery systems, bioimaging, and biosensors [27]. Nanocellulose relates to cellulose in the form of nanostructure with certain dimensions in nanoscale (18 GPa. The presence of abundant active hydroxyl groups in BC allows facile chemical modification to enhance protein absorption, hydrophilicity, surface topology, biocompatibility, and biodegradability [55]. BC-based functional materials with superior physiochemical and surface properties are often prepared by chemical modifications of BC by esterification, oxidation, acetylation, etherification, carbamation, and amidation. These alterations create reactive functional and charged groups on the BC surface by utilizing the free hydroxyl group, thereby enhancing the physico-mechanical features of BC [56]. Structurally being analogous to native ECM component collagen, BC is a highly biocompatible material with no cytotoxic, genotoxic, or mutagenic effects. Numerous studies on both in vitro and in vivo conditions have demonstrated the positive effects of BC which showed good biocompatibility with enhanced cell adhesion, proliferation, differentiation, and tissue growth in established cell lines [27]. As far as biodegradation is considered, BC is categorized as a slow or non-degrading material due to its high crystalline nature and absence of enzyme that can break the cellulose glycosidic bridges [57]. In view of slow degradation of BC, several strategies including chemical, physical, enzymatic, and genetic engineering approaches have been adopted to improve the degradability of BC without any toxic responses [58].
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In the past years, BC-based wound healing materials with different antimicrobial or regeneration inductive agents have shown quality restoration of skin defects with faster wound healing [59]. Recent studies by Vismara et al. showed that chemical modification of BC with glycidyl methacrylate and ethylene glycol dimethacrylate could be effectively used to deliver vancomycin and ciprofloxacin. The results revealed that grafting and cross-linking of BC imparted long-term antimicrobial activity with improved applicability in wound dressing applications [60]. Transfer of on-demand geometries on the surface of BC substrate was produced by guided assembly-based biolithograph. This replica-molding process generated directional alignment of individual nanofibers with memory of the transferred geometrical feature which eventually supported human keratinocyte and fibroblast migration and proliferation and additionally stimulated the healing of experimental skin wounds in mice models [61]. TEMPO-oxidized BC with silver nanoparticles exhibited high biocompatibility and significant antibacterial activities against pathogenic bacterial strains dictating to be promising candidate for wound healing applications [62]. Though BC is largely endorsed in skin regeneration, most of the research investigations are in lab scale, and commercial dissemination of BC biomedical products is still at the infancy stage. Despite of the challenges associated with BC production such as exorbitant cost and expensive labor, there are few products in the market. For example, Activa Healthcare (L&R company), UK, has commercialized polyhexamethylene biguanide (PHMB)-supplemented BC for wound healing applications. Xylos Corporation, USA, has commercialized BC wound care material marketed as XCell which can be effectively used to treat venous ulcer wounds. BC products such as Nanoderm™ and Nanoderm™ Ag from Axcelon Biopolymers, Canada, can serve as a temporary skin substitute to prevent bacterial infections during the treatment of lesions [63]. For cartilage regeneration, natural bionic nanofibrous microtissues were developed using dialdehyde BC, DL-allo-hydroxylysine (DHYL), and chitosan through electrostatic interactions. The microtissues showed improved proliferation of BMSCs and when implanted in a mice knee articular cartilage defect showed improved in vivo cartilage repair with good tissue regeneration (Fig. 4(i)) [64]. Likewise, for bone regeneration, BC is extensively studied in conjunction with HA in multiple studies, for example, using laser patterning technique honeycomb-structured BC mineralized with HA was developed with adequate biodegradable quality. The scaffolds exhibited suitable mechanical features and controlled porosity with the ability to improve the cellular activity of BMSCs [65]. Apart from tissue engineering applications, BC is proposed as a potential pharmaceutical excipient and carrier cargo for drug delivery systems. BC/pectin films incorporated with levofloxacin exhibited a maximum drug payload of 6.23 mg g 1 with improved antimicrobial effects, sustained drug release, and no cytotoxic effect [66]. A multifunctional core-shell hybrid microfiber system containing BC and a conductive polymer shell layer of poly(3,4-ethylenedioxythiophene) (PEDOT) represented to be a new smart biomaterial (Fig. 4(ii)). Diclofenac sodium-loaded hybrid microfiber system exhibited sustained release behavior and displayed to have excellent biocompatibility and electroactivity, thus proving to be an effective flexible template for the reconstruction of electrically responsive muscle
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Fig. 4 (i)-a Schematic illustration of the overall in vivo experiments design of microcarriers cultured with BMSCs in a bioreactor and implanted into a knee articular cartilage defect in mice model (Reprinted with permission from Ref. [64], Copyright 2018, Elsevier). (ii)-a Schematic representation showing the combination of coaxial spinning with a microfluidic device and subsequent dip-coating process. (ii)-b Digital photo of the coaxial laminar flow microfluidic device (Reprinted with permission from Ref. [67], Copyright 2017, Elsevier)
or nerve tissues [67]. Tremendous interest in BC for biomedical applications has grown exponentially in recent years. Despite its non-bioabsorbable issue, it has been widely investigated for diverse applications by adopting chemical and surface modifications. The versatility and customization of BC allow more relevant biomedical products to be developed in the coming years.
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Nanocellulose Hydrogels
Hydrogels are a class of soft materials with high water-holding capacity (99.9%) produced by a porous 3D network of polymeric chains. Hydrogels can be prepared from a wide spectrum of both natural and synthetic sources which are sensitive to
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specific changes like pH, ionic strength, pressure, light, temperature, and electric and magnetic field. Owing to their stimuli-responsive behavior, hydrogels are commonly tailored or customized to provide molecular bio-functions and desired mechanical features and behave similar to the native ECM microenvironment for cell growth and tissue formation [68]. Among diverse sources for hydrogel preparation, cellulose is well known for its attractive properties such as renewability, sustainability, and non-toxicity for producing water-based hydrogels. Unlike other source-derived hydrogels, cellulose hydrogels are water insoluble which forms a colloidal suspension in water rather than being in a solution form. This characteristic feature of cellulose hydrogel is attributed to the geometric dimensions and gelling network which is stabilized by chemical and electrostatic interactions [69]. Cellulose derivatives like hydroxypropyl cellulose, methylcellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, ethyl cellulose, sodium carboxymethyl cellulose, cellulose sulfate, and cellulose phosphate have been used extensively in the past decades to produce reversible or stable hydrogels for an array of biomedical applications. Among these, carboxymethyl cellulose has gained significant importance especially in wound healing applications owing to its affordability, biodegradability, biocompatibility, and ability to absorb wound exudates. To this regard, there are few commercialized carboxymethyl cellulose products in the market such as Granugel ®, UK; Intrasite® gel, UK; Regranex ® gel, UK; and Purilon ® gel, USA, used to treat chronic wounds effectively with the ability to restrict bacterial contaminations and accelerate tissue granulation [70]. Furthermore, composite hydrogels are also designed by blending cellulose with natural polymers polyvinyl alcohol, polyelectrolyte complexes, interpenetrating polymer network, and cellulose inorganic hybrid hydrogels to produce bioinspired composite gels with improved mechanical and biological properties [71]. Generally, hydrogels are cross-linked to improve the mechanical properties and to prevent hydrogel from dissolution in the solvent. In most cases, cross-linking is performed by either physical or chemical methods to improve hydrogel structure and strength which also largely governs end application efficiency [72]. Physical crosslinking forms temporal linkage due to hydrogen bonding, hydrophobic interactions, or electrostatic interactions between the polar groups, whereas chemical crosslinking forms a permanent linkage by covalent bonds with relatively stronger ionic interaction between the various functional groups of exogenous cross-linking agent [73]. For instance, CNF produced by TEMPO oxidation cross-linked with metal cations like Ca2+, Zn2+, Cu2+, Al3+, and Fe3+ demonstrated rapid gelation initiated by cation-carboxylate interactions on the nanofibrils resulting in gel formation by ionic cross-linking (Fig. 5(i)) [74]. Hybrid hydrogels developed using BC and sodium alginate cross-linked with calcium ions exhibited dual responsive release system. The hydrogels exhibited a semi-interpenetrating polymer network structure, and by changing the pH and electric field, the release of ibuprofen drug could be controlled by the action of deprotonation or protonation of calcium alginate in the hydrogels (Fig. 5(ii)) [75]. With the above few examples, it is clear that cross-linking of hydrogels determines the network structure, shape, and pore size distribution. The cross-linking density modulates the length and concentration of the fibers and the
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Fig. 5 (i) Pictorial representation of CNF aqueous dispersion and the free-standing hydrogels formed by addition of metal salt solutions to the carboxylated CNF dispersions (Reprinted with permission from Ref. [74], Copyright 2013, American chemical society). (ii) Schematic representation illustrating the preparation of the drug-loaded BC-alginate hybrid hydrogels with a semi-IPN structure (Reprinted with permission from Ref. [75], Copyright 2013, Royal society of chemistry). (iii) Gross appearance of wound healing experiments in a mice model using different concentrations of silver nanoparticles in CNF/gelatin composite (Reprinted with permission from Ref. [77], Copyright 2018, Elsevier). (iv)-a Schematic representation of injectable hydrazide-functionalized hyaluronic acid. (iv)-b Aldehyde functionalized hyaluronic acid with aldehyde-modified CNCs (Reprinted with permission from Ref. [79], Copyright 2015, American chemical society)
concentration and homogeneity of the cross-linking point’s distribution. Normally, the hydrogels are transparent, and their gross appearance changes in response to incorporation of exogenous biomolecules such as ions, proteins, polymers, and copolymers. Therefore, choosing an appropriate cross-linking technique for hydrogel preparation is necessary, and it is largely dependent on its end-use application and its requirements [72]. The unique soft and rubbery texture of nanocellulose hydrogels in swollen state tends to biomimic the native ECM in the biological tissues. Their highly porous microarchitecture allows the hydrogels to absorb small molecules within their entangled structural network and preserve them until incited by an appropriate stimuli for release of these molecules. This hydrated microenvironment is highly suitable for cellular functions in different avenues of biomedicine like tissue engineering and drug delivery applications [76].
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Green composite hydrogel prepared by incorporating silver nanoparticles in gelatin and TEMPO-oxidized CNF for wound healing applications demonstrated strong mechanical, self-recovery, antibacterial properties and satisfactory hemostatic activity (Fig. 5(iii)). It was reported that 0.5 mg/ml of silver nanoparticles in the composite hydrogel showed outstanding wound healing efficacy with appropriate balance of fluids on the wound bed (2093.9 g/m2 per day) [77]. Magnetic hydrogels developed using CNC and sodium alginate exhibited a controlled release profile of ibuprofen. The presence of magnetic CNCs within the alginate matrix enhanced the mechanical strength and integrity of the hydrogels with adequate swelling behavior which eventually favors the release kinetics [78]. Adipic acid dihydrazide-modified injectable hyaluronic acid hydrogels reinforced with CNC and functionalized with varying content of aldehyde demonstrated favorable structural, biomechanical, and biochemical properties (Fig. 5(iv)). It was reported that presence of CNC resulted in a stiffer hydrogel with compact structural organization and storage modulus of 52.4 kPa for 0.25 wt% of aldehyde modified CNC content. Additionally, the biocompatibility analysis exhibited preferential cellular supportive properties owing to the structural integrity and potential interaction of microenvironmental cues with CNC’s sulfate groups [79]. BC/acrylic acid hydrogels loaded with human epidermal keratinocytes and human dermal fibroblast cells used to treat burn wounds showed the greatest acceleration on burn wound healing with wound reduction of 77.34 6.21% on day 13. The supply of xenogenic cells indicated a greater deposition of collagen served as a potential material and cell carrier for the rapid treatment of burn wounds [80]. Magnetic BC hydrogels prepared by in situ precipitation method of Fe3+ and Fe2+ iron salts into BC pellicles to form Fe3O4 nanoparticles along the BC fibrils can potentially increase cell homing at tissueengineered vascular grafts. It was reported that magnetic BC captured magnetically functionalized cells under pulsatile fluid flow with satisfactory BC magnetization of up to 10 emu/g. Such kind of magnetic BC hydrogels can improve tissue regrowth and provide mechanical cues to cells at the luminal face of vascular grafts which are aggressive for cell survival, thereby preventing restenosis and inflammation [81]. Li et al. developed eugenol/β-cyclodextrin/carboxymethylcellulose hydrogel that demonstrated outstanding antibacterial activity under both in vivo and in vitro conditions. In addition, it was found that the hydrogel could accelerate diabetic wound healing by regulating lectin-like oxidized low-density lipoprotein receptor-1induced activation of nuclear factor kappa-B to accelerate angiogenesis and impede inflammation in diabetic wound healing [82].
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Nanocellulose Scaffolds
In TE process scaffolds are fundamental prerequisite which serve as a template to provide adequate microenvironment for cellular activities like adhesion, proliferation, differentiation, biochemical retention, diffusion of biomolecules, and mechanical support. Scaffolds provide a multi-layered matrix network, thus allowing cell penetration in order to facilitate repair of damaged and defective tissues [19]. Since
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the inception of tissue engineering technology, fabrication of scaffolds through novel techniques has been an indispensable process in obtaining different shapes of 3D structures. Scaffold fabrication technology is broadly categorized into traditional or rapid prototyping approaches. Under traditional approaches, techniques such as freeze-drying, salt leaching, gas foaming, electrospinning, and phase separation methods are commonly used, whereas under rapid prototyping approaches, technologies such as 3D bioprinting, stereolithography, laser sintering, fused deposition modelling, and injection molding are often used. However, in both traditional and rapid prototyping approaches, each technique may have its own limitations and drawbacks which may be related to energy consumption, toxicity, porosity, pore interconnectivity, rigidity, homogeneity, cost, and time. But in comparison with traditional approaches, rapid prototyping offers the possibility to individualize scaffolds for tissue-specific application with controlled morphological features [24]. Nevertheless, the choice of fabrication techniques is dependent on the bulk, surface properties and the desired function of the scaffold. Therefore, the selection of appropriate fabrication technique is highly imperative to maintain the coveted properties in the final scaffold which may strengthen their applicability in the tissue regeneration process [25]. Among the plethora of natural biomaterials used for scaffold synthesis, cellulose is extensively utilized to produce customized scaffolds with desired shape, size, orientation, porosity, structure, and mechanical features [26]. Wound dressing material developed from carboxylated brown algae cellulose nanofibers (BACNFs) represented high porosity and water absorption capacity. To impart antibacterial properties, the BACNF sponges were soaked in quaternized β-chitin/rectorite (QCR) suspension, and hybrid sponge BACNF/QCR was developed by freezedrying (Fig. 6(i)). The BACNF/QCR sponge exhibited multifunctional properties such as strong biocompatibility, prominent mechanical strength, and potent antimicrobial property and could enhance skin healing by promoting collagen synthesis and neovascularization [83]. Using thermally induced phase separation (TIPS) technique, modular multilayered scaffolds were prepared using polylactic acid (PLA) and CNC. It was reported that by varying the surface chemistry of CNC and TIPS methodology, scaffolds with ability to biomimic the different regions of articular cartilage would be developed. The multi-layer polymer nanocomposite scaffolds provided the chemical and structural cues to support the morphology, orientation, and phenotypic state of cultured chondrocytes in a spatially controlled manner (Fig. 6(ii)) [84]. CNC reinforced with poly(vinyl alcohol) (PVA) exhibited mechanical behavior similar to collagen tissues with exceptionally high water content (>90 wt%). The macroporous structure of the hydrogel showed high oxygen permeability, low protein adsorption, and high wearing comfort with excellent optical properties (Fig. 6(iii)) [85]. Hydroxyapatite/silk fibroin/CNC biomimetic scaffolds prepared by freezedrying represented average pore size and porosity of 110 7.3 μm and 90 6.2%, respectively. The composite demonstrated excellent biocompatibility and superior osteoconductivity and induced new bone formation in rat calvarial defect within 12 weeks of implantation (Fig. 6(iv)) [86].
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Fig. 6 (i) Schematic illustration of the construction of QCRs (top) and BACNFs/QCRs wound dressing composite (Reprinted with permission from Ref. [83], Copyright 2019, Royal society of chemistry). (ii) Influence of different substrate types on chondrocyte biocompatibility using DAPI and phalloidin staining (Reprinted with permission from Ref. [84], Copyright 2015, Elsevier). (iii)-a Self-standing CNC-PVA hydrogel lens. (iii)-b CNC-PVA hydrogel implant sutured to ex vivo porcine cornea (Reprinted with permission from Ref. [85], Copyright 2016, American chemical society). (iv) 3D images displaying the different repair results in rat calvarial defects assessed by μCT in 4, 8, and 12 weeks of implantation (Reprinted with permission from Ref. [86], Copyright 2016, Royal society of chemistry)
Silk fibroin/BC nanoribbon composite scaffolds were prepared to repair bone defects. The hybrid composite exhibited radial lamellar pattern and gradient lamellae gap distance which would guide cellular proliferation and allow effective transfer of metabolic products. The intercalated structure of the composite led to an eightfold enhancement in compression modulus and sixfold increase in compression strength with improved bone-cell adhesion and proliferation [87]. Biodegradable oxidized BC was prepared with different oxidation degrees using sodium periodate, and its properties were evaluated for its potential application in peripheral nerve repair. It was disclosed that the biodegradability of oxidized BC scaffolds was improved significantly and scaffolds with lower oxidation degree showed favorable porosity with interconnected pores, desired mechanical performance, good biodegradability, and excellent biocompatibility for peripheral nerve repair [88]. Doubtlessly, nanocellulose-based scaffolds exhaustively satisfy the key requirements of tissue engineering owing to their superior physiochemical and biological characteristics. Though significant achievements have been made in the past decades
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using nanocellulose, still there are few challenges which need attention such as in vivo degradability, mechanical features, and structural design. Especially poor in vivo degradation of nanocellulose is a major limitation that hinders its potential applicability in numerous biomedical applications. This is predominantly due to the lack of cellulase enzyme in the human body that initiates cellulose resorption and breakdown. Few studies have explored the option of conjugating cellulase enzyme with biomaterials to improve cellulose degradation [89, 90]. Therefore, future investigations should focus on addressing the limitations associated with nanocellulose so that transplantation of nanocellulose-based biomaterials in clinical practice is not far away.
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Nanocellulose 3D Printing
3D printing technology has revolutionized the field of biomedicine by offering the possibility to print patient-specific implants for numerous degenerative disorders. In medical 3D printing, the most commonly used 3D printing technologies are fused deposition modelling, extrusion-based bioprinting, inkjet, and polyjet printing [91]. An important criterion in 3D printing is selection of suitable bioink which depends on the end-use application, type of cells, and the bioprinter to be used. Therefore, in selected bioink significant parameters such as rheological behavior, extrudability, mechanical stiffness, biodegradability, and biocompatibility need to be validated prior to printing process so that the final printed construct can maintain its shape fidelity and provide a conducive microenvironment for cellular performance [92]. Among the wide array of available bioink, biopolymers are considered important representative within the scope of biomedical applications. A variety of natural polymers such as collagen, gelatin, elastin, hyaluronic acid, alginate, chitosan, and cellulose are commonly used in medical 3D printing with successful results. As indicated in the recent years, nanocellulose-based bioink has been commonly used in hydrogel-extrusion 3D printing mainly owing to its structural similarity to native ECM in terms of porosity, interwork framework, and fibrous topography which support crucial cellular activities. Above all, nanocellulose displays a non-Newtonian, shear thinning (viscoelastic) behavior which boosts its application in hydrogel-based 3D printing. The beneficial shear thinning behavior of nanocellulose is attributed to the orientation of nanocellulose structure in the direction of shear flow. At low shear rate, nanocellulose displays a coiled configuration which disentangles with increase in shear rate and aligns along the direction of flow. This characteristic feature allows seamless extrusion of bioink as a liquid phase [93]. Anatomically shaped cartilage structures, like human ear and sheep meniscus, were printed using hybrid bioink constituted of CNF and alginate (Fig. 7(i)). Chondrocyte-laden bioprinting demonstrated a favorable cell viability of 73% and 86% after 1 and 7 days of 3D culture [93]. Multicomponent bioink consisting of CNF and alginate with human nasal chondrocytes facilitated the biofabrication of cell-laden, patient-specific auricle construct. The 3D printed construct exhibited open inner structure, high cell density, homogenous distribution, excellent shape,
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Fig. 7 (i) Different structures printed using NFC/alginate bioink, (a) 3D printed small grids (7.2 7.2 mm2), (b) grid deformation while squeezing, (c) restoration after squeezing, (d) 3D printed human ear, (e) sheep meniscus side view, (f) sheep meniscus top view (Reprinted with permission from Ref. [93], Copyright 2015, Elsevier). (ii)-a Connection between two secluded cells on CNF/CNT guidelines. (ii)-b Attachment of SH-SY5Y cells on the CNF/CNT guidelines (Reprinted with permission from Ref. [95], Copyright 2018, Elsevier). (iii)-a BNC/alginate with an inserted PLA sacrificial template vascular tree in a kidney shape. (iii)-b Freeze-dried BNC/alginate sponge. (iii)-c SEM image of sponge microstructure (Reprinted with permission from Ref. [99], Copyright 2019, IOP publishing). (iv)-a Pictorial representation of hydrogel networks structure in printed filament. (iv)-b Swelling capacity of printed scaffold. (iv)-c 3D view of printed macro-structure scaffolds. (iv)-d 3D printed grid-like scaffold. (iv)-e 3D model of lateral meniscus with the internal architecture of 90 /0 strand structure. (iv)-f Smoothed 3D model of human meniscus. (iv)-g 3D printed human meniscus (Reprinted with permission from Ref. [100], Copyright 2019, Elsevier)
and size stability with ability to allow redifferentiation of chondrocytes and neo-synthesis of cartilage-specific ECM components [94]. Tailor-made multicomponent bioink consisting CNF and carbon nanotubes was able to print guidelines below 1 mm in diameter with electrical conductivity of 3.8 10 1 S cm 1. The 3D printed constructs promoted neuronal cell development with evident neuronal-like dendritic morphology and elongated neuritis (Fig. 7(ii)) [95]. Hybrid bioink consisting of CNC and alginate cross-linked with calcium chloride was used to print liver-mimetic honeycomb 3D structures. After deposition, the hybrid bioink exhibited excellent shear thinning property, extrudability, and shape fidelity with ability to support the cellular viability of fibroblast and hepatoma cells [96].
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Surface coating of 3D printed PCL constructs with CNF has shown to enhance the hydrophilic properties of PCL construct with improved protein adsorption properties. The presence of CNF in between the 3D printed PCL strands and pores served as a hydrophilic barrier, thereby enhancing cell seeding efficiency and proliferation. Additionally, CNF coating supported the formation of a well-organized actin cytoskeleton and cellular production of vinculin protein on the surfaces of TCP and PCL constructs, thereby enabling its potential usage as functional scaffolds in bone tissue regeneration [97]. Low-concentration CNF/gelatin methacrylate bioink was printed with good structural stability for wound healing application. In situ cross-linking of CNF by Ca2+ and UV cross-linking allowed to fine-tune the mechanical properties within the range of 2.5–5 kPa with enhanced biocompatibility towards fibroblast cells [98]. Using sacrificial template BC with complex vascular mimetic lumen structure was printed to study the proliferative behavior of endothelial cells. The presence of micro- and nanomorphology of the scaffolds facilitated endothelialization and vascularization. Furthermore, large constructs with interconnected macroporosity and vascular-like lumen structure were developed with the help of patient data from a CT scan to create a mold for casting a fullsized kidney-like construct (Fig. 7(iii)) [99]. Silk fibroin/gelatin hydrogel reinforced with BC was used to printed scaffolds with hierarchical pore structures. BC reinforcement significantly improved the mechanical property from 100 kPa to 800 kPa with good shape fidelity and self-recovery. The in vitro and in vivo studies revealed excellent biocompatibility and good biodegradability where the presence of hierarchical pore structure helped cellular infiltration. Additionally, using the multicomponent bioink, 3D scaffolds of human meniscus with high fidelity was successfully printed with excellent shape retention and hierarchical porous structure (Fig. 7(iv)) [100]. In recent times, 3D printing has been expanding voluminously in developing patient-specific implants and prostheses. This sophisticated technology has refurbished the field of biomedicine in providing personalized medicine with enhanced productivity. Moreover, with the advent of recent developments in anatomical modelling for preoperative simulations, 3D modelling software, mechanics of the printing machine, and finite element analysis have increased the availability of personalized 3D printing in biomedicine. 3D printing technology is continuously evolving to offer native-like biological constructs with an incredible potential in biomedical and pharmaceutical fields [91].
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Conclusion and Future Prospects
The field of TERM is highly supported by the clinical demand of formidable biomaterials which can be utilized effectively to repair defective tissues/organs. Unquestionably, nanocellulose is a promising material which has shown breakthrough innovations in designing tissue-specific scaffolds in TE process. In this chapter, we have comprehensively compared the properties and applications of three different types of nanocellulose (CNF, CNC, and BC) in relevance to TE. Different structures obtained from nanocellulose in the form of hydrogels, 3D
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scaffolds, and 3D printed constructs are also discussed elaborately with respect to their preparation methodologies and suitable applicability. Although significant progress has been achieved in nanocellulose-based TE applications, there are few challenges in large-scale application of nanocellulose which includes structural design with desired porosity and interconnectivity, suitable mechanical performance, in vivo degradation, and translation in clinical practice. Additionally, long-term preclinical and clinical investigations are needed to bridge the gap between research and commercialization needs [27]. In case of nanocellulose hydrogels, their structural stability and durability under demanding biological condition are uncertain. Therefore, appropriate cross-linking strategies are required to significantly improve the mechanical strength and physical stability. Moreover, attachment of biologically active ligand molecules such as pharmaceutical biomolecules, growth factors, and antigenic compounds can improve the cellular activities at tissue-specific applications. In 3D scaffolds, more detailed investigations are needed to study the mechanism of cells and nanocellulose interaction. Especially studies related to inflammatory effects of nanocellulose scaffolds are required to support their commercial application [26]. 3D printing has emerged as a powerful tool in printing a wide variety of nanocellulose-based constructs in TE applications. In spite of its intriguing studies and reports on excellent printability and shear thinning behavior, currently available 3D printers endure challenges in scalability, affordability, and bioink variability. Therefore, future studies are required to investigate different bioink compositions with diverse viscosities with the ability to move forward from lab to clinic translation [92]. Therefore, more research is needed in the abovementioned gray areas in order to effectively utilize the endless opportunities offered by nanocellulose in recapitulating defective tissues/organs. In conclusion, nanocellulose-based scaffolds in TE have emerged as an exceptional platform of next-generation biomaterials with great extent of diversity and versatility in countless TE applications. Herein the wealth of knowledge summarized in the field of nanocellulose-based scaffolds will encourage future research to progress towards nanoscale engineering methodologies to produce innovative and bioinspired new composite materials that fully biomimic the native functional tissues. Acknowledgments The corresponding author acknowledges the financial support received from the Department of Science and Technology (DST)-Science Engineering and Research Board (SERB), Government of India, through Start-up Research (SRG/2019/001157) grant.
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Nanocellulose for Vascular Grafts and Blood Vessel Tissue Engineering
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Contents 1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Criteria of Vascular Grafts and Blood Vessel Tissue Engineering . . . . . . . . . . . . . . . . . . . . . . . . . 2.1 Engineering of Different Lumen Diameters and Varying Structures . . . . . . . . . . . . . . . . 2.2 Integration of Engineered Vessels with the Host Vessels or Tissues . . . . . . . . . . . . . . . . . 2.3 Mechanical Properties of the Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4 Biocompatibility and Hemocompatibility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Unique Properties of Nanocellulose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1 A Wide Range of Mechanical Properties (Mechanical Reinforcement) . . . . . . . . . . . . . 3.2 Surface Chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3 Biological Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4 Patency Parameters of Vascular Grafts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Nanocellulose for Vascular Tissue Engineering . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1 Cellulose Nanocrystals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2 Cellulose Nanofibers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3 Bacterial Cellulose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Nanocellulose for Vascular Grafts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1 Common Biomaterials for Vascular Grafts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2 Fabrication of Bacterial Nanocellulose Grafts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3 Composite Forms of Bacterial Nanocellulose Grafts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4 Non-composited Bacterial Nanocellulose Grafts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.5 Other Nanocellulose Types . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Limitations of the Use of Nanocellulose in Vascular Grafts/Tissue Engineering . . . . . . . . . . 7 Conclusion and Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Z. Goli-Malekabadi (*) Bioengineering Center for Cancer, Department of Mechanical Engineering, Isfahan University of Technology, Isfahan, Iran e-mail: [email protected] S. Pournaghmeh Biomedical Engineering Department, Engineering Faculty, University of Isfahan, Isfahan, Iran © Springer Nature Switzerland AG 2022 A. Barhoum (ed.), Handbook of Nanocelluloses, https://doi.org/10.1007/978-3-030-89621-8_38
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Abstract
The first reason of human mortality around the world is cardiovascular diseases especially vessel dysfunction. Engineered vessels, made from vascular cells and scaffolds, and vascular grafts are suitable alternatives for replacing damaged vessels. Engineered vessels are also used in large organs tissue engineering such as heart and kidney where the inclusion of vascular networks in engineered tissues will be an important achievement. In the last two decades, various biomaterials have been utilized for fabrication of vascular grafts or scaffolds such as polyurethanes and chitosan. Nevertheless, recent documents represent a significant focus on nanocelluloses because of their unique properties in physics, chemistry, and mechanics that are necessary for a successful vascular replacement. In addition, nanocelluloses show good biological properties including biocompatibility and hemocompatibility. Despite these nanocellulose advantages, utilizing this biomaterial has still some limitations and challenges. This chapter will discuss the nanocellulose unique properties that meet the requirements of an artificial vessel including alive engineered vessel and synthetic vascular graft as well as describe the different types of nanocelluloses utilized in the fabrication of vascular grafts and tissue engineering scaffolds including cellulose nanocrystals, cellulose nanofibers, and bacterial cellulose. At the end, it will focus on the limitations of the use of nanocelluloses in artificial vessels. Keywords
Vascular prosthesis · Hemocompatibility · Scaffold · Tissue regeneration · Biomaterial · Vascular implant Abbreviations
BC BNC CNC CNFs ECM PTFE PVA SFNPs TEMPO VEGF
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Bacterial cellulose Bacterial nanocellulose Cellulose nanocrystal Cellulose nanofibers Extracellular matrix Polytetrafluoroethylene Polyvinyl alcohol Silk fibroin nanoparticles (2,2,6,6-Tetramethylpiperidin-1-yl)oxyl Vascular endothelial growth factor
Introduction
The availability of body tissues for transplantation is still a significant clinical challenge, while the number of patients in need of transplant therapy is increasing. In addition, donor tissue shortcomings seek new medical technologies to facilitate
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replacement of vital damaged tissues such as cardiac tissue, as the first reason of human mortality (one third of deaths) around the world is cardiovascular diseases [1]. Tissue engineering is an active and multidisciplinary field in several decades now that combines both biological and engineering researches such as biochemistry, biophysics, genetic, biomaterial, and biomechanical engineering and aims to regenerate a tissue that has lost its function using cells, scaffolds, and appropriate stimuli [2]. The main strategy in tissue engineering is the personalized fabrication of alive body organs using cells (differentiated or undifferentiated) that are embedded in a supporting environment (scaffold) and stimulated by different signals such as chemical and mechanical factors (appropriate stimuli). Scaffolds are made from a wide range of biomaterials including synthetic and natural polymers as well as extracellular matrix (ECM) molecules such as collagen, elastin, and hyaluronic acid. As the scaffold plays the role of the natural ECM for cells, it must have chemical and mechanical properties of the intended tissue’s ECM. This challenge indicates the importance of scaffolds for tissue engineering applications that in addition to providing proper mechanical support and helping to cell adhesion, proliferation, and differentiation, they should be biodegradable, biocompatible, nontoxic, non-mutagenic, and non-immunogenic [3]. It means the biomaterial selection for engineering of different body tissues such as the skin, lung, cartilage, skeletal muscle, heart, and vessel depends on the properties of intended tissue and leads to tissue regeneration, although with still limited clinical application. One of the most important current limitations of this field is its inability to provide enough blood supply within large and more complex transplanted organs such as the kidney and heart that leads to improper function and cell death due to insufficient delivery of nutrients and oxygen [4, 5]. Weak blood vessel formation and overgrowth of vessels results in cell death and tumorigenesis respectively [6]. The inclusion of vascular networks in engineered tissues is therefore an important challenge in the field of tissue engineering. Researches have shown that vascular structures can be included in engineered tissues by the addition of vascular cells during culture, which self-organize into rudimentary vascular networks [7]. However, these structures lack the specific hierarchical organization of physiological vascular networks, resulting in suboptimal integration and functionality. In addition, dysfunctional vessels in atherosclerosis and other vascular diseases can be replaced with tissue-engineered blood vessel [8] indicating the importance of the field of vascular tissue engineering. Body vessels are formed from three layers including the tunica intima, tunica media, and tunica adventitia that encompass endothelial cells, smooth muscle cells, and fibroblasts respectively (Fig. 1) [9]. Endothelial cells, covering the inner layer of blood vessels, play a major role in the formation of new blood vessels and blood clot prevention due to their unique properties. In fact, endothelial cells form a tight non-thrombogenic barrier [9]. There are three current strategies for vascular tissue engineering. The most common is embedding of endothelial cells within or on a scaffold so that the scaffold will be degraded after ECM synthesis by cells. Therefore, this strategy needs a suitable biomaterial as the scaffold for endothelial cells or other cells. Second strategy is needless of the scaffold fabrication and uses the
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Fig. 1 General structural features of a blood vessel [9]
natural structure and ECM of host tissues/organ in such a way that decellularized tissues/organs will be re-endothelialized. The last strategy focuses on the angiogenesis stimulation in vivo that is not also supported by the scaffold. In addition, novel microfabrication technologies such as stereolithography and microfluidics have had satisfactory results helping in vitro and in vivo vascular tissue engineering [10, 11]. Despite these different strategies, many researches are still focusing on the scaffold-based vascular tissue engineering (first strategy) that leads to seeking for suitable biomaterials and applicable fabrication method. In addition to alive engineered vessels, artificial vascular grafts (non-alive) are also a proper alternative for dysfunction and unhealthy vessels. They are usually produced from polymeric material in different lumen sizes that must have appropriate mechanical and chemical properties in accordance with natural blood vessels. There are various processes helping to scaffold fabrication of engineered vessel such as electrospinning and bioprinting [10]. It should be noticed that the selected biomaterial and utilized fabrication method are interdependent. Nowadays, many biomaterials are utilized as a scaffold to support vascular cells. For example, polycaprolactone, poly-L-lactic acid, polyglycolic acid, collagen, elastin, and a combination of them routinely have been considered as an appropriate scaffold for vascular tissue engineering in documents that have reported its clinical success in the implantation of engineered vessels, although still with some limitations [11]. In the last few decades, scientists have been interested in the use of naturalsourced materials such as chitosan, alginate, collagen, and elastin for various biomedical applications including drug delivery, wound dressings, in vivo implants,
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medical prostheses, vascular grafts, and tissue engineering scaffolds. Recently, researches have focused on the use of a biomaterial with unique properties, nanocellulose, for artificial vessel fabrication that has the potential of resolving some clinical challenges. Nanocelluloses are unique promising materials that are extracted from natural sources including plants, animals, and bacteria. Their properties such as special physical and surface chemistry properties and remarkable biological properties make them an important potential for the use as biomedical materials. Nanocelluloses combined with polymers form bio-composites that are applicable in the fabrication of tissue engineering scaffold. It should be noticed there are four common methods to fabricate nanocellulose-based tissue engineering scaffolds including electrospinning, freeze-drying, 3D printing, and solvent casting [12, 13]. In this book chapter, we provide an overview of the different types of nanocelluloses including cellulose nanocrystals (CNCs), cellulose nanofibers (CNFs), and bacterial cellulose (BC) and their applications in vascular tissue engineering or vascular grafts, along with other important topics such as criteria of vascular grafts/ tissue engineering and limitations of nanocelluloses. The main body of the text is divided into two sections: the use of nanocelluloses in vascular tissue engineering and the use of nanocelluloses in vascular grafts and the differences between them. In vascular tissue engineering, the host’s cells (stem cells or adult cells) are cultured on/within a degradable scaffold in vitro. Then, this seeded scaffold remains in an incubator for vessel formation and maturation of the structure. In fact, a tissueengineered vessel is an alive structure that has been formed by the host’s cells. After the implantation of tissue-engineered vessel to the host’s vessel, the scaffold will be gradually degraded and be replaced with the ECM that is synthetized by cells imbedded in the scaffold. In contrast, vascular grafts are made from non-degradable biomaterials that are directly implanted to the host’s vessel. This graft is a non-alive synthetic structure.
