Fiber and Textile Engineering in Drug Delivery Systems (The Textile Institute Book Series) 9780323961172, 9780323995009, 0323961177

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Fiber and Textile Engineering in Drug Delivery Systems

The Textile Institute Book Series Incorporated by Royal Charter in 1925, The Textile Institute was established as the professional body for the textile industry to provide support to businesses, practitioners, and academics involved with textiles and to provide routes to professional qualifications through which Institute Members can demonstrate their professional competence. The Institute’s aim is to encourage learning, recognize achievement, reward excellence, and disseminate information about the textiles, clothing, and footwear industries and the associated science, design, and technology; it has a global reach with individual and corporate members in over 80 countries. The Textile Institute Book Series supersedes the former “Woodhead Publishing Series in Textiles” and represents a collaboration between The Textile Institute and Elsevier aimed at ensuring that Institute Members and the textile industry continue to have access to high-caliber titles on textile science and technology. Books published in The Textile Institute Book Series are offered on the Elsevier website at store, elsevier.com, and are available to Textile Institute Members at a substantial discount. Textile Institute books still in print are also available directly from the Institute’s website at www. textileinstitute.org To place an order, or if you are interested in writing a book for this series, please contact Matthew Deans, Senior Publisher: [email protected] Recently Published and Upcoming Titles in the Textile Institute Book Series: Handbook of Natural Fibers: Volume 1: Types, Properties and Factors Affecting Breeding and Cultivation, 2nd Edition, Ryszard Kozlowski Maria Mackiewicz-Talarczyk, 978-0-12-818398-4 Handbook of Natural Fibers: Volume 2: Processing and Applications, 2nd Edition, Ryszard Kozlowski Maria Mackiewicz-Talarczyk, 978-0-12-818782-1 Advances in Textile Biotechnology, Artur Cavaco-Paulo, 978-0-08-102632-8 Woven Textiles: Principles, Technologies and Applications, 2nd Edition, Kim Gandhi, 978-0-08-102497-3 Auxetic Textiles, Hong Hu, 978-0-08-102211-5 Carbon Nanotube Fibers and Yarns: Production, Properties and Applications in Smart Textiles, Menghe Miao, 978-0-08-102722-6 Sustainable Technologies for Fashion and Textiles, Rajkishore Nayak, 978-0-08-102867-4 Structure and Mechanics of Textile Fiber Assemblies, Peter Schwartz, 978-0-08-102619-9 Silk: Materials, Processes, and Applications, Narendra Reddy, 978-0-12-818495-0 Anthropometry, Apparel Sizing and Design, 2nd Edition, Norsaadah Zakaria, 978-0-08-102604-5 Engineering Textiles: Integrating the Design and Manufacture of Textile Products, 2nd Edition, Yehia Elmogahzy, 978-0-08-102488-1 New Trends in Natural Dyes for Textiles, Padma Vankar Dhara Shukla, 978-0-08-102686-1 Smart Textile Coatings and Laminates, 2nd Edition, William C. Smith, 978-0-08-102428-7 Advanced Textiles for Wound Care, 2nd Edition, S. Rajendran, 978-0-08-102192-7 Manikins for Textile Evaluation, Rajkishore Nayak Rajiv Padhye, 978-0-08-100909-3 Automation in Garment Manufacturing, Rajkishore Nayak and Rajiv Padhye, 978-0-08-101211-6 Sustainable Fibers and Textiles, Subramanian Senthilkannan Muthu, 978-0-08-102041-8 Sustainability in Denim, Subramanian Senthilkannan Muthu, 978-0-08-102043-2 Circular Economy in Textiles and Apparel, Subramanian Senthilkannan Muthu, 978-0-08-102630-4 Nanofinishing of Textile Materials, Majid Montazer Tina Harifi, 978-0-08-101214-7 Nanotechnology in Textiles, Rajesh Mishra Jiri Militky, 978-0-08-102609-0 Inorganic and Composite Fibers, Boris MahltigYordan Kyosev, 978-0-08-102228-3 Smart Textiles for In Situ Monitoring of Composites, Vladan Koncar, 978-0-08-102308-2 Handbook of Properties of Textile and Technical Fibers, 2nd Edition, A. R. Bunsell, 978-0-08-101272-7 Silk, 2nd Edition, K. Murugesh Babu, 978-0-08-102540-6 The Textile Institute Book Series Fiber and Textile Engineering in Drug Delivery Systems

The Textile Institute Book Series

Fiber and Textile Engineering in Drug Delivery Systems Edited by

Navneet Sharma Bhupendra Singh Butola

Woodhead Publishing is an imprint of Elsevier 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States The Boulevard, Langford Lane, Kidlington, OX5 1GB, United Kingdom Copyright © 2023 Elsevier Ltd. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. ISBN: 978-0-323-96117-2 (print) ISBN: 978-0-323-99500-9 (online) For information on all Woodhead Publishing publications visit our website at https://www.elsevier.com/books-and-journals

Publisher: Matthew Deans Acquisitions Editor: Sophie Harrison Editorial Project Manager: Rafael Guilherme Trombaco Production Project Manager: Maria Bernard Cover Designer: Vicky Pearson Esser Typeset by MPS Limited, Chennai, India

Contents

List of contributors 1

Drug-releasing textile materials: current developments and future perspectives Abhishesh Kumar Mehata, Deepa Dehari, Vikas, Vishnu Priya and Madaswamy S. Muthu 1.1 Introduction 1.2 Historical development of drug-releasing textile 1.3 Classes of drug-releasing textile materials 1.3.1 Woven fabrics 1.3.2 Nonwoven fabrics 1.3.3 Nonwoven electrospun fabrics 1.4 Mechanisms of controlled drug delivery through textile materials and their pharmacokinetics 1.4.1 Temporally controlled mechanism of drug release 1.4.2 Distribution-controlled release 1.4.3 Pharmacokinetics of drug release 1.5 Fabrication of drug delivery systems 1.5.1 Coating methods 1.5.2 Encapsulation methods 1.5.3 Fiber spinning techniques 1.5.4 Hollow fibers methods 1.5.5 Bioconjugation techniques 1.5.6 Ion complexes methods 1.5.7 Plasma treatment methods 1.5.8 Nanotechnology in fabrics 1.6 Evaluation of drug-releasing textile materials 1.6.1 Morphological and chemical characterization 1.6.2 Mechanical and physical properties of textile materials 1.6.3 Estimation of drug-loading efficiency of textile materials 1.6.4 Controllability of drug release from textile materials 1.6.5 Stability study of textile materials 1.6.6 Interface reactions of textile materials 1.6.7 Antimicrobial activity test of textile materials 1.7 Drug-releasing textile materials applications 1.8 Future prospective 1.9 Conclusion

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Acknowledgments Individual authors’ contributions Compliance with ethical standards Conflict of interest Research involving human participants and animals Informed consent References 2

Current approaches in nanofiber-based drug delivery systems: methods and applications Sarika Tomar, Rakesh Pandey, Priyanka Surya, Ranjan Verma, Rishabh Singh, Ved Prakash Meena and Sweta Singh 2.1 Introduction 2.2 Electrospinning principle and its fundamentals 2.2.1 Types of material for electrospinning 2.2.2 Different governing parameters affecting nanofibers’ fabrication 2.3 Method for incorporation of drug using electrospinning 2.3.1 Blending electrospinning 2.3.2 Coaxial electrospinning 2.3.3 Emulsion electrospinning 2.3.4 Electrospray 2.3.5 Layer-by-layer self assembly 2.3.6 Core shell 2.4 Stimuli-responsive drug delivery using smart electrospun nanofibers 2.4.1 pH-responsive electrospun nanofibers 2.4.2 Thermo-responsive electrospun nanofibers 2.4.3 Light-responsive electrospun nanofibers 2.4.4 Electric field responsive electrospun nanofibers 2.4.5 Magnetic field responsive electrospun nanofibers 2.4.6 Multi stimuli-responsive electrospun nanofibers 2.4.7 Biochemical stimuli-responsive electrospun nanofibers 2.5 Clinically used electrospun nanofiber-based biomedical drug delivery systems/devices 2.5.1 AVflo 2.5.2 RIVELIN patch 2.5.3 ReBOSSIS 2.5.4 HealSmart 2.5.5 SurgiCLOT 2.5.6 PK Papyrus 2.6 Biomedical applications of electrospun nanofiber-based drug delivery systems 2.6.1 Drug delivery 2.6.2 Regenerative medicine

28 28 28 28 28 28 29

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2.6.3 Wound dressing and antimicrobial agent 2.6.4 Cancer research 2.7 Conclusion and future perspectives Acknowledgments Individual authors’ contributions Compliance with ethical standards Conflict of interest Research involving human participants and animals Informed consent References 3

Biomaterial-based fibers for enhanced wound healing and effective tissue regeneration Lalita Mehra and Payal Gupta 3.1 Introduction 3.2 Biomaterials 3.2.1 Natural polymers 3.2.2 Synthetic polymers 3.2.3 Phytoactive molecule-loaded polymers 3.2.4 Conductive biomaterials 3.3 Synthesis of fibers 3.3.1 Wet spinning 3.3.2 Melt spinning 3.3.3 Electrospinning 3.4 Characterization of fibers 3.4.1 Morphological techniques 3.4.2 Analytical techniques 3.4.3 Techniques for mechanical studies 3.5 The anatomy of skin 3.6 Wound healing and repair 3.6.1 Initial phase—hemostasis 3.6.2 Second phase—inflammation 3.6.3 Third phase—proliferation 3.6.4 Fourth phase—remodeling 3.7 Characteristics of ideal dressing and lacunae with present biomaterial dressings 3.8 Nanoparticle-based wound therapies Acknowledgments Individual authors’ contributions Compliance with ethical standards Conflict of interest Research involving human participants and animals Informed consent References

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Biomaterials and biomaterial-based fibers in drug delivery systems Kinshuk Malik, Mallika Pathak, Lajpreet Kaur, Piyush Verma, Rahul Singhal and Himanshu Ojha 4.1 Introduction 4.1.1 Intracellular targeting 4.2 Methods for drug delivery system 4.2.1 Microfluidic fiber fabrication 4.2.2 Molding method 4.2.3 Self-assembly 4.2.4 Electrospinning 4.2.5 Other methods 4.3 Biomaterials-based drug delivery 4.3.1 Biomaterials for small molecules 4.3.2 Biomaterials for bigger molecules 4.3.3 How biomaterials have evolved for drug delivery? 4.3.4 RNA delivery 4.3.5 Polymers as responsive biomaterials 4.4 Biomaterials-based fibers in drug delivery systems 4.4.1 Electrospun cellulose acetate in the therapeutic delivery system 4.4.2 Silk in drug delivery system 4.5 Conclusion Acknowledgments Author contributions Compliance with ethical standard Conflict of interest Research involving human participants and animals Informed consent References Biomedical applications of carbon nanotubes B. Vidya, Asha P. Johnson, G. Hrishikesh, S.L. Jyothi, S. Hemanth Kumar, K. Pramod and H.V. Gangadharappa 5.1 Introduction 5.2 Properties of carbon nanotubes 5.2.1 Physical properties 5.2.2 Electrical properties 5.2.3 Mechanical properties 5.2.4 Thermal properties 5.2.5 Optical properties 5.3 Types of carbon nanotubes 5.3.1 Single-walled carbon nanotubes 5.3.2 Double-walled carbon nanotubes 5.3.3 Multi-walled carbon nanotubes 5.3.4 Carbon nanotubes justified on the basis of chirality

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5.4

Characterization techniques 5.4.1 Raman spectroscopy 5.4.2 Transmission electron microscopy 5.4.3 Scanning electron microscopy 5.4.4 Proton nuclear magnetic resonance 5.4.5 Thermogravimetric analysis 5.4.6 Atomic force microscopy 5.4.7 Fourier transform infrared spectroscopy 5.5 Synthesis of carbon nanotubes 5.5.1 Arc discharge 5.5.2 Laser ablation 5.5.3 Chemical vapor deposition 5.5.4 Catalytic chemical vapor deposition 5.6 Biocompatibility, biodistribution, and biodegradability of carbon nanotubes 5.6.1 Biocompatibility 5.6.2 Biodistribution 5.6.3 Biodegradability 5.7 Toxicity 5.7.1 Neurotoxicity 5.7.2 Cytotoxicity 5.8 Carbon nanotube modification: toward reduction of its toxicity issues 5.8.1 PEGylation 5.8.2 Folate-anchored carbon nanotubes 5.8.3 Chitosan-layered carbon nanotube 5.8.4 Peptide conjugation 5.9 Biomedical applications of carbon nanotubes 5.9.1 Carbon nanotubes in biosensing 5.9.2 Carbon nanotubes in drug delivery 5.9.3 Carbon nanotubes in imaging 5.9.4 Carbon nanotubes in tissue engineering 5.9.5 Thermal therapy 5.9.6 Carbon nanotubes in dentistry 5.9.7 Carbon nanotubes in regenerative medicines 5.9.8 Other application 5.10 Future aspects 5.11 Conclusion Acknowledgment Individual authors’ contributions Compliance with ethical standards Conflict of interest Research involving human participants and animals Informed consent References

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Scope of using hollow fibers as a medium for drug delivery Ateev Vohra, Prateek Raturi and Emran Hussain 6.1 Introduction 6.2 Drug delivery systems 6.3 Hollow fibers 6.4 Types of hollow fibers 6.5 Hollow fibers for drug delivery 6.6 Ion exchange hollow fiber membranes 6.7 Fabrication techniques for hollow fibers 6.7.1 Solution-based technique 6.7.2 Melt spinning 6.7.3 Electrospinning 6.7.4 Microfluidic spinning 6.7.5 Other fabrication techniques 6.8 Drug-loading in hollow fiber 6.9 Mechanism of drug release via hollow fiber 6.10 Drug release kinetics 6.11 Drug delivery applications of hollow fibers associated with different organ systems 6.11.1 Nervous system 6.11.2 Circulatory system 6.11.3 Digestive system 6.11.4 Respiratory system 6.11.5 Endocrine system 6.11.6 Integumentary system 6.11.7 Immune system and lymphatic system 6.11.8 Renal system 6.11.9 Reproductive system 6.11.10 Skeletal system 6.12 Other drug delivery applications of hollow fibers 6.13 Prospects Acknowledgments Authors’ contributions Compliance with ethical standards Conflict of interest Research involving human participants and animals Informed consent References

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Deciphering plausible role of DNA nanostructures in drug delivery Anju Singh, Shoaib Khan, Nishu Nain and Shrikant Kukreti 7.1 Introduction 7.2 Evolution of nanoscience 7.3 Nano-bio interface 7.4 DNA nanotechnology

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7.4.1 Advantages of DNA in nanotechnology DNA nanostructures 7.5.1 Driving forces of self-assembly of DNA nanostructures 7.5.2 Formulation of DNA nanostructures 7.6 Holliday junction in designing DNA nanostructures 7.7 DNA aptamers in functionalizing DNA nanostructures 7.8 Structural DNA nanotechnology 7.8.1 2D-DNA nanostructures 7.8.2 3D-DNA nanostructures 7.9 Dynamic DNA nanotechnology 7.9.1 DNA tweezers 7.9.2 DNA walkers 7.10 Why are DNA nanostructures suitable for drug delivery? 7.11 Modes of drug delivery 7.11.1 Passive delivery 7.11.2 Self-delivery 7.12 Recent advances in DNA nanostructure-mediated drug delivery 7.13 Pros and cons of DNA nanostructures in drug delivery 7.13.1 In vitro and in vivo structural stability of DNA nanostructures/DNA origami structures 7.13.2 DNA origami in the immune system (stability and viability) 7.14 Outlook and future perspective Authors’ contribution Compliance with ethical standards Conflict of interest Research involving human participants and animals Informed consent References

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Multifaceted approach for nanofiber fabrication Thareja Rakhi, Malik Pragati, Bansal Prerna and Singh Jyoti 8.1 Introduction 8.2 Fabrication techniques 8.2.1 Template synthesis 8.2.2 Phase separation 8.2.3 Drawing process 8.2.4 Self-assembly 8.2.5 Melt blowing 8.2.6 Electrospinning 8.3 Application of nanofibers 8.3.1 Water treatment 8.3.2 Catalysis and energy storage 8.3.3 Electrodes in fuel cells 8.3.4 Lithium-ion batteries

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8

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8.3.5 Tissue engineering 8.3.6 Drug delivery 8.3.7 Wound healing 8.3.8 Cosmetics and skin treatment 8.4 Conclusions Individual authors’ contributions Compliance with ethical standards Conflict of interest Research involving human participants and animals Informed consent References 9

Electrospun nanofiber a smart drug carriers: production methods, problems, solutions, and applications Chandan Bhogendra Jha, Sanusha Santhosh, Chitrangda Singh, Sujit Bose, Kuntal Manna, Raunak Varshney and Rashi Mathur 9.1 Introduction 9.2 Advantages of electrospun nanofiber 9.2.1 High surface area-to-volume ratio 9.2.2 Nanofibers can be synthesized from a variety of polymers and materials 9.2.3 Ease of fiber functionalization 9.3 Methods of electrospinning 9.3.1 Blending electrospinning 9.3.2 Coaxial electrospinning 9.3.3 Emulsion electrospinning 9.3.4 Surface modification electrospinning 9.3.5 Electrospray 9.3.6 Coaxial electrospray 9.4 Applications of electrospinning 9.4.1 Ocular delivery 9.4.2 Transdermal delivery 9.4.3 Cancer treatment 9.4.4 Enzyme immobilization 9.4.5 Controlled release 9.4.6 Filtration 9.4.7 Tissue regeneration 9.4.8 Barrier membranes 9.4.9 Wound healing 9.5 Conclusion and outlook Acknowledgments Authors’ contribution Compliance with ethical standards Conflict of interest

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Research involving human participants and animals Informed consent References 10

11

Potential of stem cells in combination with natural and synthetic polymer hydrogel for wound healing dressing Subodh Kumar, Somya Chaaudhary, Ranjan Verma and Yogesh Kumar Verma 10.1 Introduction 10.2 Physiology of wound healing 10.2.1 Hemostasis 10.2.2 Inflammation 10.2.3 Proliferation 10.2.4 Remodeling 10.3 Approaches to heal wound 10.4 Biomaterial used in wound healing 10.4.1 Natural biomaterials 10.4.2 Synthetic biomaterials 10.5 Wound healing dressings 10.6 Application of hydrogel in wound healing 10.6.1 Natural hydrogels in market 10.6.2 Synthetic hydrogels in market 10.7 Stem cells in wound healing 10.7.1 Endothelial progenitor cells in wound healing 10.7.2 Mesenchymal stem cells in wound healing 10.7.3 Adipose tissue-derived stem cells 10.7.4 Application of stem cells loaded biomaterials in wound healing 10.8 Cell-based wound dressing 10.9 Limitation of biomaterials dressing in wound healing 10.10 Conclusion Acknowledgment Authors’ contributions Compliance with ethical standards Conflict of interest Research involving human participants and animals Informed consent Funding References Next-generation bandages to overcome oxygen limitation during wound healing/tissue repair Kirtida Gambhir, Nishant Tyagi and Yogesh Kumar Verma 11.1 Introduction 11.2 Role of oxygen in wound healing

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11.2.1 Reactive oxygen species in inflammatory phase 11.2.2 Reactive oxygen species in the proliferative phase 11.2.3 Reactive oxygen species in re-epithelialization 11.2.4 Reactive oxygen species in infection control 11.3 Conventional wound dressings 11.3.1 Traditional wound dressing 11.3.2 Modern wound dressing 11.3.3 Bioactive wound dressings 11.3.4 Tissue-engineered skin substitutes 11.3.5 Medicated dressings 11.3.6 Composite dressings 11.4 Limitations of conventional dressings 11.5 Next-generation bandages 11.5.1 Wound dressings with monitoring capacity 11.5.2 Self-healing wound dressings 11.5.3 Drug delivery dressings 11.6 Oxygen therapies 11.6.1 Hyperbaric oxygen therapy 11.6.2 Topical oxygen therapy 11.7 Conclusion Acknowledgment Authors’ contributions Compliance with ethical standards Permissions Conflict of interest Research involving human participants and animals Informed consent References 12

Fiber and textile in drug delivery to combat multidrug resistance microbial infection Deepa Dehari, Aiswarya Chaudhuri, Dulla Naveen Kumar, Gopal Nath and Ashish Kumar Agrawal 12.1 Introduction 12.2 Common textile antimicrobial agent 12.2.1 Quaternary ammonium compounds 12.2.2 Polybiguanides 12.2.3 Triclosan 12.2.4 Chitosan 12.2.5 Natural herbal products 12.2.6 N-halamines 12.2.7 Natural dyes 12.2.8 Enzymes 12.2.9 Metal and metal oxides

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Nanoparticles-based fabrics for the treatment of antimicrobial infection 12.3.1 Silver nanoparticles 12.3.2 Gold nanoparticles 12.3.3 Zinc oxide nanoparticles 12.3.4 Mesoporous silica nanoparticles 12.3.5 Chitosan nanoparticles 12.4 Electrospun-based fabrics for the treatment of antimicrobial infection 12.4.1 Drug releasing characteristic of antimicrobials-loaded electrospun nanofibers 12.5 Antibiotics-loaded fabrics for the treatment of antimicrobial infection 12.6 Application of nanoparticles against MDROs: merits and demerits 12.7 Conclusion Acknowledgement Authors’ contribution Compliance with ethical standards Conflict of interest Research involving human participants and animals Informed consent References

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Emulsion templated three-dimensional porous scaffolds for drug delivery Anilkumar Yadav, Meenal Agrawal and Rajiv K. Srivastava 13.1 Introduction 13.1.1 Drug delivery systems 13.1.2 Emulsion templating 13.2 Emulsion templated scaffolds 13.2.1 Conventional emulsion-based scaffolds 13.2.2 Pickering emulsion-based scaffolds 13.2.3 Emulsion templated 3D-printed scaffolds 13.3 High internal phase emulsion templates for drug encapsulation 13.4 Conclusion Acknowledgments Individual authors’ contributions Compliance with ethical standards Conflict of interest Research involving human participants and animals Informed consent References

367 368 370 371 372 372 374 375 376 379 380 381 381 381 381 381 381 381

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Nanotubes-based brain targeted drug delivery system: a step toward improving bioavailability and drug enhancement at the target site Parul Mittal and Puja Panwar Hazari 14.1 Introduction 14.2 Carbon nanotubes as a loaded vehicle for therapeutic delivery 14.3 Neurological disorder and requisite for drug delivery across the blood-brain-barrier 14.3.1 Blood-brain-barrier 14.3.2 Role of carbon nanotubes in neurological disorders 14.3.3 Role of carbon nanotubes in Alzheimer’s disease 14.3.4 Role of carbon nanotubes in Parkinson’s disease 14.3.5 Role of functionalized carbon nanotubes in drug delivery in Parkinson’s disease 14.4 Plausible drug delivery strategies by carbon nanotubes in brain cancer therapy 14.5 Repair and regeneration of neurons by carbon nanotubes 14.5.1 Nanomaterials act as scaffolds for neuroreconstruction 14.5.2 Improving neurocompatability of carbon nanotubes by surface functionalization 14.5.3 Applications of carbon nanotubes for neural cell function 14.6 Neurotoxicity and biocompatibility of carbon nanotubes 14.7 Cellular fate of carbon nanotubes 14.8 Conclusion Acknowledgements Individual authors’ contributions Compliance with ethical standards Conflict of interest Research involving human participants and animals Informed consent References Functional designing of textile surfaces for biomedical devices Chetna Verma, Ankita Sharma, Pratibha Singh, Manali Somani, Surabhi Singh, Shamayita Patra, Samrat Mukhopadhyay and Bhuvanesh Gupta 15.1 Introduction 15.2 Functional designing of polyester 15.2.1 Chemical functionalization 15.2.2 Plasma activation 15.2.3 Graft copolymerization 15.3 Applications of functional polyesters 15.3.1 Antimicrobial surfaces

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15.3.2 Tissue engineering 15.4 Conclusion Acknowledgments Individual authors’ contributions Compliance of interest Research involving human participants and animals Informed consent References 16

Metal/metal oxide nanoparticles reinforced biocomposites for drug delivery Isha Gupta, Sonia Gandhi and Sameer Sapra 16.1 Introduction 16.2 Nano-biocomposites 16.2.1 Nano-layered reinforced biocomposites (2-D biocomposites) 16.2.2 Nano-filamentary reinforced biocomposites (1-D biocomposites) 16.2.3 Nano-particulate reinforced biocomposites (0-D biocomposites) 16.3 Biopolymer 16.4 Nanofillers 16.5 Metal/metal oxide nanoparticles-reinforced biocomposites 16.5.1 Preparation methods for metal/metal oxide reinforced biocomposites 16.5.2 Characterization of polymer nanocomposites 16.5.3 Controlled drug delivery applications of nanobiocomposites Conclusion Acknowledgments Authors’ contributions Compliance with ethical standards Conflict of interest Research involving human participants and animals Informed consent References