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Criteria of Vascular Grafts and Blood Vessel Tissue Engineering
Vascular network of human body consists of various structures and functions. Therefore, the strategy for engineering of the vascular tissue such as biomaterial choose and cell culture depends on the vascular tissue that has been intended to be engineered. In addition, strategies of biomaterial treatment and fabrication methods have differences in vascular grafts and tissue-engineered vessels. Generally, vessel implants including both of vascular grafts and tissue-engineered vessels must be hemocompatible and biocompatible. They should be able to endure different mechanical forces that are created due to blood flow and the heart’s contraction/ expansion. Therefore, the main criteria for a successful and long survival engineered vessel are suitable mechanical properties, high compliance, and low thrombogenicity [14]. In this section we will explain the criteria for engineering of vascular implants in details.
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Engineering of Different Lumen Diameters and Varying Structures
Considering the blood vessel structure is essential in vascular tissue engineering (Fig. 1) especially choosing the appropriate biomaterial, design, fabrication method, and cell source. The structure of blood vessels, based on their sizes and roles, is significantly different. Larger vessels, called arteries and veins, have thicker walls because they transport the blood over long distances, while thinner wall of small vessels, capillaries, are arranged for optimal exchange of oxygen, nutrients, and waste products. Therefore, it justifies differences in biomaterial choose, design requirements, and approaches for engineering vessels. However, the inner layer of all vessels is the tunica intima and has some common structural features [11]. Another difference is the function of capillaries and larger vessels that must be considered. The basic function of larger vessel, naturally, is the endurance of mechanical forces applied to the vessel wall, while capillaries are in charge of material exchange. Therefore, engineered vessels that have been intended for veins and arteries must have a strong and impenetrable wall provided engineered capillary wall must allow material transmission.
2.2
Integration of Engineered Vessels with the Host Vessels or Tissues
A basic criterion is that engineered vascular tissues must be transplantable or able to stimulate the new vessel formation at the implanted site. Engineered vessels should be in accordance with the tissue in which these engineered vessels are intended to be implanted in terms of the size, structural properties, and function. In addition, the implantation process should not result in the immunologic reaction of the host tissues or host vessels. Another primary concern in the integration of engineered vessels is suitable choose of cell source as well as cell types that will affect the safety and performance. This item improves structural stability and the potential of clinical use and facilitates in vivo integration [11].
2.3
Mechanical Properties of the Structure
Vascular network always experiences different mechanical loads due to blood flow passing. Blood vessels (especially arteries) will be expanded after each heart pulse that results in applying a radial pressure to the wall of vessels (Fig. 2). This radial force stretches the vessel’s wall and causes tension stress. Additionally, passing of blood flow creates shear forces on the inner layer of the vessel wall [15]. Therefore, in the arterial wall, smooth muscle cells and endothelial cells are subjected to cyclic stretch and shear strains respectively. Vessels also experience steady stretch in both circumferential and longitudinal directions because of residual stress and tethering effects [16]. It should be noticed that blood pressure is very low (~0) in capillaries.
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Smooth Muscle Cell Radial Force
Shear Force
Endothelial Cell
Direction of Blood Flow Fig. 2 A schematic of forces applied by blood flow on the vessel wall. Blood pressure creates a radial force exerted to the vessel wall, while passing of blood flow results in shear force
So, the wall of capillaries does not experience the stretch and is subjected to low shear stress. Excluding capillaries, the main forces applied by blood on the vessel wall include tensile and shear stress (Fig. 2) Mechanical properties of engineered vessels (vascular tissue engineering) should provide structure stability until the formation of new vessel. In addition, both vascular grafts and alive engineered vessels must be able to endure mechanical forces without leakage or aneurysm formation. Just focusing on withstanding of alive engineered vessel in vivo may not be enough for it to best function. Published studies have confirmed the sensitivity of the maturation of smooth muscle cells and endothelial cells to mechanical forces [11, 17–19]. It means, in many cases, an alive engineered vessel that has not been implanted to body tissue yet needs to be matured in vitro by applying mechanical forces that the implant will experience in real conditions (in vivo). For example, pulsatile flow through the inner wall of the engineered vessel will be simulated by using a pump in a bioreactor [11]. Moreover, the stiffness of the environment of cells affects cellular behaviors separately [17, 20] which should be considered.
2.4
Biocompatibility and Hemocompatibility
Biocompatibility is the most commonly used term in describing the host response to biomaterials constitutive a medical implant [21]. Biocompatibility tests that are performed based on ISO 10993 include different evaluations such as toxicity, sensitivity, and irritation as well as hemocompatibility [22]. Hemocompatibility or blood compatibility is a critical property of biomaterials that are in contact with blood flow such as pumps, artificial valves of the heart, and vascular prostheses [23]. The complexity of biocompatibility evaluation of an implant depends on its nature and risks. Cardiovascular implants require to be tested in terms of anti-thrombogenic property in addition to other biocompatibility tests (long and short term) [11].
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This critical property will limit the range of biomaterials that can be used in cardiovascular implants specially engineered vessels.
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Unique Properties of Nanocellulose
There are three types of nanocelluloses including CNC (other definitions of nanocrystalline cellulose, cellulose whiskers, and rod-like cellulose microcrystals), CNF (other designations of nano-fibrillated cellulose and microfibrillated cellulose), and BC or microbial cellulose. This big family has unique properties making them different from traditional materials including mechanical reinforcement, rheological properties, biocompatibility, hemocompatibility, non-toxicity, biodegradability, morphological and geometrical properties, and barrier ability that are applicable in vascular tissue engineering or vascular grafts. The β-1,4-glucose contains three active hydroxyl groups in the molecular chain. It causes that nanocelluloses can readily form hydrogen bond network resulting in tunable surface modification, high mechanical stiffness, proper hydrophilicity, and good biocompatibility. In addition, nanocelluloses have liquid crystalline behavior, high specific surface area and surface chemical reactivity, water absorption, water retention, and optical transparency as well as low cost [12, 13, 24]. Associated with the book chapter’s topic, we will limit this section to properties applicable in vascular grafts and blood vessel tissue engineering. As the previous chapters have discussed in details about nanocelluloses and their properties, here we just have a quick review.
3.1
A Wide Range of Mechanical Properties (Mechanical Reinforcement)
Among the natural materials that can be used in vascular tissue engineering, collagen and hyaluronic acid have good biocompatibility, but their mechanical strength is poor. Synthetic polymers such as expanded polytetrafluoroethylene and polyethylene terephthalate that usually are utilized for artificial vascular grafts show strong mechanical properties, but do not have enough biocompatibility. Therefore, they cannot satisfy researchers to use them for the fabrication of blood vessel grafts. Despite this, nanocelluloses are a promising source for both vascular tissue engineering and vascular grafts as they have appropriate biological and mechanical properties [12]. Nanocellulose’s mechanical properties depend on the nanoparticle arrangement that includes the ordered and disordered regions called crystalline and amorphous respectively. The reason of the material flexibility is the cellulosic chains of disordered regions, while cellulosic chains in ordered regions provide the stiffness of the material. In fact, the mechanical properties of nanocellulose types are affected by their components, the crystalline domains and the amorphous fraction. It means the stiffness of CNC that has more crystalline regions is higher than the stiffness of CNF and BC fibrils that have crystalline and amorphous structures [13]. Therefore, nanocelluloses present various elastic moduli helping researchers to use them for
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Table 1 Comparison of mechanical properties of nanocelluloses 1 2 3
Type of nanocellulose Bacterial cellulose Cellulose microfibrils Cellulose nanocrystal
Average of elastic modulus ~ 114 GPa ~ 100 GPa 60–206 GPa
Ref. [13] [13] [13]
engineering of different regions of vascular network. For example, Young’s modulus of crystalline cellulose has been reported between 60 and 206 GPa, while cellulose microfibrils (involving both CNF and BC) have had longitudinal modulus of ~100 GPa. Again, documents have confirmed that BC’s stiffness is around 114 GPa [13]. Considering the feasibility of changes in the mechanical properties of nanocelluloses, they have the potential of load bearing element for various host materials. In fact, nanocelluloses having promising reinforcement transfer the stress appropriately from the host material or matrix to the reinforcing phase (nanocellulose) [13]. Table 1 presents the wide range of elastic moduli of nanocelluloses.
3.2
Surface Chemistry
Biocompatibility is a critical criterion of biomaterials especially those that are in long contact with body tissues. The surface properties and chemistry of biomaterials have vital role in the interaction between cells and biomaterials and subsequently their biocompatibility. Therefore, the material that has the feasibility of easy changes in the surface charge, wettability, surface chemistry, topography, and hydrophobic and hydrophilic domains can be an appropriate choose for implants. Nanocelluloses in addition to having tunable mechanical and physical properties can be easily controlled in terms of chemical properties due to the exposed hydroxyl groups on the surface of the fibrils. In other words, based on the different nanocellulose sources or chemical treatments, fibers can change in terms of morphology, surface chemistry, aspect ratio, and degree of crystallinity. They have a strong potential to self-associate and network formation via both intramolecular and intermolecular hydrogen bonds due to their strongly interacting hydroxyl groups [24]. On the other hand, surface chemistry and chemical properties of materials that are utilized in engineered vessels should be able to ensure hydrophilicity (helping cell adhesion) and hemocompatibility of the structure. Considering these properties, nanocelluloses are proper options for vascular tissue engineering and vascular grafts so that even a modified nanocellulose regulates blood metabolic variables [23].
3.3
Biological Properties
Our intention of the term “biological properties” is biomaterial behaviors in the body and especially in the contact with host tissue. Common and essential biological
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properties of biomaterials used for vascular tissue engineering or vascular graft fabrication are biocompatibility, hemocompatibility, biodegradability, and non-toxicity [13]. Nanocelluloses meet all these properties in an acceptable level. As previous chapters have explained these properties completely, we will just describe them briefly.
3.3.1 Biocompatibility In the past decade, a wide range of documents have evaluated the biocompatibility of celluloses with different sources and confirmed that celluloses regardless of their sources are generally biocompatible; although with poor reports on the biocompatibility of CNC and CNF. However, as the human organs do not synthesize cellulolytic enzymes, celluloses are not easily degraded by the body. This problem reduces the application of celluloses in tissue engineering [13]. One of the other important parameters that determine biocompatibility level of a biomaterial is the toxicology. Adjudication about the toxicology of nanocelluloses and their bio-composites still needs more investigations. Nevertheless, available studies have confirmed that celluloses especially BC have no serious level of cytotoxicity and genotoxicity. As an exception, pulmonary inflammation has been reported due to inhalation of plentiful nanocellulose (especially for CNC) that is dose-dependent [13]. 3.3.2 Hemocompatibility Hemocompatibility or blood compatibility is a part of biocompatibility concept that will be evaluated where the biomaterial or alive engineered tissue is bloodcontacting. Generally, reports have confirmed the hemocompatibility of nanocelluloses. For example, TEMPO-oxidized cellulose nanofibers, BC/polypyrrole, and BC/polyvinyl alcohol bio-composites as well as peptide (Arg-Gly-Asp)-modified BC membranes have shown good blood compatibility [13]. 3.3.3 Biodegradability Cellulose degradation is a positive and preferable criterion for alive engineered vessels but a disadvantage for synthetic vascular grafts. Celluloses can almost be considered non-biodegradable or very slowly degradable in vivo because the human body does not synthesize cellulase enzymes. Notwithstanding, the degree of degradation can be affected by the crystalline form of celluloses, chemical derivatization, or other modifications [13]. It can be concluded that the natural celluloses, without any treatment or modification, are appropriate biomaterials for synthetic vascular grafts. For alive engineered vessel application, celluloses need some modifications to show better degradation behavior.
3.4
Patency Parameters of Vascular Grafts
As some properties of alive engineered vessels and synthetic vascular grafts are different, in this part we will explain special criteria of vascular grafts that are
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satisfied by nanocelluloses. These criteria are the level of endothelialization, burst pressure, suture retention strength, and compliance.
3.4.1 Endothelialization In situ endothelialization is very important for long-term patency because the lack of intact endothelium layer might induce thrombogenesis and intima hyperplasia. Intima hyperplasia is the result of uncontrollable smooth muscle cell proliferation. So, for promoting endothelialization, there are strategies which can be categorized in two classes: strategies for increasing the number of captured endothelial progenitor cells and endothelial cells on implant surface. Endothelial progenitor cells can be differentiated to endothelial cells. Chemokines like integrin families were introduced to home these cells or to use antibodies to enhance endothelial progenitor cells and endothelial cells capturing. A surface with nanofibrous structure is another strategy for these achievements. Actually, this structure mimics extracellular matrix of cells and results in the enhancement of surface-to-volume ratio. It induces more potential for the adhesion of various blood cells. So, the number of absorbed proteins and platelets might increase. The second strategy for promotion of endothelialization is enhancement of endothelial cell proliferation. It has been proved that in the fiber structure arranged with the direction of blood flow, endothelial cells had more proliferation. Also, this aligned fiber structure leads to a lower platelet absorption [25]. Therefore, celluloses can be a suitable biomaterial to form intact endothelium layer. 3.4.2 Mechano-clinical Parameters Burst pressure is defined as the maximum fluid pressure that does not lead to fluid leakage. The decrease of diameter and the increase of thickness lead to a higher burst pressure [26]. For example, in carotid artery, which is known as a small-diameter vessel, the amount of burst pressure is reported to be approximately 5000 mmHg, that is, about 39 times higher than common systolic pressure (130 mmHg) [27]. Other vessels such as the human saphenous vein and internal thoracic artery have burst pressures of 2134 mmHg and 3073 mmHg, respectively [28]. These values can be used as references to evaluate various synthetic vascular grafts. For nanocelluloses, the values of burst pressure depend on the fabrication method and the nature of composite/non-composite nanocellulose. Another mechano-clinical parameter is suture retention strength that indicates the amount of tensile force which is necessary to pull suture from wall and causes implant separation from host tissue [26]. For example, for the human saphenous vein and human internal thoracic artery, suture retention strengths are approximately 1.92 N and 1.72 N [28]. Nanocelluloses have a good potential to meet this criterion. Compliance is also an important parameter in vascular grafts. In response to pressure gradient, compliance value explains the change in the amount of diameter. For example, the amount of compliance is time-dependent in native vessels that have nonlinear elasticity. Native vessels do not have steady amount of circumferential Young’s modulus. In the first step of expansion (in the toe region), the circumferential elastic modulus is about 20–50 KPa, while in the second step it changes to
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100–200 KPa [29]. Different studies indicated that BC tubes have nonlinear stressstrain diagram in comparison with ePTFE and Dacron tubes [30]. Therefore, BC grafts can be a better replacement for the native vessel. Compliance mismatch may cause to converge or diverge the flow that result in lower or higher shear stress on graft than native vessels [31].
4
Nanocellulose for Vascular Tissue Engineering
Nanocelluloses have been introduced from 2014 as an appropriate biomaterial for engineering of various tissues including liver, adipose, bone, and vessel as well as for implant coating [32]. Nanocelluloses and their bio-composites have various properties that are important in vascular implant fabrication. Nothwithstanding, pure celluloses have shown a low level of non-degradability that reduces the potential of the use for tissue engineering applications. However, bio-composites of nanocelluloses or treated nanocelluloses have better degradability. For example, combination of cellulose and nanocarbon as vascular scaffold caused an enhancement in angiogenesis and arteriogenesis as well as the growth of endothelial cells in a chick chorioallantoic membrane model [33]. Here, we describe the use of different types of nanocelluloses in vascular tissue engineering. Not considering the type of the cellulose, oxidized cellulose has the ability of initiating or accelerating blood coagulation at the place that it is applied. In fact, it is a hemostatic biomaterial. It should be reminded that tissue engineering scaffolds must be biodegradable and biocompatible as well as have appropriate mechanical properties. In the case of vascular tissue engineering, endothelialization is also an essential criterion since endothelial cell linings inhibit the thrombosis of small-diameter blood vessels [12]. Among the different types of nanocelluloses, it seems that bacterial nanocelluloses are the most promising type with the potential to be used in tissue engineering as they have low cytotoxicity and high porosity [34].
4.1
Cellulose Nanocrystals
There are different methods for the fabrication of CNCs. A common method is electrospinning that creates a scaffold with good biocompatibility for vascular tissue engineering. In fact, the interconnected porous morphology and high surface area improving cell growth and nutrient exchange make electrospun scaffolds a promising material in alive engineered vessels. Another method utilized for the scaffold fabrication in alive engineered vessel is solvent casting that results in significant improvement of mechanical properties and thermal stability. A scaffold that showed appropriate potential for small-diameter vascular tissue engineering was a combination of CNC and cellulose acetate prepared by solvent casting. As blood vessels (depended on the site) are exposed to a range of mechanical forces, vascular scaffold should be readily manipulated to have different strengths. CNCs have strong hydrogen bonding and fibrous porous microstructures that cause
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high mechanical stability and blood pressure resistance respectively. Although CNCs have had a significant progress in biocompatibility and mechanical integrity, they have shown a low level of biodegradability. This shortcoming limits their application in vascular scaffolds. Therefore, more investigations on the control of CNC’s biodegradation are necessary that can be realized by bio-composites of the cellulose [12]. Generally, both thrombogenicity reduction and improvement of mechanical properties have been reported in various electrospun nanocomposite materials [35].
4.2
Cellulose Nanofibers
CNF-based vascular scaffolds prepared by electrospinning method showed good biocompatibility and sustainable biodegradation as well as an improvement in elastic modulus, tensile strength, and indentation modulus [12]. This scaffold was a combination of poly(butylene succinate) and poly(lactic acid) with cellulose nanofibers. There are just a few direct reports about the use of CNFs in the fabrication of vascular tissue engineering scaffolds that can be because of their poor biodegradability. As a promising prospect, biodegradability of scaffolds with the base of CNFs can be improved by adding degradable polymers or suitable enzymes such as cellulases [12].
4.3
Bacterial Cellulose
Different forms of nanocelluloses for cell culture applications include hydrogels, bio-composites, electrospinned nanofibers, sponges, and membranes. Not considering the form of nanocelluloses, BCs are the most promising of celluloses in tissue engineering as they have high biocompatibility and porosity [13, 37]. The first study confirming the potential of BCs in vascular tissue engineering application functionalized BC nano-fibrous scaffolds with cell adhesion-mediating GRGDS oligopeptides that resulted in the enhancement of human vascular endothelial cell adhesion [32]. Another document concluded that differential behavior of endothelial cells can be significantly affected by fiber network arrangement in BCs [34]. Appropriate hemocompatibility was also obtained by the hybridization of heparin with the bacterial nanocellulose network that enhances bacterial nanocellulose potential for vascular tissue engineering [34]. Incorporation of vascular endothelial growth factor (VEGF) into a scaffold from BC/gelatin composites has been also reported. Growth factors especially VEGFs improve angiogenesis process and, therefore, can be an essential part of vascular tissue engineering scaffolds [24]. Although there are a few reports that introduce the different potentials of BCs for vascular tissue engineering, it seems this field needs to be developed by more investigations. For example, a study that has been recently published introduces a novel method to utilize the hydrogel form of bacterial nanocellulose for vascular tissue engineering scaffold. They created several lumens in the scaffold using needles. Lumens simulate vascular networks. Then, scaffolds were evaluated by culturing of endothelial cells. As mentioned in the previous sections, endothelial
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14 days
Fig. 3 Scanning electron images of channels that have been cultured with endothelial cells (2 and 14 days) [36]
cells cover the inner layer of blood vessels and have a main role in angiogenesis or vascular sprouting. Figure 3 shows bacterial nanocellulose scaffold that has been cultured with endothelial cells after 2 and 14 days.
5
Nanocellulose for Vascular Grafts
In response to vascular deficiencies, both endovascular activities such as angioplasty and vascular grafts which include non-synthetic and synthetic grafts have been utilized that have had significant progresses. Among non-synthetic grafts, autologous grafts are the most suitable option because they are sourced from the patient’s body. Therefore, the risk of activation of immune mechanisms is lower than other non-synthetic grafts such as allografts and xenografts. Therefore, to meet the replacement need, autologous grafts can be considered as a candidate, especially for smalldiameter (diameter < 6 mm) replacements. The internal mammary artery and the saphenous vein are commonly used as a small-diameter autologous grafts [38]. However, autografts may lead to secondary injuries [39]. Therefore, researchers switched to synthetic vascular grafts.
5.1
Common Biomaterials for Vascular Grafts
Expanded polytetrafluoroethylene (ePTFE) and Dacron are commercial nondegradable vascular grafts. These two options are applicable and have appropriate patency in large- and medium-diameter grafts. It is worth mentioning that in smalldiameter applications, ePTFE and Dacron have very lower patency in comparison with autologous grafts. For example, after 2 years of being implanted as an artificial coronary artery in rats, the saphenous vein as a subcategory of autologous grafts had patency of more than 90%, while PTFE’s patency was approximately 32% [30]. Another document reported some challenges such as the existence of thrombosis and intima hyperplasia [40]. An important reason of the thrombosis is the lack of intact endothelium layer on the surface of the graft. In fact, endothelial cells are able to prevent intima hyperplasia and thrombosis and can maintain vascular hemostasis by
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releasing molecules like nitric oxide, heparin, and plasmin [41]. Another reason can be announced as the mismatch between special properties of implant and the host tissue. Compliance mismatch is the most important example for this category [42]. In some researches, Dacron as short-length aortocoronary grafts was used, and the results were successful. Aortocoronary known as a high-blood-pressure area is placed between the aorta and coronary artery [31]. Also, the probability of selecting these materials in small-diameter grafts will be provided in the future by improving their inherent disadvantage such as low compliance and limited in situ endothelialization which are the result of rigidity and hydrophobic surface respectively. The low-compliance problem can be improved by another material as reinforcer in the form of composite material. On the other hand, the second issue can be solved by surface modifications such as plasma treatment and heparinizing that facilitate endothelialization [31]. For example, anti-CD34 increased the endothelialization from 32% to 85% [43]. In addition to Dacron and ePTFE, recent researches have focused on cellulose as a promising biomaterial for vascular graft fabrication. The importance of cellulose, especially BCs, as a non-degradable natural polymer is very clear. The first reason is that inherent properties such as nonlinear elasticity are more similar to native vessels than linear elastic behavior of ePTFE and Dacron. The second reason is the finite resources of oil as a base of ePTFE and Dacron versus a wide range of cellulosebased materials like plants in the environment [30].
5.2
Fabrication of Bacterial Nanocellulose Grafts
Bacterial nanocellulose (BNC) is the most common type of nanocelluloses utilized in vascular graft. Therefore, we will focus on S-BNC, D-BNC, and G-BNC grafts. These abbreviations represent spatial BNC constructions that were fabricated by bioreactors. This strategy in graft fabrication is based on air-liquid interface. Different types of bioreactors are generated such as a bioreactor which consists of a permeable silicone tube at the center that is surrounded by a glass tube. Another bioreactor has double permeable silicone tube. The third bioreactor has a glass rod at the center and permeable silicon tube in the external part [44]. Fabricated grafts in each bioreactor have unique properties. Grafts produced by the first, second, and third bioreactors are called S-BNC, D-BNC, and G-BNC grafts respectively. In all bioreactors, zones around permeable tubes have a greater density because of the higher oxygen concentration in near permeable tubes. Although D-BNC and G-BNC resulted unlaminat micro-morphology [45–48], various studies revealed that S-BNC conduits possess layered structure [44, 45].
5.3
Composite Forms of Bacterial Nanocellulose Grafts
Composite construction can overcome the non-appropriate properties of nanocellulose like restricted elongation and can improve vital characteristics like antithrombosis. For this purpose, various materials have been selected such as polyvinyl
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Fig. 4 The right heart of the patient being implanted with nanocellulose-polyurethane vascular graft [54]
alcohol (PVA), fibrin, cellulose acetate, and silk fibroin (Fig. 4). We briefly explain the effects of some of these materials on BNC grafts. PVA is a synthetic polymer with high elongation at break (about six times more than BNC fabricated tubes and more than the human coronary artery). Moreover, its compliance is greater than human arteries as well as mechanical properties and water permeability were improved by PVA doping on tubes. Composite properties of two fabricated vascular tubes that were results of the variety of BNC and PVA content and morphology are different. For example, porous inner surface and layered structure of S-BNC versus dense structure of D-BNC were accompanied by greater PVA content and lower BNC content. Therefore, mechanical properties of S-BNC composite are weaker than D-BNC composite, except elongation. Two composites do not possess appropriate tensile strength, suture retention strength, and elongation at break. For example, in the case of stronger composite (D-BNC), the reported tensile strength was 0.45 MPa which is lower than the human coronary artery (the ultimate tensile strength of the human coronary artery is between 1.40 and 11.14 MPa [49]), while this value is about two times more than pristine D-BNC graft. However, S-BNC composite has compliance like human veins, and D-BNC composite compliance was similar to human arteries. In the range of 80–120 mmHg, compliance for human arteries and human saphenous vein is reported between 4.5%–6.2% and 0.7%–1.5% respectively [50]. However, commercial materials like ePTFE and Dacron with 1.65% and 1.92% compliance, respectively [51], do not possess appropriate compliance. The tests indicated that BNC tubes became stiffer under high pressure. It is similar to what happens in native vessels. It is worth mentioning that this phenomenon is not observed in PVA tubes. Also, water permeability of S-BNC, as a result of its loose network, is greater than D-BNC with dense network. Notwithstanding, both of them are greater than ePTFE. Moreover, water permeability of composites can be reduced to zero which is an important achievement in vascular grafts. High water permeability of vascular grafts leads to blood leakage in adjacent tissues, while an optimum degree of water permeability facilitates transportation of nutrients [45].
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Also, effects of heparin and chitosan on D-BNC grafts have been studied and elaborated. Heparin as a highly hydrophilic material, which is constructed with negatively charged molecules, is widely consumed as anti-thrombosis for surface modifications [37]. Combination of chitosan and heparin with BNC tube improves hemocompatibility of composite, and chitosan causes higher heparin deposition which is the result of bonding of additional heparin with amino groups of chitosan. Also, chitosan leads to the delayed release of heparin molecules which is very desirable for long-term graft patency. This composite has a maximum surface roughness in comparison with pristine BNC and BNC composites which were only consisted of chitosan or heparin. The reported reason is related to heparin grafting on luminal surface of BNC that is accompanied by chitosan dissolution (as a result of using acid solution in the process of heparin grafting) and then bonding of dissolved parts with heparin molecules. The bonding of heparin molecules and water molecules in heparin deposition on BNC (without chitosan) leads to enhancement of water content and decrease of water permeability [46]. Appropriate water content is very effective to increase graft patency because it causes better nutrients and waste material transportation. Moreover, it reduces protein adsorption [52]. However, high water content in BNC tubes, which is accompanied with very low BNC content, results in weaker mechanical properties. For example, a study reported that the reason for low suture retention strength of S-BNC graft is related to the high amount of water capacity [45]. Composite of chitosan and BNC leads to smoother surface and the reduction of water content and water permeability. Three composites (chitosan-heparin-BNC, heparin-BNC, and chitosan-BNC) resulted in better mechanical properties, but burst pressure is an exception. Slight inhibition in cell proliferation is reported for the combination of chitosan and BNC [46]. Another document displays that chitosan has a potential for platelet aggregation because of its cationic nature [53]. Silk fibroin is the last material that we explain in this section. This natural polymer, which is extracted from the cocoons of silkworm Bombyx mori, has a slow rate of biodegradability, and in comparison with ePTFE, its compliance is closer to the human saphenous vein. So, the patency of this material is greater than ePTFE because of its properties that is more near to autologous grafts. For example, a graft that was made from this material and implanted in the abdominal aorta (high flow conditions) had a patency of about 85% versus ePTFE with 30% patency after 1 year [31]. Silk fibroin leads to rapid endothelialization. One group dispersed silk fibroin nanoparticles (SFNPs) in G-BNC graft and revealed its effect on G-BNC graft. SFNPs were distributed especially on the inner surface of G-BNC, and some of them are placed on the external surface of G-BNC. SFNPs do not increase hemolysis ratio but result in the enhancement of smooth muscle cell proliferation which may induce intima hyperplasia. They indicate heparin grafting on SFNPs-G-BNC leads to decrease smooth muscle cell proliferation. So, heparin grafting with appropriate dose is very important. Like chitosan that was previously mentioned, SFNPs cause the increase in the amount of heparin which was deposited on G-BNC graft which results from the existence of amino groups in silk fibroin. The slow rate of
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biodegradability of silk fibroin induces the enhancement in duration of heparin releasing that is necessary in long-term patency of grafts [47].
5.4
Non-composited Bacterial Nanocellulose Grafts
Evidences in this category focus on morphology and surface characteristics of pristine BNC grafts to suggest the importance of vascular graft properties which lead to appropriate long-term patency. One of the vital properties that influences on patency is surface roughness. As already mentioned, the intima layer of native vessels has smooth surface. The increase of implantation patency from 67% to 80% in the sheep’s right carotid artery was reported after 9 months by generating smoother and more compact inner layer and more porous external surface. The amount of burst pressure and suture retention strength is nearly 800 mmHg and 4 N, respectively [55]. Figure 5 shows two generations of vascular grafts that are made of bacterial nanocellulose. A similar previous study indicates that a novel BNC tube with the lowest surface roughness had the highest biocompatibility among other BNC tubes. The surface roughness of ePTFE was greater than novel BNC tube. However, thrombocytes that adhered on novel BNC tube were two times more than the thrombocytes on the inner surface of ePTFE after 4 h of contact with blood in a system simulating blood circulation [56]. This may be a result of larger surface of BNC tube compared with ePTFE. By comparing S-BNC, D-BNC, and G-BNC tubes in another study, the researchers found out that S-BNC had the lowest BNC content and the weakest mechanical properties which is the result of laminate orientation of nanofibers in S-BNC structure. S-BNC graft was the roughest and accompanied with the lowest time for plasma reclassification. Plasma reclassification time is defined as the time
a
b
Fig. 5 Implantation of two generations of BNC vascular grafts (tubes). (a) Surgical handling and implantation of first-generation vascular grafts and (b) modified thinner second-generation vascular grafts [55]
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which the profile obtains half maximum absorbance. D-BNC and G-BNC had better mechanical features although they are weaker than ePTFE [44].
5.5
Other Nanocellulose Types
Nanocrystalline cellulose and cellulose nanofibrils are rarely utilized for vascular graft fabrication. In a document, the effects of periodate oxidization and component ratio on properties of nanocrystalline cellulose – fibrin nanocomposite – were investigated. Oxidizing results in the enhancement of cross-links between nanocrystalline cellulose and fibrin, which induces better composite strength. It is worth mentioning that the oxidized composite leads to fragmentation of the nanocrystalline cellulose. Therefore, it accentuates the importance of oxidizing time. The comparison of different composites that were produced in various ratios and oxidizing time displayed that the best composite, which has nearly similar strength and elongation to porcine coronary artery, was fabricated through 4 h of oxidizing the nanocomposite in 1:1 ratio [57].
6
Limitations of the Use of Nanocellulose in Vascular Grafts/Tissue Engineering
Today, engineering of alive vessels with different biomaterials has reached clinical evaluation, but there are some challenges. Although the use of nanocelluloses for vascular grafts is more prevalent, alive nanocellulose-based engineered vessels are still limited. Biodegradability is the most important limitation of the use of nanocelluloses for tissue engineering application. In recent years, a significant progress has been achieved to improve the biocompatibility and mechanical integrity of nanocelluloses. However, the leak of some relevant enzymes such as cellulase in the human body causes poor biodegradability of nanocelluloses that limits the use of nanocelluloses in tissue engineering. In addition, different designs of structures and bio-composites as well as clinical implantation are still creating some challenges [12]. Despite these challenges, novel bio-composites of nanocelluloses can improve properties of pure nanocelluloses helping to vascular tissue engineering and grafts. In fact, nanocelluloses are almost non-biodegradable but can be adaptable by suitable surface treatment and various bio-composites. For example, reducing crystallinity of nanocellulose influences on suitability of nanocelluloses for tissue engineering. It should be also noticed that the form of many nanocelluloses-based scaffolds is hydrogel. Therefore, their properties in terms of structure stability and durability must be considered in clinical implantation [12]. Table 2 summarizes the effects of some bio-composites of nanocelluloses that have been used for vascular tissue engineering scaffolds or vascular grafts. The components of these bio-composites can manipulate important properties of scaffold/graft. Additionally, a new research declared that BC-based vascular grafts may have some risks for cigarette-smoking patients [58]. It shows that using nanocelluloses
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Table 2 Bio-composites of nanocelluloses and their effects on properties of vascular implants Bio-composites of nanocelluloses BC + GRGDS
Usage Tissue eng. scaffold
Results Endothelial cell
BC/Gelatin + VGEF
Tissue eng. scaffold Tissue eng. scaffold Tissue eng. scaffold Tissue eng. scaffold Grafts
Angiogenesis
24
Degradability
12
Biocompatibility
12
Hemocompatibility
34
Rapid endothelialization
47
CNF + Poly(butylene succinate) + Poly (lactic acid) CNC + Cellulose Acetate BC +Heparin BNC + SFNPs
Ref. 32
adhesion
Grafted heparin Heparin releasing duration BNC + Chitosan
Grafts
Grafted heparin
46
Heparin releasing duration BNC + PVA
Grafts
Fluid leakage
45
Ultimate strain CNC + Fibrin
Grafts
Ultimate strain
57
BNC + Heparin
Grafts
Roughness
46
BNC + Chitosan
Grafts
Roughness
46
may have other unknown side effects for patients. Based on regulations of medical device fabrication, each produced medical device should pass the required safety and performance. Nevertheless, unlimited sources and natural base of nanocelluloses encourage researchers and manufacturers of vessel grafts/implants to consider nanocelluloses as a promising biomaterial.
7
Conclusion and Remarks
Among different medical applications of nanocelluloses and their bio-composites, they are routinely utilized for vascular grafts because of their unique properties such as biocompatibility, hemocompatibility, and mechanical and chemical properties as well as their natural, unlimited, and low-cost sources. Regarding vascular tissue engineering, there are still some limitations, the most important of which is the non-biodegradable nature of nanocelluloses. It should be noticed that the size and the
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location of intended vessel affect the fabrication method and the design. In addition to artificial vessels (alive and synthetic), there are some documents that report the use of nanocelluloses in other cardiovascular implants such as heart valves and stents. A composite of BCs and iron oxide nanoparticles was a suitable coating for endovascular stents. This biomaterial caused in situ reconstruction of the tunica media in blood vessels by vascular smooth muscle cells [25]. Magnetically functionalization of a hydrogel BNC that was integrated on intracranial stents had satisfactory results for brain aneurysm treatment. This biomaterial accelerated the endothelialization process but has a reduction effect on healing time [59]. It has also been reported that some cellulose-based materials have a negative effect on cell proliferation. This effect may be useful in some cases when a low level of cell proliferation is required. For example, these materials can be used in vascular prostheses where it is necessary to limit the proliferation of vascular smooth muscle cells to avoid restenosis [60]. Nanocellulose-based scaffolds were also applicable to screen antitumor drugs [32]. Based on the mentioned evidences, nanocelluloses will have various commercial applications in the market of cardiovascular implants in the close future.
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32. Bacakova, L., Pajorova, J., Bacakova, M., Skogberg, A., Kallio, P., Kolarova, K., Svorcik, V.: Versatile application of nanocellulose: from industry to skin tissue engineering and wound healing. Nanomaterials (Basel). 9(2), 164 (2019) 33. Bacakova, L., Pajorova, J., Tomkova, M., Matejka, R., Broz, A., Stepanovska, J., Prazak, S., Skogberg, A., Siljander, S., Kallio, P.: Applications of nanocellulose/nanocarbon composites: focus on biotechnology and medicine. Nanomaterials (Basel). 10(2), 1–32 (2020) 34. Jorfi, M., Foster, E.J.: Recent advances in nanocellulose for biomedical applications. J. Appl. Polym. Sci. 132(14), 41719 (2014) 35. Domingues, R.M., Gomes, M.E., Reis, R.L.: The potential of cellulose nanocrystals in tissue engineering strategies. Biomacromolecules. 15(7), 2327–2346 (2014) 36. Sämfors, S., Karlsson, K., Sundberg, J., Markstedt, K., Gatenholm, P.: Biofabrication of bacterial nanocellulose scaffolds with complexvascular structure. Biofabrication. 11(4), 045010 (2019) 37. Bodea, I.M., Catunescu, G.M., Florian, T., Dirlea, S.: Application of bacterial-synthesized cellulose in veterinary medicine – a review. Acta Vet. Brno. 88(4), 451–471 (2019) 38. Goldman, S., Zadina, K., Moritz, T., Ovitt, T., Sethi, G., Copeland, J.G., Thottapurathu, L., Krasnicka, B., Ellis, N., Anderson, R.J., Henderson, W., VA Cooperative Study Group: Longterm patency of saphenous vein and left internal mammary artery grafts after coronary artery bypass surgery: results from a Department of Veterans Affairs Cooperative. J. Am. Coll. Cardiol. 44(11), 2149–2156 (2004) 39. L'Heureux, N., Dusserre, N., Marini, A., Garrido, S., de la Fuente, L., McAllister, T.: Technology insight: the evolution of tissue-engineered vascular grafts – from research to clinical practice. Nat. Clin. Pract. Cardiovasc. Med. 4(7), 389–395 (2007) 40. Sayers, R.D., Raptis, S., Berce, M., Miller, J.H., Surg, J.: Long-term results of femorotibial bypass with vein or polytetrafluoroethylene. Br. J. Surg. 85(7), 934–938 (1998) 41. Otsuka, F., Finn, A.V., Yazdani, S.K., Nakano, M., Kolodgie, F.D., Virmani, R.: The importance of the endothelium in atherothrombosis and coronary stenting. Nat. Rev. Cardiol. 9(8), 439–453 (2012) 42. Chong, D.S., Lindsey, B., Dalby, M.J., Gadegaard, N., Seifalian, A.M., Hamilton, G.: Luminal surface engineering, ‘micro and nanopatterning’: potential for self endothelialising vascular grafts? Eur. J. Vasc. Endovasc. Surg. 47(5), 566–576 (2014) 43. Rotmans, J.I., Heyligers, J.M., Verhagen, H.J., Velema, E., Nagtegaal, M.M., de Kleijn, D.P., de Groot, F.G., Stroes, E.S., Pasterkamp, G.: In vivo cell seeding with anti-CD34 antibodies successfully accelerates endothelialization but stimulates intimal hyperplasia in porcine arteriovenous expanded polytetrafluoroethylene grafts. Circulation. 112(1), 12–18 (2005) 44. Bao, L., Tang, J., Hong, F.F., Lu, X., Chen, L.: Physicochemical properties and in vitro biocompatibility of three bacterial nanocellulose conduits for blood vessel applications. Carbohydr. Polym. 239, 116246 (2020) 45. Tang, J., Bao, L., Li, X., Chen, L., Hong, F.F.: Potential of PVA-doped bacterial nano-cellulose tubular composites for artificial blood vessels. J. Mater. Chem. B. 3(43), 8537–8547 (2015) 46. Li, X., Tang, J., Bao, L., Chen, L., Hong, F.F.: Performance improvements of the BNC tubes from unique double-silicone-tube bioreactors by introducing chitosan and heparin for application as small-diameter artificial blood vessels. Carbohydr. Polym. 178, 394–405 (2017) 47. Bao, L., Hong, F.F., Li, G., Hu, G., Chen, L.: Improved performance of bacterial nanocellulose conduits by the introduction of silk fibroin nanoparticles and heparin for small-caliber vascular graft applications. Biomacromolecules. 22(2), 353–364 (2020) 48. Carrabba, M., Madeddu, P.: Current strategies for the manufacture of small size tissue engineering vascular grafts. Front. Bioeng. Biotechnol. 6(41), 1–12 (2018) 49. Guan, J., Stankus, J.J., Wagner, W.R.: Biodegradable elastomeric scaffolds with basic fibroblast growth factor release. J. Control. Release. 16(120), 70–78 (2007) 50. L’Heureux, N., Dusserre, N., Konig, G., Victor, B., Keire, P., Wight, T.N., Chronos, N.A., Kyles, A.E., Gregory, C.R., Hoyt, G., Robbins, R.C., McAllister, T.N.: Human tissueengineered blood vessels for adult arterial revascularization. Nat. Med. 12(3), 361–365 (2006)
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51. Zidi, M., Cheref, M.: Mechanical analysis of a prototype of small diameter vascular prosthesis: numerical simulations. Comput. Biol. Med. 33(1), 65–75 (2003) 52. Helenius, G., Bäckdahl, H., Bodin, A., Nannmark, U., Gatenholm, P., Risberg, B.: In vivo biocompatibility of bacterial cellulose. J. Biomed. Mater. Res. A. 76(2), 431–438 (2006) 53. Yao, Y., Wang, J., Cui, Y., Xu, R., Wang, Z., Zhang, J., Wang, K., Li, Y., Zhao, Q., Kong, D.: Effect of sustained heparin release from PCL/chitosan hybrid small-diameter vascular grafts on anti-thrombogenic property and endothelialization. Acta Biomater. 10(6), 2739–2749 (2014) 54. Cherian, B.M., Leão, A.L., de Souza, S.F., Costa, L.M.M., de Olyveira, G.M., Kottaisamy, M., et al.: Cellulose nanocomposites with nanofibres isolated from pineapple leaf fibers for medical applications. Carbohydr. Polym. 86, 1790–1798 (2011) 55. Weber, C., Reinhardt, S., Eghbalzadeh, K., Wacker, M., Guschlbauer, M., Maul, A., SternerKock, A., Wahlers, T., Wippermann, J., Scherner, M.: Patency and in vivo compatibility of bacterial nanocellulose grafts as small-diameter vascular substitute. J. Vasc. Surg. 68(6S), 177–187 (2018) 56. Wacker, M., Kießwetter, V., Slottosch, I., Awad, G., Paunel-Görgülü, A., Varghese, S., Klopfleisch, M., Kupitz, D., Klemm, D., Nietzsche, S., Petzold-Welcke, K., Kramer, F., Wippermann, J., Veluswamy, P., Scherner, M.: In vitro hemo- and cytocompatibility of bacterial nanocelluose small diameter vascular grafts: Impact of fabrication and surface characteristics. PLoS One. 15(6), e0235168 (2020) 57. Brown, E., Hu, D., Abu Lail, N., Zhang, X.: Potential of nanocrystalline cellulose-fibrin nanocomposites for artificial vascular graft applications. Biomacromolecules. 14(4), 1063–1071 (2013) 58. Jeong, S., Lee, S.U., Yang, H., Park, C.H.: Effect of α,β-unsaturated aldehydes on endothelial cell growth in bacterial cellulose for vascular tissue engineering. Mole. Cellular Toxicol. 8(2), 119–126 (2012) 59. Kempaiah R., Arias S.L., Pastrana H.F., Alucozai M.: A new nanostructured material for regenerative vascular treatments: magnetic bacterial nanocellulose(MBNC) conference paper, IEEE, Medellin, Colombia: 13681839 (2013) 60. Novotna, K., Havelka, P., Sopuch, T., Kolarova, K.: Cellulose-based materials as scaffolds for tissue engineering. Cellulose. 20(5), 2263–2278 (2013)
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Amandeep Singh, Kamlesh Kumari, and Patit Paban Kundu
Contents 1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Cellulose and Its Derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1 Origin-Based Classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2 Morphology-Based Classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3 Cellulose Derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Bone and Its Components . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Bone Tissue Engineering (BTE) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Nanoentities for BTE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Nanocellulose in BTE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Nanocellulose Embedded PNCS for BTE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.1 Spherical Cellulose NPs Embedded PNCs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2 CNCs/NCCs Embedded PNCs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.3 CNFs Embedded PNCs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.4 BC-NFs Embedded PNCs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.5 CNW Embedded PNCs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.6 Nanocellulose Derivatives Embedded PNCs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Toxicity and Biocompatibility of Cellulose-PNCS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 Challenges and Future Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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A. Singh (*) Department of Polymer Science and Technology, University of Calcutta, Kolkata, West Bengal, India e-mail: [email protected] K. Kumari Department of Chemical Engineering, SLIET, Longowal, Punjab, India P. P. Kundu Department of Polymer Science and Technology, University of Calcutta, Kolkata, West Bengal, India Department of Chemical Engineering, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand, India © Springer Nature Switzerland AG 2022 A. Barhoum (ed.), Handbook of Nanocelluloses, https://doi.org/10.1007/978-3-030-89621-8_39
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Abstract
Nanotechnology and nano-engineering stand to produce significant scientific and technological advances in diverse fields including medicine and physiology. Nanocellulose being a lightweight, transparent, biocompatibility, abundant, eco-friendly, and sustainable natural biopolymer has attracted more and more interest in biomedical field for advanced medical diagnosis, especially for bone tissue engineering (BTE). Various nanoforms of cellulose are used to reinforce natural as well as synthetic clinically relevant polymers. Nanocellulosereinforced polymer nanocomposites (PNCs) demonstrate an improvement in mechanical, barrier, and thermal properties. The addition of compatibilizer as a coupling agent promotes a fine dispersion of nanocelluloses in polymer. A PNC for BTE owns a polymer matrix with bioactive and well resorbable nanosized fillers. However, a solo material is not able to mimic the structure, composition, properties, and other characterization of natural bone; therefore, the PNCs are the dearest alternatives for bone cell regeneration. A PNC furnishes a suitable polymer matrix, carries worthy biological attributes, able to control tuning of release of target-based migrants, and also feasible to integrate sensor-based serial migration of multiple entities required at various stages of bone cells regeneration. Hence, a PNC is regarded as an intelligent nanocomposite biomaterial. The chief function of a PNC used for BTE is to corroborate the process of bone cell regeneration at desired target followed by in situ degradation, and then an eventual supersede by newly produced bone cells. Nevertheless, toxicity, safety standards, and challenges are also associated as usual, and they are well addressed in this chapter. Nanocellulose-based PNCs offer some important advantages over conventional synthetic materials and show great promise to advance the frontier of scientific knowledge. In this chapter, recent advances in nanocellulose incorporated PNCs based biomaterials in the context of bottom-up approaches for BTE are summarized. Keywords
Nanotechnology · Nanofillers · Biodegradation · Polymer scaffold · Biomedical polymers Abbreviations
3D AB APIs BC BTE CA CE CMC CNC
Three-dimensional Alamar Blue Active pharmaceutical ingredients Bacterial nanocellulose Bone tissue engineering Cellulose acetate Cellulose ether Carboxymethyl cellulose Cellulose nanocrystal
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CNF CNPs CNW fGO gGO GNPs GO HAp HNTs MCC MMT MwCNT NFC NPs PC PLA PNC PNPs rGO SF swCNT TEMPO US-swCNT WC
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Cellulose nanofibril Ceramic nanoparticles Cellulose nanowhisker Functionalized graphene oxide Grafted graphene oxide Graphite nanosheets or nanoplatelets Graphene oxide Hydroxyapatite Halloysite nanotubes Microcrystalline cellulose Montmorillonite Multi-walled carbon nanotubes Nanofibrillated cellulose Nanoparticles Plant-based cellulose Poly(lactic acid) Polymer nanocomposites Polymeric nanoparticles Reduced graphene oxide Silk fibroin Single-walled carbon nanotubes 2,2,6,6-tetramethylpiperidinyloxyl Ultra-short single-walled nanotubes Wood-based cellulose
Introduction
Nanoparticle is a single unit or cluster of atoms in the size range of 1–100 nm. Nanomaterials have noteworthy applications in the biomedical and nanobiotechnology fields such are diagnosis, drug delivery systems, prostheses, tissue engineering, implants, etc. Nanoscale materials integrate well into biomedical devices because most biological systems are also nanosized. Development of economic PNCs has enormous potential in the biomedical field especially in BTE. In order to improve the properties of polymers various nanoentities are used to incorporate into polymer matrixes through different methods. Such nanoentities are derived from metals, ceramics, clays, polymers, carbon, and the compounds of various metal and non-metals [1]. Nanotechnology and nano-engineering stand to produce significant scientific and technological advances in diverse fields including medicine and physiology. Nanocellulose being a lightweight, transparent, biocompatibility, abundant, eco-friendly, and sustainable natural biopolymer has attracted more and more interest in biomedical field for advanced medical diagnosis, especially for bone tissue engineering. Various nanoforms of cellulose are used to reinforce natural as well as synthetic clinically relevant polymers. Nanocellulose-reinforced polymer nanocomposites
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demonstrate an improvement in mechanical, barrier, and thermal properties. The addition of compatibilizer as a coupling agent promotes a fine dispersion of nanocelluloses in polymer. A PNC for BTE owns a polymer matrix with bioactive and well resorbable nanosized fillers. However, a solo material is not able to mimic the structure, composition, properties, and other characterization of natural bone; therefore, the PNCs are the dearest alternatives for bone cell regeneration. A PNC furnishes a suitable polymer matrix, carries worthy biological attributes, able to control tuning of release of target-based migrants, and also feasible to integrate sensor-based serial migration of multiple entities required at various stages of bone cells regeneration. Hence, a PNC is regarded as an intelligent nanocomposite biomaterial. The chief function of a PNC used for BTE is to corroborate the process of bone cell regeneration at desired target followed by in situ degradation, and then an eventual supersede by newly produced bone cells. Nevertheless, toxicity, safety standards, and challenges are also associated as usual, and they are well addressed in this chapter. Nanocellulose-based PNCs offer some important advantages over conventional synthetic materials and show great promise to advance the frontier of scientific knowledge. In this chapter, recent advances in nanocellulose incorporated PNCs based biomaterials in the context of bottom-up approaches for BTE are summarized. Development of economic PNCs has enormous potential in biomedical field. The tissue engineering approaches for bone regeneration consist of combinations of scaffolds, cells, and growth factors. Polymeric scaffolds are very important for tissue engineering and orthopedic surgery implants since they provide adequate environmental conditions for one tissue through the growth of mineralized tissue within pore space [2]. Moreover, porous scaffold system used for orthopedic implantation must be biodegradable, biocompatible, and must have adequate mechanical properties. The novel biomaterials are anticipated to be bioactive as well as degradable porous scaffold systems for regeneration of living bone tissues. Nanocellulose materials are nanosized cellulose fibrils or crystals produced by bacteria or derived from plants. These materials exhibit exceptional strength characteristics, lightweight, transparency, and excellent biocompatibility. Compared with some other nanomaterials, nanocellulose is renewable and less expensive to produce, and a wide range of applications for nanocellulose has been envisioned. The area most extensively studied includes polymer composites and biomedical applications. The nanocellulose particles are used to reinforce natural as well as synthetic polymers to be used for numerous biomedical applications. There are different types of nanocelluloses based on their morphologies and molecular arrangements such as rod-like cellulose nanocrystals (CNCs), cellulose nanofibrils (CNFs) or nanofibrillated cellulose (NFCs), cellulose nanowhiskers, BC, etc. CNFs and CNCs have been used to reinforce both thermoplastic and thermoset polymers. Due to hydrophilic nature of these materials, interfacial properties with most polymers are often poor; thus, various surface modification procedures have been adopted to improve interaction between polymer matrix and CNFs or nanocrystals. The applications of nanocellulose as a biomaterial also have been explored, including BTE, wound dressing, soft tissue repair, medical implants, etc. Nanocellulose materials for
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tissue regeneration have become commercially available, demonstrating the great potential of nanocellulose as a new horizon of biomaterials [3]. Nanocellulosereinforced polymer composites demonstrate an improvement in mechanical, barrier, and thermal properties. The addition of compatibilizer as a coupling agent promotes a fine dispersion of nanocelluloses in polymer [4]. Recently, it has come to an interest among researchers to study the applications of cellulose in tissue engineering. This is because of the suitability, availability, and almost inexhaustibility of nanocellulose biomaterial on the Earth. It is also easy to be processed into many arrays of materials. The cost, availability, sustainability, and recyclability of the substance to be used for any purpose are major factors to be considered for circular economy [5]. The outstanding properties of cellulose nanoparticles imbue them with abilities which are exploited in a variety of uses such as packaging, lightweight composites, biomedicine, and food technology and also have attracted interest in 3D printing manufacturing [6]. Different types of sources and derivation methods will result in different cellulose particles, which are bacterial cellulose (BC), fibrillated cellulose, and crystalline cellulose. These cellulose particles have been studied extensively on their potential in tissue engineering application based on their tunable chemical and physical properties, biocompatibility and biodegradability properties. Porous scaffold based on nanocellulose-PNCs is highly desired due to its inherent properties such as mechanical stability, renewability, easy mass production, inexpensiveness, biocompatibility, and biodegradability with low toxic effects and has received much attention in the field of BTE. Design of good tissue compatible plant-based polymer scaffold plays a vital role in BTE applications including biomedicine and nanomedicine.
2
Cellulose and Its Derivatives
The increased demands for products made of renewable and sustainable resources have led to the discovery of cellulose. Cellulose is an organic compound with a polysaccharide formula consisting of a linear chain of several hundred to over 10,000 D-glucose units that are linked by beta-(1-4) of glycosidic bonds. For each unit of D-glucose, it is featured with six hydroxyl groups and two glycosidic bonds. The extensive hydroxyl function has restricted polymer chain flexibility and provides greater rigidity to polymer. It is an important structural component in primary plant cell walls. Cellulose can be derived from wooden plants, non-wooden plants, and some kind of algae and bacteria. Each type of plant undergoes different mechanical or chemical treatment in order to isolate cellulose. For the past few decades, cellulose-based biomaterials have been discovered and achieved remarkable applications in various fields such as paper and paperboard, composite, food, hygiene and absorbent products, emulsion and dispersion, medical, cosmetic, and pharmaceutical. The crystalline cellulose has different allomorphs named cellulose I, II, III, and IV. Cellulose I contains parallel chains in crystalline structure and is naturally derived from a variety of sources such as trees, plants, tunicates, algae, and
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bacteria, and it forms sheets which are stacked together by hydrogen bonds and Van der Waals interactions contribute significantly to the stiffness and specific structure of cellulose. The crystalline phase of cellulose I is composed of two metastable structures, i.e., triclinic (Iα) and monoclinic (Iβ). The ratio of Iα to Iβ structures depends on the source of cellulose. Cellulose II or III is obtained from thermodynamically metastable cellulose I. Cellulose II is typically obtained by regeneration (dissolution and recrystallization) or mercerization (aqueous sodium hydroxide treatment) of native cellulose. During this conversion, the parallel chain arrangement of cellulose I changes into a more stable antiparallel chain arrangement of cellulose II. Cellulose II is considered to have the most stable structure. Cellulose III can be formed from cellulose I or II through liquid ammonia treatment and is called cellulose IIII and IIIII, respectively. Subsequent thermal treatments can be applied to form cellulose IV from both cellulose IIII and IIIII.
2.1
Origin-Based Classification
Cellulose is categorized based on its source of origin, i.e., as wood-based cellulose (WC), plant-based cellulose (PC), bacteria-based cellulose (BC), algae-based cellulose, and tunicate-based cellulose. In the long history of cellulose use, based on its abundance and cost-effectiveness, WC and PC became the most commonly known kinds of cellulose in contrast with BC, tunicate-based cellulose, and algae-based cellulose.
2.1.1 Bacterial Cellulose The cellulose produced by bacteria is called microbial cellulose, bacterial nanocellulose, biocellulose, or specifically BC. The BC was first discovered by Brown in 1886 as a strong jelly membrane onto surface of a vinegar fermentation broth. BC is synthesized by terminal complex in almost pure form (>90%) without binding to any other polymer, e.g., lignin and hemicellulose. Therefore, isolation and purification of BC are quite simple and extensive chemical or any other type of treatment are not needed, in contrast with wood cellulose and plant cellulose. Since its discovery, BC has attracted attention due to several advantages such as high purity, ultrafine fibers shapes, remarkably crystalline structure, high mechanical strength, biodegradability, biocompatibility, high water-holding capability, conducive chemical stability, and a high degree of polymerization. More importantly, BC is considered a non-cytotoxic, non-genotoxic, and highly biocompatible material, attracting interest in diverse areas with hallmarks in medicine [7]. BCs are mainly produced extracellularly by Gram negative bacteria such as Komagataeibacter xylinus, Agrobacterium, Achromobacter, Aerobacter, Azotobacter, Pseudomonas, and Rhizobium, and only one genus of Gram positive bacteria, namely Sarcina with oxygen supply (air) and a carbon source (mainly D-glucose), as well as a nitrogen source. Komagataeibacter xylinus is a most widely used species of bacteria for producing BC since it produces relatively large amounts of BC from a wide range of carbon and nitrogen sources in liquid culture. Carbon sources used for this purpose are
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commonly agro-industrial wastes, e.g., rotten fruit like pineapple peels juice and sugar as a medium. The yield of BC synthesis is up to 40% in relation to starting carbon source, although, generally, the large-scale production of BC is quite expensive. Well-separated BC nanofibers have large surface areas forming an extremely porous structure. BC consists of randomly assembled, 95%). Algal cellulose is not pure and is associated mainly with hemicellulose, protein, and lignin. Cellulose extracted from green algae has unprecedented advantages over WC, PC, and BC because of its high crystallinity (>70%), low moisture adsorption capacity, high porosity in mesoporous range, and associated high specific surface area. Overall, algal nanocellulose has excellent potential for biomedical applications such as tissue engineering because of its nontoxicity and facile chemical modification [8].
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2.1.4 Tunicate Cellulose Tunicates are invertebrate animals living in oceans in vast numbers and are only known animal source of cellulose. There are several enzyme complexes in plasma membrane of tunicate epidermal cells responsible for cellulose synthesis. Tunicatebased cellulose is obtained from outer tissue of tunicate, named “tunic,” from which a pure form of cellulose termed “tunicin” can be extracted. Purified extracted cellulose from tunic is called tunicate cellulose or tunicin. Most of the research in this field has focused on a class of tunicates known as Ascidiacea (sea squirts), which includes over 2300 species. Hundreds of CNFs are bundled in tunic. Shape and dimensions of a nanofibril bundle vary depending on species. Nanofibril bundles are deposited in a multi-layered texture parallel to surface of the epidermis. Length of tunicate CNFs ranges from 100 nm to several micrometers (typically >2 μm), width ranges from 10 to 30 nm, and aspect ratio ranges from 60 to 70. Generally dry tunic contains approximately 60% cellulose and 27% nitrogen-containing components. However, after treatment and extraction, tunicate cellulose is highly crystalline (~95%) composed of nearly pure cellulose in morphological form of high aspect ratio fibrils. Tunicate cellulose has a high specific surface area ranging from 150 to 170 m2/g. It also has a reactive surface due to hydroxyl groups. Degree of polymerization of tunicate cellulose has been reported to be in the range of 700–3500.
2.2
Morphology-Based Classification
Cellulose naturally exists or is isolated from various sources in some predetermined dimension and shape, which can simply be classified into cellulose fibers, cellulose filaments, cellulose crystals, and cellulose micro/nanofibrils. Each cellulosic particle type has a distinguished size, morphology, aspect ratio, crystallinity, and physiochemical properties. These cellulosic particles are discussed below.
2.2.1 Cellulose Fibers At the site of biosynthesis of wood or plants, cellulose is synthesized as microfibrils that are further organized to assemble cellulose fibers. Cellulosic fibers are typically found in three geometries: strand fibers (long fibers of 20–100 cm length), staple fibers (short fibers of 1 3050
5490
[21, 22]
[20]
[19]
8085
[18]
Ref [16, 17]
5169
Crystallinity index (%) 6579
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and utilized in biomedical industries. Properties of cellulose derivatives are not only determined by type and degree of substitution, but also by functionalization pattern along polymer chain. Regioselective synthesis of cellulose derivatives is limited by poor solubility of cellulose in organic solvents and high steric hindrance due to stiff and bulky cellulose main chain. Hydroxyl group is the most targeted reactive group on cellulose chain. Cellulose hydroxyl groups are relatively poor nucleophiles, resulting in requirement for fairly harsh reactions, so that taking advantage of relatively small reactivity differences between 2, 3, and 6 OH groups is difficult. Therefore, regioselective substitution is one of the remaining challenges in synthesis of cellulose derivatives. To synthesize cellulose derivatives under more general and practical conditions for commercial purposes, it is necessary to understand relationship between regio-chemical structure and their properties of cellulose derivatives [23]. Chemical derivatization of cellulose, based on hydroxyl group, generally includes etherification and esterification. Derivatives may vary in terms of essential characteristics including chemical structure, moisture sorption, water interaction, surface activity, and solubility. Furthermore, cellulose can be derived into micro- to nanosized cellulose particles.
2.3.1 Cellulose Ether Cellulose hydroxyl groups can be partially or totally etherified by different reagents, e.g., epoxides, alpha halogenated carboxylic acids, and halogenoalkanes. Solubility rate of cellulose ethers (CEs) is affected by acidity or alkalinity of solution. In acidic conditions, CE dissolves very slowly, while in alkaline conditions it dissolves rapidly. CE can be water-soluble depending on substituent chemical structure, as well as degree and pattern of substitution. Most water-soluble cellulose ethers have a degree of substitution of 0.4 to 2. Although many CE compositions have been synthesized since a century, only a few have gained commercial importance. Among all CEs, carboxymethyl cellulose (CMC), methyl cellulose, and hydroxyethyl cellulose are extensively used in formulation of industrial biomedical products due to their nontoxic profile and appropriate rheological and mechanical properties. CEs high water retention capacity and thermogelling ability are known to accelerate wound healing. These important properties of CEs depend on chemical structure of substituent and degree of substitution. Despite the success of hydrated CEs in practical biomedical applications, rather few attempts have been made to investigate CEs water retention mechanism. Methyl Cellulose Methyl cellulose is the most important commercial CE. Methyl cellulose is a simplest alkyl ether, which can be synthesized in an alkaline medium with a methylating agent, such as methyl chloride or dimethyl sulfate [24]. A different degree of substitution can be obtained via altering synthesis conditions, such as reaction time or methylating agent. Methyl cellulose dissolves in many organic solvents, depending on degree of substitution. For instance, if degree of substitution is between 1.4 and 2.0, methyl cellulose dissolves in water, and if this degree is between 2.4 and 2.8, it is generally soluble in water and some organic solvents.
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Methyl cellulose has thermo-gelling ability. Degree of cellulose substitution, molecular weight, presence and concentration of additives are parameters affecting methyl cellulose gel-formation temperature and characteristics of resulting gel. Besides, methyl cellulose is an emulsifying additive, which is useful for drug delivery systems. Methyl cellulose is mostly used for biomedical applications such as tissue engineering, wound healing, and pharmaceutical formulations.
Carboxymethyl Cellulose CMC is one type of CEs, which is commercially available and has unique features like hydrophilicity, water solubility and stability, high chemical stability, nontoxicity, biocompatibility, and biodegradability. Also, it has no known side effects to human health [25]. However, it is insoluble in some organic solvents such as ethanol. Solubility of CMC depends on degree of polymerization, degree of substitution, and on distribution of substituent. CMC can be used as effective viscosity increasing agent, rheological control agent, binder, stabilizer, and film former in biomedical field with particular attention to drug delivery and tissue engineering systems. CMC is formed by reaction of cellulose with monochloroacetic acid, where hydroxyl groups are substituted by carboxymethyl groups in C2, C3, and C6 of each glucose residue, such that substitution slightly prevails at C2 position. No secondary OH groups are formed during the reaction. Therefore, CMC chemical structure is based on carboxymethyl groups (–CH2–COOH) bound to some of hydroxyl groups of cellulose backbone. Degree of substitution of commercial CMC grades for biomedical products is typically between 0.6 and 1.25. CMC properties depend on its molecular weight, degree of substitution, and distribution of carboxymethyl substituents along polymer chains. CMC is often activated in aqueous sodium hydroxide, whereby it is transformed into its sodium form for further use.
Ethyl Cellulose Ethyl cellulose is another important commercial CE. Chemical structure of ethyl cellulose is based on converting some of hydroxyl groups on repeating glucose units into ethyl ether groups. Ethyl cellulose is prepared by reaction of alkali cellulose with ethyl chloride at about 60 C for several hours. Complete etherification of cellulose yields triethyl cellulose, although normally ethyl cellulose with 2 to 2.6 degree of substitution is used for a range of commercial products. Physical characteristic and performance of materials based on ethyl cellulose depend on degree of etherification, molecular weight, and molecular uniformity. Solubility in most organic solvents is typically achieved with degree of substitution between 2.2 and 2.6. Ethyl cellulose is a biodegradable substance that has no water solubility, no toxicity, excellent film-forming capacity, water resistance, and barrier-forming characteristics [26]. Ethyl cellulose has excellent strength at room temperature, but its strength decreases immediately with increasing temperature. Ethyl cellulose has potential for use in biomedical applications, especially drug delivery.
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Hydroxyethyl Cellulose Another CE is hydroxyethyl cellulose, which is prepared from the reaction of alkali cellulose and ethylene oxide. Chemical structure of hydroxyethyl cellulose can be easily further modified due to its reactive hydroxyl groups. Hydroxyethyl cellulose is soluble in hot and cold water and many organic solvents. Its ease of solubility makes it an appropriate candidate in many biomedical applications [27]. Further, its nontoxic nature, ease of compression, ability to host nanoparticles, and capability to accommodate a high level of drug loading are critical factors for its biomedical usage. Also, hydroxyethyl cellulose can be mixed with cellulose, enabling solventfree processing of cellulose, and making it more compatible with less-polar matrices, which might further expand cellulose applications in biomedical field. Hydroxypropyl Cellulose Hydroxypropyl cellulose is a water-soluble (both in cold and hot medium) thermoplastic in category of CEs. Chemical structure of hydroxypropyl cellulose is based on partial or complete substitution of free hydroxyls with hydroxypropyl groups. In reaction with 1,2-propylene oxide, secondary OH groups are formed. These secondary groups can further react. Therefore, chemical structure of hydroxypropyl cellulose can be easily further modified due to its backbone reactive hydroxyl groups, which may provide new properties that are of interest for biomedical applications, e.g., drug delivery and tissue engineering.
2.3.2 Cellulose Ester Cellulose ester is a commercially available class of thermoplastic biopolymers derived from cellulose. Unlike cellulose, cellulose esters have good solubility in common solvents and melt before decomposition. Various morphological forms of cellulosic particles, e.g., fibers, fibrils, or crystals, can be esterified to form cellulose ester. Cellulose esters can be utilized in biomedical applications through less complicated production processes, which are further discussed below. Cellulose Acetate (CA) It was first discovered in 1865 by Schützenberger as a thermoplastic biodegradable polymer. It is produced by esterification of cellulosic sources such as cotton, wood, sugarcane, and even recycled paper. CA is relatively cheap since it is commonly obtained from agricultural by-products, like cotton burrs, cottonseed hulls, and sugarcane bagasse. Also, existing CA preparation techniques do not need further chemical or mechanical treatment to isolate remaining cellulose from other components, which is advantageous for some biomedical applications, e.g., tissue engineering [28], wound healing, and drug delivery systems. Generally, CA synthesis approaches include ring-opening esterification and transesterification under heterogeneous or homogeneous conditions. CA is conventionally produced by acetylation of hydroxyl groups in cellulose with acetic anhydride, acetic acid (solvent), and sulfuric acid (catalyst). N-ethyl-pyridinium chloride, N,N-dimethylacetamide (DMAc)/lithium chloride (LiCl), and 1,3-dimethyl-2-imidazolidinone (DMI)/LiCl dissolve CA. These solvent systems typically need prolonged pretreatment. Ionic
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liquids have also been used as efficient solvents of CA, though their industrial application is limited due to their high cost.
2.3.3 Cellulose Nitrate Cellulose nitrate, also known as nitrocellulose or celluloid, is considered first semisynthetic polymer in advent of plastic industry. Cellulose nitrate is a versatile polymer that has been widely used since 1900s. Cellulose nitrate is commercially produced through reaction of cellulose with nitric acid, by substituting cellulose hydroxyl groups with nitrate groups. Cellulose nitrate is polynitrate ester of cellulose with a typical 2.2–2.8 nitrate groups per glucose unit within structure. Cellulose nitrate properties and applications depend on degree of nitration. Cellulose nitrates are employed as explosives, plastics, or in coating and ink industries. By lowering the degree of nitration and adding a plasticizer, a workable plasticized material could be produced. Future studies may explore possibilities of cellulose nitrate in biomedical applications. 2.3.4 Cellulose Sulfate Cellulose sulfate is a cellulose derivative with relatively simple chain structure and unique biological properties. The sulfation of cellulose is carried out using among others sulfuric acid, sulfur trioxide, and chlorosulfonic acid. Reaction is carried out either directly on cellulose (under heterogeneous condition) or on partially substituted cellulose esters or ethers (mostly under homogeneous condition). Cellulose sulfate generally has water-soluble, antiviral, antibacterial, and anticoagulant properties, which can be attributed to presence of sulfate groups and broad degree of substitution. Apart from simplicity in preparation, affordable cost, and large-scale production, cellulose sulfate’s excellent biocompatibility, film-forming ability, and biodegradability make it a frontrunner for potential biomedical applications like tissue engineering [29] and drug delivery.
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Bone and Its Components
Despite first impressions, bones are living, active tissues that are constantly being remodeled. Bones have many functions. They support the body structurally, protect our vital organs, and allow us to move. Also, they provide an environment for bone marrow, where the blood cells are created, and they act as a storage area for minerals, particularly calcium. Bones are mostly made of the protein collagen, which forms a soft framework. The mineral calcium phosphate hardens this framework, giving it strength. More than 99% of our body’s calcium is held in our bones and teeth. Bones have an internal structure similar to a honeycomb, which makes them rigid yet relatively light. Bones are composed of two types of tissue: compact (cortical) bone is having hard outer layer and is denser, stronger, durable and also it makes up around 80% of adult bone mass, whereas cancellous (trabecular or spongy) bone consists of a network of trabeculae or rod-like structures and is lighter, less dense, and more flexible. Figure 1 shows the anatomy of a long bone.
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Fig. 1 Anatomy of a long bone. (https://www.medicalnewstoday.com/articles/320444#Thestructure-of-bones [Open access under Creative Commons Attribution])
Bones consist osteoblasts and osteocytes those are responsible for creating bone, osteoclasts (or bone resorbing cells), osteoid (a mix of collagen and other proteins), inorganic mineral salts, nerves and blood vessels, bone marrow, cartilage, membranes (endosteum and periosteum), and bone cells. Bones are not a static tissue but need to be constantly maintained and remodeled. There are three main cell types involved in remodeling process. Osteoblasts cells are responsible for making new bone and repairing older bone and produce a protein mixture called osteoid that gets mineralized and becomes bone and also produce hormones, including prostaglandins. Osteocytes cells are inactive osteoblasts that have become trapped in the bone that they have created and maintain connections to other osteocytes and osteoblasts as well as are important for communication within bone tissue. Osteoclasts cells are large cells with more than one nucleus. Their chief function is to break down the bones. They release enzymes and acids to dissolve minerals in bone and digest them. This process is called resorption. Osteoclasts help remodel injured bones and create pathways for nerves and blood vessels to travel through. Various types of bone cells are shown in Fig. 2. Bone marrow is found in almost all bones where cancellous bone is present. Marrow is responsible for making around two million red blood cells every second. It also produces lymphocytes or white blood cells involved in immune response. Bones are essentially living cells embedded into a mineral-based organic matrix called extracellular matrix and is made of organic components, mainly type 1 collagen and inorganic components, including HAp and other salts, such as calcium and
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Fig. 2 Four types of cells are found within bone tissue. Osteogenic cells are undifferentiated and develop into osteoblasts. Osteoblasts deposit bone matrix. When osteoblasts get trapped within the calcified matrix, they become osteocytes. Osteoclasts develop from a different cell lineage and act to resorb bone. (https://open.oregonstate.education/aandp/chapter/6-3-bone-structure/ [Open access under Creative Commons Attribution])
phosphate. Collagen gives bone its tensile strength, namely resistance to being pulled apart. HAp gives bones compressive strength or resistance to being compressed. Bone is always being remodeled. This is a two-part process, including resorption when osteoclasts break down and remove bone, and formation when new bone tissue is laid down. An estimated 10% of an adult’s skeleton is replaced each year. Remodeling allows the body to fix damaged sections, reshape the skeleton during growth, and regulate calcium levels.