Index

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List of contributors

Ashish Kumar Agrawal Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (BHU), Varanasi, Uttar Pradesh, India Meenal Agrawal Department of Textile and Fibre Engineering, Indian Institute of Technology Delhi, New Delhi, Delhi, India Sujit Bose School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, India Somya Chaaudhary Stem Cell & Tissue Engineering Research Group, Institute of Nuclear Medicine & Allied Sciences (INMAS), Defense Research and Development Organization (DRDO), Timarpur, New Delhi, Delhi, India Aiswarya Chaudhuri Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (BHU), Varanasi, Uttar Pradesh, India Deepa Dehari Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (BHU), Varanasi, Uttar Pradesh, India Kirtida Gambhir Stem Cell and Tissue Engineering Research Group, Institute of Nuclear Medicine and Allied Sciences (INMAS), Defense Research and Development Organization (DRDO), Delhi, India Sonia Gandhi Institute of Nuclear Medicine and Allied Sciences (INMAS), Defence Research and Development Organisation (DRDO), Delhi, India H.V. Gangadharappa Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysuru, Karnataka, India Bhuvanesh Gupta Bioengineering Laboratory, Department of Textile and Fibre Engineering, Indian Institute of Technology, New Delhi, Delhi, India Isha Gupta Institute of Nuclear Medicine and Allied Sciences (INMAS), Defence Research and Development Organisation (DRDO), Delhi, India; Department of Chemistry, Indian Institute of Technology Delhi (IITD), Delhi, India

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List of contributors

Payal Gupta Department of Biosciences and Bioengineering, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand, India; Department of Biotechnology, Graphic Era University, Dehradun, Uttarakhand, India Puja Panwar Hazari Divison of Cyclotron and Radiopharmaceutical Sciences, Institute of Nuclear Medicine and Allied Sciences, Delhi, India G. Hrishikesh Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysuru, Karnataka, India Emran Hussain School of Science, Royal Melbourne Institute of Technology, VIC, Australia Chandan Bhogendra Jha Division of Radiological, Nuclear and Imaging Sciences, Institute of Nuclear Medicine and Allied Sciences, DRDO, Timarpur, Delhi, India; Department of Chemistry, Indian Institute of Technology, Delhi, India Asha P. Johnson Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysuru, Karnataka, India S.L. Jyothi Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysuru, Karnataka, India Singh Jyoti Department of Chemistry, Hansraj College, University of Delhi, Delhi, New Delhi, Delhi, India Lajpreet Kaur CBRN Protection and Decontamination Research Group, Division of Radiological, Nuclear and Imaging Sciences, Institute of Nuclear Medicine and Allied Sciences, Delhi, India Shoaib Khan Nucleic Acids Research Lab, Department of Chemistry, University of Delhi, Delhi, India Shrikant Kukreti Nucleic Acids Research Lab, Department of Chemistry, University of Delhi, Delhi, India Dulla Naveen Kumar Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (BHU), Varanasi, Uttar Pradesh, India S. Hemanth Kumar Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysuru, Karnataka, India Subodh Kumar Stem Cell & Tissue Engineering Research Group, Institute of Nuclear Medicine & Allied Sciences (INMAS), Defense Research and Development Organization (DRDO), Timarpur, New Delhi, Delhi, India

List of contributors

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Kinshuk Malik Department of Chemistry, Indian Institute of Technology Kharagpur, Kharagpur, West Bengal, India Kuntal Manna Department of Chemistry, Indian Institute of Technology, Delhi, India Rashi Mathur Division of Radiological, Nuclear and Imaging Sciences, Institute of Nuclear Medicine and Allied Sciences, DRDO, Timarpur, Delhi, India Ved Prakash Meena Division of Stem Cell and Gene Therapy Research, Institute of Nuclear Medicine and Allied Sciences, Delhi, India Abhishesh Kumar Mehata Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (BHU), Varanasi, Uttar Pradesh, India Lalita Mehra Department of Combat Sciences, Institute of Nuclear Medicine & Allied Sciences, Defence Research & Development Organisation, Timarpur, Delhi, India Parul Mittal Divison of Cyclotron and Radiopharmaceutical Sciences, Institute of Nuclear Medicine and Allied Sciences, Delhi, India; Department of Zoology, Delhi University, Delhi, India Samrat Mukhopadhyay Bioengineering Laboratory, Department of Textile and Fibre Engineering, Indian Institute of Technology, New Delhi, Delhi, India Madaswamy S. Muthu Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (BHU), Varanasi, Uttar Pradesh, India Nishu Nain Nucleic Acids Research Lab, Department of Chemistry, University of Delhi, Delhi, India Gopal Nath Department of Microbiology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India Himanshu Ojha CBRN Protection and Decontamination Research Group, Division of Radiological, Nuclear and Imaging Sciences, Institute of Nuclear Medicine and Allied Sciences, Delhi, India Rakesh Pandey Division of Stem Cell and Gene Therapy Research, Institute of Nuclear Medicine and Allied Sciences, Delhi, India Mallika Pathak Department of Chemistry, Miranda House, University of Delhi, Delhi, India Shamayita Patra Shri Vaishnav Vidyapeeth Vishwavidyalaya, Indore, Madhya Pradesh, India Malik Pragati Department of Chemistry, Acharya Narendra Dev College, University of Delhi, Delhi, New Delhi, Delhi, India

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List of contributors

K. Pramod College of Pharmaceutical Sciences, Govt. Medical College, Kozhikode, Kerala, India Bansal Prerna Department of Chemistry, Rajdhani College, University of Delhi, Delhi, New Delhi, Delhi, India Vishnu Priya Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (BHU), Varanasi, Uttar Pradesh, India Thareja Rakhi Department of Chemistry, St. Stephen’s College, University of Delhi, Delhi, New Delhi, Delhi, India Prateek Raturi School of Science, Royal Melbourne Institute of Technology, VIC, Australia Sanusha Santhosh School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, India Sameer Sapra Department of Chemistry, Indian Institute of Technology Delhi (IITD), Delhi, India Ankita Sharma Bioengineering Laboratory, Department of Textile and Fibre Engineering, Indian Institute of Technology, New Delhi, India Anju Singh Department of Chemistry, Ramjas College, University of Delhi, Delhi, India; Nucleic Acids Research Lab, Department of Chemistry, University of Delhi, Delhi, India Chitrangda Singh Division of Radiological, Nuclear and Imaging Sciences, Institute of Nuclear Medicine and Allied Sciences, DRDO, Timarpur, Delhi, India Pratibha Singh Bioengineering Laboratory, Department of Textile and Fibre Engineering, Indian Institute of Technology, New Delhi, Delhi, India Rishabh Singh Division of Stem Cell and Gene Therapy Research, Institute of Nuclear Medicine and Allied Sciences, Delhi, India Surabhi Singh Bioengineering Laboratory, Department of Textile and Fibre Engineering, Indian Institute of Technology, New Delhi, Delhi, India Sweta Singh Division of Stem Cell and Gene Therapy Research, Institute of Nuclear Medicine and Allied Sciences, Delhi, India Rahul Singhal Department of Chemistry, Shivaji College, University of Delhi, Delhi, India

List of contributors

xxiii

Manali Somani Bioengineering Laboratory, Department of Textile and Fibre Engineering, Indian Institute of Technology, New Delhi, Delhi, India Rajiv K. Srivastava Department of Textile and Fibre Engineering, Indian Institute of Technology Delhi, New Delhi, Delhi, India Priyanka Surya Division of Stem Cell and Gene Therapy Research, Institute of Nuclear Medicine and Allied Sciences, Delhi, India Sarika Tomar Division of Stem Cell and Gene Therapy Research, Institute of Nuclear Medicine and Allied Sciences, Delhi, India Nishant Tyagi Stem Cell and Tissue Engineering Research Group, Institute of Nuclear Medicine and Allied Sciences (INMAS), Defense Research and Development Organization (DRDO), Delhi, India Raunak Varshney Division of Radiological, Nuclear and Imaging Sciences, Institute of Nuclear Medicine and Allied Sciences, DRDO, Timarpur, Delhi, India Chetna Verma Bioengineering Laboratory, Department of Textile and Fibre Engineering, Indian Institute of Technology, New Delhi, India Piyush Verma CBRN Protection and Decontamination Research Group, Division of Radiological, Nuclear and Imaging Sciences, Institute of Nuclear Medicine and Allied Sciences, Delhi, India Ranjan Verma Stem Cell & Tissue Engineering Research Group, Institute of Nuclear Medicine & Allied Sciences (INMAS), Defense Research and Development Organization (DRDO), Timarpur, New Delhi, India; Division of Stem Cell and Gene Therapy Research, Institute of Nuclear Medicine and Allied Sciences, Delhi, India Yogesh Kumar Verma Stem Cell and Tissue Engineering Research Group, Institute of Nuclear Medicine and Allied Sciences (INMAS), Defense Research and Development Organization (DRDO), Delhi, India B. Vidya Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysuru, Karnataka, India Vikas Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (BHU), Varanasi, Uttar Pradesh, India Ateev Vohra School of Biosciences, The University of Melbourne, VIC, Australia Anilkumar Yadav Department of Textile and Fibre Engineering, Indian Institute of Technology Delhi, New Delhi, Delhi, India

Drug-releasing textile materials: current developments and future perspectives

1

Abhishesh Kumar Mehata, Deepa Dehari, Vikas, Vishnu Priya and Madaswamy S. Muthu Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (BHU), Varanasi, Uttar Pradesh, India

1.1

Introduction

Humans have always attempted and succeeded in increasing health and quality of life. The median lifespan has been increased by several years due to improvements in diet and sanitation. Advancements in biomedical services and facilities have also aided this, and recently, newer discoveries are further improving the quality of life. Numerous efforts have been taken to enhance the ease of treatment and searching remedies for health issues. Textile materials can be useful in this context. Therapeutic delivery is a unique component of the healthcare industry (Kankariya et al., 2021). Solid oral dosage forms (tablets, capsules, and pills), lotions for topical application, and injectables are commonly used, and there are situations where other dosage forms might be highly appropriate (Lopez et al., 2015). Some medicinal products lose their effectiveness during therapeutic application due to extensive metabolism, either in the intestine or in the liver. As a result, reasonably high drug concentrations are required to produce a therapeutic effect, which may result in the production of toxic metabolic products. Because transport via the skin bypasses the hepatic system, the dose of the drug can be reduced to get equivalent therapeutic action. Ointments are a suitable drug delivery system for medicinal substances with a wider therapeutic window (Gavhane and Yadav, 2012). Furthermore, there are cases when oral delivery is less appropriate or feasible, such as with infants, persons with ingesting problems, or people who tend to forget, such as those with dementia. In such cases, transdermal drug delivery is a viable option for in vivo applications (Thakkar et al., 2017). For long-term therapy, transdermal drug delivery systems are better than daily injectables or tablet dosage forms. Wearing comfort and fabric qualities have advanced over time, and fabrics are now an integral part of our daily lives (Bormann et al., 2021). In the case of textile materials, their morphological frameworks of textiles are more important. Additionally, production method of textile plays a crucial role in developing porous, breathable frameworks of textile materials. Textile materials are beneficial for ex vivo (outside the body) purposes due to their “breathing” capabilities. Fiber and Textile Engineering in Drug Delivery Systems. DOI: https://doi.org/10.1016/B978-0-323-96117-2.00001-7 © 2023 Elsevier Ltd. All rights reserved.

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Fiber and Textile Engineering in Drug Delivery Systems

Furthermore, people are adapted to wearing textiles, it appears sensible to investigate these fabrics as a viable option for drug delivery. A variety of drug delivery strategies have been developed and advanced over time. Out of these, transdermal patches are popularly used for topical and systemic drug delivery. The majority of transdermal patches are multilayered structures that comprise drug reservoir as well as a barrier as regulating mechanism (Ten Breteler et al., 2002b). Biocompatibility is the capacity of a substance to function with an acceptable host response. Cytotoxicity, carcinogenic effects, and associated concerns, such as mutagenicity (causing changes in genetic makeup that are transferred during cell division) and teratogenic effects, are all key aspects to be considered in terms of biocompatibility (Li et al., 2015; Liu et al., 2018). In case of biodegradable polymers, the primary material and the metabolic byproducts must be safe. Although the skin acts as a natural protection against many compounds accessing the body, extra caution must be taken for in vivo therapies. Since, in vivo therapy has patients safety is the primary criteria and drug product must be non-toxic and safe (Mehata et al., 2019). The product’s biological stability and biological degradability are two more aspects of biocompatibility. Biodegradability is not always necessary in the case of transdermal patches. However, it is recommended to have biodegradability, when it has to be implanted below the skin (Kr¨amer et al., 2020). A more or less biologically stable material is desired for the therapeutical application. Generally, in vivo formulations must be biologically degradable, eliminating the requirement for a separate procedure to remove the substance from the body (Artzi et al., 2011). The next crucial biocompatibility factor in building an excellent textile-based therapeutic carrier is interactions at the boundaries of the fabric substance and body tissue, such as the epidermis. Technologies with good controlled delivery are not useful if they cause significant contact dermatitis at the site of the application. Controllability is an additional crucial feature of a drug carrier (Jockenhoevel, 2018). As previously stated, there is risk of overdosing in some traditional drug delivery systems. A viable option for sustained drug delivery system can be used, which allows medicines to be administered in a controlled manner (Jiao et al., 2020). The therapeutic delivery system should ideally be controlled in a manner that the release is achievable within a specified range; that is, multiple release patterns should be conceivable with any given system in response to a certain patient’s requirement. The material costs are not irrelevant in the development stage, even if they are difficult to define. There is no point in designing a system if the costs cancel out the benefits. The pricing of the textile materials should be flexible for medical applications. However, the human body and the cost factor must be considered when evaluating various systems with similar goals (Radu et al., 2016). The manufacturing process is linked to the cost factor. In most circumstances, traditional production processes will be more cost-effective than specially designed new techniques; in general, the more intricate the technology, the higher will be the expenses (Qin, 2016). This chapter presents historical developments and advancements in drug-releasing textile materials and describes the different techniques utilized to incorporate medication into fabric-based textile materials. In addition, this chapter also describes in detail the drug release mechanisms and kinetics, types of

Drug-releasing textile materials: current developments and future perspectives

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therapeutics carriers, fabrication, coating methods, characterization, and application of drug-releasing textiles.

1.2

Historical development of drug-releasing textile

Medical textiles have a long history dating back to the development of wound dressings and closures thousands of years ago. During the period 5000
3000 BC, advancements in surgery led to the development of wound dressings. Natural fibers, such as flax, silk, linen strips, and cotton, were utilized to close wounds. The natural fibers were initially soaked in oil and wine to facilitate a clean wound closure technique and prevent tissue drag and infection. Cornelius Celsus, a Roman physician, documented the usage of sutures and clips in 30 AD. In contrast, Aelius Galen, a physician, reported the use of silk and catgut in 150 AD for medical applications. Suture material composed of flax, hemp, and hair has been researched by an ancient Indian physician and surgeon, Sushruta. With the invention of sterilization processes in the 1800s, more surgical and suture technique innovation was recognized and performed for medical application. The invention of synthetic polymers and fibers led to the development of synthetic closures and drug-releasing textile (Sharma and Popli, 2018).

1.3

Classes of drug-releasing textile materials

Drug-releasing textiles are primarily of three types and are made by various techniques, including the electrospinning technique that has been explored for multiple biological purposes and drug delivery systems (Toti et al., 2011).

1.3.1 Woven fabrics Woven fabrics are produced by weaving on a loom, and made of many threads woven on a warp and a weft. The preparation of woven fabrics involves linking of two orthogonal arrays of yarns. The first is the warp at 0 degree and the second is the weft at 90 degrees. Fabrics that are embedded with therapeutics or bioactive substances for medical application belong to the woven fabrics. For covalently linking the bioactive molecules, woven fabrics can be processed with drug substances or therapeutics in the vicinity of appropriate physiochemical transformers. Drug substances that are physically absorbed or adsorbed, coated, entrapped, or chemically bonded to the fiber’s surface are commonly used in woven textile materials. Drug-loaded woven fabrics have been used for biomedical dressings, artificial skin grafts, and prosthetic. Consequently, the first contemporary wound dressing was launched in the 1980s for clinical application. They were mostly multilayered materials with specialized properties (hydration control and antimicrobial) that are capable of providing an optimum wound recovery atmosphere. Semipermeable and

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Fiber and Textile Engineering in Drug Delivery Systems

translucent polyurethane-based films have also been produced that permit wound exploration and are excellent for superficial wounds with slight fluid discharge. Numerous wound dressings that can provide effective wound-healing ingredients are already widely accessible (Ng and Hu, 2018; Shah and Halacheva, 2016). In a study, Massella et al. developed bio-function textile with cellulose fabric and caffeine nanoparticles. The developed drug-releasing textile system allowed sustained release of caffeine with antioxidant properties (Massella et al., 2018). In another study, El-Naggar et al. designed a bioactive wound dressing loaded with silver nanoparticles for antibacterial activity. The developed bioactive wound dressing was able to reduce the bacterial colonies up to 100% in the case of Pseudomonas aeruginosa culture (El-Naggar et al., 2020). Few years ago, Sun et al. developed a thermosensitive microgel-loaded drug-releasing textile for controlled release microgel. Additionally, an in vitro study suggested that drug-releasing textiles were biocompatible and nontoxic. The main application of the developed textile was to treat sunburns (Sun et al., 2017). Overall, numerous studies showed zero order release kinetics of the drug released from the textile materials, which indicates that drugreleasing textiles are made up of a reservoir diffusion control system.

1.3.2 Nonwoven fabrics Generally, nonwoven textiles are commonly used in manufacturing medical consumables, such as surgical gowns, masks, wound dressings, pads, and medical filters. They can be produced in a short time, with high flexibility and low production cost. These products are single use and can be disposed. Drug-loaded nonwoven textiles are produced by gluing small threads collectively in sheets or web-like patterns by physical, thermal, or chemical entanglement of drug-bound fibers or filaments. They are commonly utilized as microbial barriers, antiseptic wraps, surgical bandages, hats, aprons, and draping. Bioactive compounds can be added to fibers throughout the spinning cycle to produce biodegradable nonwoven fabrics. By diffusing bioactive compounds from fibers and degrading the nonwoven textile, bioactive compounds can be delivered to specific regions in a sustained or controlled manner. This could lower the dose/concentration of bioactive substances utilized, which can be expensive, while retaining high local levels of active substances over an extended duration of time (Takayama et al., 2021). A broader spectrum of antimicrobial and bioactive compounds can be included at the fabric spinning step (Aslankaraoglu et al., 1999). For instance, bioresorbable and biocompatible nonwoven textiles that deliver cytostatic therapeutics over time, could be useful in treating aggressive cancers that have spread across the abdominal cavity due to intraperitoneal fluid (Kaplan et al., 2016). Due to their three-dimensional architecture and utilization of fibers with predetermined porosity and geometry, nonwoven drug-release textile materials are particularly suited for controlled/sustained release of the loaded drug (Terasaka et al., 2006). 3D biodegradable scaffolds with an interconnecting microporous structure and bioresorbability open up new opportunities for various therapeutic purposes (Hemmrich et al., 2008). The new technology is based on a novel spinning method that permits the production of bioresorbable nonwoven fabrics. The gentle preparation settings enable the integration of bioactive substances and the translation of sensitive and atypical polymers

Drug-releasing textile materials: current developments and future perspectives

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into fibers. By varying the production conditions, selecting and composing the matrix materials, fiber features such as thickness, resorption time, and localization of therapeutics delivery behavior can be tuned to meet desired therapeutic qualities. The solubility of the drug in the polymeric solutions decides the nature of polymers to be used for preparation of drug-loaded nonwoven fabrics. The production of biologically degradable drug-loaded polymeric materials is a promising development in this field. Special polymeric substances have been developed that breakdown faster in the vicinity of particular enzymes, such as those observed at areas of infection, enabling drug release form the matrix as soon as the infection begins (Lee et al., 2018; Zhang et al., 2019). In a study, Gupta et al. developed 4-acetamidophenol-loaded thermosensitive nonwoven fabrics by radiation graft polymerization reaction. It was observed that amount of drug releases at 32 C was minimal, whereas by increasing temperature up to 40 C, drug release was increased to the maximum. The reason behind the increase in the drug release was the structural changes in the graft copolymer with an increase in the temperature (Gupta et al., 2013). Recently, Wang et al. developed Centella asiatica-loaded nonwoven fabric-based wound dressing with antibacterial activity. An in vitro study showed sustained drug release and excellent antibacterial activity Staphylococcus aureus and Escherichia coli (Wang et al., 2021).

1.3.3 Nonwoven electrospun fabrics Nanofibers are an emerging group of nanometer-sized fibers with promising clinical and biological applications (Noruzi, 2016; Zhang et al., 2017). Nanofibers have low density, huge surface area, large pore volume, and small pore diameter. Nanofibers offer features that render them excellent for various therapeutic uses due to their large surface area-to-weight ratio. Nanofibrous materials have been manufactured using three different processes, namely self-assembly, phase separation, and electrospinning. As it is easy and straightforward to fabricate drug-releasing textile, the electrospinning technique is largely preferred (Valizadeh and Farkhani, 2014). The first patent on electrospinning was submitted in 1934, which has marked the beginning of the electrospinning technique. Nanofibers produced from polymeric substances can be transformed into various shapes and sizes (Tucker et al., 2012). The size of the fiber might vary from 10 to 1000 nm or more. Electrospinning can be done using either the polymeric melt or a doping solution. On the other hand, recent studies primarily concentrated on the electrospinning of polymeric solutions. Protein nanofibers have been shown to have a potential role in tissue engineering. Electrospun fibrous substances are distinguished by their large specific surface area and small pores, which are well suited to the adsorption of liquid and the inhibition of bacterial permeation, producing a favorable wound healing environment (Bhardwaj and Kundu, 2010). The benefits and drawbacks of several nanofiber fabrication techniques have been reported. Polymeric nanofibers provide a number of benefits in medical and biological applications. There is proof that the chemical nature of nanofibers and their morphology have a significant impact on cellular adhesion, stimulation, and multiplication. Moreover, antibiotics, anticancer drugs, proteins, and other medications can be loaded on to electrospun substances. The

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Fiber and Textile Engineering in Drug Delivery Systems

utilization of electrospinning method in bioengineering and drug delivery appears to hold considerable potential for future developments (Padmakumar et al., 2019). Another way to control therapeutic release is through covalent attachment of drug molecules to polymeric materials. Such conjugates are a comparatively novel drug delivery system for improving cancer therapy (Mehata et al., 2022; Wnek, 2014).

1.3.3.1 Self-assembly in fabrics Self-assembly in fabrics involves the rapid grouping of different constituents into an organized and stabilized framework. Generally, preorganized noncovalent bonds are required for the development of nanofibers via self-assembly. The self-assembly process, which involves self-organizing of molecules into shapes or architectures without the need for human involvement, is observed in both natural and industrial synthetic techniques. Nanoscale supramolecular nanostructures, such as nanofibers, can be formed through the self-assembly of biological or synthetic macromolecules. When contrasted to electrospinning, self-assembly allows for the manufacture of nanofibers with significantly lower dimensions; nevertheless, the approach is generally more difficult, and efficiency is poor (Humenik et al., 2018; Li et al., 2020; Lin et al., 2013).

1.3.3.2 Phase separation Phase separation is another technique used for preparing nanostructures, which is widely utilized to produce three-dimensional tissue-engineered scaffolds. A polymeric solution can be phase separated into a polymer-rich zone and a solvent-rich zone, and such a structure can be maintained by quenching at low temperatures. Porous polymeric scaffolds can be formed by removing the solvent via lyophilization or harvesting. Changes in temperature or the addition of a non-solvent to the polymeric solution might cause phase separation. Thermally triggered phase separation and non-solvent triggered phase separation are the two types of phase separation. The microporous structures of the scaffolds are commonly produced by these techniques. This is a straightforward procedure that does not necessitate costly specialized instruments. The key disadvantage is that it is a small-scale approach and appropriate for polymeric materials that can phase separate (Liu and Ma, 2009; Sabzi et al., 2021; Wang et al., 2018).

1.4

Mechanisms of controlled drug delivery through textile materials and their pharmacokinetics

The mechanism determines the pace of drug release from textile materials. Many traditional control drug delivery systems are set up to deliver therapeutics over a prolonged period. A variety of techniques, including naturally available biodegradable polymeric materials, have been utilized to achieve this goal. Nondegradable polymeric materials are employed in the process where the transport system can be retrieved following delivery of the drug (e.g., patches or implant withdrawal) (Cheng et al., 2018). In a study, Di et al. developed stretch-triggered drug delivery system for the delivery of

Drug-releasing textile materials: current developments and future perspectives

7

anticancer, antimicrobial, and insulin delivery. The developed elastomer films are loaded with drug deports that can be released by stretching the fingers (Di et al., 2015). The principles of polymeric material-based controlled drug delivery have been discussed in the following sections.

1.4.1 Temporally controlled mechanism of drug release 1.4.1.1 Dissolution-controlled release The inclusion of active ingredients into a hydrophobic polymeric substrate, like wax, polyethylene, or polypropylene, or the covering of the active ingredient with protecting polymeric layers of varied depth can promote controlled delivery of the drug by the dissolution of the matrix. This polymeric barrier can slow or stop the therapeutics from dissolving or diffusing out of the drug delivery system. The extent of dissolving fluid’s permeation determines the availability of drugs for absorptions. The coated pharmaceutical beads can be incorporated into drug-releasing textile for controlled release. The duration it takes for the polymeric barrier to disintegrate is proportional to its thickness, the thickness of the barrier can be adjusted to provide long-term drug release. This method has been used to deliver anti-spasmodic and hypnotic formulations, such as phenothiazine and anticholinesterase drug products (Chandrasekaran and Paul, 1982; Narasimhan and Peppas, 1997).

1.4.1.2 Diffusion-controlled release Diffusion of drug molecules is dependent on concentration gradients, which is the most common method of transporting drug substances across polymer membranes. Drugs are encapsulated in a polymeric membrane (reservoir systems) or dispersed in a polymeric matrix to generate diffusion-controlled systems. The active ingredient partitions into the barrier from the reservoir in the reservoir-based formulation and then diffuses from the barrier into the adjacent media. A steady concentration gradient of the drug is established across the barrier as long as the reservoir is full and delivers the drug at a constant rate. Zero-order drug release can maintain drug concentrations in the therapeutic range for longer durations and reducing the risk of toxicities. The concentration gradient and the drug release rate drop when the drug concentration exceeds saturation (Katz et al., 1995; Lis Arias et al., 2018; Pramanik and Garg, 2019; Siepmann and Siepmann, 2012). Diffusion and dissolution-controlled drug release has been presented in Fig. 1.1. Eq. (1.1) can be used to compute the rate of the drug diffusion (dm/dt) for the reservoir-type diffusion system. dm=dt 5 ADKΔC=l

(1.1)

1.4.1.3 Osmotic-controlled release Osmotic pumps drug-releasing system comprises a therapeutics reservoir enclosed by a barrier that is permeable to water but not to the drug. This system can deliver

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Fiber and Textile Engineering in Drug Delivery Systems

Figure 1.1 Graphical representation of dissolution and diffusion control release of drug.

therapeutics in a sustained manner over a longer duration of time. In case of oral delivery, water passes to the center across the semipermeable barrier, dissolving the drug. The osmotic and hydrostatic pressure variations on each side of the membrane control fluid movement into the system. A steady osmotic pressure gradient is generated among the reservoir and the outer liquid phase, allowing for zero-order therapeutics release (Conley et al., 2006; Ogueri and Shamblin, 2021). A laser-drilled opening is used to release the drug from the osmotic pump-based drug delivery system (Fig. 1.2) (Wu et al., 2016). For osmotically controlled administration of flurbiprofen, an asymmetrical design of the membrane of cellulose acetate was done (Choudhury et al., 2007), whereas for the controlled release of nifedipine, a bilayered-core pump approach was utilized (Liu and Xu, 2008). Additionally, utilizing osmotic pumps with controllable porosity, researchers were able to develop a prolonged and controlled delivery of glipizide (Patel et al., 2014) and water-soluble pramipexole dihydrochloride monohydrate (Rakesh et al., 2015). Further, the impact of mixing, the pH of the dissolution media, and the amount of the coated polymer and poreformers need to be evaluated for an osmotic pump drug delivery system. Another type of temporal-controlled delivery is a responsive therapeutics delivery system, in which the medicine is delivered in a pulsatile way only when the body requires it (Lin, 2020). Such a form of technology can be seen in insulin administration in people with diabetes. Because blood sugar levels fluctuate throughout the day, every patient’s insulin requirement varies. Effective diabetes treatment requires regular insulin administration and cautious glucose consumption monitoring. Proactive insulin release is a novel treatment that offers technologies that release insulin in a controlled manner in response to elevated blood sugar levels. A sensor senses environmental variations that trigger drug release, and a transport device regulates drug release cross-ponding to therapeutics delivery systems. The glucose oxidase enzyme was utilized as the biosensor that transforms glucose into gluconic acid when blood sugar levels drop. This leads to a decline in pH,

Drug-releasing textile materials: current developments and future perspectives

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Figure 1.2 Schematic representation of osmotic control drug release.

which can be used as an indicator to release insulin (Grubert et al., 2005; Kikuchi and Okano, 2002; P et al., 2017).

1.4.2 Distribution-controlled release The controlled release drug delivery system can be directly implanted into the desired site for controlled drug release. This method has been implemented to deliver antineoplastic drugs to malignant gliomas (type of cancer in the spine and brain) using poly(anhydrides). However, in a condition where the drug’s site of action is available but cannot be removed properly, a direct implantation method can be used for controlled distribution. For a number of diseases, controlled distribution of the drug can be achieved at the targeted sites by implementing biopolymeric delivery systems. Drugs encapsulated in polymeric nanoparticles and polymer-drug conjugate systems have been employed for the same purpose after being functionalized with targeting ligands (Brem et al., 1995; Petlin et al., 2017a; Spiridonova et al., 2019).

1.4.3 Pharmacokinetics of drug release Pharmacokinetics deals with drug absorption, distribution, metabolism, and excretion from the body, which can be expressed numerically as a function of time and concentration. To design the new dosage form for the patients, proper understanding of the pharmacokinetics of a drug is a prerequisite (de Campos et al., 2014). Numerous pharmacokinetics models can be applied to understand the movement of

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Fiber and Textile Engineering in Drug Delivery Systems

a drug in the body after administration. The biological system where the drug is distributed can be divided into various compartments based on its accumulation in different body parts. In the one-compartment pharmacokinetic model, the drug is considered to be uniformly distributed throughout the body, which states that any change in the drug plasma concentration shows changes in drug concentration in each body part. Whereas in the case of two-compartment pharmacokinetics model, drugs are assumed to be distributed in the central and peripheral compartments. Central compartments comprise the highly perfused organs, where drugs are distributed first, such as the lungs, heart, kidney, liver, and brain. Moreover, the peripheral compartment consists of the lesser-perfused organs, including skin, fat, and muscles. Nevertheless, the drug distribution process between both the compartments is not instantaneous. As a consequence of the one-compartment open pharmacokinetic model, understanding their fundamental pharmacokinetic parameters, such as bioavailability, rate of drug absorption, rate of drug elimination, and biological halflife, is essential (Sager et al., 2015; Shah and Halacheva, 2016). Bioavailability is considered as the fraction of drug that reaches the systemic circulation after administration. Since the drug is instantaneously available, when given through the intravenous route, the bioavailability is considered as 100%. On the other hand, when the drug is administrated through a route other than the intravenous, the bioavailability is lesser because of relatable factors such as inadequate absorption, poor biodistribution/ transport, and first-pass metabolism affecting throughout the body. The kinetics of drug elimination in the one-compartment model can be represented as either zero-order or first order. The rate of the zero-order elimination process is not dependent on the drug’s concentration in the body. It remains constant, for example, in the case of enzymatic oxidation of ethanol by alcohol dehydrogenase. After the subsequent consumption of alcohol, the enzyme starts saturating with substrates. Therefore, the elimination rate remains constant, and it is not dependent on the concentration of the alcohol remaining in the body (Kagan, 2014; LaCount et al., 2020; Sheiner and Steimer, 2000; Strand et al., 1993). In Eq. (1.2), [A] is the decrease in the concentration of a drug, A with respect to time (t), k is denoted as the zero-order elimination rate constant. d ½ A 52k dt

(1.2)

In first-order elimination, the rate of elimination of a drug is directly proportional to its concentration in the body. The enzymes responsible for eliminating a drug are not saturated in the first-order elimination process, and the rate of elimination can also be increased at higher concentrations. Eq. (1.3) shows the reaction for first-order elimination. dA 52k  A dt k is first-order elimination rate constant.

(1.3)

Drug-releasing textile materials: current developments and future perspectives

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The half-life of a drug is the time required to decrease the initial concentration of drug in body by one-half. The correlation between biological half-life, t1/2, and first-order elimination rate constant is represented by Eq. (1.4): t1=2 5

In 2 k

(1.4)

The biological half-lives of some drugs showed huge variations; for example, noradrenaline neurotransmitter exhibits a half-life with a difference of 10 minutes, whereas it is 5 months and 15 days in the case of antitubercular drug bedaquiline. After the metabolism process, few drugs can be changed to one or more active metabolites, which may alter their pharmacologic response; therefore, dose adjustment in such cases is required for optimal effects (Shah and Halacheva, 2016).

1.5

Fabrication of drug delivery systems

Various drug substances can be loaded onto the textile materials with modified drug release using numerous techniques, such as encapsulation, coating, filling of hollow fibers, formation of complexes, ion-exchange methods, and conjugation methods (Mehata et al., 2020a, 2021; Verreck et al., 2003a). The most commonly used techniques for immobilizing the biomolecules on the solid support surface are entrapment, physical adsorption, and chemical linkage. An appropriate technique of drug loading can be selected based on the physicochemical properties of the biomolecules. The application of the immobilization techniques may alter the pharmacological activity of the drugs, such as in the case of the various protein drugs losing or reducing their response due to denaturation, oxidation, or dehydration. On the other hand, physical adsorption is easy for coating the drug substances on the surfaces by using various non-covalent interactions, such as hydrogen bonding, van der Waals forces, and hydrophobic interactions. Therefore, drug substances adsorbed onto the surface can be slowly removed or released from the surface. At the same time, the drug response may reduce, if their orientation is heterogenous on the surface or with lower surface density (Gera et al., 2015; Sinha, 2021).

1.5.1 Coating methods Coating is a simple technique for loading the drug directly by dipping the material in the solution of the drug substances. The loading of the drugs by using this technique depends on the drug’s physicochemical properties and the surface properties of the fiber material. The drug substances having a higher affinity toward the surface of fiber material forms a thin and uniform layer on the surface. Sometimes, after in vivo implantation the drug-coated fiber material may release a large amount of the drug instantaneously due to less interaction. Furthermore, this technique of drug loading is inadequate for releasing drug substances for an extended period of

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Fiber and Textile Engineering in Drug Delivery Systems

time. Therefore, this method is not suitable for coating fiber materials (Helmer et al., 1995). Dispersion coating can be achieved by using different conversion machines as well as the printing press. Modifying the textile material with dispersion coating can protect them in hazardous conditions. This technique can also coat the materials at a particular side so that release of the drug substance can take place from the desired direction. A study modified the woven fabric and antimicrobial fabric into brilliant thermoresponsive material by applying the thermosensitive nano-gel of silver nanoparticles. For the same, the nanoparticles solution was applied first over cotton fabrics and kept at 30 C for 15 hour. The efficiency of the loading process of the drug onto the fiber materials relies on the physical and chemical characteristics of the drug substances and fiber materials. Moreover, various environmental factors, including humidity and temperature, also affect the loading process. The loading efficiency affects substantially, when the drugs are coated on the surface of fabrics (Ali et al., 2011; De Smet et al., 2021). Another coating process based on plasma treatment can substantially affect the characteristics of textile materials. Hot plasma treatment requires higher temperature conditions for such modification and is, therefore, suitable only for thermostable materials, such as ceramics and metals and not for thermolabile materials, including textiles. However, the cold plasma technique is a good alternative for the coating of thermolabile substances, including textile materials with plasma at the temperature conditions below or upto 100 C. Generally, these plasma treatments can be achieved either by incorporating surface-activating gases, such as helium, argon, oxygen, nitrogen, and ammonia or polymer-forming molecules. The former treatment is used to introduce different functional groups, whereas in the latter type of treatment, the vapors of the monomer are introduced into the plasma compartment so that the polymeric material can be placed over the substrate surface. The plasma treatment to employing the coating of the fabric material has been schematically presented in Fig. 1.3. Both plasma treatments have been used widely to improve the surface adhesion properties of polymeric materials. As the plasma treatment using both the therapy can be used to advance thermolabile polymers, these methods can be employed for textile materials. The cold plasma treatment can be utilized to improve the binding characteristic of the fabric materials loaded with drug substances. The loading process can be employed simultaneously by placing the textile material with a carrier gas and drug substance together (Los et al., 2019; Sadalage et al., 2020; Xu et al., 2020).

1.5.2 Encapsulation methods The diffusion process can achieve higher drug entrapment within the textile or fiber materials after soaking them in the drug solution for a sufficient time. This encapsulation technique is appropriate for the textile material, which swells after soaking in a drug solution. The process of drug loading and release is influenced by the diffusion process, which is further affected by the drug solubility and the swelling behavior of the textile material. Alternatively, adequate drug loading can be

Drug-releasing textile materials: current developments and future perspectives

13

Figure 1.3 Schematic representation of the plasma treatment for coating of the fabric material.

achieved by dissolving the drug and fiber-forming polymer (1:1) in a common solvent. This technique gives better entrapment and uniform distribution of drugs throughout the textile materials (Akbari et al., 2016; Rostamitabar et al., 2021). Moreover, suppose the drug substances have a lower solubility in the solvent in which the textile material is soluble, in such case, drug particles can be suspended over the surface of textile materials. Various researchers have reported this technique of drug loading to obtain homogenous drug-loaded fibers. This technique of drug loading in the textile materials can be achieved by various devices, including microfluidic devices, electrospinning techniques, and the wet spinning technique. Microfluidic devices and wet spinning techniques require a nonsolvent to stiffen the drug-loaded fibers, reducing drug encapsulation efficiency. In the case of the wetspinning drug-loading method, the drug and the textile material in the common solvent are forced through the spinneret in thin fibers. Following this, the extruded fibers are collected in a hardening bath and treated with a stretching operation to ensure their stability (Massella et al., 2019; Zhang et al., 2018).

1.5.3 Fiber spinning techniques Numerous techniques that can be employed to form fibers are well reported. Melt spinning technique is also one of them; however, it is not suitable for the formation of the drug-containing fibers because of the requirement of the high processing temperature. Alternatively, the wet-spinning technique can be held at normal temperature conditions. In this technique, the drug solution and polymer in homogenous ratio pass by pressure through the spinneret pits and are collected into the coagulation bath prior to being stretched. The obtained drug-containing fibers were washed and dried (Kong and Ziegler, 2012; Shang et al., 2019). Similarly, in the electrospinning technique, the drug-polymer solution has to be passed through ultrafine holes of the device to produce nanofibers. These nanofibers are widely used in the field of biomedical and tissue engineering (Bhardwaj and Kundu, 2010). Drug-loaded fibers and textile materials improve the drug’s pharmacological response due to modified-release because of their large surface area. Practically, there are four techniques that can be used to synthesize the architecture of nanofibers by complex formation, such as electrospinning, co-electrospinning,

14

Fiber and Textile Engineering in Drug Delivery Systems

tubes by fiber templates (TUFT), and wetting-assisted templating (WASTE). A microfiber matrix of micro- or nanofibers is generated using the electrospinning method. High-voltage current is applied to the liquid solution and a collector in this approach, allowing the solution to extrude from a nozzle and create a jet. During the drying process, the jet produced fibers, which were then deposited on the metallic collector. Electrospinning methods are extensively utilized to synthesize the activated functional nanofibers. The functionalized nanofiber has great success in wound healing, bone tissue engineering, and enzyme modification. Coaxial electrospinning served as a foundation for various advanced applications, including the creation of hollow and porous structures and the encapsulation of biological substances for delivery to specific body parts. Fig. 1.4 shows a diagrammatic depiction of electrospinning and the coaxial electrospinning technology. Moreover, complex formation’s TUFT and WASTE techniques generally produce high structural nanofibers with core-shell structures widely used in pharmaceutical and biomedical engineering (Henning et al., 2012; Mitschang et al., 2014; Xu et al., 2015).

1.5.4 Hollow fibers methods These fiber systems consist of tiny tubes where the drug can be loaded. A permeable membrane constitutes the hollow fiber wall, allowing for controlled release. These fiber systems offer a higher surface area-to-volume ratio, and therefore a large volume of drug solutions can be loaded within these hollow tubes. Crystalline drugs dispersed in the core of polymer can also be used. To prepare such fiber systems, a drug-loaded core granulate system is formed after mixing the drug with textile materials. Afterward, the core granulate system is passed through an extrusion process to form hollow fiber with the core, whereas the outer membrane can be formed with another polymer (Higa et al., 2019; Wu et al., 2019).

1.5.5 Bioconjugation techniques Bioconjugation techniques anchor the bioactive substance on the surface of the textile materials/polymers by using chemical and physical conjugation methods so that the drug-polymer system can attain controlled release with site-specific delivery. Therefore, the required function group should be present on the surface of textile material in sufficient quantity. Otherwise, these can also be linked with textile material using several techniques, including chemical linkage, plasma treatment, grafting, and co-spinning. In the case of plasma treatment, functional groups can be attached to the surface of fabric material by treatment with plasma. The nature of functional groups is based on the gas used to prepare the plasm. Furthermore, fabric surfaces can be made more biocompatible, and the attached functional groups can be conjugated to various extracellular components, such as fibrinogen, laminin, collagen, and gelatin. Graft co-polymerization is another promising approach to anchor the bioactive moieties on the surface of textile material by using free radicals produced by chemicals or radiation. For instance, the methacrylate group can be used to generate the sulfide groups to the surface of nonwoven polyethylene fabrics by

Drug-releasing textile materials: current developments and future perspectives

15

Figure 1.4 Preparation of nanofibers by (A) electrospinning and (B) coaxial electrospinning techniques.

their radiation-generated graft polymerization with the successively induced ringopening reaction by sodium sulfide. The sulfonic group functionalized fabric material can be conjugated with silver ions to obtain antibacterial activity. Similarly, cospinning is another technique for attaching the functional group on the surface of fibers by using pre-functionalized polymers (Elzahhar et al., 2019; Jabbari, 2011; Liu et al., 2021). In addition to encapsulation, bioconjugation technique can also be used to attach the drug molecule on the surface of textile material by physical or chemical linkage to release the drug from the textile material. To accomplish the conjugation process, the textile material should be ready or responsive to the functional group of drug substances. As discussed, various techniques are used to prepare the textile material for conjugation, such as grafting, chemical modification, and plasma treatment.

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Fiber and Textile Engineering in Drug Delivery Systems

Additionally, various extracellular body components, such as fibronectin, gelatin, and collagen, can also be conjugated to functionalized fiber materials. As the plasma penetration is significantly less inside the dense fiber materials, the plasma techniques of the conjugation are limited to their surface. Moreover, the conjugation process of such dense fabric material can also be achieved by partial surface hydrolysis (Kim et al., 2015; Tejado et al., 2011).

1.5.6 Ion complexes methods The drug-fabric complex can also be achieved by electrostatic interactions when the drug and fabric material are used with opposite charges. The exchange achieves the drug release from such fabric complexes by the counter-ions present in the body. For the same purpose, several ion-exchange polymeric materials and polymers with ion-exchange moiety are popularly used. Fabric materials prepared from such polymeric substances are treated with ionic drugs to produce fabric-drug complexes. For instance, the blends of chitosan and alginate can be utilized to prepare a complex with ionic drugs to make complexes. Various ionic drugs, such as dexamethasone and avidin, can produce complexes with chitosan or alginate-based on their surface charges. Cationic drugs, such as avidin, can be mixed into the solution of positively charged polymers such as chitosan (Lankalapalli and Kolapalli, 2009; Vikas et al., 2021). Afterward, this solution should be extruded with anionic polymers, such as alginate, to produce a drug-loaded poly-ionic complex. Similarly, anionic drugs were mixed in the alginate solution and twirled into the chitosan solution. Conversely, the interaction between cationic drugs and anionic polymers produces aggregates that fibers cannot be applied to. Ion exchange fibers carrying an electric charge can be treated with mobile counter-ions having reverse polarity (Coppi et al., 2001; Takka and Gu¨rel, 2010). The functional groups required for the cationic fibers are
AsO3,
SO3,
PO3, and
COO, whereas for anionic, these are
NH,
NH2,
NH3, and
S. The ionic exchange mechanism is mainly premised on the state of electroneutrality. In general, the exchange is a concentration-dependent diffusional process where the ion exchange rate can be estimated by diffusion either inside the exchanging layer or at the diffusing boundary layer (Hassan and Carr, 2018; Liao et al., 2016). Ion exchangers generally consume counter ions as an alternative, and because of this, an ionic drug can be released from the complexes of drugs and ion-exchange fibers. In such complexes, the drug substance works as a mobile counter-ion. The release of drugs by such complexes can be done by the similar ions present in the body and hence can change the homeostasis. Whereas, in ex vivo applications, the proportion of such ions is significantly less to disturb the homeostasis. Therefore, sodium chloride or sodium phosphate solution can be utilized to release the drug molecules by exchanging them with the sodium ions present in the solution. The salt in the solution can be entrapped in a gel substance, such as agarose, gelatin, polyvinyl alcohol, or other similar materials and then treated with a drug-containing fabric material. As a result, the salt will diffuse out of the gel matrix, leaving the drug molecule in its place, and hence, the drug can be distributed. Smopex fibers,

Drug-releasing textile materials: current developments and future perspectives

17

which have the polyethene backbone chain grafted many polymers, including polyacrylic acid (Smopex-102), polyamide (Smopex-108), and sulfonic acid (Smopex101), are commercially available ion exchange fibers that can be utilized for drug delivery. Polymers such as Smopex-301, grafted with the styryl diphenylphosphine group, can be employed to anchor the metal ions (zinc or copper). Besides the commercially available fibers, natural fibers such as silk, cotton, and wool can also be linked to the desired functional groups by chemical modification (Albano et al., 2021; Colacot, 2008; Karppi et al., 2009).

1.5.7 Plasma treatment methods In early 1960s, plasma technology was evolved for industrial applications in low temperature and low-pressure microelectronic processing. Furthermore, in the 1980s, plasma technology was applied in various industrial applications for the surface treatment of metallic and polymeric materials. Because chemical finishing on textile materials needs to be heavily regulated, new and inventive textile treatments were in high demand. Plasma technology stands out in this area due to its environmental friendliness and superior treatment outcomes. Plasma technology is now being used in textile industries (Akdo˘gan and Sirin, ¸ 2021). Plasma treatment is a technique for altering the surface characteristics of materials with implications in tissue engineering and regenerative medicine. The fundamental benefit of this technology is that it can transform a polymeric surface without changing the bulk characteristics of the polymers, keeping their existing mechanical qualities. Plasma treatment is also well-known for its rapidity, lack of solvent requirements, and scalability. This method has rapidly gained prominence in medication delivery application. Surface activation, better hydrophilicity, creation of a hydrophobic barrier layer, triggered cross-linking, and increased drug loading are all implications of plasma treatment during the production of drug delivery vehicles (Petlin et al., 2017b). In a study, Barbarash et al. developed poly-ε-caprolactone-based electrospun fibrous scaffolds, and surface modification was achieved by plasma discharge treatment. In this study, plasma treatment increased the wettability, porosity, and size of the scaffolds without changing the diameter. Additionally, it was observed that plasma treatment increased the cellular adhesion to the scaffolds (Barbarash et al., 2016). In another study, Yoshida et al. modified the surface of the polymer by plasma treatment to the enhancement of the polymer biocompatibility and control the release of the drug (Yoshida et al., 2013). Similarly, Hagiwara et al. evaluated the effects of plasma treatment on poly(ethylene-co-vinyl acetate) polymer for controlled release of the loaded drug. It was observed that plasma treatment has effectively suppressed the burst and cumulative release of the drug (Hagiwara et al., 2013). Hence, plasma treatment could be a promising approach for sustaining the drug release from the polymer. Fig. 1.5 represents plasma treatment method for textiles.

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Fiber and Textile Engineering in Drug Delivery Systems

Figure 1.5 Schematic representation of plasma treatment method for textiles processing.