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Bone Tissue Engineering (BTE)
Bone fractures and segmental bone defects are a significant source of patient morbidity and place a staggering economic burden on healthcare system. Annual cost of treating bone defects in the USA has been estimated to be $5 billion, while enormous costs are spent on bone grafts for bone injuries, tumors, and other pathologies associated with defective fracture healing. Autologous bone grafts represent the gold standard for treatment of bone defects. However, they are associated with variable clinical outcomes, postsurgical morbidity, especially at donor
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site, and increased surgical costs. In an effort to circumvent these limitations, tissue engineering and cell-based therapies have been proposed as alternatives to induce and promote bone repair [30]. The BTE aims to develop strategies to regenerate damaged or diseased bone using a combination of cells, growth factors, and biomaterials. This chapter highlights recent advances in BTE, with particular emphasis on role of biomaterials as scaffolding material to heal bone defects. Studies encompass utilization of bioceramics, composites, and myriad hydrogels that have been fashioned by injection molding, electrospinning, and 3D bioprinting over recent years, with aim to provide an insight into progress of BTE along with a commentary on their scope and possibilities to aid future research. The biocompatibility and structural efficacy of some of these biomaterials are also discussed. For tissue engineering applications tissue scaffolds need to have a porous structure to meet needs of cell proliferation/differentiation, vascularization, and sufficient mechanical strength for specific tissue.
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Nanoentities for BTE
Synthetic or non-biodegradable nanoentities have a direct impact on the environment. To overcome these problems, researchers are mainly focused on renewable resources, which are biodegradable for reinforcing the polymer. Carbon-based nanoentities such as carbon black NPs (nCB) are used as a filler to prepare polymer scaffolds for BTE. Furthermore, carbon dots, single-walled carbon nanotubes (swCNT), ultra-short single-walled nanotubes (US-swCNT), multi-walled carbon nanotubes (mwCNT), graphite derivatives such are graphite nanosheets or nanoplatelets (GNPs), graphene, graphene oxide (GO), functionalized graphene oxide (fGO), reduced graphene oxide (rGO), grafted graphene oxide (gGO), fullerenes, nanodiamonds, etc. are also widely used as a filler and reinforce material to develop PNCs. Graphene materials are considered to be superior over other carbon nanomaterials such as CNTs due to their lower levels of metallic impurities and need for less time-consuming purification processes to remove entrapped nanoparticles. However, CNTs possess some unique properties like a cylindrical shape with nanometer scale diameters, longer lengths (4100 nm), and very large aspect ratios. Moreover, other physical and mechanical properties of CNTs are important such as high tensile strength 50 GPa, Young’s modulus 1 TPa, conductivity σ in 107 S/m, maximum current transmittance Jin 100 MA/cm2, and density ρ 1600 kg/m3 [31]. Halloysite nanotubes (HNTs), clay nanoplates, β-tri-calcium Phosphate are also used. HAp is a calcium phosphate similar to human hard tissues in morphology and composition. Particularly, it has a hexagonal structure and a stoichiometric Ca/P ratio of 1.67, which is identical to bone apatite. Nanoclay such as montmorillonite (MMT), kaolinite, attapulgite is widely used to develop PNCs of desired properties for BTE. Ceramic nanoparticles (CNPs) are basically comprised of inorganic compounds, besides metals, metal oxides, and metal sulfides and they can be used in production of nanoscale materials of various shapes, sizes, and porosities. In general, CNPs can be classified according to their tissue response as being inert, bioactive, or resorbable
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ceramics and magnetic NPs. Polymeric nanoparticles (PNP) are defined as sub-micron (1 to 1000 nm) colloidal particles comprising active pharmaceutical ingredients encapsulated within or adsorbed to macromolecular polymer substances [32]. Polymer-NPs composite materials have exclusive characteristics, such as high mechanical strength, good electrical conductivity, optical and thermal properties. Different grades of poly(lactide-co-glycolide) and poly(lactide) copolymers are most successfully used biodegradable polymers to prepare polymeric nanoparticles [33]. Most widely used synthetic polymers are polylactide, polylactide–polyglycolide copolymers, polycaprolactones, and polyacrylates, among various natural polymers, alginate, albumin, or chitosan have been widely explored [34]. Various nanoparticles such as AgNPs [35, 36], AuNPs, Al2O3 [37], Fe2O3, ZnO, ZnNO3, CuSO4, TiO2 [38], CaCl2, calcium glycerophosphate salt, etc. are widely used to develop PNCs.
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Nanocellulose in BTE
For biomedical applications, it is an essential requirement to assess the biocompatibility of materials and verify their interaction with cells, especially for applications where material needs to remain in contact with living tissue and should not cause any cytotoxic or other side effects. Cellulose offers unique features of biodegradability, biocompatibility, low production cost as compared to synthetic biopolymers, abundance, sustainable resources, nontoxicity, and excellent mechanical properties. These features offer potential as bioresorbable polymers that plays an increasingly important role in biomedical applications especially BTE due to their unique ability to be resorbed entirely in pre-designed time frames ranging from months to a few years. Tissue engineering is known as an interdisciplinary field that applies principles of engineering and life sciences toward development of smart biological substitutes that potentially restore, maintain, and improve tissue functions that have malfunctions. Tissue engineering field generally utilizes biomaterials to develop constructs for intended medical interventions. Such constructs are to be exposed to living biological entities in human body, from biomolecules and physiological fluids to cells, up to tissues and organs. In terms of physical properties, regenerative tissue material must possess optimal strength, e.g., compressive strength for BTE, or tensile strength for artificial blood vessels and other soft tissue repairs. Conversely, chemical considerations such as surface chemistry of materials are crucial, and selection of materials must be rendered for specific application purposes. For instance, it is possible to tune porosity, thickness, and interconnectivity of nanocellulosic materials without compromising mechanical properties for tissue scaffold production [39]. For tissue engineering, cellulose as an additive or as primary scaffold material should have mechanical properties matching real tissues [40, 41], promote porous structures for scaffolds, or provide anchoring sites for osteoblasts, and fibroblasts. Most commonly used cellulose derivatives for tissue engineering include cellulose acetate,
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hydroxyethyl cellulose, hydroxypropyl cellulose, cellulose sulfate, carboxymethyl cellulose, methyl cellulose, and ethyl cellulose. One of the ubiquitous usages of biomaterials in tissue engineering is in the production of a biologically compatible scaffold that will support attachment, proliferation, and differentiation of living cells that contribute to promotion of tissue regeneration in vitro and in vivo conditions. Mammalian cells are not able to attach to cellulosic surfaces used in artificial tissue scaffolds due to their hydrophilic nature and low non-specific protein adsorption. However, cell adhesion to substrate surfaces in cellulosic materials can be improved by addition of matrix ligands. For example, ionic charges can be added to cellulose membranes to adsorb collagen on membrane surfaces, which can promote cellular adhesion [42]. Positively charged BC has been applied, in the absence of proteins, to enhance cell attachment. BC is a biomaterial with a huge potential in dental and oral applications. Recently, costeffective and user-friendly functional biopolymeric-based materials have been used as a promising tool for developing, repairing, and regenerating functional tissues and organs in human body. Use of cellulosic composites has been proposed in developing scaffold constructs that can be implanted in patients to replace failing or malfunctioning organs. Moreover, inclusion of appropriate reinforcement material for tissue-engineered biocomposite scaffolds is a significant factor in improving its characteristics and sustained biocompatibility. Use of cellulosic materials as reinforcement in biocomposites is now a fast-growing field, on account of their property enhancing capabilities [43]. For instance, cellulosic fibers have been demonstrated recently to improve formidability of biocomposite scaffolds in BTE applications due to their unique structure. In addition, microfibrillated cellulose remarkably increases the surface area, and its interfibrillar hydrogen bonds facilitate network formation, which is desirable in BTE [44]. Moreover, CMC stimulates adhesion, spreading, and migration of mouse fibroblasts in vitro. Also, presence of CMC decreases osteoclastogenesis by murine bone marrow progenitors, but increases osteoblast differentiation. Hydroxyethyl cellulose is a non-ionic, water-soluble polymer and has a β-glucose linkage, which makes it a suitable candidate for tissue engineering applications. Hydroxyethyl cellulose increases cell viability and substantially stimulates cell growth. It also significantly enhances cell proliferation at high concentrations of hydroxyethyl cellulose [45]. The appropriate mechanical properties of biomedical devices and materials are essential and very specific to nature of application area. For example, elastic modulus of material needs to be close to medium and/or tissue that it is replacing or reinforcing. Nanocrystalline cellulose can be a promising material for cell attachment and proliferation due to its excellent mechanical properties and biocompatible nature. One particular advantage of using nanocrystalline cellulose is fibrillar high aspect ratio building blocks, which construct a natural fiber network of fibrils or nanorods that is held together by hydrogen bonding and mechanical entanglement. Such a network could be even further reinforced mechanically by crosslinking individual nanofibers. There are numerous cellular species cultured on nanocellulose biomaterials such as hydrogels, electrospun nanofibers, sponges, composites, and membranes [46]. Among the sources of nanocellulose, bacterial nanocellulose is
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believed to be most popular choice for cell culture due to its high porosity, biodegradability, and low toxicity [47]. Usually, rate of scaffold degradation under a given condition is an important issue as it should match time of tissue formation to ensure injured tissue is completely replaced by healthy tissue, and its function is restored.
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Nanocellulose Embedded PNCS for BTE
Natural fibers are raw materials of growing importance as a reinforcing substance. This is due to their properties, especially low density at 1.2 to 1.4 g/cm3, and low production costs, this factor resulting from high yield of fibrous plants and relatively cheap labor in the countries where such plants can be harvested a few times per year. The above-mentioned factors cause that the cost of obtaining natural fibers is 3 times lower than of glass fibers, four times lower than of aramid fibers and five times lower than the cost of carbon fibers. With the low price and easy availability of various natural fibers, they may serve as cheap and ecological addition to the reinforcing fibers used in composite materials so far. The demand for new materials will stimulate economic growth of both those countries and the whole world [48].
7.1
Spherical Cellulose NPs Embedded PNCs
Nevertheless, few studies explained the preparation of spherical cellulose nanoparticles for various applications. Hakkak et al. [49] have developed a procedure for spherical cellulose nanoparticles preparation by using imidazolium ionic liquid processing and regeneration from controlled acetonitrile nonsolvent addition and drying. They have obtained spherical cellulose nanoparticles having high uniformity and size ranges from 100 to 400 nm. Minimization of moisture through solvent exchange drying results in the preparation of discrete nanoparticles, whereas presence of ambient moisture during regeneration influenced the aggregated morphologies. Chemical analyses of spherical cellulose nanoparticles disclose the presence of a high-amorphous cellulose content. This ionic liquid method is said to be simple, easy to conduct, energy efficient, and expected to serve extensive applications across other biopolymers as well as potential to prepare surface functionalized spherical cellulose NPs. Meyabadi et al. [50] have used a top-down technique to synthesize spherical cellulose nanoparticles. Researchers have reported a versatile and humble method to developing spherical nanoparticles using waste cotton fibers through enzymatic treatment and ultrasonication. Enzymatic hydrolysis as well as ultrasound treatments are considered to be green processes. Consequently, conventional chemical treatment (acid hydrolysis) can be replaced to prepare cellulose nanoparticles in order to achieve zero environmental pollution goal. Further, FESEM images as well as particle size analysis exhibits that average size of spherical nanoparticles was found to be below 100 nm. XRD data along with FTIR results established that cotton fibers retained the cellulose Iβ crystalline structure succeeding enzymatic hydrolysis and ultrasound treatment. A detailed method for synthesizing cellulose nanospheres
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having sizes 60 to 570 nm was explained by Zhang et al. [51]. This practical approach has given a linear relationship between treatment time and size of cellulose nanoparticle. The prepared hydrolyzed spherical cellulose nanoparticles were mainly cellulose II polymorphic crystalline structure and size of particles was found to be almost uniform.
7.2
CNCs/NCCs Embedded PNCs
A wide number of researches have been reported in the field of polymer nanocomposites developed from CNCs or NCCs. Patel et al. [52] have developed poly (lactic acid) (PLA)/cellulose nanocrystal (CNC) composite scaffolds using an electrospinning technique to evaluate influence of CNCs on biocompatibility and osteogenic potential of PLA. A significant enhancement of the mechanical properties occurred in composite scaffolds compared to pure polymer due to stronger interactions between polymer chains and CNCs. Composite scaffolds exhibited higher thermal stability compared to pure polymer. Excellent adhesion and proliferation were observed in the presence of fabricated composite scaffolds that indicates their superior biocompatibility. Higher mineralization was noticed onto surface of composite scaffolds. The fabricated scaffolds were significantly covered by cultured cells and exhibited greater fluorescence intensity with regard to control sample. Moreover, the fact that higher expression of osteogenic gene markers was observed in composite scaffolds approves their enhanced osteogenic potential. Bone regeneration potential of fabricated scaffold was monitored in a rat calvarial defect model after 3 weeks of treatment. Prepared scaffold established excellent biocompatibility and superior osteoinductivity. Therefore, these scaffolds possess potential to be used as a biomaterial for tissue engineering applications. Moreover, Shaheen et al. [18] have presented a study to develop chitosan/alginate/HAp/nanocrystalline cellulose scaffolds by using freeze-drying method followed by dicationic crosslinking using CaCl2. The chemical structure and morphology along with mechanical properties of the formed scaffolds respecting to various CNC contents were studied by Fouriertransform infrared spectroscopy, X-ray diffraction, scanning electron microscopy, and mechanical compression test. Chemical interaction and electrostatic attraction between chitosan and alginate with various CNC ratios were affirmed by FTIR spectroscopy. Obtained results depicted that scaffold containing CNC showed extraordinary enhancement in swelling ratio (with CNC 110% and without CNC 63%) and compressive strength. It has been found that average pore size increased with increasing of CNC up to 230 μm. Porosity was also obeyed sequence and attainted a maximum value at 93.6%. Growth and cell attachment of fibroblast cells of selected scaffold were examined prolonging to cell viability by using Alamar Blue (AB) and then confirmed using SEM. The results indicated that scaffold comprising CNC has a promising cell growth and cell adherence and thus expected to have a potent possibility for applications in bone tissue culture. Furthermore, Xu et al. [53] have presented that tissue scaffolds need to have anisotropic mechanical properties and a porous structure to meet the needs of different tissues and organs and reported
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a study on an especially designed 3D printing method with oxidized nanocellulose and gelatin, analyze the servo principle of pneumatic condensing extrusion 3D printer, and propose a hexagonal algorithm. For the purpose of this study, a printing process file was written by G code, physical and mechanical performance of the 3D scaffolds was evaluated with Solidworks simulation, the porous structure and pressure-pull performance of printed 3D scaffolds was observed by SEM, and experiments were conducted to measure their biocompatibility. The study draws the conclusion that scaffolds thus printed have a highly porous structure and anisotropic mechanical properties. The chemically crosslinked cellulose nanocrystal (CNC) aerogels consist of several properties those are beneficial for bone tissue scaffolding applications. In a study, Osorio et al. [54] have used sulfuric acid and phosphoric acid to produce CNCs with sulfate and phosphate half-ester surface groups. Hydrazone crosslinked aerogels fabricated from two types of CNCs were investigated. CNC aerogels were evaluated in vitro with osteoblast-like Saos-2 cells and showed an increase in cell metabolism up to 7 days, while alkaline phosphatase assays revealed that cells maintained their phenotype. All aerogels demonstrated HAp growth over 14 days while submerged in simulated body fluid solution with a 0.1 M CaCl2 pretreatment. Sulfated CNC aerogels slightly outperformed phosphated CNC aerogels in terms of compressive strength and long-term stability in liquid environments and were implanted into calvarian bone of adult male Long Evans rats. Compared to controls at third and 12th week, sulfated CNC aerogels showed increased bone volume fraction of 33% and 50%, respectively, compared to controls, and evidence of osteoconductivity. These results demonstrate that crosslinked CNC aerogels are flexible, porous, and effectively facilitate bone growth after they are implanted in bone defects. Furthermore, Zhang et al. [55] have presented that bone defects arising from trauma, skeletal diseases, or tumor resections have become a critical clinical challenge and biocomposite materials as artificial bone repair materials provide a promising approach for bone regeneration. Therefore, silk fibroin (SF), carboxymethyl chitosan (CMCS), CNCs (CNCs), and strontium substituted HAp (Sr-HAp) were used to prepare SF/CMCS, SF/CMCS/CNCs, SF/CMCS/CNCs/SrHAp biocomposite scaffold constructs. The characterization results showed that all SF-based scaffolds have a porous sponge-like structure with porosities over 80%. In addition, there was a significant increase in compressive strength of SF/CMCS/SrHAp/CNCs scaffold when compared to that of SF/CMCS scaffolds while maintaining high porosity with lower swelling ratio. All SF-based scaffolds were nontoxic and showed a good hemocompatibility. Comparing to SF/CMCS scaffold, scaffolds with addition of Sr-HAp and/or CNCs showed enhanced protein adsorption and ALP activity. In addition, higher expression of osteogenic gene markers such as RUNX2, ALP, OCN, OPN, BSP, and COL-1 further substantiated the applicability of SF/CMCS/Sr-HAp/CNCs scaffolds for bone related applications as such scaffolds have a potential in non-loading bone repair application. In another research, a uniform poly(lactic acid)/cellulose nanocrystal (PLA/CNC) fibrous mats composed of either random or aligned fibers reinforced with up to 20 wt% CNCs by two different electrospinning processes [56]. Various concentrations of CNCs could
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be stably dispersed in PLA solution prior to fiber manufacture. The microstructure of produced fibrous mats, regardless of random or aligned orientation, was transformed from smooth to nanoporous surface by changing CNC loading levels. Aligning process through secondary stretching during high-speed collection can also affect porous structure of fibers. With same CNC loading, fibrous mats produced with aligned fibers showed higher degree of crystallinity than that of fibers with random structure. Thermal properties and mechanical performances of PLA/CNC fibrous mats can be enhanced, showing better enhancement effect of aligned fibrous structure. This results from a synergistic effect of increased crystallinity of fibers, efficient stress transfer from PLA to CNCs, and ordered arrangement of electrospun fibers in mats. The obtained results pave a way for developing an electrospinning system that can manufacture high-performance CNC-enhanced PLA fibrous nanocomposites. Furthermore, the 3D printing technique is also being used for the development of nanocellulose-based PNCs. In this regard, Xu et al. [57] have conducted a study for 3D printing process for oxidized nanocellulose and gelatin-based nanocomposite materials and was optimized by measuring rheological properties of several batches of materials on different variables such as crosslinking times, simulation of pneumatic extrusion process. 3D scaffolds fabrication with Solidworks Flow Simulation, observation of its porous structure by SEM, measurement of pressure-pull performance, and experiments aimed at finding out vitro cytotoxicity and cell morphology were conducted. 3D printed scaffolds materials were found to be highly porous with good mechanical properties. Also, Saber-Samandari et al. [58] have presented nanocomposite scaffold of semi-interpenetrating networks (semi-IPN) cellulosegraft-polyacrylamide/nano-HAp synthesized by free radical polymerization. The scaffolds were fabricated by the freeze-drying technique. The SEM images showed that pores of scaffolds were interconnected, and their sizes ranged from 120 μm to 190 μm. Under optimum conditions, prepared scaffolds demonstrated a compressive strength of 4.80 MPa, an elastic modulus of 0.29 GPa, and 47.37% porosity. Furthermore, the apatite-forming ability of scaffolds was determined using simulated body fluid (SBF) for 28 days. The results revealed that new apatite particles could grow on surface of scaffolds after a 14-day immersion in SBF. Study suggests that prepared semi-IPN nanocomposites that closely mimic the properties of bone tissue can be potential candidates for scaffold system for BTE applications. In addition, Domingues et al. [59] have developed an anisotropically aligned electrospun nanofibrous scaffolds based on natural/synthetic polymer blends maintaining as a reasonable compromise between biological and biomechanical performance for tendon tissue engineering strategies. However, limited tensile properties of such biomaterial constructs limit their application in tissue engineering field due to load-bearing nature of tendon/ligament tissues. Therefore, CNCs (CNCs) were used as reinforcing nanofillers in aligned electrospun scaffolds based on a natural/synthetic polymer blend matrix, poly-ε-caprolactone/chitosan (PCL/CHT). The inclusion of small amounts of CNCs (up to 3%) into tendon mimetic nanofiber bundles has a remarkable biomaterial-toughing effect (85% 5%, p < 0.0002) and raises the scaffolds mechanical properties to tendon/ligament relevant range (σ ¼ 39.3 1.9 MPa, E ¼ 540.5 83.7 MPa, p < 0.0001). Aligned PCL/CHT/CNC nanocomposite
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fibrous scaffolds possess not only mechanical strength as required for tendon tissue engineering applications but also provide tendon mimetic extracellular matrix topographic cues, a key feature for maintaining morphology and behavior of tendon cells. The proposed strategy can be extended to other anisotropic aligned nanofibrous scaffolds based on natural/synthetic polymer blends and enable full exploitation of advantages provided by their tendon mimetic fibrous structures in tendon tissue engineering. In another research, Herdocia-Lluberes et al. [60] have presented that basic calcium phosphate (BCP) crystals were associated with many diseases due to their activation of signaling pathways that results in their mineralization and deposition in intra-articular and periarticular locations in bones. Therefore, HAp can be positioned in a polysaccharide network as a strategy to minimize deposition. Evaluation of fluctuating proportions of polysaccharide network, CNCs, and HAp synthesized via a simple sol-gel method was examined. The resulting biocompatible composites were extensively characterized by means of thermogravimetric analysis, powder X-ray diffraction, Fourier-transform infrared spectroscopy, dynamic light scattering, zeta potential, and scanning electron microscopy and were found that equal amount of nHAp and CNC showed maximum homogeneity in distribution of nanoparticles and their size without compromising crystalline structure. Similarly, inclusion of bone morphogenetic protein 2 (BMP-2) was accomplished to estimate the effects of interactions in constructs. Finally, the osteoblast cell (hFOB 1.19) viability assay was performed and it presented that all materials promoted greater cell proliferation whereas the nanocomposites having nHAp content greater than CNC along with BMP-2 protein were turned to be the best composites. Likewise, Zhang et al. [61] have presented poly(ethylene glycol) (PEG)-grafted CNCs (CNCs) incorporated with poly(lactic acid) (PLA) as a reinforcing filler to develop bio-nanocomposite scaffolds consisting of CNC-g-PEG and PLA using an electrospinning technique. Morphological, thermal, mechanical, and wettability properties as well as preliminary biocompatibility using human mesenchymal stem cells (hMSCs) of PLA/CNC and PLA/CNC-g-PEG nanocomposite scaffolds were characterized and compared. The average diameter of the electrospun nanofibers decreased with increased filler loading level, due to increased conductivity of electrospun solutions. DSC results showed that both glass-transition temperature and cold crystallization temperature decreased progressively with higher CNC-g-PEG loading level, which suggest that improved interfacial adhesion between CNCs and PLA has been accomplished by grafting PEG onto CNCs. Wettability of electrospun nanofibers was not affected with addition of CNCs or CNC-g-PEG and indicating that fillers tended to stay inside of fiber matrix under electrical field. The tensile strength of composite fiber mats was effectively improved by addition of up to 5% CNC-g-PEG up to 5 wt%. In addition, cell culture results showed that PLA/CNC-g-PEG composite nanofibers exhibited improved biocompatibility to hMSCs that revealed potential application of such bio-nanocomposite as scaffolds in BTE. Furthermore, Zhou et al. [62] have developed electrospun fibrous bio-nanocomposite scaffolds reinforced with CNCs (CNCs) by using maleic anhydride (MAH) grafted poly(lactic acid) (PLA) as matrix with improved interfacial adhesion between two components. Morphological,
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thermal, mechanical, and in vitro degradation properties as well as basic cytocompatibility using human adult adipose derived mesenchymal stem cells (hASCs) of MAH grafted PLA/CNC (i.e., MPLA/CNC) scaffolds were characterized. Morphological investigation indicated that diameter and polydispersity of electrospun MPLA/CNC nanofibers were reduced with increased CNC content. The addition of CNCs improved both thermal stability and mechanical properties of MPLA/CNC composites. The MPLA/CNC scaffolds at 5% CNC loading level showed not only superior tensile strength (>10 MPa), but also improved stability during in vitro degradation compared with MPLA and PLA/CNC counterparts. Moreover, fibrous MPLA/CNC composite scaffolds were nontoxic to hASCs and capable of supporting cell proliferation. Therefore, results demonstrate that fibrous MPLA/CNC bio-nanocomposite scaffolds are biodegradable, cytocompatible, and possess useful mechanical properties for BTE. Likewise, Shi et al. [63] have prepared fibrous bio-nanocomposite mats consisting of CNCs and poly(lactic acid) (PLA) by electrospinning method from a solvent mixture consisting of N,N0 dimethylformamide and chloroform at room temperature. Morphological, mechanical, and thermal properties, as well as in vitro degradation of nanocomposite mats were characterized as a function of material composition. Average diameter of electrospun fibers decreased with increased CNCs-loading level. Thermal stability and tensile strength and modulus of nanocomposite mats were effectively improved by addition of CNCs up to 5% level. The reinforcement of CNCs on electrospun mats was illustrated by observation of SEM-based morphologies on tensile fracturing process of nanocomposite mats. At CNC content of 5%, maximum tensile stress and Young’s modulus of nanocomposite mats increased by 5 and 22-folds than those of neat PLA mats, respectively. Moreover, compared with neat PLA mats, nanocomposite mats, especially at high CNC loading levels, degraded more rapidly in phosphate-buffered saline solution.
7.3
CNFs Embedded PNCs
The CNFs are incorporated into various polymer matrixes to develop PNCs of desired properties. In this order, Mousa et al. [64] have developed polymeric cellulose acetate (CA) nanofibers and traces of iron acetates salt within a polymeric solution to form electrospinning nanofibers mats with iron nanoparticles for BTE applications. Morphology of developed nanofibers indicated that average diameter of CA decreased from 395 to 266 nm on addition of iron and showed denser fiber distributions mimicking of native ECM. Furthermore, addition of iron acetate to CA solution resulted in mats that are thermally stable. The initial decomposition temperature of CA/Fe mat and pure CA was found to be 300 and 270 C, respectively. Moreover, a superior apatite formation resulted in a biomineralization test after 3 days of immersion in stimulated environmental condition. In vitro cell culture experiments demonstrated that CA/Fe mat was biocompatible to human fetalosteoblast cells (hFOB) with ability to support cell attachment as well as proliferation. These findings suggest that doping traces of iron acetate have a promising role
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in composite mats designed for BTE as simple and economically nanoscale materials. Furthermore, these biomaterials are potential candidates for BTE. Also, Maharjan et al. [65] have observed that natural hydrogel scaffolds usually exhibit insufficient mechanical strength which remains a major challenge in BTE; therefore, such restriction can be solved by imparting regenerated cellulose (rCL) nanofibers into chitosan (CS) hydrogel. Regenerated cellulose nanofibers were regenerated from deacetylation of electrospun cellulose acetate nanofibers. Regenerated cellulose-chitosan composite scaffold showed unique porous morphology with rCL nanofibers imbibed CS matrix. Compressive strength test exhibited that rCL/CS scaffold has higher compressive strength as compared to pure CS. The rCL/CS scaffold showed increased biomineralization and enhanced pre-osteoblast cell (MC3T3-E1) viability, attachment, and proliferation. Alkaline phosphatase (ALP) and alizarin red (ARS) staining results suggested that osteogenic differentiation ability was improved in rCL/CS composite scaffold. Hence, novel fabrication idea and obtained results suggested that rCL/CS composite hydrogel scaffolds can be a potential candidate as 3D bioscaffold for BTE applications. Recently, Dutta et al. [66] have developed 3D-printed hybrid biodegradable hydrogels composed of alginate, gelatin, and CNCs (CNCs) in order to provide a favorable environment for cell proliferation, adhesion, nutrients exchange, and matrix mineralization for BTE applications. Hybrid scaffolds exhibited enhanced mechanical strength as compared to pure polymer scaffolds. Biocompatibility, differentiation potential, and bone regeneration potential of 3D-printed scaffolds were evaluated by DAPI staining, live-dead assay, alizarin Red-S (ARS) staining, real-time PCR (qRT-PCR), and μCT analysis, respectively. Enhanced cell proliferation has occurred 1% CNC/Alg/Gel scaffolds compared to control sample. The cells were adequately adhered to scaffold and exhibited flattened structure. Improved mineralization was observed in 1% CNC/Alg/Gel scaffolds as compared to control sample which demonstrated mineralization efficiency of nanocomposite scaffold. A significant enhancement in expression of osteogenic-specific gene markers (Runx2, ALP, BMP-2, OCN, OPN, BSP, and COL1) has occurred with 1% CNC/Alg/Gel as compared to control sample that indicates their osteogenic potential. Moreover, improved bone formation was observed in calvaria critical-sized defects (CCD-1) model in case of nanocomposite scaffolds as compared to control sample, which suggests their improved bone regeneration potential. Therefore, fabricated nanocomposite based scaffolds have potential to explore as a biomaterial for tissue engineering. Similarly, Mansoorianfar et al. [67] have observed that low mechanical strength of cellulose nanofiber (CNF) and its lack of osteoconductivity in physiological media limit its application for bone tissue regeneration. In order to resolve such restrictions, densely packed cellulosic layers with thickness of ~50 μm impregnated by 58S bioglass (BG) nanoparticles were prepared through simple method of vacuum filtration. Developed fabrics showed uniform distribution of BG nanoparticles and effectively wrapped between CNF layers which caused sustained ion release into SBF solution. FTIR spectrum of fabric after SBF test was illustrated the presence of newly formed HA onto fabric. Alkaline phosphatase activity (ALP) and cytotoxicity evaluation were conducted in order to investigate cell treatment of fabric
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which indicated its superior osteogenic potential of developed fabric compared with pure CNF. Increase in osteoconductivity of developed fabric caused better cell attachment. Effective integration of BG nanoparticles between CNF interlayers increased Young’s modulus of developed fabric by 50% that mitigated swelling and enhanced structural stability of CNFs in SBF solution. Thus, developed fabric can be considered as an appropriate biomaterial such as a bandage around cracked bone before metallic implantation with good mechanical integrity of layered constructs obtained as well as strength and swelling. In another study, researchers have developed and characterized an injectable hydrogel with physical and mechanical properties that mimics bone microenvironment and promotes bone regeneration [68]. Injectable hydrogel was prepared with thermogelling biopolymers, chitosan, and cellulose nanofibers/nanocrystals (CNFs/CNCs). Chitosan solution undergoes sol-gel transition at body temperature, and CNFs/CNCs were used as an additive nanomaterial to enhance mechanical properties of chitosan gel and mimic bone tissue properties. CNCs significantly improve gelation kinetics (from ~24 s to 7 s) and mechanical properties of injectable chitosan hydrogel (from ~28 kPa to ~379 kPa). An increase in percent gel fraction corresponding to weight percent of CNCs incorporated in hydrogel demonstrated that incorporated CNCs were completely reacted into chitosan network, resulting in a high density of crosslinked network. Fourier-transform infrared spectroscopy analysis used to probe reinforcement effect of CNCs showed an increase of hydrogen bonding due to presence of CNCs within chitosan networks. Hydrogel formulations were found to be biocompatible as demonstrated by high cell viability in the LIVE-DEAD cell staining analysis. Presence of CNCs in chitosan gel altered cell morphology by inducing spreading morphology due to higher mechanical sensing from the CNCs. Versatility of such formulation to exhibit strong mechanical properties combined with its ability to support cell encapsulation makes it attractive as a biomaterial for bone regeneration. Also, Zhang et al. [69] have reported physical properties of scaffolds such as nanofibers and aligned structures to exert profound effects on growth and differentiation of stem cells due to their homing-effect features and contact guidance. Aligned electrospun cellulose/CNCs nanocomposite nanofibers (ECCNNs) loaded with BMP-2 were employed to investigate in vitro osteogenic differentiation of human mesenchymal stem cells (BMSCs) and in vivo collagen assembly direction for cortical bone regeneration as shown in Fig. 3. Aligned ECCNNs scaffolds loaded with BMP-2 possess good biological compatibility. Growth orientation of BMSCs followed underlying aligned nanofiber morphology, accompanied with increased alizarin red stain, alkaline phosphatase (ALP) activity and calcium content in vitro, while a rabbit calvaria bone defect model was used in an in vivo study as shown in Fig. 4, with micro-CT and histology analyses. Results suggest that combination of BMP-2 and aligned ECCNNs scaffold has great potential for bone regeneration. Aligned cellulose nanofibers induce aligned BMSCs growth and mineralized nodules formation in vitro and assembly aligned collagen and cortical bone formation in vivo. The study provides a basis for future optimization of electrospun nanofibrous scaffolds for BTE applications.
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Fig. 3 Schematic diagram demonstrating the aligned electrospun cellulose scaffolds coated with rhBMP-2 for both in vitro and in vivo BTE [69]. (Copyright © 2019 Elsevier Ltd. [Permission taken])
Fig. 4 Intraoperative image, 5 5 mm square defect was made on each side of rabbit calvaria bone, (a) empty bone defect area (black arrow) and (b) bone defect area implanted with scaffold (Yellow arrow) [55]. (Copyright © 2019 Elsevier Ltd. [Permission taken])
Other researchers, Chakraborty et al. [70] have prepared cellulose acetate solutions (9–15% w/v) in acetone-water (80:20 and 90:10 v/v) system and subjected to electrospinning for fabricating non-woven nanofibrous CA scaffolds (CAS) with average fiber diameters from 300 to 600 nm. Further, regenerated cellulose scaffold
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(RCS) was obtained by deacetylation of electrospun CAS in alkaline media for varying time periods to find ideal time required for complete deacetylation. Following deacetylation, RCS was subjected to varying temperatures (60 C, 80 C) to observe possible positive effect of heat treatment on improvement of mechanical strength. The results were analyzed and correlated with variation of composition in solvent system, deacetylation time, and heat treatment temperatures to determine optimal fabricating conditions for RCS. The in vitro studies using MC3T3-E1 osteoblast cells were also conducted on selected RCS samples to evaluate cell adhesion and cell proliferation using SEM and MTT assay analysis. Primary results indicate positive outcome regarding viability of RCS as potential biomaterial for bone tissue engineering. Similarly, He et al. [71] have developed composite of collagen-HAp (COL-HAp) with microfibrillated cellulose (MFC) as a novel bone substitute material. COL-HAp was prepared by in situ method and modified by de-hydrothermal treatment. Microfibrillated cellulose, a nature polysaccharide with plenty of hydroxyl groups, was incorporated into COL-HAp composites to improve the properties. The novel COL-HAp-MFC scaffold with different ratios of COL-HAp and MFC was fabricated by cold isostatic pressing technique and freeze-drying technology. During forming process, a 3D bone-like structure was shaped in hybrid scaffolds. Results indicated that HAp gets deposited onto collagen molecules and MFC gets bonded with COL-HAp. The results showed a good swelling capacity for scaffolds, keeping their original shapes after swelling. Compression strength and degradability of scaffold materials can be regulated by MFC content. Compression strength of COL-HAp-MFC composite scaffolds increased to 20–40 MPa, closing to that of nature bone (1–200 MPa). The obtained scaffolds were found to be good in biocompatibility with high level of cell growth rate (>70%) and suitable hemolysis rate (5%). The work provides an insight to develop efficient and alternative approach for collagen-based biomaterials with necessary properties. The COL-HAp-MFC composite scaffold showed a potential application in BTE. Moreover, Wang et al. [72] have prepared hydrogels from natural polysaccharides to serve as ideal scaffolds for tissue engineering due to their similarity to extracellular matrices. Hydrogel scaffolds with bubble-like porous structure were developed from hydroxyethyl chitosan (HECS) and cellulose (CEL) by a combination of chemical crosslinking, particle-leaching using silicon dioxide particles as porogen and freeze-drying method. HECS/CEL scaffolds showed good comprehensive performances and get reached to equilibrium swelling state in water within 20s. The results from in vitro biocompatibility evaluated using SEM, live/dead cell viability, and MTT assays demonstrated that HECS/CEL scaffolds well support the attachment, spreading, and proliferation of osteoblastic MC3T3-E1 cells and demonstrated good biocompatibility. Therefore, novel HECS/CEL scaffolds can be considered a promising for BTE applications. In same order, Park et al. [73] have used nanofibrous 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO)-oxidized BC (TOBC) as a dispersant of HAp nanoparticles in aqueous solution. Surfaces of TOBC nanofibers were negatively charged after reaction with TEMPO/NaBr/NaClO system at pH 10 and room temperature. HA nanoparticles were simply adsorbed onto TOBC
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nanofibers (HA–TOBC) and dispersed in de-ionized water. Well-dispersed HA–TOBC colloidal solution formed a hydrogel after addition of gelatin, followed by crosslinking with glutaraldehyde (HA–TOBC–Gel). Chemical modification of fiber surfaces and colloidal stability of dispersion solution confirmed TOBC as a promising HA dispersant. Young’s modulus and maximum tensile stress increased as amount of gelatin increased due to increase in crosslinking of gelatin. Well-dispersed HA produced a denser scaffold structure resulting in increase of Young’s modulus and maximum tensile stress. Well-developed porous structures of HA–TOBC–Gel composites were incubated with Calvarial osteoblasts. HA–TOBC–Gel significantly improved cell proliferation as well as cell differentiation confirming material as a potential candidate for use in BTE applications. Also, Wan et al. [74] have constructed 3D nanofibrous carbon scaffolds composed of carbon nanofiber (CNF) and HAp for potential bone tissue regeneration. CNFs were obtained by carbonization under inert conditions with 3D BC nanofibers as starting carbon sources. Resulting CNFs showed 3D fibrous structural features with diameter ranging from 10 to 20 nm. In vitro biomineralization process was performed onto surface-treated 3D CNFs. The results showed that surface treatment of CNFs in nitric acid promoted mineralization and changed morphology of HAp formed on CNFs. Surface treatment of CNFs in nitric acid increased HAp nucleation as well as growth and changed morphology of resultant HAp crystals. HAp crystals formed on as-prepared CNFs were needle-like, while surface of HNO3-treated CNFs showed some rod-like HAps. Results of this study are found to be significant in the fields of carbonaceous materials and biomaterials for BTE.