1.5.8 Nanotechnology in fabrics The drug-loaded nanoformulations, such as nanoparticles, can also be attached to the fabric materials by using the chemical reaction either directly or by using appropriate cross-linkers. For the same, the fabric material can be linked to nanoparticles by using the chemical reaction either by direct reaction or by using appropriate cross-linkers. The interactions between the drug and the textile material can alter the loading efficiency. On the other hand, the conjugation held by using commonly used chemical cross-linkers may affect the drug’s functionality (El-Naggar et al., 2018). Therefore, the selection of the cross-linkers for such conjugation reactions should be specific for individual drugs. The drug is entrapped within the nanoparticles matrix or coated by the shells/layers of the polymer. Several methods can be used to prepare drug-loaded nanoparticles, such as microemulsion, precipitation, and interfacial polymerization. To achieve efficient loading, the drug solution must be treated with the polymer before the process of nanoparticles formation starts. Alternatively, the drug solution can be incubated with blank nanoparticles. Nanoparticles can be prepared with many materials available, including polymers, oligomers, and monomers. Such materials may consist of different functional groups, such as amine, carboxylic, hydroxyl, and sulfhydryl. The polymer system can be either hydrophilic or lyophilic, which should be selected based on the solubility of the drug. Animal-based fiber materials, including wool, may contain various functional groups, including carboxylic, amine, and thiol groups, which can be used for the conjugation with the nanoparticles. On the other hand, synthetic fibers

Drug-releasing textile materials: current developments and future perspectives

19

have a limited number of functional groups (Eid et al., 2020; Mehata et al., 2020b; Xu et al., 2018). Moreover, the cellulosic fiber material only has hydroxyl groups. A bifunctional cross-linker can also be utilized to link nanoparticles with amine-reactive groups to improve the functions of cellulose fiber materials. For the fixation of the particle, a solution of textile-reactive material has to be exposed with textile material by conventional methods, for instance, dipping, soaking, fluid flow, spraying, padding, and fluid flow. After the drying stage, the fixation process occurs at the curing stage when the textile material is incubated with the nanoparticles. However, if a bifunctional cross-linker is used, first, it should be treated with the textile material and later with the nanoparticles. The reaction time should be specified, whereas their reaction time can be varied and affected by the temperature and pressure conditions (Zhao et al., 2015). Allotropes of pure carbon atoms are known as fullerenes, which are connected with single and double bonds. The resulting structure can be used to entrap the drug molecules, including metal ions. C-60 is a well-known fullerene structure that resembles a football. In addition, fullerenes can be employed as guest molecules, similar to cyclodextrin, to form a compound with drug molecules. The modified fullerenes can be linked with different compounds with suitable functional groups, including azacrown ethers. Furthermore, due to their electrophilic and olefinic character, fullerenes are attached to wool fibers and polyamide can be permanently fixed (utilizing a variety of additional processes, such as nucleophilic addition of amines) (Nomura et al., 2004; Ten Breteler et al., 2002a).

1.6

Evaluation of drug-releasing textile materials

Drug-loaded textile materials are widely used for their drug-releasing property and the release of the drug can be controlled or optimized with greater understanding and cautious manipulation of various critical factors, which affects dissolution of API, desorption of API from textile materials, and diffusion of API into different body fluids. Moreover, each mechanism involved in controlling drug release has its impact according to the textile material’s chemical, physical, and geometrical properties. The careful tailoring of one or more (all three) parameters to amend the extent of activity can give a sustained release profile that can be appropriate for specific use. For instance, in the context of drug-loaded dressing materials for wound healing, a rate of drug permeation toward the wound particularly depends upon the hydrophilic character and swelling property of the textile materials. The diameter and geometry of the fiber influence the rate of diffusion through a barrier, such as skin. The sort of fabric and its molecular alignment can alter its biodegradability and subsequently affect the discharge of the drug that occurs through the degradation process. With the aid of varying each of the three release mechanisms of drug, the release rate can be optimized to desired. Different properties related to the textile materials, such as morphological, mechanical, pharmaceutical, and drug

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Fiber and Textile Engineering in Drug Delivery Systems

release, can be evaluated by several in vitro or in vivo analytical techniques (Atanasova et al., 2021; Narendra et al., 2020; Thakkar and Misra, 2017). A few of these techniques are explained below.

1.6.1 Morphological and chemical characterization 1.6.1.1 Fourier transform infrared spectroscopy study on textile materials Infrared spectroscopy (IR) has been chiefly used for the qualitative determination of molecular structures of a chemical substance and their mixtures to examine the extent of reaction and compatibility. Numerous chemical moieties absorb IR frequency according to their individual molecular vibrational frequency. Fourier transform infrared spectroscopy analysis of textile materials is performed to evaluate the attachment of different functional groups and also to estimate the degree of reaction that happens during the interaction of bioactive moieties and textile materials (Zhang et al., 2021b).

1.6.1.2 Scanning electron microscopy of textile materials The surface characteristic of a textile material has been often used to obtain information related to its morphology, prior and after the loading of bioactive molecules and other therapeutic agents. The surface framework of drug-loaded textiles has been examined through scanning electron microscopy (SEM) to understand the morphological characteristics of textile materials. A technique known as atomic force microscopy is also employed for surface characterization. A variety of specimens are investigated with SEM at various magnifications ranging from 500 3 to 10,000 3 . Additionally, the energy dispersive X-ray technique can be utilized together with SEM to identify the elemental content present in any of each coated or uncoated textile fabric at lower and higher magnification. The textile surface study provides important information on the textile assembly, deformities, fiber size, and degradation characteristics (Restivo et al., 2014).

1.6.2 Mechanical and physical properties of textile materials The mechanical and physical characteristics of drug-releasing textile fibers are one of the significant factors that decide its applications in different fields. The standard tensile testing equipment can measure their tensile strength and fracture strain values. The obtained values are helpful in the interpretation of the mechanical sturdiness of textile materials over time in both the cases loaded with or without bioactive molecules. The use of drug-releasing textiles for tissue regeneration in the medical field is mainly decided by their mechanical integrity. It was reported that the adequate strength of textile materials is required to support the proper tissue repair (Koh et al., 2015; Nada et al., 2019).

Drug-releasing textile materials: current developments and future perspectives

21

1.6.3 Estimation of drug-loading efficiency of textile materials The drug-loading capacity of textile materials can be measured by extracting the drug molecule into the solvents and subsequently utilizing analytical techniques for their quantification. An in vitro drug release study can be carried out in pH 7.4 phosphate buffer saline (PBS) that mimic the body fluids. The drug released from the textile materials is then quantified with the help of best suited analytical methods. Concisely weighed quantity of drug-loaded textiles are suspended into the media (simulated body fluid) like (PBS 7.4 pH) along with continuous stirring. At certain time intervals, the known volume of media is withdrawn and examined for the amount of drug content by utilizing the analytical techniques, namely UV-vis spectroscopy, high-performance liquid chromatography (HPLC), and calorimetry, etc. (Massella et al., 2017). The selection of the analytical tools for quantification of drug content depends on a number of factors that include molecular weight, stability, the sensitivity of the instrument, and physicochemical property of a drug. Furthermore, the biodegradation property and biostability also influence drugloading in to the textiles. Studies should be carried out to evaluate drug degradation characteristics in which simulated body fluids are used as media in combination with distinct enzymes to resemble the in vivo conditions. In a study, the weighed piece of textile material is soaked in a degradation medium. Simultaneously, morphology, molecular weight, and mechanical strength alterations are observed at different time points to get the extent of degradation in vitro. These studies should be conducted at physiological temperatures to obtain precise results (Mohamed et al., 2020).

1.6.4 Controllability of drug release from textile materials Controllability of the drug release from textiles depends on several factors that include nature of fabric, thickness, wettability, porosity, and biodegradability of the textile materials (Malengier et al., 2015). Cyclodextrin complexes are one of such examples to illustrate these several factors, in which difficulties lie in the practically proven fact that nearly each cyclodextrin derivatives and their drug combinations have its unique release profile. It is mainly due to differential interactions that reflect the strength of complex. When the complexation occurs in a weak manner, the dilution serves as a guiding factor considering the shift of equilibrium among absorption and desorption. Moreover, in the case of strong complexation between drug and cyclodextrin, the competing displacement and binding of the drug to proteins turn out to be vital (Bezerra et al., 2020). Furthermore, by altering the pH environment, the discharge of the loaded therapeutics can be delayed, in particular, the pH-sensitive drug delivery textiles that show less solubility in water at lower pH; however, at neutral or alkaline pH, they are soluble due to ionization of acidic functional group. Additionally, in the case of oral administration, the release of the drug can be retarded until the complexes have surpassed through the gastric region and reaches the intestine. Besides, the ion exchange fibers can be utilized to modify drug release in numerous ways (Pinho et al., 2014).

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Fiber and Textile Engineering in Drug Delivery Systems

The release of the drug has been boosted by decline in electrolytes concentration that can be elucidated by checking the drug equilibrium. It has to be highlighted that the lowering of solute concentration reflects the expansion of external volume. When an equal quantity of electrolyte is utilized, the peripheral volume might be more significant. Consequently, the shift of equilibrium will be toward drug release. In spite of that, the reduction in electrolyte concentration subsequently boosts the electrostatic interaction among drug molecules and fiber (Yoshida et al., 2019). A completely different outcome was found when the identical external volume is utilized for a different concentration of electrolytes. Broadly, in the case of ion exchange textile fabrics, the discharge of drugs can be restrained to some level by using suitable drug-fabric composites and with the aid of altering electrolyte concentration, pH, and composition. In the case of hollow fibers, the unique attributes of fabric membranes have a considerable impact on the rate of drug release. Generally, the release rate of the drug can be regulated by several mechanisms, such as chemical reaction, solvent activation, and diffusion. Although the drug molecules are available as a crystalline form, the quantity of solubilized drugs is identified by their saturation solubility. Additionally, rate of drug release can be managed via altering fiber diameter and porosity (Vuorio et al., 2003). However, by selecting the well-suited membrane with appropriate thickness, a unique release profile can be obtained. In contrast, if the release of the drug is not controlled by diffusion, modification in the release environment, including the composition of the solvent, can be utilized to control the drug release. In the case of nanoparticles, the design of particle-matrix or shell can be prepared according to release requirements ranging from sustained release, prolonged release, and control release (Lan et al., 2021). Moreover, the nanoparticles can also be prepared that can sense the different external environment and provide stimuli-sensitive release by altering several parameters, including temperature, electrolyte concentration, pH, pressure, magnetic field, electric field, and co-solvent composition. Additionally, the drug-loaded and nonloaded textile fibers can be mixed together, whether biodegradable or nonbiodegradable (Hu, 2011).

1.6.5 Stability study of textile materials Assessment of drug-releasing textile materials’ degradation characteristics can give knowledge about their in vivo suitability and drug release performance. Usually, simulated body fluids (SBF) are used to study the degradation pattern of textile materials under physiological conditions such as pH, temperature, salts, and enzymatic conditions. Generally, a weighed quantity of drug-releasing textiles has to be incubated with the SBF. Furthermore, changes in various parameters, such as morphology, molecular weight, tensile strength, etc., are examined as a function of time. Moreover, an enzyme can be added to the media (SBF) to quicken the degradation process (Imran et al., 2015; Obaidat et al., 2018; Tipre and Vavia, 2002). Thus, stability studies of the drug-releasing textiles provide an idea of their stability in the physiological condition.

Drug-releasing textile materials: current developments and future perspectives

23

1.6.6 Interface reactions of textile materials Textile materials may irritate or sensitize the skin when administered with drugs. There is inadequate scientific information regarding the biocompatibility of regularly used chemicals in the manufacturing of drug encapsulated fabric materials, for example, cyclodextrins and their derivatives, aza-crown ethers, and fullerenes. The safety analysis has shown that C60 is irritant; hence, fullerene exposure to eyes and skin must be prevented, while it is uncertain that how this setting and additional complex formation might affect its biocompatibility (Shi et al., 2019; Zhang et al., 2021a). The selection of structural components in hollow fibers might cause discomfort. The finished textile materials should be convenient to attire without causing skin irritation. Furthermore, textiles treated with nanoparticles are common materials that people are familiar with, the textile materials themselves are unlikely to have any unwanted consequences. Polymers with wellknown and favorable interaction characteristics should be utilized for drug encapsulation. The drug-loaded fibers may not undergo interface reactions as long as the polymeric materials used in the fabrication, are deemed to be safer. On the other hand, drug loading may influence the characteristics of the primary materials used in the fabrication of the drug-loaded textiles. One potential problem associated with drug-releasing textile materials is that the emergence of surface changes, which might be harmful and may produce interfacial reactions. Silver-containing wound dressings are an example of the interlinkage among biologically active chemicals in the fabric and the skin surface. Silver-based materials in wound bandage have to be applied on to the wound superficially. Combining silver ions in the bandage with dermal components is a complicated procedure employing numerous elements that trigger the delivery of silver ions into the wound, as illustrated in Table 1.1. Once the silver ions have been released from the bandage and utilized in their antibacterial effects, they must be taken up by biotransformation pathways and eliminated from the human body (Qin, 2016).

1.6.7 Antimicrobial activity test of textile materials Typically, AATCC Test Method 147 is employed to evaluate the antibacterial properties of textile fabrics (Han et al., 2017). A parallel streak is used to inoculate an agar surface in this procedure. The sample is then placed onto the inoculation disk and incubated at 37 C. Antibacterial properties of drug-releasing textiles have to be evaluated when each stripe’s reduction in microorganism growth is found at the opposite end and a spot. The agar diffusion technique, such as Kirby-Bauer, can be utilized for evaluation of the antibacterial activity of fibers (Biemer, 1973). This is a semiquantitative approach for assessing the antibacterial activity of soluble antibacterial compounds-treated textile fabrics, which is a reasonably rapid and simple method. Bacterial isolates against which drugreleasing textile has to be tested must be swabbed over sterile nutrient agar plates after a suitable dilution (e.g., 100 3 ) from the culture. The control and test fabrics are then lightly pushed onto the plate’s surface in ten-millimeter disks. Then the plates are incubated for 18
24 hours at 37 C. The materials’ antibacterial effectiveness is determined by measuring the diameter of the inhibition zone with respect to a reference textile specimen (Haider et al., 2021).

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Fiber and Textile Engineering in Drug Delivery Systems

Table 1.1 Textiles based drug delivery and their application in biomedical field. Textile materials/ drug carriers

Loaded drugs/therapeutics

Application

Reference

Cotton fabric loaded with polyε-caprolactone nanoparticles Cotton fabric loaded with polyε-caprolactone nanoparticles Nonwoven fabric loaded with thermoresponsive gel Cotton fabric

Caffeine

Antioxidant activity for transdermal application Transdermal delivery of melatonin

Massella et al. (2018)

Aloin and curcumin

Wound healing activity

Wang et al. (2014)

Sodium hypochlorite

Antimicrobial activity Treatment of chronic venous insufficiency Antiinflammatory activity Model for control drug delivery

Zhou et al. (2016) Menezes et al. (2017)

Anticancer activity against graffi myeloid tumor Anticancer activity against malignant glioma

Toshkova et al. (2010)

Polyamide textile loaded with lipid core nanocapsules. Microparticles loaded cosmetotextile Sintered electrospun polycaprolactone

Electrospun quaternized chitosan

Electrospun biodegradable microfiber implants

1.7

Melatonin

Hesperetin

Indomethacin

Rhodamine B, Rose Bengal, and albumin-fluorescein isothiocyanate conjugate as model drugs Doxorubicin

Paclitaxel

Massella et al. (2017)

Zafar et al. (2017) Chaparro et al. (2019)

Ranganath and Wang (2008)

Drug-releasing textile materials applications

Paraffin-impregnated gauze and plain gauze are two old-style dressings commonly utilized as drug carrier for in vivo application. On the other hand, modern medicated dressings integrate novel compounds with therapeutic potentials for overcoming the limitations of the topical drug delivery system. Dressings such as

Drug-releasing textile materials: current developments and future perspectives

25

hydrocolloids, alginates, hydrogels, silicone gels, polyurethane foam/films are now used for carrying bioactive compounds to wounds (Gizaw et al., 2018). Fibers and textiles have structures that respond to the incorporation of active compounds and hence have a promising potential in building controlled drug delivery systems with targeting capabilities. A variety of commercial transdermal drug delivery systems already exist in the market, such as patches and bioactive wound dressings (Goh et al., 2013). Wound treatment, antimicrobial protection, and antineoplastic treatment are among the applications for which drug-releasing textiles have been produced. Because of their tiny pore sizes, woven and nonwoven textiles have been explored as textiles-based drug delivery systems (Saghazadeh et al., 2018). They provide regulated fluid movement and inhibit the invasion of microorganisms, which are responsible for causing infection. One of the first papers on medicinal electrospun nonwovens focused on polyethylene-vinyl acetate (PEVA), a nondegradable polymer. Electrospun fabrics were produced in chloroform from PLA and PEVA or a similar mixture of both polymers. The drug-releasing fabric was developed by utilizing tetracycline hydrochloride as a standard drug. PEVA demonstrated faster drug-releasing rates than PLA (Wnek, 2014). When compared to commercially available DDSs, the drug release profiles have demonstrated good results. Nonwoven textiles loaded with mefoxin were prepared, which was able to reduce the development of S. aureus, and aided the curing of wounds in rats (Suganya et al., 2011). Electrospun nanofibers are commonly utilized to carry insoluble medicines for increasing their dissolvability. Because of their high surface area, they are frequently used to load drug-loaded polymers. PVA-based nanofiber mats were designed using the electrospinning technique as a drug carrier for a TDDS. Many studies reported with the incorporation of a variety of NSAIDs with variable model drugs of high-water solubility (Valizadeh and Farkhani, 2014). The properties of the reference drugs determine the shape of drug-loaded electrospinning mats. The rate and extent of drug release from the drug-loaded electrospinning PVA mats were also found to be inversely related to the model drug’s molecular weight. The electrospun PVA mats with drugs had substantially superior release properties than the drug-loaded as-cast layers for model pharmaceuticals (Mishra et al., 2021). As the molecular weight of encapsulated medication increases, the pace and total amount of drug release has been dropped. It has been demonstrated that electrostatic spinning was used to develop a dosage form with controlled dissolution qualities than a basic physical combination and solvent-melt or cast-extruded drug delivery system. The glutaraldehyde process was used to immobilize lysozyme, resulting in antimicrobial activity of wool materials. The material preserved 43% of its lysozyme activity after five washing cycles, showing that the covalently attached lysozyme was relatively resistant. Furthermore, nonwoven and woven transdermal drug delivery systems for the delivery of bioactive agents/drugs for treating a variety of ailments have been developed. For example, itraconazole-loaded fabrics have been intended for treating fungal infections, which have been developed by electrospunning of the water-soluble HPMC fibers (Verreck et al., 2003b). Adjusting the factors, such as drug-to-polymer ratio and fiber diameter, can alter the aqueous dissolving profile of a water-insoluble medication. Troxerutin, a medicine used to treat

26

Fiber and Textile Engineering in Drug Delivery Systems

hemorrhoids and varicose veins, was grafted within polyamide materials using an inclusion complex, which has been made of β-cyclodextrin, resulting in drugreleasing fabrics that can be used for the treatment of venous insufficiency, hemorrhoids, and capillary fragility. According to an in vitro study, physically coupled medications are released faster than chemically bonded drugs. In vivo experiments on male Wistar rats produced comparable results (Nichifor et al., 2009). The development of drug-releasing fabrics has benefited regenerative medicine and tissue engineering. Soft tissue repair and regeneration scaffolds have been produced using woven and nonwoven textile structures. Because they are made from ultrafine threads with a high aspect ratio, porosity, and variable pore diameter and size distribution, nonwoven electrospun fibers are extraordinarily interconnected structures and porous that can reproduce the native extracellular matrix. These structures may be helpful in proliferation, adhesion with cells, differentiation and migration. Also, nonwoven structures can transmit bioactive chemicals like growth factors and chemotherapeutic medications, which help stimulate tissue regeneration and provide a place for progenitor cells to connect to the scaffold, allowing them to differentiate into tissues. Growth factors like morphogenetic protein have been put on nanofiber surfaces to promote osteogenesis and nerve regeneration. A new biomaterial surface with localized hemostatic and infection resistance properties has been reported in a study. Ethylenediamine has been used to incorporate functional groups in woven Dacron material (Chandy et al., 2000). The antibacterial effect of the treated textile surface was preserved for five days longer than that of the untreated fabric. Surface thrombin activity on thrombin surfaces was 105 and 2.6 times greater than on ciprofloxacin-dyed surfaces and non-specifically linked thrombin, respectively. Researchers reported that ciprofloxacin and thrombin could be mixed on a biodegradable polymeric surface while retaining their physiological properties (Boateng et al., 2008; van Langenhove, 2015).

1.8

Future prospective

Soft tissue repair products, heart valves, endovascular grafts, neurovascular stents, and load-sharing scaffolds all utilize biomedical textile framework as functional components of a device. Using the proper textile-forming processes, a material structure must be specially developed depending on an application and biomimetic criteria. As a result, finding the best suitable material to fulfill a patients’ criteria is a critical stage in the designing of a drug-release fabric materials. The goal of a drug delivery system is to distribute a certain extent of medications properly, accurately, and in a predetermined time period. The introduction of new materials and technology will also significantly influence the pharmaceutical delivery of the drug. Both non-biodegradable and biodegradable substances would be utilized in the production of drug-releasing fabrics. Materials utilized have a substantial impact on the drug-release process, determining whether the bioactive molecules are released by diffusion on their own or in conjunction with material degradation. Textile

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fabrics will be used selectively based on the demands of the drug delivery system. Due to its high surface area and porous and flexible structure, which can be altered depending upon the needs. Textile materials typically shows a good response to bioactive agents binding. Furthermore, their surfaces can be functionalized to allow the attachment of certain bioactive agents, increasing their versatility. Anticancer medicines, antibiotics, DNA, and proteins are among the bioactive substances that can be administered. Electrospinning techniques were found to have an important role in producing therapeutics delivery fabrics materials since it is a very flexible process. A variety of drug-loading strategies may be used with different electrospinning procedures, including coatings, drug loading, and surface functionalization. By adjusting the processing parameters and textile architectures, a drug delivery system with improved drug kinetics can be produced. However, electrospun technology has been employed in the lab to develop drug-releasing textiles but significant obstacles associated with scale up and clinical application must be addressed. Moreover, to meet the necessities of medical device standards, drug-releasing textiles production facilities must adhere to high standards, which require strict safety protocols. The advancement and deployment of novel biodegradable textiles via enzyme functionalization is another crucial element that will significantly influence the architecture of the stimuli-responsive drug release. Intelligent and smart polymers will be critical in developing a forthcoming textile-based drug delivery system. A stimulimediated drug delivery system might be produced using nanosized sensors, which can be implanted to change the medication/bioactive molecules incorporated in woven fabrics. When stimuli-responsive drug-releasing textiles exposed to stimuli, release of loaded drug from pH-responsive, thermoresponsive, and electrolytesensitive nanoparticles occurs. For example, insulin delivery can be initiated by encapsulating glucose-responsive nanoparticles into the textile assembly. Drug release can be planned based on the microenvironment of body fluid. Recent breakthroughs in 3D printing technology have the promise to develop flexible and stiff materials. Because of the interference between the printed textile’s linkage, 3D materials may be simply molded into static shapes for the production of drug delivery systems. Recent technological breakthroughs have expanded the potential of 3D printing in numerous tissue-engineering applications and medical devices. Another point to emphasize is that there has been a substantial body of research on the ex vivo administration of medicines using fabric-based therapeutics delivery systems; nevertheless, more studies are required to understand the in vivo nature of the therapeutic delivery system and its applicability. Textiles-based drug delivery systems for biomedical application has been tabulated in Table 1.1.

1.9

Conclusion

Textile materials serve as a crucial junction between humans and their surrounding world. These are suitable transporters for therapeutics or bioactive compounds that can be delivered to the dermal or other regions of the body due to their distinctive physiochemical

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properties. Due to the broad categories of fiber-producing polymeric materials and fiber production processes, there is significant potential for developing innovative drug-loaded textiles for clinical benefits. Numerous researches have been done to develop and optimize textile-based drug delivery. In this chapter, we have compiled the basic information and current status of the drug-releasing textiles. Additionally, we have discussed historical developments, classes of drug-releasing textiles, mechanism of controlled drug delivery, and their pharmacokinetics. Further, we have discussed the fabrication and evaluation of the textile-based drug delivery system and its application, including future developments. Overall, textiles are the best carrier for the topical drug delivery and suitable for all age group of the patients.

Acknowledgments The authors acknowledge the Indian Institute of Technology (BHU), Varanasi, India and the Ministry of Education (MoE), Government of India, for providing scholarships.

Individual authors’ contributions Abhishesh Kumar Mehata responsible for the concept, design, and writing of the book chapter, Deepa Dehari collected literature data and drafted the book chapter, Vikas and Vishnu Priya assisted in the writing the book chapter, Madaswamy S. Muthu is responsible for project administration, supervision, and writing, review, and editing.

Compliance with ethical standards Not applicable.

Conflict of interest We have no conflicts of interest.

Research involving human participants and animals Not applicable.

Informed consent Not applicable.

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1570.

Current approaches in nanofiberbased drug delivery systems: methods and applications

2

Sarika Tomar, Rakesh Pandey, Priyanka Surya, Ranjan Verma, Rishabh Singh, Ved Prakash Meena and Sweta Singh Division of Stem Cell and Gene Therapy Research, Institute of Nuclear Medicine and Allied Sciences, Delhi, India

2.1

Introduction

Increase in the number of challenges in healthcare system in terms of management of chronic diseases, rise in mortality and morbidity rates and management of quality of life with certain ailments, necessitate the discovery of new drug candidates. However, only a few make it to market but still face challenges associated with several side effects, such as unfavorable kinetics, incomplete penetration, lack of site specificity, toxicity, etc. Drug delivery systems (DDSs) offer the potential benefits by modulating absorption, distribution, metabolism, and elimination properties as well as toxicity, which improve the potency of drug and minimize the side effects. Discovery of nanotechnology has revolutionized the drug delivery research that enables the use of various techniques, such as nanoparticle, microparticle, nanogel, microspheres, nanofibers, etc. These nanocarriers can carry agents that are unstable when free, insoluble/low bioavailability, lack specificity, toxic, rapidly cleared, etc., and minimize these drawbacks and improve the efficacy of the drug (Patra et al., 2018; Shi et al., 2010). DDSs have been evolved for the targeted delivery of various therapeutic/diagnostic agents in specific concentrations at defined time intervals. For enhancing drug effectiveness and safety, various factors come are to be considered, such as drug release rate, target site specificity, delivery time, and longer circulatory life. Different polymeric micro/nanofibrous or micro/nanoparticle materials have been widely studied as therapeutic/diagnostic agent delivery vehicles (Adepu and Ramakrishna, 2021). However, these classical DDSs have some drawbacks, such as toxicity and poor drug loading efficiency that lead to use of carrier materials in excess, which further increases the burden on system. Drug delivery by polymer nanofibers has recently garnered a lot of attention (Liu et al., 2016). Electrospun nanofibers have several advantages over other DDSs and show better control over sustained and prolong release along with added benefits of high surface area, interconnected and tunable porosity, microchannel in nanofiber mesh that mimic the tissue microenvironment, greater scope of functionalization that allow higher drug loading, better biocompatibility, higher mechanical strength, and tunable Fiber and Textile Engineering in Drug Delivery Systems. DOI: https://doi.org/10.1016/B978-0-323-96117-2.00014-5 © 2023 Elsevier Ltd. All rights reserved.

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Fiber and Textile Engineering in Drug Delivery Systems

pharmacokinetics. Electrospinning, first reported in 1934, is a simple process used for the production of superfine nanofibers having diameters ranging from microns to nanometers using a high-voltage supply source throughout the process. The term electrospinning is derived from words “electrostatic spinning,” patented by Formhals in 1934. Since 1980s, this process has gained a lot of attention due to its increasing applications in tissue engineering as well as different nanotechnology applications (“US1975504A Process and Apparatus for Preparing Artificial Threads - Google Patents,” n.d.; “US2158415A - Method of Producing Artificial Fibers - Google Patents,” n.d.; “US2349950A - Method and Apparatus for Spinning - Google Patents,” n.d.). Electrospinning is a versatile technique used for the assembly and fabrication of ultrafine fibers resulting in production of diverse novel structured materials, as the nanofibers are porous and structurally mimic the native extracellular matrix, which attracted great attention for use in various biomedical applications, especially in DDSs, biosensing, tissue regeneration, wound dressings, enzyme immobilization, and healthcare (Xue et al., 2019). A DDS with controlled-release pattern must possess two major properties, that is, it should be able to regulate the release behavior and target site, and must have an adequate time window for controlled release for effective therapeutic behavior (Hosseinkhani and Hosseinkhani, 2009). For successful designing and enhancement of controlled DDSs, several combinatorial methods of material science and technology are applied to achieve best results. The characteristics of a desired material, such as physical, chemical, morphological, and surface properties, as well as its biocompatibility and biodegradability, are all important as they affect different aspects of a delivery system (Davis and Leach, 2011; Thompson et al., 2006). By minimizing the initial burst release, the aim of a controlled-release system is to be able to provide an assimilated dose of integrated agents over a prolonged time. Based on drug and delivery system interaction, it can be classified into two major classes: affinity-based delivery systems (ABDSs) and reservoir-based delivery systems (RBDSs). ABDSs are characterized as systems in which interactions occur between the delivery mechanism and therapeutic drugs that lead to manipulation and regulation of drug loading as well as controlled release. Functional active binding sites can be found naturally in the biomaterials or they can be functionally modified. Some of the examples of interactions between therapeutic drugs and the functional sites are non-covalent bonding, hydrogen bonding, ionic bonding, and Van der Waals forces. These DDSs emerged as attractive options for delivery of different therapeutics that circumvent the challenges seen in other release systems. It is useful for preventing burst release behavior and, thus, provides tunable sustained release profiles due to its transient interaction with the surrounding delivery matrix and polymers. Common examples of ABDS include scaffolds showing sustained release of heparin-binding proteins, such as fibroblast growth factor-2 (FGF-2) and vascular endothelial growth factor (Vulic and Shoichet, 2012; Vulic et al., 2015; Wang and von Recum, 2011). In RBDSs, the polymer structure encloses the therapeutic drug within, and its biomaterial properties influence and modulate the drug’s release pattern. Drugs are non-covalently incorporated in the porous polymer structure in these types of systems. It also incorporates micro technology for several oral, dermal, and implantable

Current approaches in nanofiber-based drug delivery systems: methods and applications

41

application systems and offers possible targeting of drugs to sites that are generally inaccessible and avoids systemic exposure (Yang and Pierstorff, 2012). Microspheres, hydrogels, and electrospun nanofibers and their combination are mainly used in RBDSs for the distribution of various bioactive molecules and drugs. This chapter emphasizes on the significant potential of electrospinning technique in fabrication of nanofiber-based DDSs, parameters affecting the nanofibers synthesis, smart polymeric DDSs, and applications of DDSs in various biomedical fields such as cancer, wound healing, and tissue regeneration.

2.2

Electrospinning principle and its fundamentals

Qi et al. first showed the in vitro drug release kinetics of loaded bovine serum albumin (BSA) and reported the release up to 12 hours as compared to BSA loaded in naked microsphere, where drug release was for 10 hours. Furthermore, Fu et al. documented successful loading and release of recombinant human bone morphogenetic protein-2 (rhBMP-2) in PLGA/HAP electrospun nanofibers without losing its conformation and integrity. After this major research evidence, electrospun nanofibers drew huge attention that furthered the research and development of several nanofiber-based DDSs for their unremitting release profiles, making it a potential useful therapeutic application. Generally, electrospun nanofibers are fabricated using biocompatible and biodegradable natural and synthetic polymers for loading and delivery of water soluble/insoluble drugs, growth factors, and other biologically active molecule to the targeted sites (Rutledge and Fridrikh, 2007). Electrospinning is a relatively simple micro-processing technique with a basic setup, consisting of a high-voltage system, syringe pump, spinneret, and collector for producing ultrafine nanometer range fibers (Fig. 2.1). Its inherent ease of

High Voltage

Solution in syringe

Taylor Cone Collector Syringe Pump

Figure 2.1 Basic setup of electrospinning.

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Fiber and Textile Engineering in Drug Delivery Systems

operation and cost-effectiveness make it a very popular technique for various kinds of biomedical applications. During electrospinning, small droplets come out of the syringe due to surface tension. After a certain voltage is applied, the solution becomes charged and repulsive electric forces surpass the surface tension and polymer solution flows in the direction of the electric field and cause the deformation of droplet into Taylor cone and charged solution is ejected out as a jet. Ejected solution first is released as a straight jet and then it stretches out as an ultrafine diameter fiber and deposited in the collector (Yu et al., 2009). Pore structure, diameter, and size of the nanofibers are influenced by several operating parameters, such as voltage, concentration, flow rate, needle diameter, distance between spinneret and collector, solvent, conductivity of polymer solutions, and viscosity.

2.2.1 Types of material for electrospinning 2.2.1.1 Electrospinning of organic polymer The most commonly used materials for electrospinning are organic polymers, as they can be used directly for electrospinning. More than 100 types of natural and synthetic polymers have been electrospun to produce nanofibers for different applications. Collagen, gelatin, chitosan, alginate, dextran, and fibrinogen are some examples of natural polymers that have been explored and electrospun into nanofibers. Synthetic polymers such as polycaprolactone (PCL), polyethylene oxide (PEO), poly (lactic acid) (PLA), poly (lactic-co-glycolic acid) (PLGA), and polyurethane are also being used for the production of nanofibers because of their great flexibility in synthesis, processing, modification, good mechanical properties, biocompatibility, and biodegradability for biological application. Polyvinyl chloride (PVC), polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP), and polystyrene (PS) are also electrospun into nanofibers for different industrial and environmental applications.

2.2.1.2 Electrospinning of colloidal particle Recently, electrospinning of colloidal particle has been explored, which is a comparatively new field and only few reports are available. Electrospinning of colloid is more complex due to additional parameter, that is, presence of two phase (disperse and continuous phase) in addition to chemical, physical, and process parameters. Colloidal particle size and cross-linking between particle and viscosity are critical parameters considered during production of stable nano/microfibers through electrospinning. Several metal, metalloids, and their oxides, hydroxyapatite, aluminosilicates have been electrospun in different types of template polymers. Silver and gold nanoparticles have been the most explored colloidal particles for electrospinning. Different sizes of silver nanoparticles have been electrospun in various kinds of synthetic and natural polymer, that is, PVA, PEO, PVP, PVC, PS, polyacrylonitrile, and chitosan/gelatine sol, etc. Electrospinning of gold nanoparticles (AuNPs) is mostly

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done in hydrophilic polymer solutions, such as PEO and PVP. Electrospinning of AuNPs in polylactic acid (PLLA) and polystyrene was done after hydrophobic coating on nanoparticles surface to ensure homogenous dispersion in hydrophobic polymer solution. In some cases, gold and silver nanoparticles have been directly synthesized in polymer solution by using laser ablation or in situ reduction. Apart from silver and gold, other transition metals like Ti, Co, Cu, and Zn nanoparticles have been electrospun for different applications. Metal oxide nanoparticle of titanium, iron, zinc, copper, aluminum, silica, and other mixed oxide were spun for variety of applications. SiO2, TiO2, Fe3O4, ZnO, Al2O3, and MgO were spun in various hydrophobic and hydrophilic matrixes. Inclusion of homogenous dispersion of nanoparticle along the fibrous polymer matrix showed more interconnected nano-structural hierarchy in final material complemented with higher surface-to-volume ratio.

2.2.1.3 Electrospinning of composite Electrospinning of composite material is more complex than polymeric material as it depends on nature of sol gel material, viscosity conductivity, and nature of carrier polymer. Sol and gel precursor are mixed together in a polymer, taking into consideration that they should not react before electrospinning. Different steps of sol gel, that is, hydrolysis, condensation, and gelation process, should take place when solution comes in contact with external environment at the time of ejection. A continuous network of inorganic material forms in the polymer matrix that results in nanofibrous material of composite and polymer. Also, the process of hydrolysis, condensation, and gelation affect the electro spinnability of composite material as these processes occur just after ejection. Hydrolysis and gelation can block the spinneret and change the viscosity during the process, which affects the stretching and fiber formation. The most commonly used sol gel components are metal salts (acetates, chlorides, nitrates, sulfates, and alkoxides). In addition to the main components, sometimes, additives are also used such as acids to control the hydrolysis and gelation process and stabilization of solution for electrospinning. One of the reports showed the formation of TiO2/PVP uniform nanofibers by using PVP and titanium tetraisopropoxide (Ti(OiPr)4), sol gel precursor.

2.2.1.4 Electrospinning of small molecules Nanofibers can be produced directly from small molecules through electrospinning if they possess sufficient ability for intramolecular interaction and can self-assemble. Amphiphiles (Hunley et al., 2007; Jørgensen et al., 2015; McKee et al., 2006), small peptide, and cyclodextrin-based molecules (Nuansing et al., 2014; Xu et al., 2013) are reported to be electrospun into nanofibers. Like other materials, small molecule electro spinnability depends on types of solvent used, concentration, conductivity, and structure of molecule, that is, self-assembling properties. Phospholipid forms micelles when its concentration critical micelle concentration and if concentration increases further, lipid particles arrange in cylindrical shape and further entanglement leads to formation of

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Fiber and Textile Engineering in Drug Delivery Systems

nanofibers. Phospholipid-based nanofibers have been demonstrated and are the first type of amphiphilic nanofibers. Electrospun nanofibers of the hydrophilic PVP and soybean lecithin were also reported. Recently, different short peptide (poly) and oligopeptide based electrospun nanofibers have been reported (Hamedani et al., 2020; McKee et al., 2005; Nuansing et al., 2012; Singh et al., 2008; Yoshida et al., 2014; Zhang et al., 2018). Peptides with both natural and non-natural amino acids have been electrospun into bead-free, homogenous, solid nano and microfibers. Development of pure peptide nanofibers is still in infancy and holds great potential in drug delivery and tissue regeneration.

2.2.2 Different governing parameters affecting nanofibers’ fabrication A variety of parameters are tuned to get desired morphology, diameter, structure, secondary structure, and alignment of nanofibers, which can be divided into three major categories: solution properties, process parameters, and environmental parameters. The solution parameters include molecular weight, conductivity, viscosity, and surface tension. Processing parameters include the distance between tip and collector, the applied electric field, and the flow or feeding rate solution. Environmental parameters include few parameters, such as temperature and humidity of the environment, as they play significant role in determining the diameter and morphology of electrospun nanofibers. Each parameter has an important impact on fiber formation, morphology, and diameter and by appropriately adjusting these parameters, nanofibers with the desired characteristics can be electrospun.

2.2.2.1 Concentration Concentration is one of very first parameters that needs to be optimized before any other parameter. A minimum concentration of solution is needed for nanofiber fabrication in the electrospinning process and its critical concentration for particular electrospinning solution. As the concentration of the solution rises, the shape of the bead changes from spherical to spindle-like fibers (Greiner and Wendorff, 2007). However, a combination of beads and fibers may be developed at low solution concentrations. As the concentration increases owing to higher viscosity resistance, uniform filaments with greater diameters are produced. A power law relationship has been identified in many investigations attempting to establish a link between solution concentration and fiber diameter, demonstrating that as solution concentration increases, so does fiber diameter (Zeng et al., 2003). Surface tension and viscosity of the solution influence the concentration range at which continuous fibers may be formed in electrospinning (Deitzel et al., 2001).

2.2.2.2 Molecular weight Molecular weight of polymer is another crucial parameter that has affects diameter and morphology of electrospun fiber as it influences electrical and rheological

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characteristics, such as surface tension, viscosity, dielectric power, and conductivity (Haghi and Akbari, 2007). It has been revealed that a polymer solution with low molecular weight tends to generate beads rather than fibers, whereas a solution with high molecular weight leads to formation of fibers with larger average diameters (Tan et al., 2005).

2.2.2.3 Viscosity Solution viscosity is again a critical parameter that determines fiber diameter and morphology during electrospinning process. If the viscosity is very low, continuous fibers will not be formed, and if viscosity is very high, ejection of jets from the polymer solution will be an issue. Hence, optimal viscosity is prerequisite for the formation of nanofibers (Sukigara et al., 2003). Polymer solutions with very high viscosity have longer time for stress relaxation that inhibits the expelled jets from fracturing during electrospinning (Han and Steckl, 2019; Venugopal et al., 2005). These findings suggest that every polymer need to have specific or suitable range of viscosity for electrospinning as it has substantial role in fiber formation and diameter of nanofibers.

2.2.2.4 Surface tension For electrospinning of viscous solution, the applied voltage needs to reach a critical value that can induce strong electrostatic repulsion to surpass the surface tension and viscoelasticity. Surface tension is a main feature of the solvent compositions that determines the development of droplets, beads, and fibers (Athira et al., 2014). By lowering the surface tension of solution, fibers can be produced without beads; however, a lower value of surface tension of a solvent does not always imply that it is better for nanofibers fabrication. The electrospinning process is typically inhibited by a solution’s high surface tension as it causes the breakup of jets and produces droplets (Hohman et al., 2001). There is a sensitive balance between surface tension and the electrical field that affects the morphology of nanofibers.

2.2.2.5 Surface charge density/conductivity With the exception of a few dielectric materials, polymers are mainly conductive in nature. It is not possible to electrospun a non-conductive polymer as the charged ions presents in the polymer solution have a critical role in the formation of Taylor cone during electrospinning process. Conductivity of solution depends on polymer, solvent, and presence of ionizable salts in the solution. The diameter of electrospun nanofibers reduces considerably with increase in electrical conductivity of the solution and as the conductivity of the solution drops, there is no sufficient stretching of jet by electrical force to produce uniform nanofiber, which may lead to formation of beaded structures (Hayati et al., 1987; Zong et al., 2002). In the presence of large electric fields, highly conductive solutions have been demonstrated to be exceedingly unstable, resulting in drastic bending instability and a wide diameter dispersion. The jet radius was found to be inversely proportional to the cube root of the

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Fiber and Textile Engineering in Drug Delivery Systems

solution’s electrical conductivity (Baumgarten, 1971; Fong et al., 1999; Huang et al., 2001).

2.2.2.6 Polymer solvents As the very first and most critical step in the electrospinning method is the choosing of right solvent for specific polymer, as it has significant influence on its spinnability. Properties of solvent, such as high boiling point, volatility, and vapor pressure as well as the capacity to keep the polymer solution intact, are desirable (Pattamaprom et al., 2006). Types of polymers solvent intermolecular interaction depend solely on the solvent type (Zhang et al., 2002). The phase separation process is influenced by solvent volatility, which plays an important role in the creation of nanostructures. The viscosity of solution is governed by the polymer content, whereas the surface tension is determined by both the polymer and the solvent. A solvent with a lower surface tension is not always ideal for fabrication of nanofibers. In electrospinning, a solvent serves two purposes: first, it dissolves the polymer molecules required to form the electrified jet, and second, it transports the dissolved polymer molecules to the collector (Lannutti et al., 2007).

2.2.2.7 Applied voltage Threshold value of voltage is needed to induce the electrostatic repulsion to surpass the surface tension to eject the jet. The applied voltage is directly associated with the charge generation and degree of electrostatic repulsion between charged ions (Guo et al., 2022). According to several reports, higher applied voltage results in formation of fiber with lower diameter (Sill and von Recum, 2008). Generally, increased stretching of the solution is induced by a higher voltage owing to greater columbic forces as well as a stronger electric field present in the jet, and these effects result in a reduction of fiber diameter, as well as rapid solvent evaporation from the fibers.

2.2.2.8 Feeding/flowing rate Another processing parameter is the flow rate of polymer from the syringe, since it affects the jet velocity, material transfer rate, and also influences the charge density. A slower flow rate is ideally preferable as the solvent gets more time to evaporate. It has been observed that increasing the polymer flow rate increases fiber diameter and pore size, and that these morphological changes can be slightly altered by manipulating the flow rate. High flow rates offer beaded fibers, as fibers do not get sufficient time for drying before reaching the collector (Megelski et al., 2002; Zong et al., 2002)

2.2.2.9 Tip to collector distance The distance between tip and collector has some impact on nanofiber diameter and morphology as it provides optimum time for evaporation of solvent before hitting

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the collector; otherwise, beaded fibers have been seen (Bhardwaj and Kundu, 2010). Flatter fibers have been observed when tip and collector placed closure, whereas rounder fibers have been produced at a larger distance (Doshi and Reneker, 1995).

2.2.2.10 Ambient parameters In addition to process and solution parameters, there are several atmospheric determinants, such as humidity and temperature that may affect the morphology of the electrospun nanofibers. The viscosity and temperature have diametrically opposite relationship (Casper et al., 2004). The solvent can quickly dry in low humidity because of faster rate of evaporation (Caicedo-Casso et al., 2019) (Table 2.1).

Table 2.1 Various parameters and their affects during electrospinning process. Parameters

Effects on fiber

Co-related to

References

Solution parameters Viscosity

Molecular weight

Concentration of Polymer

Surface tension

Conductivity

If very high, inhibition ejection of jet from tip of the needle and if too low continuous fiber formation does not occur Show the number of entanglements of polymeric chain in solution, represents its viscosity

Concentration of polymer, molecular weight

Deitzel et al. (2001), Greiner and Wendorff (2007)

Viscosity, surface tension, conductivity

On increasing the concentration diameter of fiber increases. A threshold concentration is needed. If very low concentration, there will not be sufficient entanglement to sustain the jet (beads formation occur) When all other requirement is achieved, surface tension determines boundaries of the electrospinning window. The conductivity is directly proportional to stretching of the jet hence thinner fiber

Surface tension, viscosity

Han and Steckl (2019), Hohman et al. (2001), Athira et al. (2014), Sukigara et al. (2003), Venugopal et al. (2005) Han and Steckl (2019), Athira et al. (2014)

Athira et al. (2014)

Voltage

Hayati et al. (1987), Zong et al. (2002)

(Continued)

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Fiber and Textile Engineering in Drug Delivery Systems

Table 2.1 (Continued) Parameters

Effects on fiber

Co-related to

References

Processing parameters Voltage

Feed rate

Tip to collector distance

Formation of fiber takes place once threshold voltage reached. Thinner fibers are produced at higher voltage as it causes the stretching of the solution which results formation of thinner fiber, however, very high voltage induces instability in the jet and also increases fiber’s diameters Determine the quantity of material transfer per unit time and influences the jet velocity. Higher feed rate leads to formation of thicker fibers as greater quantity of polymer to be electrospun in per unit time It defines the traveling time of solution from tip to collector and adjusted in such a way that complete evaporation of solvent takes place

Conductivity, feed rate, tip to collector distance

Guo et al. (2022), Sill and von Recum(2008)

Tip to collector distance, applied voltage, viscosity

Megelski et al. (2002), Zong et al. (2002)

Voltage, feed rate

Bhardwaj and Kundu (2010)

Ambient parameters Humidity

Temperature

2.3

There should no humidity as it might result in pores formation on the surface of fiber Higher the temperature, lower the viscosity hence decreases fibers diameter

Casper et al. (2004)

Viscosity

Caicedo-Casso et al. (2019)

Method for incorporation of drug using electrospinning

Electrospinning uses an electrical field to produce nanofiber from a conductive polymer or composite solution (Agarwal et al., 2008; Hu et al., 2015; Xue et al., 2019). With recent advancements in the medical field, this technique is incessantly being used for DDSs, enabling the administration of several therapeutics (with improving properties,

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better efficiency, reliability, and minimal cytotoxicity) in the human body (Luraghi et al., 2021; Meng et al., 2011). Over the past 15 years, research activity emphasizing the potential of ES to enhance DDS increased exponentially, as it imposes better control and predictability during drug delivery as compared to conventional ones. Electrospinning devices use electro-hydrodynamic techniques to load any drug bioactive on nanofibers, composites, and polymers for drug delivery. Several methods include blending, coaxial electrospinning, electrospray, surface modification electrospinning, emulsion electrospinning, and coaxial electrospray, are used to incorporate drugs with the aim of preserving the therapeutic effects (Fig. 2.2).

2.3.1 Blending electrospinning In this method, solution is prepared by dissolving and dispersing drug in polymer before electrospinning process, resulting in the formation of nanofibers with encapsulated drug that shows a prolonged-release profile. Also, this method enhances the mechanical and physicochemical properties of drug-loaded nanofibers (Singh et al., 2021). The physicochemical properties of polymer affect the interaction between polymer and loaded drug and improve the drug encapsulation efficiency, drug dispersion into fibers, and the release rate. Blending electrospinning is used to incorporate various therapeutics, for instance, antibiotics, cytostatics, and anti-inflammatory drugs. Recent studies suggest that this technique allows efficient incorporation and delivery of small molecules, even though it is successfully used to encapsulate antimicrobial peptides (Song et al., 2016). However, direct blending electrospinning for protein delivery does not improve the delivery due to the harsh environment during the encapsulation process, as it uses Method of drug incorporation using electrospinning

Coaxial

Emulsion

Blending

Electrospray

Drug Polymer

Drug-polymer emulsion

Drug-polymer blend

Core shell drug loaded nanofibers

Figure 2.2 Methods of drug incorporation in electrospun nanofibers.