7.4
BC-NFs Embedded PNCs
Although first identified in the early twentieth century, the number of publications on BC has increased significantly during recent years. BC is usually prepared by static suspension culture of Gluconacetobacter xylinus (also called Acetobacter xylinum) in a liquid medium. Under such conditions, a gelatinous material (termed a pellicle) is deposited at the air–medium interface with thickness increasing over time. The pellicle consists of nanofibers with diameters of less than 100 nm and a total water content of approximately 99%. Much of the interest in BC is due to the purity of the cellulose compared with plant-derived cellulose, as well as the long fiber length, high degree of crystallinity, web-like structure of the secreted material and nanoscale fibril dimensions. In particular, however, interest in BC for medical applications is increasing due to its unique combination of mechanical properties (high wet strength), interconnected porosity, biocompatibility, and ability to absorb and hold large quantities of water. In addition, as a material derived from microbial activity, BC is free of animal products (xeno-free) and its production has the potential for significant scale-up. Recently, Khan et al. [75] have developed a nanocomposite scaffold for BTE using BC and β-glucan (β-G) through free radical polymerization and freeze-drying technique. HAp nanoparticles (nHAp) and graphene oxide (GO) were added as reinforcement materials. Resultant scaffolds showed remarkable
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stability, aqueous degradation, spongy morphology, porosity, and mechanical properties. Antibacterial activities were performed against gram negative and gram positive bacterial strains. BgC-1.4 scaffold was found more antibacterial as compared to BgC-1.3, BgC-1.2, and BgC-1.1. Cell culture and cytotoxicity were evaluated using MC3T3-E1 cell line. More cell growth was observed onto BgC-1.4 due to its uniform interrelated pores distribution, surface roughness, better mechanical properties, considerable biochemical affinity toward cell adhesion, proliferation, and biocompatibility. Methacrylated gelatin (GelMA)/BC composite hydrogels were successfully prepared by Gu et al. [76] by immersing BC particles into GelMA solution followed by photo-crosslinking. The morphology of GelMA/BC hydrogel was examined by scanning electron microscopy and compared with pure GelMA. The hydrogels had very well interconnected porous network structure, and the pore size decreased from 200 to 10 μm with the increase of BC content. The composite hydrogels were also characterized by swelling experiment, X-ray diffraction, thermogravimetric analysis, rheology experiment, and compressive test. The composite hydrogels showed significantly improved mechanical properties compared with pure GelMA. In addition, the biocompatibility of composite hydrogels was preliminarily evaluated using human articular chondrocytes. The cells encapsulated within the composite hydrogels for 7 days proliferated and maintained the chondrocytic phenotype. Thus, the GelMA/BC composite hydrogels might be useful for cartilage tissue engineering. Also, Dubey et al. [77] have explored the potential of low dose BMP-2 treatment through tissue engineering approach, which amalgamates 3D macro/microporousnanofibrous BC (mNBC) scaffolds and low dose BMP-2 primed murine mesenchymal stem cells (C3H10T1/2 cells). Initial studies on cell-scaffold interaction using unprimed C3H10T1/2 cells confirmed that scaffolds provided a propitious environment for cell adhesion, growth, and infiltration, owing to its ECM-mimicking nanomicro-macro architecture. Osteogenic studies were conducted by preconditioning cells with 50 ng/mL BMP-2 for 15 min, followed by culturing on mNBC scaffolds for up to 3 weeks. Results showed an early onset and significantly enhanced bone matrix secretion and maturation in scaffolds seeded with BMP-2 primed cells compared to unprimed ones. Moreover, mNBC scaffolds alone were able to facilitate mineralization of cells to some extent. These findings suggest that, with the aid of osteoinduction from low dose BMP-2 priming of stem cells and osteoconduction from nano-macro/micro topography of mNBC scaffolds, a cost-effective BTE strategy can be designed for quick and excellent in vivo osteointegration. Similarly, Klinthoopthamrong et al. [78] have developed an active non-resorbable guided tissue regeneration (GTR) membrane from BC membrane (BCM) by conjugating with plant-derived recombinant human osteopontin (p-rhOPN), an economically produced and RGD-containing biomolecule as shown in Fig. 5. BCM was initially grafted with poly(acrylic acid) (PAA) brushes to form poly(acrylic acid)-grafted BCM. Multiple carboxyl groups introduced to BCM by PAA can serve as active anchoring points for p-rhOPN conjugation and yielded p-rhOPN-BCM. Amount of p-rhOPN adhered onto membrane was quantified by enzyme-linked immunosorbent assay. Immunocytochemistry, two-stage quantitative real-time reverse transcriptase
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Fig. 5 Preparation of the PAA-BCM followed by p-rhOPN immobilization [78]. (Copyright © 2019 Elsevier Ltd. [Permission taken])
polymerase chain reaction, and in vitro mineralization analyses strongly suggested that p-rhOPN-BCM elicits biological functions leading to enhancement of osteogenic differentiation of human periodontal ligament stem cells as effective as BCM conjugated with commercially available rhOPN from mammalian cells (rhOPNBCM), suggesting its potential to be used as GTR membrane to promote bone tissue regeneration. Furthermore, collagen (COL) and BC were chemically recombined by Schiffbase reactions [79]. In this order, 3D porous microsphere of COL/BC/bone morphogenetic BMP-2 with multistage structure and components was developed through template method coupled with reverse-phase suspension regeneration. Microspheres were found to be full of pores and a rough surface. Particle size ranged from 8 to 12 μm, specific surface area (SBET) 123.4 m2/g, pore volume was 0.59 cm3/g, and average pore diameter was found to be 198.5 nm. Adsorption isotherm of microspheres on N2 molecule belongs to that of mesoporous materials. Microspheres demonstrated good biocompatibility. 3D porous microspheres with multiple structures and components effectively promoted adhesion, proliferation, and osteogenic differentiation of mice MC3T3-E1 cells. The study can provide a theoretical basis for application of COL/BC porous microspheres in field of BTE. The hybrid materials based on BC and HAp for guided bone regeneration (GBR) were developed by Luz et al. [80]. However, for some GBR, degradability in physiological environment is an essential requirement. Present study aimed to explore the use of oxidized BC (OxBC) membranes, associated with strontium apatite, for GBR applications. BC membranes were produced by fermentation and purified, before oxidizing and mineralizing by immersing in strontium chloride solution and sodium bibasic phosphate for 5 cycles. Hybrid materials (BC/HAp/Sr, BC/SrAp, OxBC/HAp/Sr, and OxBC/SrAp) were characterized for biodegradability and bioactivity and for their physicochemical and morphological properties. In vitro cytotoxicity and hemolytic properties of materials were also investigated. In vivo
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biocompatibility was analyzed by performing histopathological evaluation at 1, 3, and 9 weeks in mice. Results showed that samples presented different strontium release profiles and that oxidation enhances degradation under physiological conditions. All hybrid materials were found to be bioactive. Cell viability assay indicated that materials are non-cytotoxic and in vivo studies showed low inflammatory response and increased connective tissue repair, as well as degradation in most of materials, especially oxidized membranes. Study confirms the potential use of BC-derived hybrid membranes for guided bone regeneration. Recently, Kamel et al. [81] have designed a novel NFCs/cyclodextrin-based 3D scaffolds loaded with raloxifene hydrochloride for bone regeneration. Scaffolds were prepared using two different types of cyclodextrins, namely beta-cyclodextrin and methylbeta-cyclodextrin. Results showed that prepared scaffolds were highly porous, additionally, scaffold containing drug/beta-cyclodextrin kneaded complex (SC5) exhibited most controlled drug release pattern with least burst effect and reached almost complete release at 480 h. In vitro cytocompatibility and regenerative effect of chosen scaffold (SC5) was assessed using Saos-2 cell line. Results proved that SC5 scaffold was biocompatible. Furthermore, it improved cell adhesion, alkaline phosphatase enzyme expression, and calcium ion deposition, those are essential factors for bone mineralization. The obtained observations presented a novel, safe, and propitious approach for bone engineering. Similarly, Aki et al. [82] have presented a novel polyvinyl alcohol (PVA)/hexagonal boron nitride (hBN)/BC composite. Bone tissue scaffolds were fabricated using 3D printing technology. Results demonstrated that addition of BC affects the characteristic properties of blends. Morphological studies revealed homogenous dispersion of BC within 12% PVA/0.25%hBN matrix. Tensile strength of scaffolds was decreased on incorporation of BC and 12%PVA/0.25%hBN/0.5%BC showed highest elongation at break value (93%). A significant increase in human osteoblast cell viability on 3D scaffolds was observed for 12%PVA/0.25%hBN/0.5%BC. Cell morphology on composite scaffolds exhibited that BC doped scaffolds appeared to adhere to cells. The present work deduced that BC doped 3D printed scaffolds with well-defined porous structures have considerable potential as a suitable tissue scaffold for BTE. Also, Torgbo and Sukyai [83] have synthesized nanocomposite scaffold for BTE using BC with magnetite (Fe3O4) and HAp nanoparticles through ultrasonic irradiation. Physicochemical analysis of composite (BC–Fe3O4 HAp) revealed uniform dispersion of nanoparticles in BC matrix with calcium to phosphorus (Ca/P) ratio of 1.63 and 1.56 for surface and cross section, respectively. Crystallinity index of BC decreased from 82.5% to 62% in composite. Magnetic field responsive behavior of magnetic nanoparticle incorporated BC sheets investigated by vibrating sample magnetometry, showed a decrease in saturation magnetization of nanocomposite from 15.84 to 3.94 emu/g after deposition of HAp with superparamagnetic characteristic. Swelling and porosity studies showed significant decrease in swelling ability with incorporation of nanoparticles while maintaining high degree of porosity around 80% in nanocomposite scaffold. Cell culture experiment demonstrated that scaffold is nontoxic to mouse fibroblast L929 cells and biocompatible for osteoblast (MC3T3-E1 cell line) attachment and proliferation. Likewise, Zhang et al. [84] have
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prepared a bi-layered polylactic-co-glycolic acid (PLGA)/multiwall carbon nanotubes (MWNTs)/BC composite membrane through vacuum freeze-drying and electrospinning to be used for guided tissue regeneration. These membranes were subjected to repair maxillary canine periodontal defects in beagle dogs. The bi-layered membrane comprised a lower fibrous BC film layer and an upper electrospun PLGA/MWNTs film layer with a 3D network structure. Histological results demonstrated that bi-layered membrane promoted periodontal tissue regeneration. BC/PLGA/MWNTs membrane could be an ideal guided tissue regeneration membrane candidate and thus has potential therapeutic applications in periodontal disease. In the same order, Yan et al. [85] have developed alginate/bacterial CNCschitosan-gelatin (Alg/BCNs-CS-GT) composite scaffold by combined method involving incorporation of bacterial CNCs (BCNs) in alginate matrix, internal gelation by HAp-d-glucono-δ-lactone (HAP-GDL) complex, and layer-by-layer (LBL) electrostatic assembly of positively charged chitosan (CS) and negatively charged gelatin (GT). Characterization results revealed that Alg/BCNs-CS-GT composite scaffold exhibited good 3D architecture with well-defined porous structure, improved compressive strength, and regulated biodegradation. In particular, excellent biocompatibility and reinforcing effect of BCNs and outer GT chains containing repetitive motifs of arginine-glycine-aspartic (RGD) sequences favored attachment, proliferation, and differentiation of osteoblastic MC3T3-E1 cells. BC/HAp composite possesses good bioaffinity but its poor mechanical strength limits widespread applications in BTE. BC/gelatin (BC/GEL) double-network (DN) composite showed excellent mechanical properties but rarely used in biomedical fields [86]. In this regard, a multi-component organic/inorganic composite BC-GEL/HAp DN composite was synthesized, which combined advantages of BC/HAp and BC/GEL. Compared with BC/GEL, BC-GEL/HAp exhibited rougher surface topography and higher thermal stability. Compression and tensile testing indicated that mechanical strength of BC-GEL/HAp was greatly reinforced compared with BC/HAp and was even higher than that of BC/GEL. In vitro cell culture demonstrated that rat bone marrow-derived mesenchymal stem cells (rBMSCs) cultured onto BC-GEL/HAp showed better adhesion and higher proliferation and differentiation potential than cells cultured on BC/GEL. Resultant BC-GEL/HAp composite can be used as ideal bone scaffold platform. Also, Huang et al. [87] have developed porous BC scaffold modified by combining with gelatin through different crosslinking methods and HAp coating. Results claimed about successful modification and formation of interconnecting microstructure suitable for cells and tissue growth. Young’s modulus, maximum load, and compressive strength results showed a significant increasing in property in an order from BC, BC/Gel, BC/PA/Gel to BC/PA/Gel/HAp scaffolds. Comparisons among cytocompatibility of four scaffolds revealed that best adhesion, viability, proliferation, and osteogenic differentiation of hBMSCs appeared on BC/PA/Gel/HAp scaffold, followed by BC/PA/Gel, BC/Gel, and BC scaffolds. In vitro and in vivo investigation on nude mice and rabbits showed same order of new bone formation from high to low as BC/PA/Gel/HAp, BC/PA/ Gel, BC/Gel, and BC scaffolds. Modification of BC by gelatin combination and HAp coating greatly promoted properties, biocompatibility, and osteoinductivity of
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pure BC scaffolds. Thus, such biomaterials can be used as a potential orthopedic implant for bone repair applications. In another study, researchers have produced modified-BC scaffolds with a greater degree of microscale porosity by including paraffin beads in bacterial culture medium that were removed from scaffolds before use to leave microscale voids Zaborowska et al. [88]. Microporous BC scaffolds were seeded with a mouse osteogenic cell line in order to determine suitability for BTE. Greater cell ingrowth was observed in microporous BC scaffolds as compared to with standard (nanoporous) BC and a significant degree of mineralization was observed by Alizarin Red staining. Using a similar microporous scaffold, Andersson et al. [89] have developed porous BC scaffolds by fermentation of Acetobacter xylinum in the presence of slightly fused wax particles with a diameter of 150–300 μm, which were then removed by extrusion. It demonstrated that primary chondrocytes may grow into the structure of such scaffolds, populating the microscale pores and secreting significant quantities of characteristic glycosaminoglycans. Several studies have sought to modify BC scaffolds in a variety of ways in order to improve their bioactive properties. With a view to BTE, Fang et al. [90] have modified BC by biomimetic mineralization of HAp to produce BC–HAp composite scaffolds. When compared with unmodified BC, the BC–HAp scaffolds supported increased adhesion and proliferation of human bone marrow-derived mesenchymal stem cells and induced an increased osteogenic differentiation, both spontaneously and under osteoinduction conditions. In an alternative approach, BC scaffolds were used as a carrier for BMP2 by Shi et al. [91]. It has been found that BMP2-loaded BC increased in vitro proliferation and osteogenic differentiation of C2C12 mouse myoblast cell line. When implanted subcutaneously in an in vivo mouse model, the BMP2-loaded BC attracted greater ingrowth of cells and led to greater mineralization as compared to BC without BMP2. In another approach, Wang et al. [92] have modified-BC scaffolds by adsorption of gelatine followed by crosslinking to produce a fibrillar BC–gelatine composite. The presence of gelatine broadly improved biocompatibility of scaffolds for culture of a fibroblast cell line and proved to be a relatively low-cost and scalable method of modification. In another study, Brackmann et al. [93] have highlighted simultaneous imaging of scaffold material, cells, and extracellular matrix collagen in samples consisting of osteoprogenitor MC3T3-E1 cells seeded on microporous BC, a potential scaffold material for synthesis of osseous tissue. BC and collagen were visualized by second harmonic generation (SHG) microscopy, and verification of collagen identification on cellulose scaffolds was carried out on sectioned samples by comparison with conventional histological staining technique. Both methods showed similar collagen distributions and a clear increase in amount of collagen when comparing measurements from two time points during growth. For investigations of intact cellulose scaffolds seeded with cells, SHG was combined with simultaneous coherent antiStokes Raman scattering (CARS) microscopy for visualization of cell arrangement in three dimensions and to be correlated with the SHG data. Results showed that osteoprogenitor cells were able to produce collagen already during first days of
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growth. Further on, developed collagen fiber networks can be imaged inside compact regions of cells located in cellulose micropores. Collagen production, initial step of tissue mineralization, demonstrates potential of BC as a scaffold material for BTE. Also, Bäckdahl et al. [39] have proposed a novel method to develop 3D nanofibril network scaffolds with controlled microporosity. By placing paraffin wax and starch particles of various sizes in a growing culture of Acetobacter xylinum, BC scaffolds of different morphologies and interconnectivity were prepared. Paraffin particles were incorporated throughout scaffold, while starch particles were found only in outermost area of resulting scaffold. Porogen particles were successfully removed after culture with bacteria and no residues were detected with electron spectroscopy for chemical analysis. Resulting scaffolds were seeded with smooth muscle cells (SMCs) and investigated using histology and organ bath techniques. SMCs were selected as cell type since main purpose of resulting scaffolds is for tissue-engineered blood vessels. SMCs attached to and proliferated on and partly into the scaffolds.
7.5
CNW Embedded PNCs
The cellulose nanowhiskers are also used for the preparation of polymer nanocomposites. In this order, Fragal et al. [94] have presented that CNWs with different surface compositions can be used to generate biomimetic growth HAp. Hybrid materials primarily consist of CNWs with HAp content below 24%. CNWs were produced by different inorganic acid hydrolyses to generate cellulose particles with surface groups to induce HAp mineralization. The use of CNWs prepared from hydrochloric acid, sulfuric acid, and phosphoric acid was evaluated. HAp growth was obtained from biomimetic method using a SBF concentration of 1.5 M. Sulfonate and phosphonate groups onto CNW surface have a direct impact on nucleation and growth of HAp. HAp/CNWs were also compared with physical mixture method using HAp nanoparticles developed by chemical precipitation. Bioactivity and biocompatibility of hybrid materials were analyzed by cell viability studies using fibroblast cells (L929). Materials obtained from biomimetic method have superior biocompatibility/bioactivity compared to material synthesized by wet chemical precipitation method with an incubation period of 24 h. Also, Kim et al. [95] have accessed tunicate cellulose nanowhiskers (CNW) film for their suitability for osteoblasts. Sulfuric acid hydrolysis extraction of tunicates integuments was conducted to obtain CNWs, which were found to be acceptable for adhering, growing, and differentiating osteoblasts without cytotoxicity. Mechanical stress enhanced osteoblast differentiation, and cell survival rate was recovered at around day 3, although there was a slight increase in cell death at day 1 after stimulation. It has also been found that intracellular flux of calcium ion was related to increased differentiation of CNWs under mechanical stress. Suitability of tunicate CNWs as a scaffold for BTE was developed by making a complex system based on CNW for osteoblast growth and differentiation that expected to be useful for bone substitute fabrication.
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Nanocellulose Derivatives Embedded PNCs
7.6.1 Carboxymethyl Nanocellulose The carboxymethyl nanocellulose possesses several characteristic properties those further enhance the applicability of nanocomposites. Recently, Zennifer et al. [96] have developed a water-soluble derivative of cellulose CMCs by chemical attack of alkylating reagents on activated non-crystalline regions of cellulose. It is first FDA approved cellulose derivative that can be targeted for desired chemical modifications. CMC and modified-CMC can be engineered to prepared scaffolds for tissue engineering applications. CMC and its derivatives have been developed as smart bioinks for 3D bioprinting applications. From these perspectives, applications of CMC in tissue engineering have a great potential. Also, Sharmila et al. [97] have presented a study focused on fabrication of a novel herbal scaffold using medicinal plants Spinacia oleracea (SO) and Cissus quadrangularis (CQ) extracts incorporated with alginate (Alg) and CMC by lyophilization method. The biocompatible nature of plant-based polymer scaffold was assessed using MG-63 human osteosarcoma cell line. The investigation of biocompatibility study showed that Alg/CMC/ SO scaffold expressed higher cell viability than Alg/CMC/SO-CQ scaffold, which possess better cellular biocompatibility. Outcomes of study suggested that plantbased Alg/CMC/SO scaffold serve as a potential biopolymer scaffold that can be further exploited for bone tissue applications. Similarly, He et al. [98] have developed a porous collagen-carboxymethyl cellulose/HAp (Col-CMC/HAp) composite using a biomimetic template of Col and CMC protein-polysaccharide bi-molecules. It was found that nano-HAp homogenously distributed onto surface of Col-CMC bi-templates while composite presented 3D porous structure with pore size from 100 μm to 300 μm. Porosities of composites were found to be in range of 71%–85%. Also, compressive strength of composites was highly depended on ratio of Col to CMC in organic template. Optimized composite in respect to physical properties showed a compressive strength as high as 7.06 MPa, quite close to that of natural bone. High relative growth rate of wild-type mouse embryonic fibroblasts cells was found for composite, indicating a good biocompatibility. Organic-inorganic composite also behaved good in collagenase resistance and could be biodegraded in 8 weeks, with about 50% of initial weight left at ratio of Col to CMC of 1:9. Outcomes show that Col-CMC/HAp composite by bi-molecular template method was a rational and safe method to prepare biomaterials with tunable properties. In addition to that, Matinfar et al. [99] have demonstrated porous scaffolds of CS and carboxymethyl cellulose (CMC) reinforced with whisker-like biphasic and triphasic calcium phosphate fibers fabricated by freeze-drying method. Effect of addition of CMC, fiber type, and content on mechanical, physicochemical and biological properties of composite scaffolds was evaluated. Fibers were synthesized by homogenous precipitation method and were characterized. Biphasic fibers contained two phases of HAp and monetite, and triphasic fibers consisted of HAp, β-tricalcium phosphate, and calcium pyrophosphate and were 20–270 μm and 20–145 μm in length, respectively. Composite scaffolds exhibited desirable microstructures with high porosity (61–75%) and interconnected pores in range of
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35–200 μm. Addition of CMC to CS led to a significant improvement in mechanical properties (up to 150%) but could not affect water uptake ability and biocompatibility. Both fibers improved in vitro proliferation, attachment, and mineralization of MG63 cells on scaffolds as evidenced by MTT assay, DAPI staining, SEM, and Alizarin red staining. Triphasic fibers were more effective in reinforcing scaffolds and resulted in higher cell viability. Composite scaffolds of CS and CMC reinforced with 50% triphasic fibers were superior in terms of mechanical and biological properties and showed compressive strength and modulus of 150 kPa and 3.08 MPa, respectively, which is up to 300% greater than pure CS scaffolds. Also, Hasan et al. [41] have aimed to synthesize highly efficient nanocomposite polymeric scaffolds with controllable pore size and mechanical strength. Nanocomposite (CCNWs-AgNPs) of silver nanoparticles (AgNPs) decorated on carboxylated-CNWs (CCNWs) were developed which serves dual functions of providing mechanical strength and antimicrobial activity. Scaffolds containing chitosan (CS) and CMC with varying percent of nanocomposite were fabricated using freeze-drying method. Results revealed highly crystalline structure with AgNPs (5.2 nm dia) decorated on ~200 nm long CCNWs surface. FTIR analysis confirmed the interaction between CCNWs and AgNPs. Incorporation of nanocomposite during scaffolds preparation helped to achieve desirable 80–90% porosity with pore diameter ranging between 150 and 500 μm and mechanical strength was also significantly improved matching with mechanical strength of cancellous bone. Swelling capacity of scaffolds decreased after incorporation of nanocomposite. Scaffold degradation rate was tuned to support angiogenesis and vascularization. Scaffolds apart from exhibiting excellent antimicrobial activity also supported MG63 cells adhesion and proliferation. Incorporation of CCNWs also resulted in improved biomineralization for bone growth. Overall, these studies confirmed excellent properties of fabricated scaffolds, making them selfsustained and potential antimicrobial scaffolds (without any loaded drug) to overcome bone related infections like osteomyelitis. Furthermore, Ao et al. [43] have electrospun the nanofibrous scaffolds from cotton cellulose and nHAp for BTE. Solution properties of cellulose/nano-HA spinning dopes and their associated electro-spinnability were characterized. Biocompatibility of electrospun cellulose/nHAp nanocomposite nanofibers (ECHNN) was accessed with human dental follicle cells (HDFCs). SEM images indicated that average diameter of ECHNN increased with a higher nano-HA loading and fiber diameter distributions were found to be within range of natural ECM fibers (50–500 nm). ECHNN exhibited extraordinary mechanical properties with a tensile strength and Young’s modulus up to 70.6 MPa and 3.12 GPa, respectively. Furthermore, it was discovered that thermostability of ECHNN can be improved with incorporation of nHAp. Cell culture experiments demonstrated that ECHNN scaffolds were quite biocompatible for HDFCs attachment and proliferation, suggesting their great potentials as scaffold materials in BTE. Also, Singh et al. [100] have prepared novel silk fibroin (SF) and CMC composite nanofibrous scaffold (SFC) to investigate their ability to nucleate bioactive nanosized calcium phosphate (Ca/P) by biomineralization for BTE application. Composite
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nanofibrous scaffold was prepared by free liquid surface electrospinning method. Developed composite nanofibrous scaffold was observed to control the size of Ca/P particle (100 nm) as well as uniform nucleation of Ca/P onto surface. XRD and EDX analysis showed the development of apatite-like crystals onto SFC scaffolds of nanospherical in morphology and distributed uniformly throughout surface of scaffold. Furthermore, hydrophilicity as a measure of contact angle and water uptake capacity is higher than pure SF scaffold representing superior cell supporting property of SF/CMC scaffold. Effect of biomimetic Ca/P on osteogenic differentiation of umbilical cord blood derived human mesenchymal stem cells (hMSCs) studied in early and late stage of differentiation shows enhanced osteoblastic differentiation capability as compared to pure silk fibroin. Obtained result confirms positive correlation of APA, alizarin staining, and expression of runtrelated transcription factor 2, osteocalcin and type1 collagen representing biomimetic property of scaffolds. Therefore, developed composite has potential to be a scaffold for BTE application. Similarly, Gaihre and Jayasuriya [101] have developed CMC microparticles through ionic crosslinking with the aqueous ion complex of zirconium (Zr) and further complexing with chitosan (CS) and determined physiochemical and biological properties of these novel microparticles. In order to assess the role of Zr, microparticles were prepared in 5% and 10% zirconium tetrachloride solution. SEM along with EDS results showed that Zr was uniformly distributed onto surface of microparticles as a result of which uniform groovy surface was obtained. Zr improves surface roughness of microparticles and stability studies showed that it also increases stability of microparticles in PBS. Response of murine pre-osteoblasts (OB-6) when cultured with microparticles was investigated. Live/ dead cell assay showed that microparticles could not induce any cytotoxic effects as cells were attaching and proliferating on well plate as well as along surface of microparticles. In addition, SEM images showed that microparticles support attachment of cells and they appeared to be directly interacting with surface of microparticle. Within 10 days of culture most of top surface of microparticles was covered with a layer of cells indicating that they were proliferating well throughout surface of microparticles. It has been found that Zr improves cell attachment and proliferation as more cells were present on microparticles with 10% Zr. These promising results show potential applications of CMC-Zr microparticles in BTE applications. Also, Sainitya et al. [102] have developed biocomposite scaffolds containing chitosan (CS), CMC with varied concentrations of mesoporous wollastonite (m-WS) particles through freeze-drying method. m-WS particles at 0.5% concentration in CS/CMC scaffolds showed significant improvement in biomineralization and protein adsorption properties. Addition of m-WS particles in CS/CMC scaffolds significantly reduced their swelling and degradation properties. CS/CMC/m-WS scaffolds also showed cyto-friendly nature to human osteoblastic cells. Osteogenic potential of CS/CMC/m-WS scaffolds was confirmed by Ca deposition and expression of an osteoblast specific microRNA, pre-mir-15b. Thus, investigations support the use of CS/CMC/m-WS scaffolds for BTE applications.
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7.6.2 Hydroxyethyl Nanocellulose The polymer nanocomposites for biomedical applications are also developed from Hydroxyethyl nanocellulose. In this regard, Chahal et al. [45] have developed a novel scaffold material that mimic ECM, architecturally and functionally, and becoming highly important to meet the demands of advances in BTE. Natural polymer cellulose derived hydroxyethyl cellulose (HEC) based nanostructured scaffolds were prepared with uniform fiber morphology through electrospinning. PVA was used as an ionic solvent for supporting electrospinning of HEC. SEM and ImageJ analysis showed formation of non-woven nanofibers with well-defined porous architecture. Interactions between HEC and PVA in electrospun nanofibers were studied by DSC, XRD, DMA, TGA, FTIR, XPS, and UTM. Mechanical properties of scaffolds were significantly altered with different ratios of HEC/PVA. Further, biocompatibility of HEC/PVA scaffolds was evaluated using human osteosarcoma cells. SEM images revealed favorable cells attachment and spreading onto nanofibrous scaffolds and MTS assay showed increased cell proliferation after different time periods. Thus, these results indicate that HEC based nanofibrous scaffolds could be a promising candidate for BTE. Also, Chahal et al. [103] have used modified cellulose for BTE. Randomly oriented nanofibrous scaffold with an average diameter in between 117 nm and 500 nm of MC and PVA were synthesized by electrospinning technique. Blend solutions of MC/PVA with different weight ratio of MC to PVA were developed using water as solvent to fabricate nanofibers. These results showed that MC/PVA nanofibrous scaffold provides a beneficial frame for BTE. Recently, Wu et al. [104] have developed organic–inorganic composite scaffolds with 3D porous structures, sufficient mechanical properties, excellent cytocompatibility, osteoconductivity, and osteogenic potential. A novel epichlorohydrin (ECH)-crosslinked HEC/soy protein isolate (SPI) porous bi-component scaffold (EHSS) with HAp functionalization (EHSS/HAp) was fabricated for bone defect repair through combination of lyophilization and in situ biomimetic mineralization. Results indicated that prepared scaffolds exhibited an interconnected porous structure, a biomimetic HAp coating onto their surfaces, improved mechanical properties in compression and a controllable degradation rate. In particular, semiquantitative analysis showed that Ca/P ratio of EHSS/HAp with 70% SPI content (1.65) was similar to that of natural bone tissue (1.67) according to EDS data. In vitro cell culture experiments indicated that EHSS/HAp with 70% SPI content showed improved cytocompatibility and was suitable for MC3T3-E1 cell attachment, proliferation, and growth. Consistently, in vitro osteogenic differentiation studies showed that EHSS/HAp with 70% SPI content can significantly accelerate expression of osteogenesis-related genes (Col-1, Runx2, OPN, OCN) during osteogenic differentiation of MC3T3-E1 cells. Moreover, when applied to repair of criticalsized cranial defects in a rat model, EHSS/HAp with 70% SPI was capable of significantly promoting tissue regeneration and integration with native bone tissue. Microscopic computed tomography (micro-CT) results demonstrated that bone defect site was nearly occupied with newly formed bone at 12 weeks after implantation of EHSS/HAp with 70% SPI content into defect. Hematoxylin and eosin (H&E) staining and Masson’s trichrome staining of histological sections further
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confirmed that EHSS/HAp with 70% SPI markedly promoted new bone formation and maturation. Consequently, results revealed the potential of EHSS/HAp scaffolds with 70% SPI for successful bone defect repair and regeneration.
7.6.3 Cellulose Acetate Natural polymer based fibrous scaffolds have been explored for BTE applications; however, their inadequate 3-dimensionality and poor mechanical properties are among the concerns for their use as bone substitutes. In this study, pullulan (P) and CA, two polysaccharides, were electrospun at various P/CA ratios (P80/CA20, P50/CA50, and P20/CA80%) to develop 3D fibrous network [105]. The scaffolds were then crosslinked with trisodium trimetaphosphate (STMP) to improve the mechanical properties and to delay fast weight loss. The lowest weight loss was observed for the groups that were crosslinked with P/STMP 2/1 for 10 min. Fiber morphologies of P50/CA50 were more uniform without phase separation and this group was crosslinked most efficiently among groups. It was found that mechanical properties of P20/CA80 and P50/CA50 were higher than that of P80/CA20. After crosslinking strain values of P50/CA50 scaffolds were improved and these scaffolds became more stable. Unlike P80/CA20, uncrosslinked P50/CA50 and P20/CA80 were not lost in PBS. Among all groups, crosslinked P50/CA50 scaffolds had more uniform pores; therefore, this group was used for bioactivity and cell culture studies. Apatite-like structures were observed on fibers after SBF incubation. Human Osteogenic Sarcoma Cell Line (Saos-2) seeded onto crosslinked P50/CA50 scaffolds adhered and proliferated. The functionality of cells was tested by measuring ALP activity of the cells and the results indicated their osteoblastic differentiation. In vitro tests showed that scaffolds were cytocompatible. To sum up, crosslinked P50/CA50 scaffolds were proposed as candidate cell carriers for BTE applications.
7.6.4 Aerogel Cellulose The composite materials comprised of biopolymeric aerogel matrices and inorganic nHAp fillers have received considerable attention in bone engineering, although with significant progress in aerogel-based biomaterials, brittleness and low strengths limit the application. An alkali urea system was used to dissolve, regenerate, and gelate cellulose and silk fibroin in order to fabricate composite aerosol by Chen et al. [106]. A dual network structure was shaped in composite aerosol materials interlaced by sheet-like silk fibroin and reticular cellulose wrapping n-HA onto surface. Through uniaxial compression, density of composite aerogel material was close to one of natural bone, and mechanical strength and toughness were high. Result indicates that composite aerogel has same mechanical strength range as cancellous bone when ratio of cellulose, n-HA, and silk fibroin was kept as 8:1:1. In vitro cell culture showed HEK-293 T cells cultured on composite aerogels had high ability of adhesion, proliferation, and differentiation. Thus, obtained biodegradable composite aerogel has application potential in BTE.
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7.6.5 Oxidized-Cellulose Nanofibers In another study, Salama et al. [107] have prepared TEMPO oxidized-cellulose nanofibers (T-CNF) from cellulose pulp extracted from bagasse. Soy protein hydrolysate (SPH) was grafted onto T-CNF through amidation of carboxylic groups. Biomineralization was assessed through Ca/P precipitation in twice-simulated body fluid until formation of a new bioactive material. Protein was efficiently grafted without alteration of morphology and nanofibrils packing. Highly crystalline calcium phosphate deposits were detected with a Ca/P ratio equal to 1.63, in agreement with native bone apatite composition. In vitro response of human MSCs confirmed biocompatibility. The presence of calcium phosphates tends to cover nanofibrillar pattern, inducing inhibition of cell proliferation and promoting ex-novo precipitation of mineral phases. All results suggest a promising use of these biomaterials in repair and/or regeneration of hard tissues such as bone.