Drug-incorporated nanoparticles

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polymers such as PCL, PLGA, PU, and their respective solvents that change protein conformation, resulting in decreased delivery of protein-based drugs. To overcome this problem, Buzgo et al. developed PVA nanofiber stabilized by PEG-based cross-linker to modulate drug release. By modulating the cross-linking ratio, they regulated the release time of model active molecules; for instance, polar polymers are used to deliver proteins such as silk fibroin nanofibers with BMP-2 for stimulation of bone cells (Buzgo et al., 2018; Hu et al., 2015). Single-phase materials are frequently used in blended nanofibers, which consist of single or combination of biomaterial along with bioactive component for several transdermal nanofiber’s DDSs.

2.3.2 Coaxial electrospinning The setup for coaxial electrospinning uses two needles coaxially placed together and stimulates the co-spinning of two polymeric materials. The spinneret forms droplets of polymer composite; the inner (core) polymeric solution is ejected via an inner needle, and the outer (shell) material is ejected with the help of outer needle in the presence of electrical field charged droplet forms that leads to formation of composite electrospinning jets that result in core/shell fibers. These types of fibers have high surface area and three-dimensional network and are used successfully to load biological agents, such as proteins, growth factors, and antibiotics for drug delivery. It is a well-established electrospinning procedure aimed to produce drugreleasing nanofibers with a core-shell structure (Tipduangta et al., 2016). Moreover, the core-shell structure also enhances biomolecule functionality and drug efficacy, and maintains its bioactivity. In this technique, the outer polymer encapsulates the biomolecule to protect it from the external environment, while the inner polymer maintains the sustained release of the drug (Lu et al., 2016; Qin, 2017).

2.3.3 Emulsion electrospinning This electrospinning method was developed to overcome the disadvantages of blended and coaxial electrospinning and combine both these procedures along with emulsification approaches. Emulsion electrospinning uses a single nozzle to form a core-shell structure and encapsulate various drugs into the core of nanofibers using water-in-oil or oil-in-water emulsion. During emulsion electrospinning, the oil phase is prepared by an emulsion of drug or bioactive molecule, such as protein in a polymer solution, followed by electrospinning. It avoids burst release of the drug or bioactive molecule as it is encapsulated in the core matrix section of nanofibers. Thus, this technique enhances drug bioavailability as well as encapsulation efficiency to achieve targeted drug release (Hu et al., 2015; Lu et al., 2016).

2.3.4 Electrospray It is one of the simplest and effective drug incorporation methods used to synthesize nanoparticles and nanospheres. Under the influence of the electric field, liquid comes out from the nozzle and forms a Taylor cone due to surface tension. As the

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intensity of the applied electric field increases, the Taylor cone disintegrates into highly charged droplets, which further turn into nanoparticles or microparticles. During the electrospray procedure, some factors, such as the gauze diameter of needle, flow rate, voltage, and distance between needle and conductor collector, are considered for efficient drug incorporation. This technique has zero-dimensional nature, increased scalable synthesis, reproducibility, and elevated encapsulation capacity, and therefore is used in various medicinal and pharmaceutical applications. Moreover, using this technique, nanoparticles loaded with drugs or bioactive molecules showed improved drug carrier rate, specificity, adhesion, and reactivity. For this stratagem, natural gliadin’s nanoparticles loaded with cyclophosphamide anticancer drug have been observed to treat retinoblastoma and various other cancers, and results showed that more than 72% of drug loading was achieved, with nanoparticles with an approximate average diameter of 218 nm (“Handbook of Polyester Drug Delivery Systems,” 2017).

2.3.5 Layer-by-layer self assembly This method produces nanofibrous material by depositing multilayer coatings of oppositely charged materials on the nanoparticle’s surface either to enhance single property or to introduce multiple properties (Song et al., 2016). Various techniques, including immersion, spin, spray, electromagnetic, and fluidics methods, can be used to accomplish this goal. The mild, aqueous assembly conditions allow incorporation of nanomaterial with the biological agent without affecting parameters, such as pH value, ionic strength, temperature that can destabilize the resultant compound. Because of these properties, this approach is convincingly used for drug delivery in the field of cancer, tissue engineering, and regenerative medicine.

2.3.6 Core shell The drug-loaded nanofibers fabricated using core-shell method is when the in vivo environment can deactivate the medication-loaded nanofiber’s function, before its ability to perform the required function (Song et al., 2016). Thus, the drug is contained in the core shell, which allows the shell to shield it from harsh in vivo environment before its required biological activity. Due to core-shell nanofibers’ ability to carry various drugs, they are now used in wound dressing and tissue engineering applications.

2.4

Stimuli-responsive drug delivery using smart electrospun nanofibers

For the intended and controlled drug release over time, various efforts have been made to improve activation and other feedback regulation factors for electrospun nanofiber-based DDS. The idea of controlled-release medication treatment is to

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distribute a predefined quantity of medicine in a controlled manner over certain duration. There are two distinguished types of responsive DDSs: (1) those that are responsive to the internal stimulus in biological system, such as pH, temperature, and biochemical, thereby modulating the release rate of drug (called closed loop and self-regulated mechanism) and (2) those that are responsive for external stimuli such as light, electric, and magnetic field, showing transient release of drug upon external trigger (Alvarez-Lorenzo and Concheiro, 2008; Sridhar and Ramakrishna, 2013) (Fig. 2.3). Nanofibers are typically used to deliver a drug through a local distribution method (Alvarez-Lorenzo and Concheiro, 2014). Such types of nanofibers are known as smart electrospun nanofibers, as they adapt to external and internal stimuli changes automatically. As a result, medication release takes place exclusively at the target site, hence reducing the unwanted systemic distribution of drug that can cause harmful consequences in patients. Recent attempts have been made to improve the activation and response parameters for electrospun nanofibers-based DDS to deliver specific concentration of drug with regulated release kinetics over predefined time.

2.4.1 pH-responsive electrospun nanofibers For several biomedical applications, the drug delivery that works on the body pH is necessary for efficient therapeutic benefits, especially useful in administration of oral and anticancer medications. This is why the pH-responsive smart DDS attracted more attention for overcoming the challenges associated with conventional drug formulations. The regulation of acid-base homeostasis in the human body maintains the pH of arterial blood between 7.38 and 7.42 (Alvarez-Lorenzo and Concheiro, 2014). pH of the body varies throughout the system and different types of enzymes work in different pH conditions, such as the pH of gastric acid is

Figure 2.3 Stimuli based smart drug delivery systems and release kinetics.

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1.5 3.5, lysosomes is pH 4.5 5.0, and pancreatic secretions have pH of 8.0. Cu et al. prepared the pH-responsive conjugate having anticancer drug doxorubicin (DOX) with poly (methacrylic acid), containing pH cleavable hydrazone bond immobilized on polydopamine capsules for intracellular drug delivery. This conjugated DDS showed limited release of DOX in normal physiological pH, while significant burst release in lysosomal pH. The polymers having weak acidic or basic groups are ideal for the development of pH-responsive systems, as it undergoes rapid changes in the state of ionization at the required pH of interest. Da Costa et al. combined Eudragit L-100 with block copolymers PE-b-PEO, and then loaded with nifedipine as the model drug (Weng and Xie, 2015). Sustained release kinetic was observed at pH 6.8 when it was fabricated into electrospun nanofibers. In addition to organic materials, several inorganic materials also hold potential as pHresponsive DDSs, such as gold, carbon, silica, and calcium phosphate-based nanostructures.

2.4.2 Thermo-responsive electrospun nanofibers The temperature fluctuations in the body abruptly affect the release of therapeutic drugs in the system. Polymers such as poly(N-isopropylacrylamide) (PNIPAAm) and its copolymers or poly (N-vinylcaprolactam) (PNVCL), PMVE that can reversibly change its physical properties with temperature and its phase transition temperature is close to physiological temperature, making it an attractive option for thermo-sensitive DDSs (da Costa et al., 2015; Li et al., 2018b). At different temperatures, these materials undergo separate hydrophilic and hydrophobic phase transitions. PNIPAAm shows an abrupt phase shift from linear to globular in aqueous solution at the lower critical solution temperature of around 32 C. It quickly transitions from hydrophilic to hydrophobic as temperature increases. An external stimulus such as an alternating magnetic field may also generate local temperature increase, which can activate the thermo-responsive drug release. Although dual responsive polymers that respond to both pH and temperature are widely studied, only few reports have shown successful fabrication of pHand temperature-responsive nanofibers. The wide applications of thermo-responsive nanofibers as DDSs have been seen in tissue engineering, wound healing, and biosensing; however, still much work is needed to develop new and better synthetic strategies leading to development of novel thermo-responsive polymers with improved biocompatibility and fine-tuned thermo-responsive behavior.

2.4.3 Light-responsive electrospun nanofibers Electrospinning is also used in the fabrication of photo-responsive nanofibers by anchoring photochemical groups on polymers (Yadavalli et al., 2015). Photochromic materials recently showed advancements and increasing interest due to its varied range of applications, from medical devices to industrial-fields (de Sousa et al., 2010). The two types of photoisomerization behaviors have been used in light-responsive

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nanofibers: open-closed ring transition (e.g., Spiropyran (SP) and its derivatives) and cis-trans conversion (e.g., Azobenzene) (Alvarez-Lorenzo and Concheiro, 2014; Nakatani et al., 2016; Yang and Pierstorff, 2012). When exposed to ultraviolet (UV) light, hydrophobic SP changes to a hydrophilic polar isomer termed merocyanine, which then reverts back to SP when exposed to visible light (Bunker et al., 2003; Higuchi et al., 2014). de Sousa et al. (2010) fabricated photochromic spiropyrancyclodextrin derivative (βCDSP)-modified poly (methacrylic acid) electrospun nanofibers, which showed reverse photochromism with an open-closed ring transition. The measurement of water contact angles and recurrent UV exposure was given to confirm the presence of the photo reversibility of SP on the nanofiber surface. As spiropyrans can be integrated into a variety of organic and inorganic matrices, the photochromic capabilities of the polymer-SP mixture reported in this study opens up new possibilities for light-responsive nanomaterials. Azobenzene is another photo-responsive compound that upon exposure to UV light transforms reversibly from a more stable and a polar trans-state to a more polar cis state and vice versa, in the presence of longer wavelength or thermal relaxation (Higuchi et al., 2004). Azobenzene-modified polymers also showed reversible photochemical cis-trans isomerization on exposure to different wavelengths. Chen et al. showed light-responsive behavior in azobenzene-modified PCL nanofibers.

2.4.4 Electric field responsive electrospun nanofibers There are three major types of electric field responsive polymers, that is, electroactive polymers, ion-doped conducting polymers, and polymer composites/bends/ coatings (Liu et al., 2009). These electrosensitive material changes size and shape due to swelling/de-swelling under the influence of an electric field and are extensively studied as transdermal delivery methods. Electrosensitive hydrogels can be used to produce electrospun nanofibers, and the drug released from the nanofibers responds to changes in the electric field in a predictable and repeatable manner, making them an effective tool to precisely control the quantity of medication released (Palakodeti and Kessler, 2006; Smela, 2003) Electro-conductive molecules, such as multi-walled carbon nanotubes, PVA, PAA [poly (acrylic acid)], can be used as smart drug delivery carriers. The variations in the applied electric voltage considerably regulated swelling of the nanofibers as well as release profile of the drug (Carpi et al., 2011).

2.4.5 Magnetic field responsive electrospun nanofibers The magnetic field outperforms all other stimuli in terms of effectiveness. The living tissues, including human body composed mainly of water, are made up of diamagnetic molecules that repel in negligible range even under powerful magnetic field, whereas applied heat or light can reach up to four inches beneath the skin. The human body is tolerant to high strength magnetic field up to 7 tesla, but the high intensity light or heat can cause DNA damage, mutations, and even cell death

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(Schenck, 2005; Shvedova et al., 2003; Yun et al., 2011). For the generation of magnetically responsive nanofibers, super-paramagnetic nanoparticles (SPNs) are incorporated in the polymer solution during electrospinning. These SPNs consist of ferromagnetic and ferromagnetic nanoparticles that flip their magnetism under the influence of temperature change. Thus, the use of Fe-based magnetic nanoparticles Fe3O4 or Fe2O3 is extensively practiced due to their low cytotoxicity and high biocompatibility. These nanoparticles can be moved to the target site in presence of an external magnetic field, without influencing the release profiles of the drug (Li et al., 2005; Wang et al., 2004; Weissleder, 2001).

2.4.6 Multi stimuli-responsive electrospun nanofibers The multiple stimuli-responsive nanofibers that respond to a combination of two or more stimuli are developed for the greater tunability and effectiveness of DDS. These are fabricated through blending of two or more stimuli-responsive polymers and surface coating of nanofibers to make it responsive to multiple stimuli, such as cations, pH, anions, and temperature (Hussain et al., 2005). For instance, at the site of infection where both pH as well as temperature shift are observed. Chen and Hsieh have produced electrospun nanofibrous mat made up of blending of two polymers: PNIPAAm and PVA to make it dual stimuli responsive toward pH as well as temperature. Various studies demonstrate potentially controlled release of drugs in multi-responsive electrospun nanofibers-based DDS (Hussain et al., 2005). However, developing such smart systems with desirable combinations in response to multiple stimuli under physiological conditions is still a developmental challenge.

2.4.7 Biochemical stimuli-responsive electrospun nanofibers Enzyme-based smart DDSs work in the environment that shows overexpression, a concentration gradient of certain enzymes or both in tissue microenvironment due to pathological condition. MMPs overexpressed in certain malignant tissues are known to preferentially cleave peptide bonds between non-terminal amino acids (Li et al., 2018a; Zhang et al., 2017). Enzyme-responsive delivery systems are specifically designed to shield their cargo from disintegration during transport and triggers its releases specifically at the site by overexpressed enzyme (Davis et al., 2008). Fabricating enzyme-responsive polymer assemblies using enzyme substrates covalently bonded to amphiphilic copolymers is a widely used process. Enzymeresponsive materials-based nanomaterials have shown improve permeability, retention (EPR) effects, as well as site-specific dispersion (Maeda et al., 2013; van Rijt et al., 2015). Van Hove et al. have demonstrated an enzymatically sensitive PEG loaded with pro-angiogenic peptides against cancer cells having overexpressed MMP2, which releases the pro-angiogenic therapeutic peptide in the cancer microenvironment, thereby decreasing inflammation and killing cancer cells (van Hove et al., 2014).

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Clinically used electrospun nanofiber-based biomedical drug delivery systems/devices

Over the past few years, a slew of companies have began selling nanofiber-based products for different biomedical applications. Electrospun nanofibers-based artificial scaffolds that can mimic natural tissue, controlled drug release nanofibrous patches, and implant covers that reduce immune system rejection are among the clinically used electrospun fibers. The following are some examples of clinical electrospun material that are nearing or have reached commercialization.

2.5.1 AVflo It is a first hemodialysis patient’s artificial vascular access graft, constructed from electrospun nanofibers of biocompatible polycarbonate urethane and silicone copolymers. It’s made up of four distinct layers: the inner layer that encounters the blood and is intended to prevent platelets from adhering to each other; the intermediate layer resembles a blood vessel and has self-healing characteristics, reducing bleeding time. The barrier layer’s reduced porosity prevents serum and molecule diffusion while providing strength and flexibility, and the outer layer promotes surrounding tissue growth and development and contributes to the self-healing function. Its fibrous construction offers unobstructed blood flow; enables dialysis within 24 48 hours after implantation; and self-seals in less than 5 minutes when the dialysis needles are removed. The needle punctures and suture holes do not bleed, making it easy to implant and sew to blood arteries. AVflo is robust enough to resist blood flow pressure while being thin enough to allow blood flow to be sensed through it (Stoddard et al., 2016; van Hove et al., 2014; Wijeyaratne and Kannangara, 2011).

2.5.2 RIVELIN patch It is a mucosal adhesive patch with targeted drug delivery used to treat serious and painful oral lesions. It is a two-layer nanofibrous patch with a mucoadhesive layer containing drug and a protective layer that ensures closure and unidirectional drug delivery into lesion. The patch’s ability to adhere to the mucosa provides direct, controlled, and longer-term drug administration. Drugs that are administered directly into the skin have higher efficacy, smaller dosages, and lesser bystander toxicity (Boulanger et al., 2014)

2.5.3 ReBOSSIS It is a biosynthetic, bio-absorbable bone-void-filling material with hydrophilic characteristics of cotton, consisting of tricalcium phosphate, PLLA, and silicone-containing calcium carbonate, which promotes bone formation. It contains 1% silicon by weight, which is comparable to the amount found in natural bone (ClinicalTrials.Gov, n.d.). The network of interconnecting pores allows formation of new bone and development of blood vessels due to the interconnected macro- and micro-porous structure (Nepola

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et al., 2019). The design of product allows for a wide range of handling options and convenience of usage.

2.5.4 HealSmart It is the smart personalized wound care dressing, made up of microfiber technology consisting of both hydrophobic and hydrophilic polymers. It is FDA approved and clinically being used in trials to evaluate efficacy as a personalized treatment option. It is composed of an antimicrobial agent polyhexamethylene biguanide and hyaluronic acid that accelerates wound healing along with protection from microbial infections that delays the healing process. Hyaluronic acid being naturally occurring glycosaminoglycan found in extracellular matrix and connective tissues are well known to assist in wound healing (Omer et al., 2021).

2.5.5 SurgiCLOT It is the first and only fibrin-based sealant designed for cancellous bone bleeding. It is composed of fibrin dextran-based nanofibers that contain bolus of clotting proteins, that is, fibrinogen and thrombin, which promote the cascade of instantaneous natural fibrin clotting to aid bone healing.

2.5.6 PK Papyrus It is a thin, electrospun fibrous polyurethane coronary stent with great elasticity and flexibility to seal perforations. Perforation of a coronary artery during percutaneous revascularization is linked to high rate of morbidity and mortality. The PK Papyruscovered stent acts as a physical barrier, sealing ruptured arteries and preventing complications such as death. The PK Papyrus-enveloped stent is aimed to address the limitations of current therapies, make device distribution easier, and treat coronary artery perforations more successfully (Kandzari and Birkemeyer, 2019).

2.6

Biomedical applications of electrospun nanofiberbased drug delivery systems

Electrospinning is a cost-effective and simple method of encapsulation for medical and pharmaceutical research due to high loading capacity, high encapsulation efficiency, and ease of use of the generated fibers/polymers/mats. This method is wellsuited for a wide range of applications due to the ease with which it can be scaled up for the mass production. Electrospinning is critical in biological applications, such as tissue engineering, drug release, wound dressing, enzyme immobilization, etc. Advances in synthetic tissue fabrication and drug delivery have been made possible by the usage of biocompatible polymers in the biomedical sector (Fig. 2.4). A wide range of polymers are available that can be modified or functionalized to

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Figure 2.4 Different applications of nanofibers-based drug delivery systems.

become bio-absorbable and to minimize the risk of rejection by the immune system along with several other biomedical applications (Boudriot et al., 2006; Jeong et al., 2019; Lu et al., 2009). Nanofiber-based polymeric biomedical products can also be produced using a variety of electrospinning techniques. These nanofibers are generated by electrospinning and can be employed in both upstream and downstream biomedical processes because of their precise topology and composition.

2.6.1 Drug delivery Blending is the most common method of electrospinning wherein pharmaceuticals are integrated into the polymer solution. The physicochemical characteristics of the drug as well as polymer must be taken into consideration to improve drug encapsulation, distribution in the fiber, and the release kinetics (Boudriot et al., 2006). An improved version of this technology was developed by Ma and his colleagues (Ma et al., 2011) to produce extremely porous nanofibers from electrospun chitosan/PEO mix solutions. Porous nanofibers were then dipped into the drug solution and subsequently incorporated into hydrogel, which contained 4% hyaluronic acid (Ma et al., 2011). Another approach was demonstrated wherein multiple drugs can be electrospun within a suitable polymer(s) to develop a system for multiple drug delivery. Wang et al. developed a chain-like structure of core-shell nanofibers with a different release characteristic of multiple drugs, wherein drugs were loaded in the polymer sheath as well as in core nanoparticles. In another study, a hydrophilic model of BSA drug-loaded chitosan microspheres has been constructed and suspended in PLLA solution having

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hydrophobic model drug (benzoin) and PVP as a release controller (Nair et al., n.d; Wang et al., 2010). Electrospun fibers are delivered orally, topically, and as an implantable device. The transdermal drug delivery system uses the skin to deliver medicines either locally or systemically. It’s an ideal delivery system for medications that can’t be given orally, either because of significant gastro-intenstinal degradation or extensive metabolization. Transdermal delivery of the electrospun fibers is commonly used for the administration of anti-inflammatory, vitamins, and antioxidant drugs (Fig. 2.4). In the study conducted by Taepaiboon et al., vitamin A and vitamin E have been loaded into cellulose acetate polymer-based electrospun fibers and solvent cast films. The result demonstrated that the electrospun fiber mats gradually and consistently increased the cumulative vitamin release in comparison to the corresponding solvent cast film. For the treatment of oral mucositis, Reda et al. synthesized ketoprofenloaded Eudragit L and Eudragit S electrospun nanofibrils. In this formulation, drug molecules were prevented from aggregating in nanofibrous structures because of solvent evaporation during electrospinning (Im et al., 2010; Ngawhirunpat et al., 2009; Suwantong et al., 2007, 2008; Taepaiboon et al., 2006, 2007; Xu et al., 2011).

2.6.2 Regenerative medicine Regenerative medicine encompasses the fields of biomedicine, engineering, and materials science. This field makes use of scaffolds to support the cells at the injury site so that cells can repopulate the damaged area. ECM majorly comprises glycosaminoglycan and proteins that separates tissues, provides support for cells and anchors them to one other. Electrospinning proves to be a boon for this field as it generates 3D porous mats with high porosity and surface area, which can imitate the structure of the ECM, making it an excellent choice for the field of tissue engineering. Biocompatibility and biodegradability are two of the most important characteristics of a material that can be employed for tissue engineering purpose. Also, the structure of the scaffold is critical to cell attachment (Stevens and George, 2005). Scaffolds with nanoscale topology provide larger surface area facilitating high protein adsorption along with more binding sites for cell membrane receptors. The cell attached to these micro-scale scaffolds spread and flatten as if they are grown on a flat surface. Further, these scaffolds provide an edge over traditional ones by giving the opportunity to the adsorbed protein to modify their conformation. The selection of relevant biomaterial becomes quite important in regenerative medicine in terms of mechanical properties and porosity as it is crucial for particular type of tissue regeneration and degradation properties, as rate of degradation is important and specific for tissue types and electrospinning, which provides the opportunity to fine tune these properties as per requirement. Many natural and synthetic biomaterials like alginate, gelatine chitosan, PLA, PCL, PGA, and their copolymers are commonly used for directing the organization, growth, and differentiation of cells in the process of forming functional tissues (Bhattarai et al., 2018). Ramakrishna et al. found that the smooth electrospun PLA surface was shown to be superior than the rough electrospun surface in terms of cell viability of human vascular endothelial cells (Xu et al., 2004). The findings of Bini et al. revealed that neuronal stem cells C17.2 grown on polyethylene, PLGA (lactide-co-glycolide), nano and micro scaffolds, were

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shown to be firmly attached and differentiated toward the fiber’s direction (Bini et al., 2005). Many questions, such as the probable interplay of scaffolds with the biological system, mechanical properties, controlled degradation, end product toxicity, and extensive in vivo studies, etc., need to be performed before this method can be used for solving real-world problems.