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Toxicity and Biocompatibility of Cellulose-PNCS
Toxicity is a major concern for materials to be used in biomedical applications. Cellulosic particles are extracted from sources with no or negligible toxicity, but dimension, surface modification, hydrophilization, hydrophobization, and aggregation might influence their cytotoxicity as well as biocompatibility. Generally, nanoscale dimension of particles has been recognized as a potential factor generating toxicity of materials that are composed by these particles. Conflicting reports on in vitro research exist on cyto-, geno-, and immunotoxicity of cellulosic nanoparticles [108]. Moreover, inflammation is often occurring after exposure to cellulosic nanoparticles as a normal biological response to a foreign material. It may disappear after a while. Attempts have been made to correlate cellulosic nanoparticle size and rigidity of a specific type and chemical function to cell toxicity in acute tests. Therefore, more research is needed on long-term in vivo effects of cellulose nanomaterials, since this may provide different results from those obtained by acute and in vitro studies. Biocompatibility of a material means “the ability of a material to perform with an appropriate host response in a specific situation.” It involves not only the material used, but also the surrounding cells/tissue. The interaction of biomaterials and cells is very complex. The biocompatibility as well as suitability toward bone cells of prepared biomaterial scaffolds from nanocellulose-PNCs material is of great concern as far as BTE is concerned. The scaffolds developed from nanocellulose-PNCs were found to be suitable for bone cells, show excellent proliferation of cells, and hemocompatibility. To understand the possibilities to orchestrate biomaterial-cell reactions, an elucidation of their interactions is needed. Moreover, BC web structure can be used on the beginning stage to particular assignments, i.e., bone regeneration, which establishes a micro-sized pores nanocomposite. Nanocellulose-PNCs can be of enthusiasm for bone regeneration as its sustenance osteoblast ingrowth with mineralized tissue developing. For the allowance of initially cell-free polymers to elicit infiltration of cells, this interaction is of pivotal importance. Under
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physiological conditions, cells will, among others, bind to the surrounding extracellular matrix via ligands. Many proteins interact with cells and thereby evoke a myriad of responses. In general, enhancing the biocompatibility of a biomaterial can be achieved by altering the surface characteristics of the substrate, which in turn can lead to enhancing or reducing protein adsorption.
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Conclusion
PNCs filled with nanocellulose represent a new class of material alternative to conventional filled polymers in the field of BTE and possess some extremely interesting properties such as high strength and stiffness combined with low weight, biodegradability, and renewability. The research and development of nanocellulosereinforced polymer composites have dramatically increased in recent years due to the possibility of exploiting their potential in different sectors and also their abilities to address the property performance gap between renewable and nonrenewable petroleum-based polymers. Owing to their good mechanical properties, renewability, biodegradability, biocompatibility, low-cost production, low density, flexibility, high aspect ratio, low abrasivity, and reactive surface, nanocellulose fibers serve as a promising potential candidate for preparing different kinds of bionanocomposites especially for BTE. Although the optimization of reinforcing effect and investigation for the reinforcing extent by cellulose whiskers is still in progress, in general, it was concluded that modified cellulose whiskers may overcome the dispersion problems to some extent. However, there are several challenges still confronting the production of cellulose-based nanocomposites for BTE on a large scale. The present development in novelty of nanocellulose-based biomaterials in the medical field shows huge potential for nanocellulose loaded PNCs for BTE. Nanocellulose in the form of either CNCs or NFCs imparts the reinforcement to the PNCs. Also, different types of nanocellulose are used in various forms of reinforcement, including distributed reinforcements, planar reinforcements, or continuous networked structures.
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Challenges and Future Perspective
Cellulose fibers are being used as potential reinforcing materials because of so many advantages such as abundantly available, low weight, biodegradable, cheaper, renewable, low abrasive nature, interesting specific properties, since these are waste biomass and exhibit good mechanical properties. Beside numerous advantages of nanocellulose as reinforcement for PNCs, they present some disadvantages, i.e., high moisture absorption, poor wettability, incompatibility with most of polymeric matrices, limitation of processing temperature, quality variations, low thermal stability, and poor compatibility with the hydrophobic. Lignocellulosic materials start to degrade near 220 C and this character restricts the type of matrix which can be used with natural fillers. To fully utilize the potential of nanocellulose as reinforcement in composite materials, the hydrophilic nature of cellulose should be altered to
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make it more compatible with organic solvents and nonpolar polymer matrices. This alteration improves both the incorporation of cellulose into composite materials, which results in more homogeneous composites, and the interfacial adhesion between nanocellulose and matrix in final composite. Cellulose fibers also have some disadvantages such as applications of nanocellulose are mainly considered to be in paper and packaging products, although construction, automotive, furniture, electronics, pharmacy, and cosmetics are also being considered. For companies producing electroacoustic devices, nanocellulose is used as a membrane for high quality sound. Additionally, nanocellulose is applied in membrane for combustible cells (hydrogen), additives for high quality electronic paper (e-paper), ultra-filtrating membranes (water purification), and membranes used to retrieve mineral and oils. There are two basic approaches for creating nanostructures: bottom-up and top-down. The bottom-up method involves construction on a molecular scale from scratch using atoms, molecules, and nanoparticles as building blocks. This method uses chemistry- and physics derived technologies which are based on chemical synthesis or strictly controlled mineral growth. The top-down method in producing nanofiber involves the disintegration of macroscopic material to a nanoscale by the following methods: mechanical (e.g., grinding), chemical (e.g., partial hydrolysis with acids or bases), enzymatic (e.g., treatment with enzymes hydrolyzing cellulose, hemicellulose, pectin, and lignin), and physical (e.g., techniques using focused ion beams or high-power lasers). The possibilities of degradable polymers are steadily increasing and in fact are currently overwhelming. Material design traditionally starts with the synthesis of a new material, which is then characterized chemically, biologically, and mechanically, and then a suitable application can be identified. Computational modeling may speed up this process by predicting the behavior of polymers under various conditions. Libraries containing thousands of individual polymer compositions can be used to predict material characteristics like elastic modulus, degradation time, and glass-transition temperature as a function of the manufacturing process and implantation time. Also, the time-dependent properties of polymers under static and dynamic loading conditions can be predicted. Using such databases, design factors like shape, surface topography, and chemical composition can be controlled to ensure that implants will meet the appropriate requirements of the specific application. Furthermore, customized implants can be created by freeform fabrication and polymer scaffold libraries. Solid freeform fabrication allows for 3D printing of custom designs using CAD drawings. Polymer scaffold libraries allow determining appropriate cell-scaffold combinations that will be successful in tissue engineering applications. Polymer expert systems such as these will prove helpful if not mandatory in designing new implants of degradable polymers and thereby enhance the tissue engineering process. The orchestration of an appropriate host tissue response is not only guided by the biocompatibility (intrinsic) issues of polymer but also by biofunctionality issues, which we consider to be implantation site, vascularization of scaffold, presence/ absence of micromotion, dynamic loading regime, and visualization in vivo. Critical biocompatibility problems such as fibrous encapsulation have been studied
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extensively and can likely be circumvented via direct bone apposition onto the surface. Despite the fact that biofunctionality of degradable polymers such as mechanical loading of polymeric scaffolds requires further investigation as well as adaptation of mechanical testing of materials, pivotal biofunctionality issues are often overlooked. Since biodegradable polymers are part of a comprehensive field of research, a multidisciplinary approach is crucial and convergence of various scientific fields should lead to a cost-effective, patient-friendly strategy to treat bone defects. Once pre-mineralization, growth factor release systems and other biomimetic approaches are clinically available and have had proper mechanical test runs, degradable polymers will get their second chance in clinical practice. Computational modeling will be helpful in selecting appropriate polymers out of thousands and predict their properties during manufacturing and their behavior after implantation for bone tissue regeneration over the degradation process.
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Nanocelluloses in Wound Healing Applications
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Raed M. Ennab, Alaa A. A. Aljabali, Nitin Bharat Charbe, Ahmed Barhoum, Alaa Alqudah, and Murtaza M. Tambuwala
Contents 1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1 Structure of the Human Skin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2 Types of Skin Injuries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Wound Healing Stages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Ideal Wound Healing Dressings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Wound Healing Biomaterials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Nanocelluloses for Wound Healing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1 Bacterial Cellulose (BC) in Wound Healing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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R. M. Ennab Department of Clinical Sciences/Vascular Surgery, Faculty of Medicine, Yarmouk University, Irbid, Jordan e-mail: [email protected] A. A. A. Aljabali (*) · A. Alqudah Faculty of Pharmacy, Department of Pharmaceutics and Pharmaceutical Technology, Yarmouk University, Irbid, Jordan e-mail: [email protected]; [email protected] N. B. Charbe Departamento de Quimica Orgánica, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, Macul, Santiago, Chile e-mail: [email protected] A. Barhoum NanoStruc Research Group, Chemistry Department, Faculty of Science, Helwan University, Helwan, Cairo, Egypt National Centre for Sensor Research, School of Chemical Sciences, Dublin City University, Dublin, Ireland e-mail: [email protected] M. M. Tambuwala (*) SAAD Centre for Pharmacy and Diabetes, School of Pharmacy and Pharmaceutical Science Ulster University, Coleraine, UK e-mail: [email protected] © Springer Nature Switzerland AG 2022 A. Barhoum (ed.), Handbook of Nanocelluloses, https://doi.org/10.1007/978-3-030-89621-8_41
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5.2 Cellulose Nanocrystals in Wound Healing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3 Cellulose Nanofibers in Wound Healing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4 Cellulose Hydrogels in Wound Healing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Conclusion and Future Prospects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Abstract
Wound healing involves three distinct but related stages: inflammation, tissue development, and restructuring. While injury repair is an inherent capacity of any multicellular organism, special safeguards are required in some instances. Autolytic debridement of necrotic tissue may be allowed using highly hydrated hydrogels where surgical excision is not conceivable. Such products are used as legitimate substitutes for wound healing applications because they can trap water until a thousand times by their dry weight. Due to their high biocompatibility, biodegradability, and is relatively inexpensive, the use of cellulose-based hydrogels is now widely known. Experimental methods toward producing more functional wound dressings have lately been tested, such as adding antimicrobial characteristics using a mixture of antibiotics and/or antibacterial polymers. Keywords
Nanocellulose · Wound healing · Dressings · Nanomedicine
1
Introduction
Throughout the body, the skin is the largest organ. The skin comprises three layers: the epidermis, dermis, and fat layers called the hypodermis. The epidermis is the outer surface that maintains the body’s internal environment’s homeostasis and simultaneously protects the body against extreme environmental changes and possibilities of bacterial infections. The dermis comprises all of the capillaries, follicular of the scalp, oil, and sweat glands. From its native condition, the skin is dry and acidic (pH 4–6.8), and the skin cells contain skin lipids that sustain moisture levels and keratinocytes. Distorted skin integrity could be caused by structural causes, including the person’s dietary deficiencies, arterial illnesses, diabetes, heart disease, etc., or by extrinsic episodes such as injuries, immobility, strain, and surgical procedures. When humans experience significant injury in large parts of the skin, such as burns, the loss of the local function, dehydration, and infection can lead to limb loss or mortality. A full variety of biological pathways to preserve skin barrier (preventing dehydration and infection by bacteria) are involved in the healing process. However, skin regeneration and incision remedy may be slow in patients with additional systemic impairments, leading to chronic inflammation [1]. Wound healing is often a gradual mechanism that may be disrupted in broad or chronic wounds that are difficult to treat. In these instances, biopolymers can be used to facilitate or activate the natural dermal and epidermal wound healing process where autologous skin grafts are not usable [2]. Wound healing is structured into four
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correctly and well-programmed stages: hemostasis, proliferation, inflammation, and renovation as just a natural biochemical mechanism within the organism. The four stages should take place at the correct time for a wound to heal correctly. Many causes may interact with one or more steps of this procedure and trigger injury-causing repair to be unsuitable or disabled [3, 4]. These wounds also arise due to the prolonged, unfulfilled, or disorganized mechanism of cure in the case of pathologic inflammation. Many permanent conditions include ischemic ulcers, diabetes, endothelial dysfunction, or pressure that may interfere with wound healing. Wound healing is a complex sequence with four simultaneous and specific alternating steps. The actions of each stage must be correct and controlled. Disruptions or abnormalities may lead to delayed healing of the wounds or a chronic wound injury. The preceding events take place in adult humans as well: (1) accelerated angiogenesis; (2) reasonable inflammation; (3) mesenchymal cell differentiation, migration, and proliferation to the wounded site; (4) sufficient angiogenesis; (5) rapid epithelialization (regrowth of tissues over even a wound surface); (6) collagen synthesis, alignment, and cross-linking providing a scaffold for tissue to heal [3, 5]. The first stage of hemostasis starts through the vascular constriction and forming the fibrin clot shortly after wounding. Clots and damaged tissues around the organ produce proinflammatory cytokines as well as growth factors like transforming growth factor (TGF-β), platelet-derived growth factor (PDGF), epidermal growth factor (EGF), and fibroblast growth factor (FGF). When bleeding is controlled, proinflammatory cytokines migrate to the wound (chemotaxis) and facilitate an inflammatory stage distinguished by neutrophil, lymphocyte, and macrophage sequential infiltration [6, 7]. Several causes can lead to impairment of wound cure. The variables impacting repair should usually be listed locally and structurally. Local influences determine the wound’s features, while structural causes impact the individual’s physical health or illness. Most of these factors are associated, and structural factors influence wound healing by local effects [8, 9].
1.1
Structure of the Human Skin
Our skin is indeed a complex architecture multifunctional organ forming a barrier shielding infectious bacteria or the outside world. Our epidermis, dermis, and hypodermis comprise three distinct tissue layers that make our skin. The exterior epidermal layer is a densely cellular yet somehow vascularized structure that provides the principal protection against environmental damage, like viruses, ultraviolet radiation (UVR), contamination, and sweating [10]. Stem cells transdifferentiate into keratinocytes at the epidermal baseline layer, another major epidermal cellular category that shapes the epidermis’ surface layers. In around 4 weeks, the cells shed the nuclei to form corneocytes forming an interface between the skin and air [11]. Compared to a keratin protein family, which is also frequently expressed in the various stages of differentiation by keratinocytes, the epidermis is also abundant in vimentin, desmin, and internecine nestin. The epidermal layer could be divided into four microlevels (from the exterior: the stratum corneum, the stratum granulosum,
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stratum spinosum, and the stratum basale) [12]. The stratum corneum comprises a firmly packed corneocyte sheet, serving as a significant obstacle to inflammation, damage, and dehydration [12]. It can reach extreme compressive stresses and is abrasive and penetrating resistant [13]. The stratum granulosum and the stratum spinosum comprise mostly lipid-released keratinocytes that advance in other corneocyte development [12]. The epidermis’ innermost layer comprises one progenitor layer of keratinocytes that serve as a propagation origin and regularly repairs tissue on the surface epidermal layers [14]. The dermal-epidermal interface forms the cellular interface between physiologically active and vascularized epidermal layers and abundant vascular dermis protecting the extracellular matrix [15]. The dermal layer mostly consists of a thick endothelium matrix that protects the skin and sensory nerve cells and includes organelles like sweat glands and hair follicles. Such cells synthesize a dynamic structural matrix made up of collagen-bearing loads, robust fibrous tissue, and hyaluronic acid. There are also less plentiful matrices, such soluble proteases, proteolytic enzymes, and cytokines, alongside these main components. The collagens have such a particular distribution of spatial-spectral material, with diverse molecular structures overlapping. Its principal pattern is formed by a repetitive series of glycine-X-Y wherein X and Y can differ among repeat sequences but usually are residual in proline or hydroxyproline [16]. Collagens comprise a threefold helical region, which is stabilized by proline hydroxylation. Some collagen fibers have more than one triple helix dominance among non-helical (globular) entities [17, 18].
1.2
Types of Skin Injuries
Skin injuries result from natural tissue pathology, categorized as acute or permanent by the type of healing procedure involved [19]. Acute wounds, including shallow scratches and burns, recover fully even without scars for around 3 weeks. Chronic wounds, including diabetic ulcers and deep burns, begin to develop if, beyond 3 months, the acute wound is not healed. Etiology, form, complexity, and clinical presentation are the basis of wound classifications [20]. Wounds can be categorized into four major categories based on wound complexity, thickness, origin, and age, as summarized in Table 1. Furthermore, wounds can be divided into cuts (lacerations, tears, and gashes), scratches (scrapes, floor burns), and abrasions. A cut is a deep incision in the skin that results in tearing and opening of the skin. Most cuts cause bleeding simultaneously. Scratches are small skin scrapes attributable to a sharp edge. The skin is typically not torn or opened by scratches. Many bruises are unblemished. Abrasion is placed in which the skin is scraped or ground off. Rubbing or pressure (for instance, rug burn) is commonly the source of abrasion. In general, only the skin surface is affected. The knees and elbows are more likely to be abrased. Bleeding may occur or may not occur [22].
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Table 1 Summary of wound classifications based on their complexity, thickness, origin, and age. Adapted from [21] Wound complexity Wound thickness
Wound origin
Wound age
2
Combined Simple Full Partial Superficial Stab wound Incised Lacerated Superficial Contused Secondary Old Fresh
Affect several tissues Affect only one type Loss of the dermis layer and subcutaneous layer Loss of the dermis/epidermis Loss of the epidermis alone Resulted from pointed weapons Resulted from surgical procedure Torn tissues with sharp objects Break-in skin surface Under the skin injury Ulcers (diabetic, pressure, venous, etc.) More than 8 h from the injury time Less than 8 h from injury time
Wound Healing Stages
An efficient healing process contributes to tissue integrity regeneration, which happens in a highly structured multistage process involving different cell types. Currently, approaches for wound healing evaluation lack a systematic framework for the examination of objective criteria. We have a specific predictive evaluation approach focused on histological standards for wound healing phases. Different injury recovery stages were extensively studied, and many significant recovery incidents have been documented in the literature [23, 24]. The healing process is a multistage mechanism involving a variety of cells and activities. At first, the development of a blood coagulant and inflammation are involved in wound healing. The inflammation requires the distribution of dermal and epidermal cells and matrix synthesis to fill the injuries void and reestablish the skin barrier [25]. Finally, the tissue restructures, and differentiation causes the skin tissues to recover completely, and tissue esthetics can be recovered. In literature, the assumption is that even the advancement of tissue regeneration and wound healing is initially directed at covering the void entirely, the wound will then be re-epithelized and the skin restored [26]. Skin injury involves various layers, such as epidermis, hypodermis, dermis, connective tissue, and blood vessels, including all skin components. The processes are assessed by observing the skin properties and alterations in the skin cells’ physiology, including proliferation, migration, segregation, and tissue remodeling. Whether any procedures fail and the skin’s biochemical properties are compromised, careful care will prevent additional skin injury and encourage appropriate recovery [27]. One of the significant factors for the wound healing process involves re-epithelialization, which is generally recognized as one of the key wound healing pathways that guarantee significant restoration. Reports of wound healing indicated that keratinocytes move through the wound gap at the very early healing
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stages. They may migrate across any wound’s matrices, including clot-related waste, in contrast to the traditional belief that keratinocytes are limited to migration through a newly formed matrix (i.e., granulation tissue) [27]. The inflammatory response is also an essential mechanism formed in the initial stages of healing. The preliminary immune response requires the mobilization of cells that resist probable bacterial infection and enable cytokines’ production to initiate subcutaneous and epidermal pathways. Besides, once the swelling goes past a specific limit, it leads to a healing deficiency and a stop to recovery advancement. Besides, continued chronic inflammatory response contributes to an ECM breakdown and necrotic core development [24, 28]. Besides, collagen synthesis is commonly recognized as a vital stage in the healing process [24]. Researchers believe that the fibroblasts’ significant proliferation is the first expression of the first matrix detected after the initial inflammatory reaction was attenuated. Instead of mature granulated tissue associated with collagen fibers deposition in the final phases of the injurious recovery process, the widespread proliferation is in close contact with the production of early granulated tissue [29]. In the last stages of recovery, wounds are fully epithelized, and the next steps are taken in dermal reorganization. During that phase, the damaged skin restores its force and flexibility and reorganizes the dermis in collagen and elastic fibers. Normal dermal remodeling also leads to the improvement of the scar tissue at some other curing point. While the wound may not be biological, histopathological studies often show a small portion of the wounded region, marked by a skin-follicle gap. This step ends the recovery process as all other criteria measured have recovered to the pre-wounding stage. Complete tissue reshaping is evaluated using the bursting chamber system to calculate skin strength [30].
3
Ideal Wound Healing Dressings
Moist fabrics can improve the process of wound healing relative to dry dressings. Renewed skin can only occur in a wet setting without inflammation and scars enhancement [31, 32]. The moisture dressings were therefore deemed appropriate for the treatment of the wound. The following characteristics must accompany an optimal dressing of wounds: (1) the inspection of moisture around the wound, (2) colossal gas distribution, (3) the absence of excessive exudates, (4) the preservation of wounds from pathogens and microorganism, (5) the decrease of wound necrosis, (6) mechanical protection, (7) easily replaced, (8) biocompatible, safe elastic, and biodegradable, (9) act as a pain reliever, and (10) relatively inexpensive [33, 34]. It has been reported that the ideal wound dressing should have specific features, including the permeability to high moisture and vapor content once applied to the wound. The material composition should not adhere to the covered tissue with enhanced absorption of liquids and moisture in the targeted area. Once applied to the selected area, the dressing will provide a barrier to the external microbial contaminants preventing wounds infection. As these are medical tools, their ability
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Fig. 1 The mechanism of wound healing splits into inflammation, progress, and maturation stages and causes. Codependency is accomplished through various conditions and signaling routes. AMPs, molecular patterns related to damage, pathogen-specific molecular design (PAMPs), pathogen-associated molecular patterns (HMGB1), extracellular matrix (ECM), growth factor-β transforming (TGF-β)
to be sterilized is paramount for the recovery process. Wound dressings are typically generated from hypoallergenic materials with excellent adhesion to the tissues and wound area. The material used to produce the dressing should be comfortable to the skin, produced from biodegradable with enhanced mechanical properties, and cheaply produced (Fig. 1) [35, 36].
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Wound Healing Biomaterials
Biomaterials are broadly defined as nanomaterials of biological origin. Such products could contact blood and other body fluids and tissue for extended durations, producing minor detrimental effects [37]. Biomaterials are categorized in this way, either inorganic (synthetic) or organic (natural). Natural nanomaterials are obtained from plants or animals. Another benefit of organic biomaterials is that they are identical to their body materials. Bionanomaterials that operate within biological
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restrictions are expanding steadily and account for 2–3% of the global medical expenses in developing countries. The following fields contain several materials that are currently in medical applications such as heart braces, artificial coronary vessels, relaxing the heart, stents, synthetic legs, knees, shoulders, scoliosis, urinary tract replacement components, synthetic colloidal lenses, skin, ear ossicles, and dental roots [38]. The current understanding of silk’s biological properties that aid in the wound treatment process would be outlined within this section. For cutaneous wound healing applications from recent decades, a range of silk varieties, including silkworm silk fibroin, silk sericin, native spider silk, and recombining silk material, were investigated. Several techniques were employed to create practical biologically active dressings and useful bioengineered grafts to harness silk’s regenerative properties in recent years. Silk is a biomaterial of the protein produced by various insects, including silkworms, butterflies, spiders, mites, and scorpions. Silk made of silkworms and spiders has been studied extensively for numerous biomaterials. Silk is a complex definition and is sometimes referred to as the insect-spun protein fibers; nevertheless, it differs between organisms and functions [39]. Silk structural existing platform in the crystalline domain (heavy chain) is mainly made up of a bulky amino acid side chain glycine, alanine, serine, and tyrosine (GAGAGSGAAG(SG(AG)2] 8Y) and a short, amorphous (light chain) domain of bulkier aspartic acid side chain. This amino acid sequence enables the silks to shape a secondary structure with a parallel β-platen sheet, allowing its distinctive mechanical and physical properties [40]. Fibroin promotes cells such as fibroblasts binding and production. Fibroin is oxygen and water vapor permeable and has a comparatively slight thrombogenicity and a low inflammatory response [39, 41]. The whole protein becomes appropriate for skin regeneration and skeleton and tendon repair because of the RGD series (L-arginine, glycine, and L-aspartic acid) [42]. Spiders could make silk proteins 16 times stronger yet 2–3 times more elastic than nylon. Silk, particularly when submerged into liquid materials, can also subcontract. Silk fibroin is developed for medical applications in gels, powders, film production, matrices, and scaffolds or materials formation [43, 44]. Waxes like carnauba wax, shellac wax, or bee wax are used to coat silk fibroin to improve mechanical performance comparable to uncoated fibroin fiber. In comparison, the covered fibroin fabrics bind less to in vitro pig skin wounds’ surface area than petrolatum mesh wound dressings (Sofra-Tulle ®), which renders dressing changes to the recipient sufficiently less painful and the wound tissue less delicate [45, 46]. Findings of enhanced physical characteristics provided, swelling, and deterioration, as well as increased adhesion of L929 fibroblasts, were also reported. Silk fibroin combined with chitosan, gelatin, alginate, or synthetic material such as polyvinyl alcohol or poly(lactide-co-glycolic acid). In vivo studies have also demonstrated improved angiogenesis and collagen arrangement using these composite nanomaterials [47, 48]. Sericin would be a silk protein that is extracted out from the silk cocoon. Sericin has many protective properties, mostly on the skin’s stratum layer, contributing to increased skin barrier functioning. Cell proliferation and differentiation are facilitated by sericin scaffolds consisting of different
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Fig. 2 Some of the attractive features of silk-based biomaterials that make them ideal for wound healing applications, including their biocompatibility, bioresorbable, non-immunogenic materials, and abundance in nature, the ability for their surface functionalization, and their biodegradability with the ability of regenerative properties
polymers and cross-linkers. They have also been reported to speed up injury repair in vivo (Fig. 2) [49].
5
Nanocelluloses for Wound Healing
Natural polymers such as polysaccharides are safe, low-cost, and easily degradable nanomaterials. Almost all of the planet’s organic substances are polysaccharides (approximately 75%) [50]. Polysaccharide-based wound treatment biomaterials may be categorized into different classifications: acidic (cellulose, β-glucans, dextrans), simple (chitin, chitosan), or sulfated (chondroitin-based sulfate, sulfate of the dermatan sulfate, sulfate of the keratan, heparin) [51]. An overview will be given to applying functionalized bioavailable polymeric materials like pectin, hyaluronic, gelatin, derivative chitosan, and other derivatives. Chitosan is a linear amino polysaccharide consisting of glucosamine and N-acetyl-glucosamine units connected by b(1–4)glycosidic bonds of chitin’s parent polymer N-deacetylation. Chitin, the second most common polysaccharide, is present mostly in crustacean exoskeletons and the fungal cellular membranes. This section will focus on chitosan products considered to facilitate accident care. In the literature on wound care, other chitosan derivatives produced for other purposes are listed. During wound healing, chitosan associates with several cell functions. Chitosan coatings were proven to cause low adverse outcomes and to have protection against infectious diseases, to minimal or even no fibrous encapsulation. When used as powders, nano-size, and micro-pieces,
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gelatin, sponges, or composites with many other materials, chitosan can also improve wound healing. Chitosan is active in all wound healing stages. In the early healing stages, chitosan exhibits its unique weather characteristics and facilitates macrophage and neutrophil penetration and relocation [52]. During wound healing, chitosan associates with several cell functions. Chitosan dressings were proven to cause common adverse health effects and protect against infectious diseases, with negligible or even no fibrous encapsulation. It has been reported that the polymer chitosan is involved in the promotion of polymorphonuclear neutrophils and plays a role in granulation through the induction of cellular proliferation and dermal fibroblasts. Chitosan was shown to take part in all wound healing phases. Chitosan demonstrates its special hemostatic abilities during the preliminary healing processes and facilitates neutrophils and macrophages infiltration and redistribution. The lesions are cleaned by external and granular tissue types, which permit the formation and re-epithelization of fibrous tissue [53]. In chronic wounds caused by excess collagen formation throughout the restructuring process, chitosans will reduce the scar tissue, thereby enabling a successful re-epithelization. The production of signaling pathways suggested in the recovery process is influenced by chitosan. The formation of TGF-b1 and the synthesis of collagen in the pre-injury period (day 3), as seen in burning wounds in mice, enhance and promote tissue repair. At the late after-injury point (day 7), chitosan reduces TGF-b1 expression, facilitating scars development. Such modulation is meant to speed up the process of wound healing [54].
5.1
Bacterial Cellulose (BC) in Wound Healing
Well , even before the term “nanocellulose” first appeared in ProQuest, WOS, and PubMed databases, bacterial cellulose was used in skin restoration. It was just named “bacterial cellulose,” but it is a hydrogel that comprises nanofibrils of cellulose. Bacterial cellulose pellicles for bacterial skin are a “temporary skin replacement” for the treatment of brushes, abscesses, bruises, and another skin injury, which is the first study from 1990 [55]. The new format in treatments for preventing and closure in wound burn wounds includes early excision and the thorough coverage of the exposed area necrotic tissue. The effective wound dressing should retain moisture, permit oxygen exchange, absorb wound exudate, promote re-epithelization, minimize discomfort and curing times, and avoid infection in all these skin lesions. However, further and specific treatments are needed, adapted to every single lesion’s needs. These things require an inventive, inclusive, and adaptable dressing implementation (Fig. 3) [56]. The bacterial cellulose is a nanofibril hydrogel, which imitates the natural extracellular matrix fibrillary material. Bacterial cellulose is highly moisturizing, and it has mechanical properties, including power, Young’s modulus, elasticity, and adaptability [57]. BC is a bacterial biomaterial with many attributes over plant cellulose, including quality, porosity, fluid and gas permeability, high water absorption, and mechanical strength. BC may also be implemented to achieve antimicrobial
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Fig. 3 BC-based nanomaterials for wound dressings. The list represents BC’s intrinsic properties that hold a great advantage for wound dressing applications such as malleability, liquid permeability, safety, and purity. With additional properties such as anti-inflammatory, antimicrobial activities, and tissue regeneration. BC has unique properties from water uptake, biodegradability, cellular adhesion, materials porosity, biocompatibility, and mechanical strength, making them ideal nanomaterials for wound dressing materials
responses and potential local medication delivery characteristics and biocompatibility. The growing influence of consumer goods on BC is also the effect of industrial material handling simplicity. Fresh BC pellicles could be synthesized into any type of vessel so that the guided increase of the desired measurements can be carried out [58]. The difference in water levels in BC primarily affects their viscoelastic and electrochemical characteristics. Because of the BC’s improved electron transport resistance, the liquid is 50–80% [59]. In wound dressing implementations in which the water content is a must, this observation was especially significant. In comparison to water-soluble polymers such as CMC, methylcellulose (MC), and poly(vinyl alcohol) (PVA), the moisture content of undried and replenished BC
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was determined to affect reswollen BC [60, 61]. On the other side, Bottan et al. developed directed assembly-based biology as a strategy for modifying BC’s topography on the surface of human dermal cells, fibroblasts, and keratinocytes in terms of migration routes and configurations [62]. The BC fibers’ structures include mechanical characteristics, significantly elevated amounts (84–89%) of the crystalline phase, and the absence of other contaminating composites, distinguishing BC from plant-based polymers, providing for such a quick purification process. Besides, the various hydroxyl groups in glucose can form associations with more than 90% water molecules, resulting in a high fluid retention ability [63], along with biocompatibility, low cytotoxicity, economic performance, dimensional stability, lightness, as well as the fact that the BC composition is highly adjustable and therefore can integrate supplementary materials, like antibiotics, through its pores, proving the ideal fundamental functionalities for applications of the wound dressing. Furthermore, the water content and water-residing characteristics, to sustain the injury moisturized and be capable of absorbing large volumes of exudates, are critical features required for wound dressings, especially in the treatment of burn (Fig. 4) [64]. Effective oversight of humidity typically improves developmental outcomes, prevents wounds against infections, decreases discomfort, and decreases global healthcare costs. Besides, water extraction or retaining power enables the charging mostly on wound dressing content of liquid drugs and bioactive agents [65]. The ability to preserve moisture also protects wounds from being dehydrated so that the skin does not bind to the injury, thus shielding the tissue from contamination and minimizing discomfort during the dressing process. It is recognized that exudates
Fig. 4 Comparison between BC wound dressings and BC/Alginate/PHMB dressing, comparing their advantages and disadvantages as wound dressing tools
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tend to cause the wound to separate tissue layers, thus slowing the curing phase. Therefore, abscesses from a wound must be removed as well, as the excellent capability for drainage would be a decisive criterion for dressing applications [66]. To this end, numerous experiments were performed to evaluate new platforms for wound dressing throughout the condiments concerning the capacity to hold much water and release water. In specific, there have been significant improvements in the water retention capacity and water release rates in the composition of the surface, the pore diameter accessibility, and the existence of hydrophilic substances in the BC framework. The water vapor transmission rate is yet another consistency index for wound dressings [67]. Aloe vera lotion also was a valuable part of wound dressings. The water holding capacity is improved by aloe vera gel by around 1.5 times over unaltered materials, as it is incorporated in the BC framework at a gel concentration of less than 30% during the biosynthetic pathway. In response to BC/aloe vera gel, improved water vapor permeability was also reported [68]. The physicochemical characteristics for wound dressing HOBC/chitosan/alginate films were recently characterized by Chang and Chen (2016). BC films’ water vapor transmission rate was prepared with 98.0%, 98.5% gel formulations, 2865 and 3034 g m 2 day 1, and comparable to optimal dressing overall. It was not favorable for molding the less liquid gel solution with a 98.0% water content. The 98.5% water gel solution has the most attractive mechanical qualities, wettability, and water vapor transmission rate [69]. BC formulated as a polymer matrix utilizing glycerin has enabled a remarkable hydrating effect on the skin. This substance in treating dry wounds, including rheumatoid arthritis and psoriatic arthritis, indicates improved compliance and improved malleability [70] (Table 2).
5.2
Cellulose Nanocrystals in Wound Healing
Driven by Nickerson and Habrle’s research, Ranby initially recorded colloidal nanocellulose suspensions in 1951 [90, 91]. Even more, studies have shown that the degradation of high-quality wood pulp celluloses with hydrochloric acid and sonification allowed microcrystalline cellulose (MCC) to be manufactured in commercial applications. Since the amorphous and crystalline regions may show cellulose microfibrils, separate nanomaterials may be removed from the amorphous area using amorphous hydrolyses such as microcrystals, whiskers, nanocrystals, nanoparticles, microcrystallites, or nanofibers. They may also be commonly referred to as celluloses, nanocellulose, or nanophase [91]. CNCs can be produced from virtually any cellulose fibers in principle. Plants, tunicates, and green algae are some of the predominant origins. Catalase comprising CNCs and calcium peroxide nanocomposite have been reportedly shown to increase cell density in L-929 fibroblasts and accelerate wound healing and sterilization [92]. Fibroblast cell growth and promotion were also demonstrated to benefit and facilitate three-dimensional starch CNCs with regulated porosity, mechanical strength, and biodegradability. The
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Table 2 Overview of common in vivo BC or BC-based wound healing dressings Type of BC formulation BC-containing vaccarin
Wound type Wound of full thickness
BC-collagen combined hydrogels
Wound of full thickness Wound of full thickness
BC-comprising Zingiber officinale root purified extract
BC-dextran hydrogel nanocomposite
Wound of full thickness
Composite of BC-acrylic acidcontaining cells
Wound of full thickness
Hollow BC micro-nanospheres
Wound of full thickness Dermatomeperpetrated wound
BC loaded with sericin silk and polyhexamethylene biguanide
BC loaded with lidocaine
Thirddegree burns
Hydrogel particulate BC-acrylamide microparticles
Partialthickness burns
BC formulation with biguanide and silk sericin polyhexamethylene
Fullthickness wound
Clinical outcome The wound healing properties of BC-vaccarin membranes are reported to have faster and better effects on promoting endothelial cell proliferation Faster and improved curing BC-collagen hydrogel was reported in vivo and in vitro The aqueous extract from BC-containing Zingiber officinale was slower in wound treatment than the constituents alone, and it shows an overall improved repair Dextran facilitates fibroblasts’ growth and enhancement throughout the reshaping phase, which speeds up the wound healing procedure The repairing technique is accelerated by both the standalone and the hydrogel comprising the cells. The hydrogel containing cells were quicker in healing times BC hollow microstructures displayed quicker heal even than BC and BC bulk Little change in injury or pace rendered the wounds even less severe for the patients, with the BC-based dressings making it less painful Lidocaine-loaded BC does not interfere with BC’s capacity to treat normal wounds, and lidocaine was effective in acting as a local anesthetic The hydrogel composites increased the mechanism of recovery by facilitating re-epithelialization and fibroblast proliferation Composite polymer displayed antibiotic efficacy and a quicker treatment than Bactigras alone
Refs [71]
[72]
[73]
[74]
[75]
[76]
[77]
[78]
[79]
[80]
(continued)
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Table 2 (continued) Type of BC formulation BC loaded with amoxicillin
Wound type Fullthickness wound
BC comprising TiO2 NPs
Thirddegree burns
BC comprising thymol
Thirddegree burns
BC- chitosan biocomposites coated in vitamin K, protamine sulfate, or kaolin with silk fibroin or silk fibroin/ phosphatidylcholine
Femoral artery injury
BC with a patterned 10 μm sticky stripes
Deep-skin injury
Acid, acidic, and alkaline BC membranes composites
Fullthickness wound
BC comprising ZnO NPs
Thirddegree burns
BC comprising various types of metallic NPs (Cu, Na, Ca)
Partialthickness burns
BC-based nanocomposite either covered with nano-skin or nanoskin alone
Fullthickness wound
Clinical outcome The antibiotic BC-containing formulations demonstrated quicker wound healing recovery time and cure The antibacterial property, as well as an improved injury cure, re-epithelization, and angiogenesis were illustrated with significant improvement Wound dressing demonstrated antimicrobial inhibiting potential and improved wound injury process In contrast with ordinary bandages in both stable and diabetic rats, these composite materials are superior to the hemostatic dressings packed with kaolin Striped BC suppressed inflammatory reaction and lowered fibroblast aggregation, substantially reducing scar dimensions than non-patterned BC pH has influenced typical BC curative performance and is also the acidic conditions with the highest curative efficiency The wound dressings demonstrated antimicrobial activity and improved injury heal times The dressings displayed antimicrobial properties and enhanced wound healing scars and recovery times Both BC-based grafts have greater repairing efficacy than the grafts alone
Refs [81]
[82]
[83]
[84, 85]
[86]
[87]
[82]
[88]
[89]
examples above demonstrate that CNCs can be used for high-order tissues engineering and the reconstruction of the injured or diseased component of the body. Nanocellulose is a nanometer spectral cellulose or crystallite cellulose-based nanocrystals with a needlelike or rodlike structures. Nanocellulose measurements focus on the origin and preparation process; the CNC wood generated has a diameter
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of approximately 3–5 nm and a length of 100–300 nm and therefore is subject to research as a drug excipient and wound dressings. A biocompatibility evaluation is critical for each form of nanocellulose used in procedures in which it comes into contact with humans. Biosignificance studies on crystalline CNCs have also been carried out [93, 94]. A synthetic coat composed of 45S5 of bioactive inorganic glass, coated and intertwined on CNCs, was sprayed on stainless steel 316 L to enhance bone touch to implant and speed up the bone heal phase. This coating significantly accelerated the fixation and spreading of the in vitro osteoblast progenitor cells in the mouse and the extracellular matrix formed by such cells [95]. Type of NCCs formulation NCCs
Wound type Generic wound
Drug loaded Antibiotic ciprofloxacin
NCCs
Generic and burn wounds
Curcumin, vitamin B12, and diclofenac therapeutics
NFCs
Skin burnt on mice model
Combined with ZnO
Poly(lactic-coglycolic acid)/ cellulose nanocrystals/ carboxymethyl chitosan (PLGA/ CNC/CMCS) Curcumin/gelatin microspheres/ collagen/cellulose nanocrystal (Cur/GMs/Col-CNC)
Full-thickness skin burn in rat models
Curcumin and angiogenin
Full-thickness skin artificial burn in rat models infected with Pseudomonas aeruginosa
Curcumin
Not determined
Octenidine
Nanofibrillar bacterial cellulose/ polyethylene oxide (PEO)/polypropylene oxide (PPO) arranged in a triblock structure (NFC- PEOx-PPOyPEOx)
Remarks Development of electrospinning technique for drug delivery to the desired site of infection Generated very stable nanocomposites with: The vitamin B12 was nearly 100% The curcumin release was up to 70% The diclofenac release was 80% Enhanced wound healing and tissue regeneration activity Increased angiogenin expression levels which lead to improvement in wound healing
Nanomaterials exhibited antimicrobial activities in vivo with higher epithelization rates Downregulation of bacterial infection on the injured site
Refs [96]
[97]
[98]
[99]
[100]
[101]
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Nanocelluloses in Wound Healing Applications
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Cellulose Nanofibers in Wound Healing
Much like bacterial nanocellulose, nanocellulose extracted from plants has proven to be very impressive, remarkably since it has changed its chemical and physical properties. Its high design to hold fluids and form translucent films nanofibrillar cellulose (NFC) has also been evaluated for wound treatment implementations. Besides unhealed and chronic injuries, such characteristics are necessary if the exudates must be managed appropriately. Furthermore, NFC’s translucency helps the wound improve despite having to strip the dressing [102]. Cellular nanofibrils (CNFs), for instance, have been changed either via TEMPOmediated oxidation or by using (2,3-epoxypropyl)trimethyl ammonium chloride (EPTMAC) to add a positive charge [103]. Unmodified (u-), anionic, and cationic (c-) CNFs were developed in a study conducted by Skogberg et al. [103] using an evaporation-inducted glass droplets system using either the solid wood kraft (u-CNF) or the softwood kraft pulp (e-CNF). Nanofibers have demonstrated a considerably higher orientation pattern in one regular pattern on c- and u-CNF interfaces than on a CNF surface in the atomic force microscopy. The connection, the expansion, the viability, and the proliferation of embryonic fibroblasts in the mouse all endorsed a-CNF and c-CNF, although the cell output on a-CNF was noticeably more apparent. The cells on oriented c-CNF interfaces are displayed; however, a parallel orientation can direct cell division. Only recently were transferable free-standing nanocellulose materials generated in tandem with evaporating liquid boundary line with a similar alignment of CNFs [104]. Human dermal fibroblasts in the DMEM medium were observed to be grown on cellulose meshes with 10% of the bovine’s fetal serum and 40 μg/ml of gentamycin. The cellulose mesh surface has been fitted with two distinct types of nanocellulose solutions: c-CNF and a-CNF. Together with c-CNF and a-CNF, cellulose mesh surface properties for adhesion and proliferation were expected to be enhanced by cellular adhesion and proliferation. On the cellulose mesh surface, a 0.15 wt.% c-CNF solution formed a thin film, while 0.15 wt.% a CNF solution filled single cellulose microfibers to fill the broad areas within them (Fig. 5) [104]. In a clinical trial in burn patients, the healing potentials of NFC nanomaterials were evaluated. A split-thickness dressing of the skin graft donor positions was added. The Suprathel lactocapromer dressing (PMI Polymedics, Denkendorf, Germany) was contrasted with the NFC dressing. The donor tissue site was epithelial, quicker than Suprathel® when protected by the NFC dressing. Since it was biocompatible, it was quickly applied to the wound site and stayed in place until the donor site was renewed. NFC dressing proved to be a promise to treat skin graft sites. It also distinguishes itself from the epithelial skin [105]. Cross-linked to calcium ions, the NFC (produced from industrial, never-dried sulfite bleached dissolving softwood pulp) also exhibited hemostatic potential, in particular when supplemented with collagen or kaolin. Furthermore, NFC polymers’ static nature in cytokine secretion and reactive oxygen species development have been reported in inflammatory response experiments with blood-borne mononuclear cells. NFC hydrogens’ ability to preserve a
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Fig. 5 Schematic illustration of cellulose-based nanofibers and their incorporation with drugs of choice on the medical patches to be applied to the patient
sufficiently moist state for different wounds was seen in water retention experiments [106, 107]. In oxidized cellulose (OC) adjusted in inert argon plasma, weather potential was also observed. The OC modified by plasma was acidic and had a wider surface and more excellent water absorption capabilities. For adequate hemostasis, these aspects are essential. Furthermore, plasma-modified OC acidity improved its antibacterial capacity. Therefore, plasma modifications can be used to autonomously modify and even sterilize the OC hemostat in a single simple step [108]. Comparably, nanofibrillated pulp fiber cellulose, formulated in film shapes with TEMPO-induced oxidation, hindered the advancement of recurrent wound bacterial infection of Pseudomonas aeruginosa and contributed to a more significant death of microbial species than Aquacel® commercial counterpart [109]. The very same NFC again shows action against Pseudomonas aeruginosa PAO1 during suspension and aerogel action. Biofilm formation accumulation in aerogels’ event decreased with a reducing porosity and substrate surface roughness [110]. The incorporation in chitosan/poly(vinyl pyrrolidone) composite membranes of cellulose nanocrystals (derived from Hibiscus cannabinus) established for tissue engineering purposes strengthened their antibacterial activity which can be seen in Pseudomonas aeruginosa and Staphylococcus aureus. The antibacterial function has further been increased by the hydrophobic stearic acid covering of these membranes, which hamper bacterial cell adhesion [111]. For example, cellulose acetoacetate and (3-aminopropyl)triethoxysilane, prepared by cross-linking CNF, demonstrated superior antibacterial performance against
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Staphylococcus aureus and Escherichia coli and showed bactericidal levels of about 99.9% [112]. Other compounds of concern include alkaline, shikonin, and its derivative products, found naturally with wound-related repairing and antibacterial, antiinflammatory, antioxidant, and antitumoral function. For the first time, such substances were inserted into electrospinning cellulose acetate nanofibrous meshes for potential wound dressings in a study by Kontogiannopoulos et al. [113]. The pH-sensitive hydroxyethyl cellulose/hyaluronic acid complex hydrogen has been incorporated as isoliquiritigenin, a phenolic compound discovered in licorice. Similar composite materials demonstrated antimicrobial activity against Propionibacterium acnes. Accordingly, acne treatment was considered encouraging.
5.4
Cellulose Hydrogels in Wound Healing
Polymer hydrogels have been extensively investigated over the last decades with their unique characteristics making them ideal for a wide range of applications. Mostly in the biomedical field, for example, drug delivery, regenerative medicine, and injury dressing, hydrogels play an essential role [114]. Hydrogels are commonly classified as three-dimensional polymer networks in terms of hydrophilicity. Owing to the unique arrangement, hydrogels are enabled to swell in the water interstitial spaces in concentrations up to 1000 times their dry weight and to capture water molecules without dissolution immersed in a solution. Hydrogels may be categorized as physical (also known as reversible hydrogels) or chemical (also known as permanent) by the nature of the polymer matrix’s cross-linkages. During the first scenario, the connections can be based on physical interconnections, H-bonding, or hydrophobic/ionic interactions. The latter instance is a mixture of polyelectrolytes and opposing charges (e.g., calcium alginate and poly(L-lysine)), which is composed of the polyelectrolytes complex (PECs). On the other hand, chemical hydrogels are built upon covalently linking frameworks resulting from chemical ligands, including ethylene glycol dimethacrylate (EGDMA) [115]. Various microorganisms actively secrete BC as nanofibers, namely, Gluconacetobacter and Agrobacterium. This polymer has an intrinsic hydrogel-like nature that makes it suitable for wound healing applications in which a moist atmosphere is required. A remarkably crystalline structure, resulting in outstanding physical and mechanical properties including higher tensile strength, and water retention. Moreover, because BC is incredibly clean, it is naturally biocompatible and biodegradable without severe purification [116]. Several research pieces on this substance in different sensing areas were carried out with all that in mind, emphasizing its use in wound healing. The BC-based scaffold construction with enriched bioactivity has been defined in a study by Lin et al. [117]. Physically pointed for consistent polymer matrix holes and coated by alginate solution, which contains various extracellular matrices (ECMs), including elastin, collagen, and hyaluronic acid, with several growth factors (i.e., B-FGF, H-EGF, and KGF), a macroporous configuration has been created. CaCl2 has been applied to maximize the combination of the alginate gel coat. In physiological conditions, the escape of hyaluronic acid, collagen, and the dissemination of
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growth factors are measured, with a healthy release behavior and a progressive rate for all materials. Polymers were also tested for biocompatibility with fibroblasts (HS 68). Of cellular seeds of collagen and H-EGF scaffolds, considerably higher cell viability has been reported, whereas cells’ proliferation has been decreased if the concentrations have been raised [117]. The same method was indicated in recent research, which contrasts a BC/collagen (BC/COL) hydrogel’s antimicrobial properties with a commercial collagenase ointment. BC material was created by shredding and combined to form a gel of collagen. In vivo experiments were carried out in three sections to evaluate the BC/COL (GI), industrial ointment (GII), and control (GIII), respectively. During the first stages of the healing phase, GI displayed quicker re-epithelization and improved adhesion relative to GII. In the treated group with a hydrogel of BC/COL, a moderate inflammatory reaction took place on day 3, but in the three groups, no substantial difference was noticed on day 7. The greater efficiency of tissue repairs demonstrated by the dressing can be due to the bacterial cellulose’s biological properties (Fig. 6) [72]. BC formed a polymer with agarose, a biodegradable polysaccharide with low mechanical properties, and an overcapacity to take water in the analysis carried out by Awadhiya et al. A homogenizer was used to refine the BC membrane to produce a fine slurry and an agarose and glycerol solution. The films’ power was measured with a maximum improvement of 140% compared to pure agarose for the 20% w/w composition of BC. Higher cellulose levels resulted in lower intensity, possibly attributable to a low agarose concentration, which induced tension or agglomeration in cellulose fibers to be unable to sustain and distributed. A reduction in liquid absorption values was reported for the identical BC/agarose mixture, from 700% (pure agarose) in terms of 37 C to 350% in terms and 4 C as a result of lower temperature agarose chains’ decreased mobility. This is because nonporous cellulose fibers, unlike BC membranes, cannot contain water [118]. Fig. 6 Nanocellulose-based gels for wound healing and wound dressings. Such gels consist of nanocellulose polymers connected to form superabsorbent hydrogels to be applied on specific areas of burnt skin or compromised skin due to the injury
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Much research was based mostly on the loading of antimicrobial materials, in particular in nanostructures. Mekkawy et al. identified a process of combining for the fungal extract reduction of silver nitrate. The resulting silver nanoparticles (AgNPs) also were treated utilizing various agents, including polyethylene glycol (PEG) 6000, SDS (sodium dodecyl sulfate), and ß-cyclodextrin (β-CD), to generate antibacterial hydrogel dressings. Included in this, 20% w/w propylene glycol is a gelling agent of the sodium carboxymethyl cellulose (Na-CMC) and hydroxypropyl methylcellulose (HPMC). Agar well diffusion test tested the products’ antibacterial properties, with Na-CMC hydrogel showing a potent inhibition in bacterial growth. Besides, it showed optimum viscosity levels, so the in vivo experiment was chosen. The group obtained with the AgNP hydrogel was quicker than the placebo group treated with silver sulfadiazine, wound healing, and better makeup. Furthermore, a swift and higher bacterial growth inhibition was found, with a 2.7% bacterial count for the silver hydrogel and 30% for silver sulfadiazine detected in the untreated community [119]. Creating a silver dressing method by loading an interchangeable fluorescent compound onto carboxymethylcellulose (Na-CMC) was very promising in research from 2015. The [Ag(IMD)2]ClO4 matrix was generated by summing AgClO4 in dry acetonitrile to a resolution of dance imidazole (IMD). Na-CMC and polyethylene glycol are solvent dissolved, and a homogeneous solution was added to the silver complex. The padding was then dried, such that the remaining solvent was removed and laid between clean bandages and an operative circle. The release rate of silver ions has been examined, indicating a slow release of 1% of the silver complex composition during the first 8 h and surprisingly a slow release of 0.5% of the silver complex in the first 3 h, followed by a linear release in 24 h. This has been clarified by a faster cationic interchange of silver ion concentrations because of the lower mobility resistance of foreign ions within the system. A positive result was shown in the antimicrobial test on Escherichia coli, and Staphylococcus aureus relative to other AgNP coating products was with lower MIC values [120]. Various antimicrobial substances were packed into cellulose-based hydrogels as leachable substances. Significant research conducted in 2016 showed that galantine was incorporated into cellulose hydrogel through cyclosporiasis (Cys) complexation. The galanin is a flavonoid that has been shown to inhibit the action of methicillin-resistant S. aureus, contributing even to intrinsic antibacterial activity. In the first 5 h, a release of the burst was observed for all hydrogels, possibly because galangin dissolved from the ground. Increased escape was presumably induced by the more significant interaction with cyclodextrin for cellulose hydrogel than control (i.e., cyclodextrin-cellulose hydrogel). Staphylococcus aureus was then tested for the antibacterial activities of the hydrogels [121].
6
Conclusion and Future Prospects
Nanocellulose is an auspicious material for several uses, including regenerative medicine, wound healing and manufacturing, science, bioengineering, and pharmacy. A primary area of study is to resolve significant problems associated with the
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healing phases in the cellulose wound dressings. Hydrogels minimize the dressing change’s discomfort to guarantee that necrotic tissue can be extracted, and tissue regeneration occurs in a wet environment. Furthermore, due to its inherent architecture and mechanical features, bacterial cellulose membranes represent an ideal material for the manufacture of skin substitutes. Consequently, nanocellulose as a temporary transport medium is a prospective approach to delivering cells and drugs to wounds and supporting cell attachment and proliferation.
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Kavitkumar Patel, Jahara Shaikh, and Tabassum Khan
Contents 1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Wound Repair and Regeneration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Criteria for Wound Healing Materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Chemical Modification of Nanocellulose for Wound Healing . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Cellulose Nanocomposites for Wound Healing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Nanocellulose Decorated with Nanoparticles for Wound Healing . . . . . . . . . . . . . . . . . . . . . . . . 7 Nanocellulose Functionalized with Antibacterial Agents for Wound Healing . . . . . . . . . . . 8 3D-Printed Nanocellulose Materials for Wound Healing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Abstract
Wound healing is a specific physiological phenomenon that is associated with the natural phenomenon of growth and tissue repair. The process of healing takes place naturally and is a continuous process that can be divided into four phases – hemostasis, inflammation, proliferation, and remodeling with tissue formation. There are several biomaterials and novel approaches explored and reported for clinical management of wounds. Nanocelluloses are lucrative biomaterials that provide a biocompatible alternative with added attributes of biodegradability and low toxicity. Nanocellulose has high porosity and is capable of water retention
K. Patel (*) Department Pharmaceutical Chemistry, University of Mumbai, Mumbai, India e-mail: [email protected] J. Shaikh · T. Khan Department Pharmaceutical Chemistry, SVKM’s Dr. Bhanuben, Nanavati College of Pharmacy, Mumbai, Maharashtra, India e-mail: [email protected] © Springer Nature Switzerland AG 2022 A. Barhoum (ed.), Handbook of Nanocelluloses, https://doi.org/10.1007/978-3-030-89621-8_42
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capacity that helps to keep the wound moist and warm that is optimal for the healing process. The rationale to use nanocellulose lies in its attractive physicochemical and biological properties that make it a cost-effective and renewable option in skin tissue engineering. Chemical modification processes of nanocellulose like acylation, esterification, and oxidation can impart suitable physical properties to nanocellulose making them amenable to customization for various applications. Nanocomposite systems of nanocellulose are widely explored in wound healing research. Nanocellulose loaded with nanoparticles such as metal nanoparticles (silver, gold, and zinc) possesses low toxicity and good antibacterial properties. Nanocellulose derived through surface grafting and functionalization of different nanoparticles and incorporation of antibacterial agents has improved the performance of nanocellulose in wound healing. This chapter presents a comprehensive review of the versatility of nanocellulose in wound healing applications. Keywords
Wound repair · Cellulose nanocrystals · Bacterial cellulose nanocomposites · Nanoparticles · 3D bioprinted nanocellulose · Antibacterial Abbreviations
3D 2D AA AFM AgNPs AgSD bFGF BB BC BCP BNC CAGR CAP CNC CNF DABC DABC DF DH DMTA DP ECM EDC EGF
Three-dimensional Two-dimensional Acrylic acid Atomic force microscopy Silver nanoparticles Silver sulfadiazine Basic fibroblast growth factor Bambusa bambos Bacterial cellulose Bacterial cellulose pellicle Bacterial nanocellulose Compound annual growth rate Chloramphenicol Cellulose nanocrystal Cellulose nanofiber 2,3-dialdehyde cellulose 2,3-dialdehyde cellulose Dermal fibroblasts Dendrocalamus hamiltonii Dynamic mechanical thermal analysis Degree of polymerization Extracellular matrix 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Epidermal growth factor
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EGDMA EK FGF FTIR GGM GeIMA GMA IL-1 KGF K.P. LP LPS MFC MMPs NaOH NCC NFC NGF NHS P.A. PDA PDGF PHMB PVA PVP SA S.A. S.E. SEM SPP SMA TEMPO TEM TH TGA TGF TiO2 TNF-α TPP VEGF XG XPS XRD ZnO ZnONPs
Ethylene glycol dimethacrylate Epidermal keratinocytes Fibroblast growth factor Fourier transform infrared spectroscopy Galactoglucomannan Gelatin methacrylate Glycidyl methacrylate Interleukin-1 Keratinocyte growth factor Klebsiella pneumonia Laser profilometry Lipopolysaccharide Micro-fibrillated cellulose Matrix metalloproteinases Sodium hydroxide Nanocrystalline cellulose Nano-fibrillated cellulose Nerve growth factor N-hydroxysuccinimide Pseudomonas aeruginosa Polydopamine Platelet-derived growth factor Poly-hexamethylene biguanide Polyvinyl alcohol Polyvinylpyrrolidone Sodium alginate Staphylococcus aureus Staphylococcus epidermis Scanning electron microscopy Solvent plasma process α-smooth muscle actin 2,2,6,6-Tetramethylpiperidin-1-yloxyl Transmission electron microscopy Tetracycline Thermogravimetric analysis Transforming growth factor Titanium dioxide Tumor necrosis factor-alpha Sodium tripolyphosphate Vascular endothelial growth factor Xyloglucan X-ray photoelectron spectroscopy X-ray diffraction Zinc oxide Zinc oxide nanoparticles
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Introduction
The breakdown of protective epithelial cells of the skin in diverse physiological and medical conditions results in skin or tissue damage called wounds. Based on the nature of wound repair process, wounds can be classified as acute and chronic wounds [1]. An acute wound is minimal tissue injury that occurs immediately after certain trauma and is completely healed within 8–12 weeks. Chronic wounds arise from tissue injuries that take time to heal slowly, and it fails to improve the normal healing processes in an orderly and timely manner [2]. Wound healing is an intricate dynamic tissue regeneration process that occurs in four phases: coagulation and hemostasis phase (after injury); inflammatory phase after which swelling takes place (shortly after tissue injury); proliferation phase (neovascularization); and remodeling phase, in which formation of new tissues takes place [3]. Several factors affecting the wound healing process can be classified as local and systemic. Local factors such as hypothermia, pain, foreign body, infection, radiation, and oxygenation directly influence the wound, while systemic factors such as age, gender, and overall health and disease of an individual affect the capability to heal the wound [4]. In the elderly people, chronic wounds are mostly seen. In the United States, open wounds exist in 3% of the population of more than 65 years of age. The US government predicts that the elderly population will be over 55 million by 2020, indicating that chronic wounds in this population will continue to be an increasingly recurring issue. Overall, 2% of the entire population is supposed to be affected by chronic wounds in the United States [5]. There is major demand for wound care products in the world’s biggest wound dressing markets, which are the United States and Europe. The annual cost of wound treatment worldwide was an estimate of USD 19.8 billion in 2019, and the worldwide wound care industry is expected to hit USD 24.8 billion by 2024, at a CAGR (compound annual growth rate) of 4.6% from 2019 to 2024 [6]. With the technical development now various forms of wound dressing material for all sorts of injuries are available. But it is important to pick the right material for a specific wound for quicker treatment. Based upon their nature of production, polymers are classified as natural and synthetic. Examples of natural polymer are cellulose, chitosan, dextran, alginates, gelatin, and silk fibroin, and examples of synthetic polymers are polylactic acid, polyglycolic acid, polyacrylic acid, polyvinylpyrrolidone, polyvinyl alcohol [7], and polyethylene glycol [8]. Cellulose is the world’s most plentiful, sustainable, affordable, and readily accessible polysaccharide among natural polymers and is a plant-based material obtained from lignocellulosic biomass producing around 1011 and 1012 tons each year [9]. Cellulose is a major component of lignocellulosic biomass (35–50%) and is composed of linear homopolysaccharide of β-1,4-linked anhydro-D-glucose units with the repeating unit of cellobiose [10] (Fig. 1). The variety of allomorphs of cellulose depends on the source and method of treatment form lignocellulosic biomass. Cellulose allomorphs are groups in four types: I, II, III, and IV [11]. Nanocellulose is generally extracted from cellulose which generally has a size range of less than 100 nm in diameter and length in several micrometers with density of 1.6 g/cm3[12]. Various sources of nanocellulose are plants (cotton, wood), animals (tunicate), and microorganisms (Acetobacter xylinum,
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Fig. 1 Chemical structure of cellulose
Gluconacetobacter sacchari). It has special geometrical properties, morphological proportions, high crystallinity, large surface area, mechanical strength, arrangement and orientation, liquid crystallinity action, and rheological characteristics and is biodegradable, biocompatible, and nontoxic. Owing to these immense and special characteristics, various applications have been developed for practical purposes such as structural reinforcement or rheological alteration to biomedical applications such as tissue engineering [13], wound healing, and drug delivery [11, 14]. Based upon the differences in their structures and morphologies, nanocellulose is classified as nanocrystalline cellulose (NCC), also called as cellulose nanocrystals/cellulose microcrystals/cellulose nano-whiskers; bacterial cellulose (BC), also called as microbial cellulose [15]; nano-fibrillated cellulose (NFC), also known as cellulose nanofibrils (CNFs)/cellulose nanofibers (CNFs); and microfibrillated cellulose (MFC) [16]. Nanocellulose isolated from various treatment such as enzymatic treatment [17] via enzymatic hydrolysis, chemical treatment [18] through acid hydrolysis, alkaline hydrolysis and TEMPO-oxidation [19], and mechanical treatment such as refining and homogenization, ball milling, microfluidization, and grinding are the method used in various pharmaceutical application. The surface modification [20] techniques such as esterification, polymer grafting, and functionalized CNF reactions by carboxylation and adsorption have shown tremendous potential for wound healing [21, 22]. Cellulose nanocomposite modifications have enhanced its properties and capability for wound healing. For example, BC/gelatin has improved it mechanical strength [23], BC/SOD/poviargol used for treatment of third degree burns[24], and CNC/chitosan/PVA nanocomposites [25]. Though cellulose polymer does not have antimicrobial activity, still its nanocomposites with antimicrobial agents such as silver, zinc oxide, and copper have shown an immense potential in wound healing property with good biocompatibility and degree of functionality of this biopolymer, contributing to antimicrobial application [26]. Nanocellulose has immense potential in 3D bioprinting for wound healing due to their ability to form 3D hydrogel with excellent biocompatibility nature [9]. Various applications of nanocellulose for wound healing are achieved through chemical modification of nanocellulose, cellulose nanocomposites, nanocellulose decorated with nanoparticles,
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Fig. 2 Applications of nanocellulose for wound healing
nanocellulose functionalized with antibacterial agents, and 3D-printed nanocellulose materials for wound healing (Fig. 2). Characterization of the cellulose nanomaterial with various techniques has made it possible for the determination of the morphological, physical, and chemical properties for its biomedical application [27]. Some commercially available wound dressing materials are Bio Fill ®, Derma Fill™, X-cell ®, and Bioprocess ® [28].
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Wound Repair and Regeneration
The largest organ of the body is the skin that fulfils important function such as sensation, regulation of temperature, physical protection, and insulation [29]. There are three layers of the skin: the epidermis, the dermis, and subcutaneous tissue (Fig. 3). The epidermis is the outermost layer composed of keratinocytes and dendritic cells that are stratified, squamous epithelium layer. The dermis is the middle layer composed of collagen, a fibrillary structural protein. The subcutaneous tissue or hypodermis comprises of small lobes of fat cells called lipocytes that function as cushion against physical trauma [30]. A wound is a breakdown in the skin epithelial cells that can be followed by damage to the structure and function of normal tissue surrounding it [31]. Wound healing is a complex and biological process that results into the repair and regeneration of the damaged skin tissue [32]. The aim of wound repair is to restore epithelial cells and to recover the skin’s function, integrity, and strength [29]. The four phases of wound repair (Fig. 4) are as follows: hemostasis, inflammation, proliferation, and remodeling with tissue formation [33].
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Fig. 3 Cross section of the skin, illustrating its three layers
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Epidermis Dermis Subcutaneous fatty tissue
Hemostasis Cell types − Platelets
Inflammation Cell types − Platelets, Neutrophils, Macrophages
Proliferation Cell types − Macrophages, fibroblasts, lymphocytes, endothelial cells, keratinocytes
Remodelling and tissue formation Cell types − Fibroblasts
Fig. 4 Phases of wound healing
Table 1 The three clotting cascades and their mechanism Sr. no. 1.
Pathway Intrinsic
2.
Extrinsic
3.
Platelet activation
Mechanism • The activation of factor XII (Hageman factor) results when the subendothelial tissues get exposed due to damage in the endothelial tissues • The activation of factor X initiated by proteolytic cleavage cascade via activation of factor XII results in conversion of prothrombin to thrombin, further converting fibrinogen to fibrin and leading to formation of fibrin plug • The damage of the endothelial tissue activated factor VII and further results in activation of thrombin • The activation by thrombin, thromboxane, or adenosine diphosphate (ADP) causes platelets to undergo transition in morphology. The activated platelets get adhered and clump at the exposed sites of collagen to form a platelet plug • The fibrin and von Willebrand factor, as well as the actin and myosin filaments inside the platelets, reinforce this plug
Hemostasis is the first stage of acute wound healing that occurs immediately after injury to form a provisional wound matrix and is completed after some hours. This phase is also known as lag phase, which initiates the inflammatory phase [34]. The clotting cascades get activated to prevent the blood loss during hemostasis and coagulation phase are as follows: intrinsic pathway, extrinsic pathway, and platelet activation. The mechanism clotting cascade is explained in Table 1 [35].
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Table 2 Growth factors involved in wound repair process Sr. no. 1.
Growth factor PDGF
2.
TGF-α
3.
TGF-β
4.
VEGF
5.
TNF-α
6. 7.
Thromboxane A2 IL-1
8.
Leukotrienes
Source Platelets Fibroblasts Endothelial cells Macrophages Macrophages Epithelial cells Platelets Platelets Fibroblasts Macrophages Neutrophils Platelets Neutrophils Platelets Mast cells T lymphocytes Macrophages Platelets Platelets Macrophages Endothelial cells Lymphocytes Leukocytes Platelets
Function Chemotaxis Fibroblast proliferation and collagen deposition Mitogenic
Formation of granulation tissue Stimulates proliferation of epithelial cells and fibroblast Chemotaxis Mitogenic for fibroblasts to myofibroblasts Collagen matrix construction Stimulates angiogenesis and wound contraction Neovascularization Stimulate angiogenesis Chemotaxis Nitric oxide release and activation of other growth factor Fibroblast proliferation Vasoconstriction Platelet aggregation Neutrophil chemotaxis
Leukocyte adhesion Vascular permeability increased
PDGF platelet-derived growth factor, TGF transforming growth factor, VEGF vascular endothelial growth factor, EGF epidermal growth factor, TNF tumor necrosis factor, IL-1 interleukin-1.
Platelets plays a crucial role in wound repair process. Platelets such as leukocytes, fibroblasts, and other platelets are attracted by chemotactic factors that are released by platelets. This further activates the inflammatory phase via release of cytokines and growth factors [36]. The growth factors and their key role in wound healing are listed in Table 2 [37]. Inflammation is the second most important stage of wound healing process that is activated during the hemostasis phase. The inflammation phase can be divided into early phases, characterized by neutrophils migration, and late stage, characterized by the appearance and conversion of monocytes. During inflammation the foreign substances are removed from the body and disposed of dead tissue, while the mediators are liberated by participating cellular species to enhance and maintain the activities [29]. The immediate activation of pro-inflammatory cytokines and
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chemokines draws circulating leukocytes to the injury site. Increased pro-inflammatory cellular penetrate are mainly composed of neutrophils and macrophages [36]. Neutrophils act by removing debris and bacteria by phagocytosis and subsequent enzymatic and oxygen radical pathways as a first line of protection in infected wounds [29]. Neutrophils from injured vessels drawn by cytokines and chemokines like interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-α), and bacterial endotoxins such as lipopolysaccharide (LPS) are recruited into the wound early after injury [38]. After the task completion, neutrophils either undergo apoptosis, are sloughed from the wound surface, or are phagocytosed by macrophages [35]. Macrophages enter the injury site about 3 days after injury and assist the immature stages by conducting phagocytosis of pathogens and cell debris [34].Macrophages possess a wide reservoir of growth factors, such as TGF-α, TGF-β, platelet-derived growth factor (PDGF), epidermal growth factor (EGF), and vascular endothelial growth factor (VEGF), which are essential for inflammatory response regulation, angiogenesis stimulation, and enhancement of tissue granulation formation [39]. A description of the cells involved in inflammation is illustrated in Table 3 [35]. During this process, the activated phenotype of wound macrophages is generally the “M1 phenotype” [40]. In all stages of wound healing, macrophages play a key role in organizing the overall process. Macrophages exhibit pro-inflammatory activity during the early inflammatory process, such as immune response, phagocytosis, and inflammatory cytokines production and promote wound healing by growth factors [29]. Table 3 List of cells involved in inflammation Sr. no. 1.
Cell type and time of action Platelets (seconds)
2.
Neutrophils (peak at 24 h)
3.
Keratinocytes (8 h) Lymphocytes (72–120 h)
4.
5.
Fibroblasts (120 h)
Function Formation of thrombus Coagulation cascade activation Inflammatory mediators release of PDGF, FGF, EGF, TGF-β, histamine, bradykinin, serotonin, thromboxane, and prostaglandins Bacterial phagocytosis Debridement of wounds Augmentation in vascular permeability Proteolytic enzyme release Production of free radicals from oxygen Inflammatory mediators release Migrating keratinocytes Controls the proliferative process of wound healing Deposition of collagen Cytokines can be released in certain wounds Synthesis of granulation tissue, collagen Produce elements of extracellular matrix (fibronectin, collagen, hyaluronic acid) Inflammatory mediator release
FGF fibroblast growth factor, EGF epidermal growth factor, TGF transforming growth factor, PDGF platelet derived growth factor
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Proliferation is the third stage of wound healing repair process. In proliferation the primary focus of the healing process is on covering the wound surface (re-epithelialization), development of granulation tissue, and regeneration of the vascular network (approx. 3–10 days after injury) [34]. The proliferative process of healing is marked by widespread activation of tissue repair, matrix deposition, and angiogenesis by macrophages, keratinocytes, endothelial cells, and fibroblasts [1]. Epithelialization of wound healing happens within hours of damage. The epithelial cells move upwards in the normal pattern with an intact basement membrane, as happens in a first-degree skin burn, whereby the epithelial progenitor cells remain unchanged under the wound, and in 2–3 days the normal layers of epidermis are restored [41]. Keratinocyte migration and proliferation are required in re-epithelialization. The current wound edge keratinocytes start to migrate within an hour to 1 day after injury. The established wound edge keratinocytes start to migrate within a few hours to one day after injury. Keratinocytes at the basal cell layer of the wound boundary and epithelial stem cells from surrounding hair follicles or sweat glands continue to proliferate approximately 2–3 days after injury to create more cells to cover the wound [42]. Migration is caused by lack of inhibition of contact and physical tension in the structures of cell adhesion, i.e., desmosomes and hemidesmosomes, which stimulate membrane-associated kinases, resulting in increased permeability of the membrane to calcium [43]. When the cells get in close contact, and new adhesion structures are formed, migration stops. To repair the basement membrane, keratinocytes secrete proteins [44]. A number of woundrelated signals, e.g., nitric oxide, which is primarily synthesized by cytokines, macrophages, and growth factors, such as IGF-1, epidermal growth factor (EGF), keratinocyte growth factor (KGF), and nerve growth factor (NGF), are released by different cell types in the wounds, which can promote re-epithelialization [45]. During wound healing, the development of new capillaries (neovascularization) from preexisting blood vessels is due to increased nutritional and oxygen demand, which primarily occurs as angiogenic formation [40]. The growth factors that commence angiogenesis are platelet-derived growth factor (PDGF), tumor necrosis factor-alpha (TNF-α), vascular endothelial growth factor (VEGF), serine protease thrombin, transforming growth factor (TGF), and fibroblast growth factor (FGF) that activate endothelial cells of current blood vessels in wounds [46]. The temporary wound matrix formed during hemostasis is replaced during the proliferation process by granulation tissue, consisting of a large number of fibroblasts, granulocytes, macrophages, and blood vessels, in a matrix of collagen fibers, partly retaining the structure and function of the injured skins [47]. Fibroblasts play a key role in formation of granulation tissue via processes such as breaking fibrin clot, formation of extracellular matrix (ECM), and collagen structures that reinforce other cells required for successful wound healing. The platelets and macrophages in the wounds are produced by cytokines and growth factors such as transforming growth factorbeta (TGF-β), platelet-derived growth factor (PGDF), and basic fibroblast growth factor (bFGF) [48]. The migration of fibroblasts into the provisional wound matrix promotes proliferation of fibroblasts, generates proteinases such as matrix metalloproteinases (MMPs), and deteriorates provisional matrix via transferring the
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Fig. 5 Remodeling phase determines the healed skin and the balance between the formation and breakdown of ECM. Copyright 2011, Elsevier [40]
collagen and extracellular matrix components such as hyaluronic acid, proteoglycans, fibrin, fibronectin, and glycosaminoglycans that fill the wound cavity to form granulation tissue and provide a scaffold [49]. Remodeling process is responsible for the production of fresh epithelium and final granulation tissue formation as the final step of wound healing [3]. Apoptosis (i.e., programmed cell death) is found in most endothelial cells, macrophages, and myofibroblasts or are expelled from the wound and abandon a mass of few cells composed mainly of collagen and other extracellular matrix proteins [39] (Fig. 5). Mechanical tension and cytokine such as TGF-α discriminate between fibroblasts and myofibroblasts expressing α-smooth muscle actin (SMA) and contracting the wound. During apoptosis, collagen III that has been rapidly developed in the ECM is replaced by collagen I, with a higher tensile strength but longer deposition period. Thus, it reduces the blood supply of the new blood vessels and produces a mature avascular and acellular environment [50]. After severe injury some skin elements, such as the hair follicles and the sweat gland, cannot be restored. Just 80% of the initial traction power can be achieved with the recovered skins [51].