2.6.3 Wound dressing and antimicrobial agent Electrospun material possesses all ideal characteristics that are needed for wound dressing, that is, homogeneity and porosity to ensure the adequate oxygen diffusivity and presenting the barrier for infection. In the past, skin substitutes were mainly produced by freeze drying (FD) of fibroblasts and/or keratinocytes on collagen scaffolds, which causes structural heterogeneity. Wound dressing materials could be easily produced using electrospinning. The natural polymer, collagen, was used by Powell et al. to compare the skin substitutes generated by FD and electrospinning (Powell et al., 2008). These skin substitutes were used in a thymic mouse and compared for cell proliferation, maturation engraftment, and wound healing efficiency. All other parameters were similar in both the fibers but wound contraction was found to be reduced with electrospun scaffold, which may result in lowering the morbidity in patients treated with electrospun collagen skin substitutes. To aid in wound healing and avoid the infections, Alhusein et al. used PCL and (PEVA) poly (ethylene-co-vinyl acetate) to create electrospun tetracycline HCl fibers that could be used in the future. A regulated release and greater antibacterial effectiveness were found in the in electrospun-based three-layered scaffold as compared to already available drugs (Alhusein et al., 2012). This group of researchers also found that the fiber matrices designed by them have a high level of biological activity in complex biofilm models. In addition to killing and inhibiting the formation of new biofilms, the fibers also killed already-established biofilms along with the older dense colonies of Staphylococcus aureus MRSA252 (Alhusein et al., 2013). In a study, nanofiber of poly(3-caprolactone) (PCL) were generated by electrospinning silver-loaded zirconium phosphate nanoparticles (nanoAgZr) with PCL solution and then used for in wound dressing applications. Antimicrobial analysis indicated that these fibers retained the antibacterial properties of Ag as seen in nanoAgZr against the bacteria strains tested [Gram-positive S. aureus (ATCC 6538) and Gram-negative Escherichia coli (ATCC 25922)] along with no signs of discoloration (Sheikh et al., 2009). The encouraging results from the various studies conducted hint toward the immense potential of electrospun polymers in the preparation of antimicrobial wound dressing material and scaffolds.

2.6.4 Cancer research Considerable adaptability, economical nature, and a vast potential for expandability of these electrospun fibers have encouraged the development of novel cancer research methodologies. Electrospun nanofibers have been used in all dimensions of cancer research, that is, generation of in vitro 3D model, detection of cancer, and therapeutic delivery of drugs (Fig. 2.4). Electrospun nanofibers of the polymers mimic the complex

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matrix structure of the ECM, hence used in the development of 3D tumor model for in vitro screening of the drug, preclinical research, and deciphering the mechanistic details. Various approaches suggest that these multifunctional and stimuli-responsive electrospun patches can be effectively used for controlled and sustained topical release of medicines with better therapeutic efficacy and minimal side effect (Cavo et al., 2020). Electrospun nanostructured mats are also an appealing sensor platform that could be employed for early cancer detection (Ali et al., 2015). An implanted DDS using electrospun nanofibers is one of the most successful techniques for localized cancer treatment as it allows on-site administration of anticancer medicines and decreases the chances of systemic toxicity to the normal cells (Fig. 2.4). Liu et al. conducted a study to assess the efficacy of doxorubicin in PLLA fiber mat during the focal chemotherapy to assess its potential against subsequent liver cancer. The drug was promptly released from the fiber and localized in the liver tissue within 24 hours. The drug also slowed down the tumor growth and increased the median lifespan of the mice (Liu et al., 2012). In another study, green tea phenol electrospun with polycaprolactone/multi-walled carbon nanotube (PCL/MWCNT) showed considerable inhibition of A549 and Hep G2 carcinoma cells (Shao et al., 2011). Achille and colleagues demonstrated an interesting approach, gene silencing for tumor inhibition, where plasmids used for the translation of short hairpin (sh) RNA specifically designed to target cyclindependent kinases (CDK2) was electrospun with biodegradable polymer. Viability along with the proliferation of the breast cancer cells (MCF-7) was found to be inhibited in these scaffold for more than 21 days as plasmid DNA was sustainably released during the degradation of the fiber (Achille et al., 2012). Electrospun scaffolds have made significant advances in cancer diagnosis and treatment, but extensive in vivo investigations are still required before they can be used in clinical trials and medical devices.

2.7

Conclusion and future perspectives

Nanofiber-based DDSs have gained huge importance in diverse biomedical applications due to their versatility, cost-effectiveness, and ease of fabrication in any research facility, even with little financial resources. Fiber geometries have grown in complexity, and their biomedical uses are fast expanding. Further clinical studies are required to optimize drug incorporation in nanofibers for its acceptance in administration form to patients. There is a wealth of scientific information on electrospun composite biomaterial biocompatibility and its favorable characteristics that advocate its potential for a wide range of applications in biomedical field. More research is needed to take these compounds from laboratory scale to clinical research. Although researchers were able to change the apparatus and solution conditions to imitate genuine tissue structure and morphology, these processes still need to be fully characterized, including clinical trials, before they can be employed in applications for treating medical disorders. Furthermore, by tailoring the diameters, shapes, morphologies, and orientations of the fibers according to the desired therapeutic

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application, physicians and bioengineers could tackle unknown regenerative therapies. Electrospinning these materials in the future will be influenced by mimicking the structural and functional characteristics of natural tissues. Although neuronal and vascular structures, as well as many heterogeneous cells, are one of the key obstacles in tissue engineering and organ models, sophisticated organ architectures can be engineered using electrospinning in tandem with 3D printing technology. Future research should be focused on developing 3D nanofibrous scaffold that incorporate growth factors and high-viability cells, as well as improving infiltration. As a result, ongoing research and development as well as the advancement in improved electrospinning technologies will usher in a new era of drug delivery and tissue regeneration.

Acknowledgments We would like to thank Director, Institute of Nuclear Medicine and Applied Sciences (INMAS), for his continuous support. This work was funded by Defence Research Development Organization, India. The images are created using Biorender.com.

Individual authors’ contributions Conceptualization: Sarika Tomar, Sweta Singh, Rakesh Pandey; Design of work: Sarika Tomar, Priyanka Surya, Sweta Singh; writing—original draft preparation: Sarika Tomar, Rakesh Pandey, Ranjan Verma, Priyanka Surya; writing—review and editing: Sweta Singh, Rishabh Singh, Ved Prakash Meena; Supervision: Sweta Singh; Project and Funding administration: Sweta Singh. All authors have read and agreed to the published version of the manuscript.

Compliance with ethical standards Not applicable

Conflict of interest The authors declare no conflict of interests.

Research involving human participants and animals Not applicable.

Informed consent Not applicable.

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Biomaterial-based fibers for enhanced wound healing and effective tissue regeneration

3

Lalita Mehra1 and Payal Gupta2,3 1 Department of Combat Sciences, Institute of Nuclear Medicine & Allied Sciences, Defence Research & Development Organisation, Timarpur, Delhi, India, 2Department of Biosciences and Bioengineering, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand, India, 3Department of Biotechnology, Graphic Era University, Dehradun, Uttarakhand, India

3.1

Introduction

The skin is the largest organ in the human body and acts as a protective barrier against various mechanical, thermal, and physical injuries. It is thus vulnerable to a variety of external factors that result in different types of skin damages and injuries. The skin performs vital functions and any damage to this barrier can disrupt the immune system and make the body susceptible to various kinds of infections (Winter, 1962). Although dermatological emergencies are rare, if not treated at a primary stage, they can lead to complications by delayed wound healing and eventually can cause mortality (Yannas and Burke, 1980). A wound shock is characterized by increased capillary permeability, increased hydrostatic pressure across the microvasculature, protein and fluid movement from the intravascular space into the interstitial space, increased systemic vascular resistance, reduced cardiac output, and hypovolemia requiring fluid resuscitation, which can ultimately lead to multi-organ failure (Hardaway, 2004). Extensive use of biomaterials in wound healing, tissue repair, and regeneration helps explore a wide range of biopolymers of various origins. Numerous natural biopolymers and synthetic biomaterials have been explored in this area within the past 30 years. In this chapter, we briefly discuss (1) natural (chitosan, hyaluronic acid, proteins, collagen, gelatin, and silk fibroin); (2) synthetic (PVA, PLA, PGA, PCL, PEG, PLGA); (3) phytoactive molecules-loaded polymers; and (4) conductive biomaterials. We provide an overview of various types of biomaterials used in wound healing and regeneration. The boons and banes of these biomaterials are also discussed.

3.2

Biomaterials

The National Institute of Biomedical Imaging and Bioengineering (NIBIB), US has defined biomaterials as natural or synthetic materials that find applications in medicine, wherein they support, enhance, or replace damaged tissues to repair various Fiber and Textile Engineering in Drug Delivery Systems. DOI: https://doi.org/10.1016/B978-0-323-96117-2.00005-4 © 2023 Elsevier Ltd. All rights reserved.

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biological functions of the body. They have revolutionized modern medicine by restoring biological functions and accelerating wound healing. A variety of natural or synthetic origin polymers are used in biomaterial synthesis.

3.2.1 Natural polymers Plant and animal-derived natural polymers are widely accepted for biomaterial development and finds applications in medicine (Williams, 2009). Based on their chemical nature, natural polymers are broadly divided into two groups: polysaccharides and polypeptides (Singh et al., 2016). The natural polymer-derived biomaterials are preferred for use in biomedicine due to their morphology, versatility, biodegradability, biocompatibility, modifiable properties, antigenicity, and 3D structure similarity (Ogueri et al., 2019). Natural polymers include chitin, silk fibroin, fibrinogen, collagen, hyaluronic acid, alginate, cellulose, etc. Some of these polymers are discussed further in detail.

3.2.1.1 Chitosan It is a polymer composed of β-1,4-linked N-glucosamine (N-GlcNAc) monomers that are randomly distributed (Gupta et al., 2021a) (Fig. 3.1A). It is an amino-

Figure 3.1 Chemical structure of (A) chitin and (B) chitosan, where the linking of two monomeric units is depicted.

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polysaccharide that finds a variety of applications in food, cosmetics, agriculture, textile, paper industry, and biomedicines (Islam et al., 2017). Chitin is found in abundance in crustacean shells, and some amount is also present in fungal cell walls (Chien et al., 2016). After cellulose, chitin is the second most abundant biopolymer on earth. The partial deacetylated form of chitin is chitosan and has more potential in scaffold formation due to its cationic nature (Chandy and Sharma, 1990) (Fig. 3.1B). Because most polysaccharides are either neutral or negatively charged in an acidic environment. The cationic charge of chitosan favors its blending with negatively charged polymers and thus facilitates multilayer structure synthesis (Venkatesan and Kim, 2010). Chitosan possesses antimicrobial, antiviral, antioxidant, and antitumor activities, which are dependent on its degree of deacetylation. It is a polymer widely used in wound healing and tissue engineering scaffold preparation (Cheung et al., 2015). Chitin serves as raw material for chitosan production using a broadly outlined conventional scheme consisting of demineralization, deproteinization, and decolorization (Jung et al., 2006; Percot et al., 2003). The chitin isolation technique and source decides the quality of chitosan, and based on the degree of deacetylation a variety of chitosan is available in the market (Nwe et al., 2014). NMR, X-ray diffraction, and infrared spectroscopy are used for determining the degree of deacetylation in chitosan (Cheung et al., 2015). Due to free amino groups, chitosan easily reacts with other molecules or polymers under mild conditions and is thus capable of forming myriad combinations to be used in biomaterial fabrication.

3.2.1.2 Hyaluronic acid In 1934, Meyer and Palmer isolated an extremely high molecular weight polysaccharide from the vitreous of bovine eye, known as Hyaluronic acid (HA) (Meyer and Palmer, 1934). It belongs to the glucosaminoglycan (GAG) family and consists of alternatively connected units of N-acetyl-D-glucosamine and glucuronic acid (Fraser et al., 1997). HA is highly biocompatible, mucoadhesive, ubiquitously distributed in extracellular matrix (ECM) of mammals with antioxidant, antiinflammatory, and wound healing properties. It is widely used in the cosmetic and pharmaceutical industry for biomaterial synthesis and drug delivery (Ehsanipour et al., 2019; Fakhari and Berkland, 2013; Sieni et al., 2020). Hydrogels of HA are the most favored form in tissue repair techniques due to the presence of carboxylic acid and alcohol groups in HA, which facilitate cross-linking among themselves (Manna et al., 1999). With time, HA has been modified as per usage in terms of chemical modifications, physical blending, and cross-linking (Birajdar et al., 2021).

3.2.1.3 Collagen It is an animal-derived polymer that exists in a triple helix formed by three polypeptide chains in the form of sheet and fibrillar structures. It is the most preferred alternative to cellular scaffolds in the human body (Naomi et al., 2021). It is the major protein component of ECM that makes up to 90% of human skin and occurs

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in the form of a heterodimer or trimer. Nearly 20 different types of collagens are known so far to constitute collagen superfamily, which differ structurally in terms of the number of α-chains. In a right-handed triple helix, the members having three α-chains are homotrimers (type II, III, VII, VIII, X) while those having two or more different chains are heterotrimers (type I, IV, V, VI, IX, XI). Type I and type II are the two most extensively explored collagen members for tissue engineering, where the shortcoming of the former can be surmounted by type II in reference to chondrogen output (Higuchi et al., 2012; Pieper et al., 2002). Although type II is a preferred polymer for cartilage regeneration, however, safety studies are required to be performed (Irawan et al., 2018; Lu et al., 2010). Nevertheless, collagen needs modifications to serve the biomedical purpose because it elicits antigenicity, and is mechanically less stable. Advancement in dissociation and mechanical strength will surely enhance their usage in tissue engineering of strength-demanding body tissues (Reis et al., 2008). This can be achieved by the synthesis of collagen and other polymer blend scaffolds (HA, chitosan, PVA, etc.) (Matsiko et al., 2012).

3.2.1.4 Gelatin The hydrolyzed form of collagen type I is known as gelatin. It is a proteinaceous polymer and its primary structure consists of different amino acids present in varied proportion (Nikkhah et al., 2016). Gelatin is smooth, sensitive to protease, and easily digestible as compared to collagen (Naomi et al., 2021). The biological functional moiety in gelatin structure is an arginine-glycine-aspartic acid sequence, which facilitates its attachment to cells (Alihosseini, 2016). Furthermore, the structure of gelatin varies with the extraction process; for instance, acid extraction results in type A positively charged form while alkaline extraction gives type B negatively charged gelatin (Narayanaswamy et al., 2016; Van Vlierberghe et al., 2014). Gelatin has poor mechanical strength but is highly water-soluble, biocompatible, and bioabsorbable (Mohiti-Asli and Loboa, 2016). Moreover, gelatin can be easily modified as per the requirement and suits various biomedical roles. Although gelatin is the most demanded polymer for tissue engineering scaffolds and wound dressing-related patches due to its thermal instability even at body temperature, its wide usage is not encouraged. Therefore, different physical and chemical crosslinking methods were adopted to increase the thermal and mechanical stability of gelatin. Some common cross-linking agents or methods often employed for crosslinking in gelatin are glutaraldehyde, transglutinase, heat, pH, and microwave radiations (Bello et al., 2020). Moreover, blending gelatin with other polymers (PCL, PLGA, PVA, HA) for biomaterial fabrication is nowadays a widely adopted approach to make use of its advantages and overcome the disadvantages (Echave et al., 2019).

3.2.1.5 Silk fibroin It is a macromolecular, proteinaceous polymer that consists of two types of proteins, fibroin and sericin, wherein the former is hydrophobic and the latter is

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hydrophilic glue (Choi et al., 2018). Similar to other natural polymers, silk fibroin (SK) is biodegradable, less immunogenic, non-toxic, and biocompatible but has good mechanical strength and thermal stability over others (Cheng et al., 2018). SK is produced by spiders, silkworms, scorpions, etc. Structurally, SK consists of two fibroin strands coated with sericin wherein fibroin consists of a heavy and light polypeptide chain interconnected by a disulfide bond (Koh et al., 2015). Heavy chain contributes to the fibrous nature of SK and consists of a few common amino acids: glycine, serine, and alanine (Huang et al., 2018). In addition to traditional use in textiles, SK-based biomaterials are gaining popularity due to their wellestablished ability in promoting stem cell attachment, growth, and differentiation (Floren et al., 2016; Melke et al., 2016). Further, SK can be developed in the form of fibers, mats, etc., which extends its usage as a biomaterial for fixing wounds, reconstruction of tissue, and other skin engineering applications (Holland et al., 2019). Intriguingly, a fluorescent variant of SK has been developed in recent years to monitor the surgical and healing processes, as well as drug delivery. This has revolutionized modern drug delivery and biomedicine (Lee et al., 2020). For exploiting SK in drug delivery and bone tissue regeneration, they are often blended with synthetic polymers that enhance their solubility, and make them suitable for fibers synthesis/biomaterial production.

3.2.2 Synthetic polymers With increase in demand for biomaterials in biomedicine, adoption of synthetic fibers for the purpose has been determined and several synthetic polymers-based biomaterials have been developed. Aliphatic polyesters are the class of synthetic polymers that are primarily used in the synthesis of biomaterial for tissue engineering applications (Cameron and Shaver, 2011). The structure of synthetic polymers is well-studied, easily tunable, no immunogenicity concern (Magnusson et al., 2011). In contrast, natural polymers are immunogenic, possess microbial contamination, quick degradation, and low mechanical strength (Abbasian et al., 2019; Rouchi and Mahdavi-Mazdeh, 2015). The only drawback of synthetic polymers is their inability to adhere to cells and needs chemical modifications to become adherent. Synthetic polymers are biodegradable; the ester group in the polymer’s backbone undergoes hydrolysis. Some FDA-approved synthetic polymers that are majorly used for the synthesis of tissue engineering and wound healing biomaterial include polyethylene glycol (PEG), poly lactic-co-glycolic acid (PLGA), poly (ε-caprolactone) (PCL), polyglycolic acid (PGA), etc.

3.2.2.1 Polyvinyl alcohol It belongs to polyether and is produced by hydrolysis of polyvinyl acetate. The degree of hydrolysis results in two types of polyvinyl alcohol (PVA); partially hydrolyzed and fully hydrolyzed where the latter one finds applications in the food industry (Halima, 2016) (Fig. 3.2A). PVA is a water-soluble, thermostable, biocompatible, biodegradable polymer that exhibits multiple physio-chemical properties

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Figure 3.2 The chemical structure of (A) polyvinyl alcohol; (B) polylactic acid; (C) polyglycolic acid; (D) poly(ε-caprolactone); and (E) polyethylene glycol.

due to which it finds a role in biomaterial and other biomedical fields (Pathan et al., 2015). PVA fibers have high tenacity, high Young’s modulus, low elongation, low creep, and excellent resistance to severe weather (UV) and chemicals (alkali, acid, oil, etc.). It was first developed by Haehnel and Hermann in 1924 and was one of the most popular polymers used for gel preparation (Arefian et al., 2020). The fibers of PVA can be synthesized using almost all commercial techniques stretching from traditional to nano-spinning. Blending PVA with other synthetic or natural polymers is easy and this will enhance the property of both individual polymers.

3.2.2.2 Polylactic acid It is a hydrophobic, semicrystalline polymer composed of water-soluble lactic acid (LA) monomers, especially L(1)-LA enantiomer as it naturally occurs in the human body as part of metabolism (Fig. 3.2B). Due to the necessity of purity of LA for biomedical-grade polylactic acid (PLA) synthesis microbial fermentation route is often preferred as it gives the optically pure form of PLA over chemical synthesis (Singhvi et al., 2019). However, depending on the enantiomeric of LA, two optical isomers of PLA are ploy(L-lactic acid) and poly(DL-lactide), which are different from one another in their physical and chemical characteristics (Garlotta, 2001). PLA is a widely accepted biomaterial for various biomedical applications because water molecules easily hydrolyze the polymer backbone by interacting with ester bonds (Casalini et al., 2019; Gupta et al., 2007). The PLA contains extra methyl groups that make them more hydrophobic than PGA. Indeed, PLA scaffolds take more time to dissociate or disintegrate (Guo and Ma, 2014). In addition to biodegradability and compatibility, PLA offers engineering of its physical and chemical properties by optimizing its molecular weight, co-polymerization, and blending. PLA-based biomaterials find applications in almost all biomedical fields like orthopedic, cardiac, general surgery, oncology, dentistry, etc. Moreover, PLA-based

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nanocomposites also serve as drug carriers (Singhvi et al., 2019). PLA-based fibrous scaffolds have a very well-established role in tissue engineering and regenerative medicines, wherein they were combined with other polymers and/or some drug molecules to solve the purpose (Magiera et al., 2017).

3.2.2.3 Polyglycolic acid The most popular polymer for fibrous scaffold synthesis is PGA. It is a linear, aliphatic polymer with a high degree of crystallinity due to its chain-structural similarity (Fig. 3.2C). It is biodegradable, wherein the breakage of the ester backbone results in release of glycolic acid that through TCA cycle is excreted out as CO2 and H2O from the body (Gunatillake et al., 2003). PGA is readily degradable in aqueous environment depending on the molecular weight, physical structure, and environmental conditions, in more or less 2 to 4 weeks of time. The first synthetic polymer-based absorbable sutures were made from PGA and, in fact, even today it is the most promising polymer used in tissue engineering scaffold fabrication (Cameron and Shaver, 2011; Seyednejad et al., 2011).

3.2.2.4 Poly(ε-caprolactone) Poly(ε-caprolactone) is a biocompatible, non-toxic, bioresorbable, FDA-approved easily moldable polymer due to its low melting temperature and its superior viscoelastic properties (Jung et al., 2016; Mondal et al., 2016) (Fig. 3.2D). It is a semicrystalline synthetic polymer that is easily degraded by enzymes, intracellular metabolic pathways, and microbes under normal physiological conditions. PCL has a very low glass transition temperature of about 260 C due to which it is a highly permeable material (Labet and Thielemans, 2009). If the degradation rate of PCL is compared with PLA, PGA, and PLGA, it is the slowest one (McNeil et al., 2011). Due to the delayed degradation, PCL is a more suitable polymer for implants and drug delivery-related applications over tissue regeneration (Chang et al., 2013). PCL is often blended with natural polymers and/or loaded with drugs that are used for the synthesis of the scaffold that is capable of absorbing wound exudates, avoiding antimicrobial invasion, and ensuring gaseous exchange (Figueira et al., 2016; Kakkar et al., 2014).

3.2.2.5 Polyethylene glycol It is a biocompatible, hydrophilic, non-immunogenic polymer and is most extensively investigated for tissue engineering application (Fig. 3.2E). It is an etherbased polymer that is suitable for wound healing biomaterial synthesis as growth factors (EGF) have a good affinity toward PEG and thus can be bonded (Shahverdi et al., 2014). Intriguingly, the benefit of PEG in wound healing scaffold is that it avoids scar formation and after degradation does not get accumulated in the body (Krsko et al., 2009; Potter et al., 2008). Furthermore, the suitability of PEG in the biomedical field is increased by stabilizing its chemical, thermal, and mechanical properties through blending with chitosan and PLGA. PEG facilitates the growth

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and proliferation of skin cells as well as collagen deposition at the wound site in diabetic patients (Jeon et al., 2007).

3.2.2.6 Polylactic-co-glycolic acid It is a copolymer of PLA and PGA consisting of random ring openings. It promotes cell adhesion and exhibits controlled degradation rate and optimal mechanical properties without cytotoxicity (Haghighat and Ravandi, 2014). The varying ratio of PLA and PGA regulates properties of PLGA; like degradation rate, shape, and size (Alizadeh-Osgouei et al., 2019; Bharadwaz and Jayasuriya, 2020). The tunability of PLGA promotes its use in skin grafts or substitutes (Baoyong et al., 2010). The hanging methyl group in the PLGA ring makes its surface hydrophobic like PLA (Wang et al., 2010). For organ/tissue regeneration, the PLGA, along with its parent polymers, is used to restore or regenerate damaged tissue as it has well-defined biocompatibility and toxicity profile, as they degrade via hydrolysis of the ester bond. PLGA upon degradation in vivo releases lactic and glycolic acids, which are eliminated through the TCA cycle (Okamoto and John, 2013). To ensure the success of PLGA-derived scaffolds in tissue repair/wound healing, the epithelization rate is in harmony with the polymer degradation rate by blending it with another polymer (Chen et al., 2005).

3.2.3 Phytoactive molecule-loaded polymers Natural bioactive molecules are a blessing to humankind as they have solutions for all health-related issues since ancient days. Essential oils (EOs) constitute one of the most potential and investigated class of bioactive molecules (Harvey et al., 2015). In the past few decades, detailed investigations on exploring the role and mechanism of action of various components of EOs have been investigated that were either renowned or hidden for their wound healing and tissue regenerative potency in ancient literature. Cinnamon, eugenol, thymol, cymene, eucalyptol, citral, etc. are some of the widely studied molecules (Gupta et al, 2021; Yadav et al, 2022). Despite so many advantages and no side effects, EOs have disadvantages such as volatility and insolubility in water. Encapsulation of these hydrophobic molecules in hydrophilic polymer helps address the problem that hinders their biomedical applications (Kayaci et al., 2013). Moreover, encapsulation of EOs in polymer matrix also ensures controlled release as well as targeted delivery. PVA, PCL, PEG, gelatin, chitosan, alginate, etc., are the polymers used for EO loading, where the polymer serves as a vehicle and in return EOs impart medicinal properties to the non-remedial polymer. This increases the applicability of fibers in biomedicine (Rather et al., 2021).