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Criteria for Wound Healing Materials
The required dressing material must be used depending on the wound condition, and various types of wound dressing materials are bandages, foam, films, nano-gels, hydrogels, and nanofibers scaffold (Fig. 6). The different types of nanocellulose and modified nanocellulose in wound healing are presented in Table 4.
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Fig. 6 Classification of wound healing
The choice of dressing should be dependent on its ability as follows [91]: i. ii. iii. iv. v. vi. vii. viii. ix.
4
Provide or sustain a moist condition Improve epidermal migration Facilitate angiogenesis and synthesis of connective tissue Enable gas exchange between wounded tissue and the environment Maintain sufficient tissue temperature to improve blood flow to the wound site and improve epidermal migration Offer protection against bacterial infection Should be non-adherent to the wound and quick to clean after healing Provide debridement action to increase movement of leukocytes and encourage enzyme accumulation Should be sterile, nontoxic, and nonallergic
Chemical Modification of Nanocellulose for Wound Healing
Chemical modification or surface modifications of nanocellulose are done to improvise the drawbacks of the nanocellulose and to enhance its biocompatibility and mechanical properties for the treatment of wound healing process. For the incorporation of either charged or hydrophobic moieties, nanocellulose surface modification techniques are usually oxidation, silylation, etherification, esterification, polymerization, polyacrylamide, sulfonation, and phosphorylation [92–94].
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Table 4 Different types of nanocellulose and modified nanocellulose used in wound healing Sr. no. 1.
Nanocellulose Bacterial nanocellulose
Modified nanocellulose for wound healing Bacterial nanocellulose grafted with GMA and crosslinked with EGDMA loaded with ciprofloxacin and vancomycin has shown a good antimicrobial property Bacterial cellulose modification by chitosan/sodium alginate/hydroxypropyl cellulose/2-propanol hydrogel is the most promising fabrication for wound healing Bacterial cellulose coated with collagen forms a nanocomposite scaffold with good cytocompatibility as a wound dressing material Bacterial cellulose coated with kaolin composites found to decrease the rate of blood clotting and composites can be used as wound dressing material Bacterial cellulose coated with chitosan composites showed a significant growth inhibition in antibacterial test and is considered as potential scaffold for wound healing Bacterial cellulose and acrylic acid-based hydrogel found to be nontoxic and biocompatible with human dermal fibroblast skin cells indicating a potential use against wound healing Bacterial cellulose-zinc oxide nanocomposites showed 66% of wound healing activity and 90% of antibacterial activity indicating a compatible dressing material Bacterial cellulose-TiO2 nanocomposites showed 71 2.41% wound contraction indicating a good healing property Bacterial cellulose-silk sericin biomaterials showed good fibroblast proliferation but did not enhance keratinocyte growth indicating a good wound healing process Bacterial cellulose-zinc oxide composites synthesized via solution plasma process showed strong antibacterial activity and could be used as wound dressing material Bacterial cellulose fabricated with silver nanoparticles on reducing with silver nitrate showed a strong antibacterial activity and good biocompatibility for wound dressing material Bacterial cellulose pellicle with silver nanoparticles results in 100% antibacterial activity with high biocompatibility for wound healing Bacterial cellulose-silver nanoparticles prepared via in situ process from hydrolytic decomposition showed strong antimicrobial activity Bacterial cellulose synthesized via in situ process of SiO2 coated with Cu nanoparticles showed good antibacterial property
Reference [52]
[53]
[54]
[55]
[56]
[57]
[58]
[59]
[60]
[61]
[62]
[63]
[64]
[65]
(continued)
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Table 4 (continued) Sr. no.
2.
Nanocellulose
Nanofibrillated cellulose
Modified nanocellulose for wound healing Bacterial cellulose and casein impregnated with iron nanoparticle showed good antibacterial property for wound healing applications Bacterial cellulose with silver nanoparticles synthesized via chemical process results in nanocomposites that showed no cytotoxicity with epidermal cell proliferation and decreases inflammation and facilitate wound healing Bacterial cellulose impregnated with silver nanoparticle showed an effect of expression of gene in wound healing indicating its utility for wound dressing Bacterial cellulose and montmorillonite nanocomposite films showed an antibacterial effect against wound healing Bacterial cellulose with sericin and antimicrobial agents as poly-hexamethylene biguanide showed a decrease in wound size and increase in collagen formation against wound healing Bacterial cellulose loaded with octenidine as an antiseptic drug was stable for 6 months and exhibit antibacterial property against wound healing Bacterial cellulose with bromelain showed an improved antimicrobial activity for wound healing Bacterial cellulose loaded with octenidine and povidone-iodine showed antibacterial effect against wound healing Bacterial cellulose modified to 2,3-dialdehyde cellulose loaded with chloramphenicol showed cell proliferation and fibroblast adhesion against wound healing Bacterial cellulose impregnated with silver sulfadiazine and sodium alginate to form a composite film that has good biocompatibility and antibacterial activity Nano-fibrillated cellulose was incorporated with different hemicellulose (GGM, XG) and with different ratios to form a composite hydrogel. The hydrogels have highest efficacy in cell growth and proliferation and could be promising scaffold for wound healing Nano-fibrillated cellulose hydrogels crosslinked with calcium showed good antibacterial and physicochemical property against wound healing management Cellulose nanofibers-alginate hydrogels showed an improved cell growth, bio-adhesion, and noncytotoxic property. CNFT-alginate gels might have wound healing property Cellulose nanofibers hydrogel with gelatin and alginate showed a good biocompatibility with 90% wound
Reference [66]
[67]
[68]
[69]
[70]
[71]
[72] [73]
[74]
[75]
[76]
[77]
[78]
[79] (continued)
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Table 4 (continued) Sr. no.
3.
Nanocellulose
Cellulose nanocrystals
Modified nanocellulose for wound healing healing efficacy and would be useful material for wound healing Nano-fibrillated cellulose with copper composite aerogels showed an angiogenic effect and enhances the gene expression while promoted the fibroblastendothelial cell interaction indicating a good wound healing material TEMPO-oxidized cellulose nanofibers with polydopamine hydrogels showed an excellent pH/NIR responsive ability for drug delivery against wound healing management C-periodate cellulose nanofibers have been used as bio-ink to form 3D structure for wound dressing materials Cellulose nanofibers modified by double crosslinking with Ca2+ and 1,4-butanediol diglycidyl ether form 3D hydrogel structure with improved cell proliferation and rigidity against wound healing TEMPO-oxidized cellulose nanofibers with 1 w/v% gelatin methacrylate form 3D bio-ink with good biocompatibility and noncytotoxic property for wound healing Cellulose nanofiber crosslinked with Ca2+ and alginate to form 3D bio-composite gels showed significant mechanical properties for wound dressing Cellulose nanocrystals modified with dialdehyde via Schiff base linkage and crosslinked with CMC to form hydrogel as a promising scaffold for wound healing Cellulose nanocrystals with different molar ratios (7%, 15%, and 18%) were loaded in polyvinyl alcohol to form xerogels. The 18% loaded nanocrystals loaded with PVA were found to have wound dressing properties Bacterial cellulose-zinc oxide composites synthesized via solution plasma process showed strong antibacterial activity and could be used as wound dressing material Cellulose nanocrystals with silver nanoparticles synthesized via peroxidate oxidation showed a good antibacterial property against wound healing Cellulose nanocrystals with silver nanoparticles synthesized via in situ process showed strong water absorption capacity and antibacterial property
Reference
[80]
[81]
[82]
[83]
[84]
[85]
[86]
[87]
[88]
[89]
[90]
Vismara et.al have done a study on chemical modification of bacterial nanocellulose and incorporation of bioactive molecules as potential application in wound dressing. The modification of BNC by grafting with glycidyl methacrylate (GMA) and crosslinking ethylene glycol dimethacrylate (EGDMA) via radical process
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involves hydrogen peroxide and iron salt (Fenton reagent) and the generation of cellulose carbon-centered radicals scavenged by methacrylate structure. The BNC was compared with the modified BNCs (BNC-GMA, BNC-EGDMA, and BNC-GMA-EGDMA) to find the suitable BNCs for wound dressing. The hydrogel condition of modified BNCs was retained until the value of 1 was reached by the methacrylate residue per glucose unit (MS) calculated by Fourier transform infrared (FTIR) analysis. The adsorption and release experiments on BNC and modified BNCs loaded with ciprofloxacin and vancomycin show that BNC-EGDMA with MS ¼ 0.5 and BNC-GMA-EGDMA with MS ¼ 0.6 really hold vancomycin. The results show that BNC-GMA-EGDMA retains 50% of loaded bioactive molecules with high substitution degree (0.7–1) that can be further examined for antimicrobial activity against Staphylococcus aureus (S.A.) and Klebsiella pneumonia (K.P.) with no colony growth. Thus the study emerges as a better option in biomedical application for topical wound dressing [52]. Liu et al. have done preparation of hemicellulose-reinforced hydrogels with CNFs for wound healing application. Using various forms of hemicellulose (galactoglucomannan (GGM), xyloglucan (XG), and xylan) as crosslinkers at different weight ratios, the structural and mechanical properties of hydrogel scaffolds could be tuned. The effects of these properties on cellular activity during the operation of wound healing were subsequently studied. The CNF was prepared via two method as pre-sorption and in situ adsorption. XG was shown to have the highest adsorption potential of 23 kDa than the GGM with 31 kDa. The overall mechanical properties with highest reinforcing effect on CNFs in the range of 10–100 kPa, resulting in the highest effectiveness in promoting fibroblast cell growth and proliferation (NIH 3T3). These composite hydrogels have shown promising potential to promote cell adhesion, formation, and proliferation and to provide supportive networks for wound healing system [76]. Basu et al. developed a calcium ion-crosslinked TEMPO-oxidized cellulose nanofibrillated (CNFs) hydrogel for wound healing. The water retention and physicochemical properties were determined at a rate of 204 g/m2 per day in comparison to various degrees of wound with higher water vapor transmission at a rate of 279 g/m2 that showed that hydrogels were capable of maintaining a humid environment and mechanical stability. The great potential of ion-crosslinked TOCNF hydrogels for the production of advanced wound dressings was demonstrated. The effect of crosslinking agents (calcium or copper ions) on antibacterial properties against various kinds of bacterial strains was examined. The calcium ion-crosslinked TOCNF hydrogels were found to inhibit colonization of Staphylococcus epidermidis and prevent the development of Pseudomonas aeruginosa biofilm, while copper ion-crosslinked TOCNFs blocked growth of Staphylococcus epidermidis and were bacteriostatic to Pseudomonas aeruginosa. Thus, TOCNFs hydrogel with tunable hydrogel properties can be used for wound dressing material [77, 95]. Huang et al. developed an injectable hydrogel for deep partial-thickness burn wound based on water-soluble carboxymethyl chitosan (CMC) and dialdehyde modified cellulose nanocrystals (DACNC). When using amino acid solution at wound dressing changes, the hydrogel could be eliminated by on-demand
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dissolving, which could accelerate deep partial-thickness burn wound healing and reduce discomfort at wound dressing changes, as well as avoid scar formation. The mechanical strength of CMC/DACNC hydrogels for wound healing is 1 kPa. The CMC/DACNC-48 hydrogel and hydrogel have great potential and are relatively nontoxic with molar ratio 2. Thus, modified injectable hydrogel could be a promising material for wound healing [86]. Pramanik et al. prepared bio-composite xerogels from nanocellulose and polyvinyl alcohol (PVA) for wound healing. By the process of acid hydrolysis, nanocellulose crystals were prepared and loaded with PVA. Nanocellulose is placed into the polyvinyl alcohol (PVA) matrix with a mass ratio of 7%, 13%, and 18%, followed by thermo-morpho-mechanical characterization. With the incorporation of lower concentrations of nanocellulose crystals, mechanical properties improve; however, above 18% nanocellulose crystal reinforcement, the creation of mechanically poor cellulose-rich regions allows xerogels to rupture. Characterization of the physical arrangement of nanocellulose in PVA matrix was performed by SEM (scanning electron microscopy), and TEM showed rupture of weak nanocelluloserich region and increase in brittleness because of fibrous microstructure of nanocellulose. Thus optimum level of nanocellulose in PVA can be an effective tool for application in wound healing [87]. Rojewska et al. modified bio-nanocellulose membrane for drug release. Biocompatible polymers such as sodium alginate (ALG) and hydroxypropyl cellulose (HPC) were used to improve mechanical properties of bacterial cellulose. Further by the use of acetate buffer, bacterial cellulose was modified with carboxymethyl (mBNC) for the deposition of chitosan loaded with curcumin, and 1-ethyl-3(3-dimethylaminopropyl)carbodiimide (EDC)/N-hydroxysuccinimide (NHS) was used to immobilize the surface of mBNC. The loading capacity of curcumin and sodium alginate in 2:100 weight ratio was found to be best for further studies. Characterization of microsphere results showed a controlled and sustained release of curcumin from the unbounded particles. Thus, a stable and bioactive material which has shown an effective activity for wound healing was obtained [53].
5
Cellulose Nanocomposites for Wound Healing
Nanocomposite is a two-phase substance with a nanometer scale range in one phase. Because of its remarkable properties, cellulose is a promising candidate for cellulose nanocomposite production. One of the most difficult aspects of the fabrication process is the cellulose’s hydrophilic design. By sonicating freeze-dried cellulose suspension in a mixture of dimethyl-sulfoxide and N,N-dimethylformamide with a small amount of water, organic solvent-based nanocomposites can be made. Surface functionalization of the surface hydroxyl group can be used to obtain homogeneous dispersion of hydrophobic polymer matrix [96]. Zhijiang et al. have prepared bacterial cellulose (BC) nanocomposites that have been fabricated with collagen. By the process of freeze-drying, the wet bacterial cellulose film obtained from Acetobacter xylinum was immersed in collagen acetic
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acid solution to get the BC/collagen composites. After drying SEM analysis data shows that nanofibers were well coated with collagen but also penetrate inside BC with a diameter of 40 μm and pore size of 15 μm, which has shown good mechanical property with a well-organized 3D network structure. Characterization by Fourier transform infrared (FTIR), X-ray diffraction (XRD) of BC results in high mechanical properties with high crystallinity, while thermogravimetric analysis (TGA) results in improvement of thermal stability after incorporation of collagen. The Mechanical test such as Young’s Modulus and tensile strength have both increased significantly, whereas the elongation at break has decreased slightly, according to tensile test results. The cytocompatibility test revealed that BC/collagen scaffolds were bioactive with appropriate cell adhesion that indicate the scaffolds can be used for wound healing [54, 97]. Wanna et al. have prepared nanocomposite film of bacterial cellulose and kaolin (BC-K composite). The bacterial cellulose gels and ultrafine kaolin particles were added in appropriate proportion and under pressure filtration slurries were passed to form very thin sheets of less than 0.5 mm and were dried at 80 C to get flexible sheets. The SEM results in BC fibre will have a higher C concentration, which will reduce near the BC–kaolin barrier, while the levels of O, Al, and Si will rise. The mechanical testing conducted on 15:85 and 30:70 composites results in wellnetworked film. The results suggest that BC-K composites have potential for wound healing as well as for blood clotting [55]. Lin et al. have prepared bacterial cellulose and chitosan composites for wound healing. The composites were prepared by immersing wet BC membrane in chitosan solution dissolved in 1% citric acid aqueous solution. The solution was freeze-dried to get the composites. Mechanical strength for BC-chitosan was found to be 10 MPa, and the elongation at break was 29%. The water absorption capacity was found to be 97%, and the antibacterial study was conducted against the E. coli and S. aureus. The overall study revealed that BC-chitosan was found to have good potential for wound healing treatment [56]. Siqueria et al. have studied nanocellulose-alginate hydrogels for wound healing. TEMPO- oxidized cellulose nanocrystals (CNCs) and cellulose nanofibers (CNFTs) to form hydrogels. The mechanical properties of gels in the range of 1.00–10.0 MPa for tensile strength and 20–60 MPa for compressive strength were reported. The cytotoxicity and cell cultures analysis of CNCTs and CNFTs on L929 fibroblast cells show moderate cytotoxicity and good cytocompatibility. The TEMPO-oxidized nanofibers in alginate show improvement in the porous structures with diameter of 150 μm as compared to nanocrystals with diameter of 40 μm. The nanocellulose (CNFs)-alginate gels can have an immense potential for wound healing [78]. Loh et al. have developed 3D scaffold membrane of bacterial cellulose (BC) with acrylic acid (AA) hydrogel for wound healing. The gel was synthesized via electron beam irradiation. SEM results in decreased pore size from 46050 μM and water vapour transmission were examined on BC/AA hydrogel was found to be 2175 to 2280 g/m2/day. The study states that the BC/AA hydrogel has shown potential in carrying cells to deliver human epidermal keratinocytes (EK) and dermal fibroblasts (DF) for wound healing. The hemolytic index of BC/AA hydrogel was
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biocompatible with blood in as low as 0.80–1.30%. These observations indicate BC/AA hydrogel as a promising wound healing material [57, 98, 99]. Liu et al. have prepared a nanocomposite hydrogel from carboxylated cellulose nanofibers (CNF), silver nanoparticles, and gelatin. The noncovalent crosslinked hydrogels were freeze-dried, and characterization of the nanocomposites through scanning electron microscopy, X-ray diffraction, blood clotting, and platelet adhesion was determined. The results demonstrated strong mechanical strength, selfrecovery, hemostatic efficiency, antibacterial property, and acceptable fluid control on the wound site for 0.5 mg/mL Ag-NH2 (CNF/G/Ag0.5). The CNF/G/Ag0.5 has shown better mechanical, antibacterial, and hemostatic properties with appropriate fluid equilibrium of 2093.9g/m2 per day on wound bed. Thus, the overall performance shows an improvement in wound healing and useful for designing wound dressing materials and illustration of nanocomposites hydrogel made from CNF/G/Ag (Fig. 7) [79]. Khalid et al. have developed nanocomposite bacterial cellulose (BC) and zinc oxide nanoparticles (ZnONPs) for wound dressing materials for burn wounds. Antimicrobial properties and characterization of BC/ZnONPs were determined. The activity of bacterial cellulose-zinc oxide nanocomposites against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Citrobacter freundii was found to be 90%, 87.4%, 94.3%, and 90.9%, respectively. Thus the study proposes that bacterial zinc oxide nanocomposites could be a promising system for wound healing [58]. Khalid et al. developed a novel wound dressing material for cutaneous wound treatment particularly specially for burns. Bacterial cellulose (BC) and titanium dioxide (TiO2) nanocomposites were prepared, and characterization of nanocomposites through FTIR and SEM image indicates that BC nanofibrils were attached to TiO2 nanoparticles, and the XRD results showed the semicrystalline nature of BC and BC-TiO2. With 71 2.41% of wound contraction, the composite bandage showed a strong healing pattern. The biofilm shows antimicrobial activity against S. aureus and E. coli; thus BC-TiO2 should be used a wound healing system [59].
Fig. 7 Schematic illustration of hydrogel nanocomposites made from CNF/G/Ag
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Lamboni et al. developed a nanocomposite from bacterial cellulose (BC) and silksericin (SS) for wound healing treatment. For the controlled release of silk sericin from the composites, bacterial cellulose was functionalized with silk sericin to stabilize the hydrogen bonds. The various concentrations of silk sericin were used to determine swelling ratio, indicating the smallest ratio showed more than 20 folds the weight loss of dry samples. The composites thus enhanced the proliferation of fibroblast and improve cell viability. Thus, BC-SS composites serve as promising candidates for wound healing [60]. Wang et al. have developed a bio-composite from nano-fibrillated cellulose and mesoporous bioactive glass containing copper (Cu-MBG). The biocompatibility assay of Cu-MBG for the release of Cu2+ on 3T3 fibroblasts was examined, and the results showed that the below 10 mg/L of Cu2+ composites, aerogel possesses an angiogenic effect in 3D spheroid culture system of human umbilical vein endothelial cells. The composites showed antibacterial activity against E.coli, thus stating that bio-composites can be used for chronic wound healing and angiogenic promotion [80]. Janpetch et al. synthesized composite membrane from bacterial cellulose and zinc oxide (ZnO) nanocellulose for wound healing. By the use of solvent plasma process (SPP), zinc oxide was successfully prepared without the inclusion of reducing agents and subsequently deposited into bacterial cellulose. The SEM images indicate crosslinked nanofiber network in BC. The TGA thermograms showed a major weight loss between 275 C and 375 C due to dehydration and depolymerization. Antibacterial activity against S. aureus and E. coli has been examined for ZnO/BC composite through SPP, which showed a good antibacterial activity without any photocatalytic reaction. Thus, ZnO deposited on bacterial cellulose has shown a potential activity for wound healing treatment [61]. Poonguzhali et al. developed a bio-nanocomposite for wound healing application from chitosan, polyvinylpyrrolidone (PVP), and cellulose nanocrystals (CPNC). By the process of salt leaching method, the nanocellulose was incorporated into chitosan and PVP with one side coated by 3% of stearic acid to form a hydrophobic and hydrophilic surface. Characterization of the bio-nanocomposites with SEM and TEM showed a porous structure with smooth hydrophobic surface. The hydrophobic surface of CPNC-3%S bio-nanocomposites has shown good water repellent and anti-adhesion activity to E. coli, whereas the hydrophilic surface shows an outstanding antibacterial activity and bacterial cytotoxicity. Thus, the CPNC has shown great capability to be used in treatment of wound healing [88].
6
Nanocellulose Decorated with Nanoparticles for Wound Healing
Tabaii et al. have developed an antimicrobial membrane composed of silver nanoparticles (AgNPs) and bacterial cellulose (BC). AgNP/BC membranes have been formed in the presence of sodium tripolyphosphate (TPP) and sodium hydroxide (NaOH) by reducing silver nitrate as a substrate and permeated into bacterial
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cellulose membranes. The analysis of both the membrane one treated with TPP and NaOH has been done by SEM, UV-visible spectroscopy, and X-ray diffraction. The results obtained showed that water holding capacity was found to be 164. The AgNP/BC membranes has shown inhibition against E. coli and S. aureus with 100% and 99.99%, respectively. Thus, both nanocomposite membranes indicated strong antibacterial activity, good biocompatibility, and no cytotoxicity, indicating a promising material for wound healing [62]. Wu et al. studied bacterial cellulose pellicle (BCP) with silver nanoparticles (Ag) for wound healing. The BCPs were oxidized by using TEMPO/NaClO/NaBr at pH-10 to form TEMPO-oxidized BCP (TOBCP). Subsequently, TOBCP was ion exchanged in AgNO3 solution to form TOBCP/Ag+, and thermal reduction on TOBC nanofiber by silver nanoparticles (AgNPs) with a diameter of ~16.5 nm has been synthesized to form TOBCP/AgNPs without the use of a reducing agent. Analysis of TOBCP/AgNPs was confirmed by technique such SEM, X-ray diffraction, TGA, and FTIR. The SEM results showed 3D network of BC nanofibers on the surface of TOBCP indicating successful synthesis of nanofibers. TOBCP/AgNPs have shown significant effect for antibacterial activity to inhibit E. coli and S. aureus. The prepared TOBCP/AgNPs have good biocompatibility and thus can be used for wound healing application and illustration of TEMPO-oxidized bacterial cellulose (TOBC) nanofibers (Fig. 8)[63]. Drogat et al. have developed a wound healing gel from cellulose nanocrystals and silver nanoparticles (AgNPs). Cellulose nanocrystals are oxidized to generate aldehyde function, by periodate oxidation to reduce Ag+ into Ag0. Transmission electron microscopy results showed spherical silver nanoparticles with diameter of 20–45 nm, and ultraviolet-visible absorption spectroscopy showed the absorbance at 425 nm was used to characterize the nanoparticles. The spherical shape of AgNPs has been found to be 20–45 nm from the microscope studies (TEM). Thus the studies state that AgNP colloidal suspension was found to be a promising material for wound healing [89]. Barud et al. have developed a nanocomposite membrane from bacterial cellulose and silver nanoparticle composites for wound healing. Composites were prepared by hydrolytic decomposition of silver nitrate (AgNO3) solution using triethanolamine (TEA) as a reduction and complexing agent by in situ preparation of Ag
Fig. 8 Schematic figure for TEMPO-oxidized bacterial cellulose (TOBC) nanofibers
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nanoparticles. The SEM images of BC-Ag-TEA showed that spherical silver particles attached to BC membranes and the UV absorption of nanoparticle was found to be 427 nm. The mechanical strength of the bacterial cellulose was found to be 11GPa and tensile strength as 98 MPa with 1.2% elongation. The antimicrobial activity against S. aureus and E. coli was found to effective for wound healing [64]. Ma et al. have synthesized an antibacterial membrane for wound healing. The bacterial cellulose (BC) was synthesized by in situ process with SiO2-coated Cu nanoparticles. Characterization of CuSiO2/BC membranes via XRD has shown board reflection peak at 22 , and X-ray photoelectron spectroscopy (XPS) is used to determine the chemical properties and morphologies of CuSiO2/BC membrane. The antimicrobial activity against S. aureus and E. coli showed that it could be suitable biofilm for wound healing treatment [65]. Patwa et al. have developed injectable hydrogels from casein, alginate, and iron nanoparticles loaded on bacterial cellulose (BCF). An amide and ionic crosslinking of alginate-casein with incorporation of BCF was found to have supramolecular interaction. According to morphological analysis, iron oxide nanoparticles were impregnated within the bacterial cellulose network with a loading of 20 wt%, and swelling studies revealed that water uptake of hydrogels was around 4000%, making them good wound dressing materials. The porous internal structure facilitated cell viability, which was confirmed by the fibroblast MTT assay. The overall results state that alginate-casein hydrogels loaded with BCF could be a promising approach for wound healing treatment [66]. Singla et al. have designed a nano-bio-composite in the form of film and ointment from cellulose nanocrystals (CNCs) and silver nanoparticles (AgNPs). By the in situ synthesis process, the AgNPs were impregnated into the cellulose nanocrystal matrix. The film and ointment were characterized by using techniques such as SEM image that revealed the smooth, porous, and ribbon shape of chemically treated fibers as compared to raw fibers. TEM micrographs showed uniform sized of DH-CNCs as 18 0.5 nm and 272 52 nm and BB-CNCs as 20 1 nm and 385 97 nm. The cellulose nanocrystals obtained from Dendrocalamus hamiltonii (DH) and Bambusa bambos (BB) were used and examined for tensile strength obtained from DH/CNC/Ag as 0.024 0.005 MPa and BB/CNC/Ag as 0.032 0.008 MPa. Both the composites have shown good water uptake capacity and antibacterial activity against Staphylococcus epidermis (S.E) and Citrobacter freundii (C.F). Thus, the dual properties of both composites make it a versatile material for wound healing [90]. Wu et al. developed a composite film from bacterial cellulose (BC) and silver nanoparticles (AgNPs). For the controlled release of Ag+ and to reduce toxicity, the silver nanoparticles were synthesized through in situ process with bacterial cellulose as template. A controlled release of Ag+ with no toxicity of nanoparticles was observed. Antibacterial activity against E. coli, P. aeruginosa, and S. aureus was examined that showed a good antimicrobial activity of AgNP-BC. Characterizations of AgNP-BC through SEM results showed that 3D porous structure has pore size of 100s nanometer between the BC nanofibers and AgNPs. The study revealed that AgNP-BC could decrease inflammation and facilitate the healing of wounds [67].
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Moniri et al. developed nanocomposite films from bacterial nanocellulose and silver nanoparticles (AgNPs). Within the BNC structure, spherical AgNPs with particle sizes ranging from 20 to 50 nm have been synthesized and impregnated. The antibacterial activity against S. aureus, S. epidermis, and P. aeruginosa with inhibition ranges from 7 0.25 to 16.24 0.09 mm was seen by the resulting nanocomposites. The genes TGF-β1, MMP2, MMP9, CTNNB1, Wnt4, hsa-miR29b-3p, and hsa-miR-29c-3p play a significant role in wound healing based on bioinformatics databases. Thus, the results state that BNC/Ag has potential activity against wound healing [68].
7
Nanocellulose Functionalized with Antibacterial Agents for Wound Healing
Liu et al. developed a pH/near-infrared (NIR)-responsive composite hydrogel. Cellulose nanofibrils were treated with TEMPO-mediated oxidation to form TOCNF hydrogel. Polydopamine (PDA) was physically crosslinked with TOCNF hydrogels to enhance the composite hydrogels for multi-responses such NIR and pH that could increase the drug loading capacity and controlled drug release. The fabrication of TOCNFs by calcium chloride solution with various concentration of PDA was examined, and drug loading ratio of tetracycline (TH) loaded on PDA/TOCNFs hydrogels was further prepared. The SEM image of the TOCNFs hydrogel showed a 3D porous network of fine threads interconnected with thicker nanofibril strand. The drug release ratio of TH-PDA/TOCNFs was found to be 77% as a good drug released profile. The in vitro antibacterial test of TH-PDA/TOCNFs has shown an excellent antibacterial activity against Staphylococcus aureus and Escherichia coli. The results propose that composite hydrogels have good wound healing ability [81]. Ul-Islam et al. prepared nanocomposite film of bacterial cellulose and montmorillonite (MMT) for wound healing and tissue regeneration. Various elements such as Na, Ca, and Cu were used to modify MMT via ion exchange reactions. The composites of BC-Na-MMT, BC-Ca-MMT, and BC-Cu-MMT were examined for antibacterial activity against S. aureus and E. coli. Composites prepared with 2% and 4% MMT from BC-Cu-MMT revealed consistent clear zones for E. coli (20 and 22 mm, respectively) and S. aureus (19 and 20.5 mm, respectively). Thus the results suggest that BC-Cu-MMT showed excellent antibacterial activity and has a great potential for wound healing [69]. Napavichayanun et al. have done a study based on bacterial cellulose loaded with an antimicrobial agent as 0.3% w/v poly-hexamethylene biguanide (PHMB) and an accelerative wound healing agent as 1% w/v sericin. Studies based on in vivo and in vitro on L929 fibroblasts and clinical studies were carried out. The overall studies state that bacterial cellulose loaded with antimicrobial agent showed a future potential as a novel membrane for wound healing [70]. Moritz et al. have done studies based on bacterial nanocellulose (BNC) loaded with octenidine for wound healing. The wound dressing membrane was investigated
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for mechanical characteristic, antimicrobial efficacy, and drug loading and release capacity. The antimicrobial efficacy against S. aureus and BNC loaded with octenidine was examined with JIS L 1902. Thus, BNC loaded with octenidine has shown immense potential for wound healing that can be kept for 6 months without losing its antimicrobial activity [71]. Ataide et al. prepared wound dressing material from bacterial nanocellulose and bromelain. The BNC membrane was immersed in bromelain solution, and through the enzymatic activity the BNC loaded with bromelain was calculated. The mucoadhesive property of BC-bromelain membrane showed that maximum strength value was reduced from 0.493 3.6 N to 0.112 0.1 N, while the SEM result showed a crosslinked structure with void space distributed randomly. Thus bromelain with BNC was found to be a promising dressing material for wound healing [72]. Mattos et al. investigated bacterial nanocellulose as a carrier for octenidine and povidone-iodine for wound healing treatment. The diffusion profiles, uptake, and release of three FITC molecules of dextran, octenidine, and povidone-iodine were determined. Molecular weight-dependent mobility from BNC to an agarose gel was demonstrated by the uptake and release ability of FITC dextran molecules. BNC loading potential was also inversely proportional to the antiseptics (octenidine and povidone-iodine) molecular weight. A continuous and sustained release is seen for octenidine, while povidone-iodine was released quicker. A better dose-dependent efficacy against S. aureus was shown by both antiseptic solutions when combined with BNC. These state that bacterial nanocellulose with antiseptic solution can be an efficient approach for wound healing [73]. Lacin et al. developed cellulose-based hydrogel from bacterial cellulose (BC) loaded with chloramphenicol (CAP). Two membranes were examined: one with CAP-BC and other modified bacterial cellulose to 2,3-dialdehyde cellulose (DABC) by oxidation loaded with chloramphenicol (CAP-DABC). Characterization of both the membrane through FTIR demonstrates the interaction between them. The water retention capacity of the BC and DABC was found to be 65.6 1.6% and 5.3 0.3%, respectively. The findings of the MTT test indicate that fibroblast adhesion and proliferation are significantly greater on CAP-loaded DABC membranes than on CAP-loaded BC membranes. Owing to its unique properties of biodegradability, biocompatibility, and antimicrobial potency, this recently formulated medication containing DABC membranes tends to be highly appropriate for wound healing [74]. Shao et al. developed composite membrane from bacterial cellulose (BC) and sodium alginate (SA) loaded with silver sulfadiazine (AgSD). Characterization of the novel BC/SA- AgSD was examined through surface morphology indicating that BC/SA matrix is interconnected with porous structure of BC and was impregnated successfully with silver sulfadiazine. Escherichia coli, Staphylococcus aureus, and Candida albicans were screened for the antibacterial efficiency of the BC/SA-AgSD composite. BC/SA-AgSD composites have outstanding antibacterial activities and good biocompatibility, demonstrating their effectiveness as future wound dressing materials [75].
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3D-Printed Nanocellulose Materials for Wound Healing
3D bioprinting is a technique in which biomaterials and living cells can be deposited in a complex 3D structure. A computer-controlled bio-plotter can be used for the deposition of the nanocellulose materials. In general, bioprinting involves the following three steps: (a) first, the compilation of detailed information on tissues and organs for the identification of the model and the selection of materials; (b) second, the conversion of information to the electrical signal to regulate the printer for tissue printing; (c) third, the development of a stable structure [100, 101]. The following are the studies done by various researchers on 3D-printed nanocellulose materials for wound healing and schematic 3D printing process with two-stage nanocellulose hydrogels (Fig. 9). Rees et al. have done a study based on 3D bio-ink nanocellulose for wound dressing. Nanocellulose was prepared by two different processes: TEMPO-mediated oxidation and a combination of carboxymethylation and peroxidate oxidation. A homogeneous material with small nanofibrils with widths