3.2.4 Conductive biomaterials A recent and sophisticated category of biomaterials is conductive biomaterials. These biomaterials are composed of conductive polymers, carbon nanomaterials,

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metals, etc., which are in the range of conductivity of human skin (Guo et al., 2013; MacDiarmid, 2001; Urie et al., 2018). These biomaterials are in different forms, including films, fibers, and membranes (Karim et al., 2016; Talikowska et al., 2019). These biomaterials could also be overlaid/loaded with bioactive or phytoactive molecules to enhance the therapeutic activity of the material. Both natural and synthetic polymers are together used for fabrication of these biomaterials as none of the polymers could alone serve the purpose and avoid drawbacks. Physical mixing of polymer solutions or cross-linking techniques are used to achieve the biomaterials with desired traits. The majority of polymers discussed in this chapter are used for the synthesis of conductive biomaterials (Koh et al., 2018; Korupalli et al., 2021). The wound healing potency of conductive biomaterials is better in nearly all tested wound healing models (Balint et al., 2014; Dong et al., 2020; Korupalli et al., 2021). So far, PosiFect RD and Procellera are the two FDA-approved wearable electric dressings that stimulate the healing of open wounds (Yu et al., 2022).

3.3

Synthesis of fibers

3.3.1 Wet spinning It is the classical and most expensive method of fiber synthesis as it is applicable only to polymers soluble in non-volatile solvents and temperature-sensitive polymers (Lawrence, 2010). In this method, the polymer is dissolved in a non-volatile solvent and with the help of a pump, the polymer solution is extruded through the spinneret into the coagulation tank (Fig. 3.3). The coagulation tank contains the

Figure 3.3 A diagrammatic representation of wet spinning set up for the synthesis of long fibers.

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solvent in which the polymer is insoluble and thus facilitates precipitation of polymer as fibers. Next, these fibers pass through the warm air chamber where the residual solvent is evaporated and the fibers are collected either directly or after certain specific treatments into yarn onto bobbins (Ozipek and Karakas, 2014). The only advantage of the wet spinning technique is its capacity in handling large tows. However, the disadvantage of this method includes extra washing steps to remove impurity/chemicals, and a slow synthesis rate. Wet spinning is suitable for VinyonPVA, spandex, lyocell, etc. Wet spinning has a variant that is suitable for polymers that solidify by warm air and thus eliminate the need for coagulation known as the dry spinning technique. In this technique, the polymer is dissolved in volatile solvent after filtration extruded through the spinneret and passed through the warm air chamber instead of entering into a coagulation tank. The dry spinning eliminated the requirement of washing/purification.

3.3.2 Melt spinning For majority of the thermoplastic polymers, melt spinning technique is employed where the polymers are heated to melt to a consistency so that they easily pass through the spinneret (Fig. 3.4). The emerging fibers were cooled down, converged, and then collected in a yarn (Hufenus et al., 2020). It is the most convenient and economical spinning technique as no solvent is recovered or used and spinning rate is fairly high. The holes in the spinneret controls the number of filaments produced that further decides crystallinity, orientation, and uniformity of fibers, which reflects in the yarn.

Figure 3.4 A diagrammatic representation of melt spinning technique.

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Figure 3.5 The electrospinning techniques for synthesis of nanorange of fibers.

3.3.3 Electrospinning It is one of the oldest spinning techniques that produces fibers at a very low rate compared to conventional techniques. Indeed, before 1990, most industries preferred melt spinning that was capable of synthesizing micrometer-sized fibers at a rate of 200 1500 m/min. Intriguingly, electrospinning gained the deserving popularity in tissue engineering and regenerative medicine field of biomedical science (Haider et al., 2018). The electrospinning technique is capable of synthesizing fibers ranging in size from micrometers to nanometers using a wide variety of polymers and their blends loaded with drugs. The major components of electrospinning instruments are: a power supply, syringe with spinneret, needle, and metallic collector. Based on the positioning of collector, electrospinner instruments are horizontal and vertical (Ibrahim and Klingner, 2020). As soon as the electric charge moves into the polymer solution through a needle, the electrospinning process begins and induction of charge occurs in the polymer solution (Fig. 3.5). Due to this charge, the force generates and polymer solution flows in the electric field direction. At the tip of the needle, the polymer forms a cone, which emerges as a fine fiber upon further increase in electric field. The fine cone of polymer solution formed at the end of needle is known as the Taylor cone. The fine fiber emerging out of the Taylor cone gets collected on the collector (Bae et al., 2013; Haider et al., 2018). The applied voltage, distance between needle and collector, solution flow rate, concentration, conductivity, and viscosity of polymer solution are the parameters that affect the fiber diameter and uniformity.

3.4

Characterization of fibers

Polymer-derived scaffolds need to be characterized using a myriad of physiochemical and analytical techniques to confirm the suitability of the synthesized fiber to a desired application (Sanjay et al., 2019). The techniques employed for

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fiber characterization are broadly divided into three groups: morphological, analytical, and mechanical.

3.4.1 Morphological techniques The topological, geometric, and dimensional estimation of the synthesized fiber/ scaffold is visualized and measured using high-resolution microscopy, which includes scanning electron microscopy and atomic force microscopy. The microscopic visualization provides minute details regarding the thickness of fibers, pore size in the scaffold, and surface roughness that help decide whether the scaffold is suitable for the desired application (Gupta et al., 2021b). The sample preparation for microscopy is simple without any chemical treatment or staining. A small piece of fabricated fiber is directly visualized under the microscopes. The captured images on different resolutions are then further analyzed by various software for surface and dimension parameters calculation (Mishra et al., 2021a).

3.4.2 Analytical techniques The molecular structure or compositional investigation of polymer scaffolds is performed to find out any chemical interactions/linkage between the polymers or monomeric subunits of polymer. The commonly used techniques are XRD, XPS, NMR, and FTIR. X-ray diffraction crystallography is employed for phase detection of crystalline material. The obtained XRD peaks of biomaterial are compared with the spectra of pure individual compounds where new peaks depict interaction among polymer components of the scaffold. The Fourier-transform infrared spectroscopy gives compositional information about the biomaterial and thus signifies the bonding between polymers at a molecular level (Kimber and Kazarian, 2017). FTIR gives both qualitative as well as quantitative details about the synthesized scaffolds. FTIR scan is performed from 400 to 4000 cm21 and the obtained peak positions and chemical stretching in spectra represent the chemical nature of the scaffold (Sanjay et al., 2019). For both XRD and FTIR, a fine powder of sample is used where KBr is mixed with the sample for FTIR analysis.

3.4.3 Techniques for mechanical studies The mechanical strength, thermal stability, and tensile strength of the biomaterial need to be investigated for deciding its suitability in the biomedical field. The robustness of the fabricated scaffold is needed to be established as per ISO and FDA norms for ensuring its application in tissue engineering and wound healing bandages. In this line, tensile strength is the first parameter that needs to be investigated where the strength of various materials is estimated at a same condition to directly compare it with known materials. Tensile strength measuring instruments are available of different makes and models. Young’s modulus and elongation at break are two other parameters usually studied to completely define the mechanical strength of a fiber (Balaji and Nagarajan, 2017). The thermal stability of fiber is

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measured using thermogravimetric analysis (TGA). In TGA, the reduction in weight of fiber with respect to increasing temperature gives the estimation of thermal stability of polymer (Mishra et al., 2021b). The sample is heated in a nitrogen environment at a constantly increasing rate. The drug encapsulated fibers/scaffolds for wound healing activity, and swelling index is very important as it determines the watery exudate absorbing ability of scaffold. As fast as and as long as the scaffold keeps the wound dry, the healing become faster, and the chances of microbial colonization is least. The amount of water absorbed by fiber with time is measured and the time point at which it loses its structural integrity completely is critical for deciding its application in wound healing.

3.5

The anatomy of skin

The skin acts as a protective barrier against various external agents and regulates the temperature regulator of the body (Kanitakis, 2002). Skin has three layers, epidermis, dermis, and hypodermis, or subcutaneous layer (Cormack and Lamberty, 1994). The first layer, the epidermis is the waterproof outermost layer of the skin and is composed of several layers of differentiated keratinocytes, which enable the skin to control the moisture in the body (Natarajan et al., 2014). Approximately 90% of the epidermis is made up of keratinocytes and the rest 10% are melanocytes, Langerhans cells, and Merkel cells (Pasparakis et al., 2014). The four layers of the epidermis include the stratum basale (the deepest portion of the epidermis), stratum spinosum, stratum granulosum, stratum lucidum, and stratum corneum (the most superficial portion of the epidermis), and the fifth is stratum lucidum, the palms of the hands, and the soles of the feet. The second layer, dermis; is a connective tissue layer between the outermost layer epidermis and innermost hypodermis, which accounts for approximately 90% of the weight of the skin. It also forms the foundation of the organ system because of its substance and structure (Pappas, 2015). The dermis maintains the skin morphology and protects its deeper layers, assist in thermoregulation, and aid in sensation (Brown and Krishnamurthy, 2020). The dermis consists of ECM, collagen, elastic tissues, vascular endothelial cells, and fibroblasts, along with adipose glands, sweat glands, hair follicles, blood vessels, and nerve endings. The main dermal cells, fibroblasts, release collagen and elastin, which eventually provide elasticity and mechanical strength to the skin (Vig et al., 2017). The last layer, hypodermis, is the innermost subcutaneous tissue layer of the skin consisting of cells storing fat, blood vessels, nerves, and loose connective tissue. The fat of the hypodermis provides cushioning to the internal organs, muscle, and bones, and thus protects the body from injuries (Wong et al., 2016) (Fig. 3.6).

3.6

Wound healing and repair

Wound healing is a complex multiple-phase cascade of reactions, wherein the compromised cellular structures and tissue layers were supplanted by healthy cells and

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Figure 3.6 Histology of rat skin.

tissues (Dehkordi et al., 2019). The wound healing process can be divided into four sequential, but partly overlying phases; the hemostasis phase where clotting occurs to stop the bleeding, the inflammatory phase where damaged cells, pathogens, bacteria, and tissue debris were removed from the wound area, and the proliferation phase (cell division to regenerate the tissue, angiogenesis, and matrix deposition), and the remodeling phase where the arrangement of the matrix occurs in the newly generated tissue (Selimovi´c et al., 2015).

3.6.1 Initial phase—hemostasis After tissue injury, bleeding is the first response for which the body initiates the process of vasoconstriction and coagulation to stop the bleeding and leads to the deposition of clotted blood at the injury site, which eventually forms the scab leading to the process of hemostasis. So hemostasis is widely known as the physiological process that stops bleeding at the injury site while maintaining normal blood flow elsewhere in the body (Gale, 2011). This scab is also the body’s defensive mechanism against germs, infections, and debris at the wound site.

3.6.2 Second phase—inflammation The second phase, the inflammatory phase, initiates within the first 24 hours with hemostasis and chemotaxis (Wallace et al., 2017). Inflammation in the wound site can last up to 2 weeks in normal injuries with significantly prolonged time in chronic non-healing wounds (Schultz et al., 2011). Inflammation is characterized by

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edema, pain, and erythema. The inflammatory process is accelerated by the leukocytes (white blood cells) and the thrombocytes (platelets) by releasing cytokines as the inflammatory mediators to the wound site.

3.6.3 Third phase—proliferation The third phase, the proliferation phase, lasts up to 4 weeks, starts with the tissue granulation at the wound site followed by contraction of wound margin and finally, re-epithelialization. In the proliferation stage, several processes work in a synchronized manner like fibroplasia, matrix deposition, angiogenesis, and reepithelialization. From the hemostasis and inflammation phase several growth factors and cytokines are released. The fibroblasts migrate into the wound and tear down the fibrin clot, promote collagen formation, and help in the formation of collagen-based scar tissue, thus creating the new extracellular matrix by laying the foundation of matrix deposition (Bainbridge, 2013). The migration and replication of epithelial cells help in the formation of new blood vessels, thus stimulating the process of angiogenesis and re-epithelialization. Epidermal growth factors play important role in wound healing. Few fibroblasts differentiate themselves into myofibroblasts, which increase the mechanical stress within the wound site leading to wound contraction and effective wound healing.

3.6.4 Fourth phase—remodeling In the remodeling phase, the collagen is reorganized and reoriented; the wound undergoes more contraction by the specialized fibroblasts termed myofibroblasts. This phase can last up to a year. Up to 3 months, the wound achieves its maximum tensile strength, that is, approximately 80% of the re-epithelized skin.

3.7

Characteristics of ideal dressing and lacunae with present biomaterial dressings

Of the various characteristics of an ideal dressing, minimally, it should provide (1) protection to the wounded area, (2) should have anti-bacterial properties, (3) should be compatible to the shape and size of the wound, (4) the act of application, removal, and reapplication should be patient friendly, (5) the dressing should maintain optimum temperature and pH at the wound site, (6) it should be biodegradable, (7) it should not release any toxic by-products or irritants to the wound site, and (8) the dressing should enable the exchange of gases; last but not the least should be cost effective. Conventionally cotton gauze or non-woven combinations were extensively used as wound dressing materials because they are inexpensive, easy to use, and readily available. But as these dressings are dry, they cannot control the moisture level of

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the wound and can adhere to the wound that can post removal cause a lot of mechanical trauma and pain. The boom in the preparation of wound dressings using different biomaterials and techniques led to the rise in usage of various kinds of dressings like films, forms, hydrogels, and scaffolds. They are available in different physical states like sheets, powders, films, and paste. They are usually best for dry wounds as they can maintain a moist environment by rehydration. But these types of dressings are usually non-adherent and require secondary dressings to secure it. Of the many drawbacks of using synthetic biopolymers as a wound dressing material, one is that such type of dressing requires subsequent change and it can re-injure the wound upon removal, which further damages the wound and delays the healing.

3.8

Nanoparticle-based wound therapies

Nanoparticles (NPs) are small particles that can only be seen microscopically and range from 1 to 100 nanometers (nm) in size. NPs have resulted in driving tremendous strides in the field of industry, medicine, and pharmaceuticals. They have revolutionized the healthcare industry in both therapeutics and diagnosis approaches owing to their unique physicochemical properties (Yin and Zhong, 2020). NPs possess different physical and chemical properties from their parent materials. Das and Baker (2016) extensively studied nanoparticle-based wound therapies (Das and Baker, 2016). To mention a few; metal nanoparticles for effective wound healing in normal and diabetic mice, antibiotic-loaded nanoparticles for advanced therapeutics targeting multidrug-resistant microbes, nitric oxide-releasing nanoparticles, polymer nanoparticles, and lipid nanoparticles for accelerating the wound healing process (Archana et al., 2013; Blecher et al., 2012; Han et al., 2001; Mashaghi et al., 2013; Tian et al., 2007). Green synthesized nanoparticles use plant-based products that are cost effective and less toxic and their nanocomposites can be used for enhancing wound healing and antimicrobial activity (Liu et al., 2012).

Acknowledgments P.G. acknowledges financial support from the Department of Biotechnology (DBT), Government of India, under DBT-RA scheme.

Individual authors’ contributions Both the authors contributed equally in writing and editing.

Compliance with ethical standards NA.

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Conflict of interest Authors have no conflicts of interest.

Research involving human participants and animals Not applicable.

Informed consent Not applicable.

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Kinshuk Malik1, Mallika Pathak2, Lajpreet Kaur3, Piyush Verma3, Rahul Singhal4 and Himanshu Ojha3 1 Department of Chemistry, Indian Institute of Technology Kharagpur, Kharagpur, West Bengal, India, 2Department of Chemistry, Miranda House, University of Delhi, Delhi, India, 3CBRN Protection and Decontamination Research Group, Division of Radiological, Nuclear and Imaging Sciences, Institute of Nuclear Medicine and Allied Sciences, Delhi, India, 4Department of Chemistry, Shivaji College, University of Delhi, Delhi, India

4.1

Introduction

A drug molecule is carried to various target sites in the body. These target sites are macromolecules, most of which are proteins (also known as receptor proteins), enzymes, or nucleic acids composed of a long chain of nucleotides. The drug molecule forms ionic, covalent, as well as non-covalent interactions with the target site. For example, a positively charged group on the drug molecule will get attached to the negatively charged moiety on the target molecule. However, sometimes, the drug molecule while entering the body, faces resistance from reaching its target. Thus, the drug may reach some unintended site or eliminated from the body through excretion without any therapeutic effects. Hence, scientists are searching for ways to overcome these restrictions and achieving the therapeutic effect of the drug molecule (Richard et al., 2015). For many years, there has been tremendous research intended to discover novel methods of subcellular targeting therapeutic delivery. Some reviews on intracellular drug delivery such as disruption of the cell membrane, delivery of antibodies by protein transduction, intracellular drug delivery by electroporation, liposome, etc., have been reported (Gehl, 2003; Hong et al., 2016; Maity and Stepensky, 2015). These methods were useful in withholding the drug molecule for a longer time and also enhancing the circulation time in the body. A cell alone or a group of cells where the drug reaches are surrounded by an extracellular matrix (a soft gel-type tissue) that surrounds the enclosure to provide it structural support and allows them to join to form a tissue (Achilleas et al., 2016), which is another barrier for the molecule since it inhibits the latter from reaching the cell membrane. The drug can have different target sites in the cell, such as cytoplasm, mitochondria, or nucleus,

Fiber and Textile Engineering in Drug Delivery Systems. DOI: https://doi.org/10.1016/B978-0-323-96117-2.00003-0 © 2023 Elsevier Ltd. All rights reserved.

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reflecting their therapeutic efficacy (Patra et al., 2018). The molecules even face problems inside the cells. For example, protein in cytoplasm resists the molecule from traveling toward the mitochondria or nucleus. Also, the nucleus and mitochondrial membranes are not permeable to drug molecules (Li et al., 2018a,b).

4.1.1 Intracellular targeting Cellular activities require energy, which is obtained from mitochondria by oxidative phosphorylation. Mitochondria carries two membranes, outer and inner. The outer one has more number of pores, while the inner one has a large number of saturated phospholipids and proteins. It also regulates the tricarboxylic acid and urea cycle, oxidation of fatty acids, metabolism of amino acids, etc. Hence, abnormality in mitochondria can prove to be fatal and cause several fatal diseases like Wilson’s disease (caused by a malfunctioning in the metabolism of copper), cancer, Friedreich’s ataxia (caused by malfunctioning of mitochondria in transporting iron), etc. (Bhatti et al., 2017; Protasoni and Zeviani, 2021). In addition, it also acts in cell death after apoptosis. So, concisely, it can be said that targeting mitochondria for drug delivery is highly necessary to cure or control the disease related to it (Abate et al., 2020). Mitochondrial targeting helps in increasing the drug concentration up to a therapeutic level and prevents nonspecific distribution. There are two necessary steps in this process, first, entry of drug molecules in the cell, and second, selective targeting toward mitochondria. The first step is needed for drugs to reach mitochondria, while for some drugs, both actions are important. Non-fibrous-based drug delivery systems like vesicles and micelles are also used in drug delivery where the drug molecules are entrapped. At the same time, few scientists have worked on using redoxsensitive and pH-sensitive materials as drug carriers to obtain efficient therapeutic responses (Allemailem et al., 2021; Weissig et al., 2006). However, in the case of vesicles, microparticles, or nanoparticles, the drugs are released suddenly, thus offering little therapeutic efficacy. Various fibrous-based nanoformulations have been developed for intracellular target drug delivery because of their high surface area per unit volume, proper drug release profile, high mechanical properties, and ease of fabrication (Sharifi et al., 2016). Zeng et al. (2003) mentioned the use of electrospun fibers in drug delivery and reported that non-fibrous means of drug delivery were non-compatible for in situ or local chemotherapy in the treatment of cancers. They said that employing electrospun fibers for the same job revealed almost zero-order kinetics of therapeutic release (Zeng et al., 2003)

4.2

Methods for drug delivery system

Different methods of fiber fabrication for drug delivery have been described in Fig. 4.1.

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microfluidic fiber fabrica electrospinning mold based techniques self- assembly rotary spinning wet spinning

Figure 4.1 Different methods of fiber fabrication for drug delivery.

4.2.1 Microfluidic fiber fabrication In this approach, the preparation of fibers is carried out by running sheath and core liquid coaxially in a micro-channel. It is a simple, versatile, and continuous method that makes use of non-cytotoxic and biocompatible materials. High temperature, pressure, and electric currents are not required, which further enhances the biological comfort of the method. Also, it promotes high drug loading capacity for better effects on pathogens. The approach has been further classified based on the solidification approach. The first method is phase insertion, in which solvent in the core fluid is quickly eliminated by extraction or evaporation to solidify polymeric fiber immediately. The second approach is photo-polymerization, where pre-polymeric molecules are solidified by carrying out free radical reactions in the micro-channel, which leads to quick and facile production of solid fibers as well as helps maintain shape and size. In the chemical reaction approach, ions such as Ca2 1 or small molecules promote the bonding of pre-polymer molecules. Despite being a useful method of producing fibers, microfluidic fiber fabrication has low production rate due to the flow being in a laminar fashion. Also, there are chances of clogging in the micro-channel caused by unwanted shear force, which arises from differences in the characteristics of fluids or improper flow rate ratio. Stimuli-responsive polymers have been proven to be very useful. They are cheap and lead to high production rate, ease of fabrication, biocompatibility, and equal distribution of particles into fibers. Several changes like applying roller mechanism, better continuous manufacturing methods, and making fibers using tri-block copolymers are implemented in conventional microfluidic fiber production methods to promote better fiber functionality. In place of polydimethylsiloxane (PDMS), glass has also been used to make microfluidic chips as it shows better optical properties. The method involved the development of spherical vesicles from microfibers that act as intermediates in concluding drug vehicle formation. Kang and team (Kang et al., 2012) reported an

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approach based on PDMS for developing microfibers by using cylindrical channels made by developing a fine PDMS layer. The method was further expanded to develop rectangular molds. Considering that fiber dimensions play a significant role in drug delivery, Su et al. (2009) used a roller-assisted microfluidic system to make alginate microfibers. They were then passed through a single micro-channel. After that, they were cross-linked using calcium chloride, which was gathered using a roller, producing a microfiber. The roller decreased the diameter to the order of 1 μm and altered its shape. Controlling the release rate of the drug is also one of the concerns to be considered for which Marimuthu et al. (2010) prepared micro-fibrous scaffolds consisting of amphiphilic tri-block copolymers by micro-fluidics controlling its porosity. This protocol could be used in gene therapy and many other medicine delivery agents. PPDO-co-PCL-b-PEG-b-PPDO-co-PCL, an amphiphilic ABA copolymer, was used because of its ability to promote drug delivery. The process is cheap, robust, and can be altered for drug use (Bahadur et al., 2007).

4.2.2 Molding method This technique reported by Yoo and Ghosh (2014) can be used to produce solid and hollow microfibers to obtain morphological and mechanical characteristics. They used a hollow fiber microfiltration membrane to use as a mold, and a solution of calcium chloride was used as a crosslinker where calcium ions get radially diffused, forming a solid fiber. The method is useful in drug delivery because of reasonable control over strength and morphology and no requirement for high voltage and pressure or cytotoxic materials. However, micro-fiber production on a larger scale is difficult using this process. Also, fiber length is restricted to mold dimensions.

4.2.3 Self-assembly Fibers prepared by the self-assembly method show special characteristics, making them good choices in drug delivery. Drug molecules supported on fibers prepared by self-assembly method show stability and retention of characteristics in the intercellular compartments. This method benefits those drug molecules to bind with fibers by physical encapsulation that cannot form covalent bonds with the fibers, as well as drugs that can be loaded with higher capacity and efficiency by this method. The self-assembly method has drawbacks due to the size and non-capability of some molecules to exist in encapsulated form with fibers. Shah et al. (2010) reported that the synthesis of nanofibers by self-assembly method resulted in a higher survival rate. Self-assembly was capable of generating nanofibers that could create microenvironments, allowing vascular smooth muscle cell employment. In another study, heparin-interacting peptide amphiphiles were utilized to produce nanofibers, which revealed betterment in pancreatic islet engraftment, again proving the potential application of self-assembly in therapeutic delivery. In addition, Nagai et al. (2006) investigated that by regulating nanofiber-diffusant molecular interactions, the release profile of those drugs could be modified, which are united to

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hydrogel scaffold consisting of self-assembled peptides. Another proof of the versatility of this method is replacing dental caries having dental stem cells. The scaffolds showed themselves as a good biological alternative to inert materials for replacing damaged dental structures. Also, self-assembly-prepared electrospun peptide scaffolds hybridized with polyethylene oxide (PEO) were used as a usable biomaterial in bone tissue engineering.

4.2.4 Electrospinning Electrospinning is a flexible approach to developing continuous micro and nanoscale fibers in which electrostatic interactions are used to stretch fibers from viscoelastic polymer solutions/suspensions or melts. It is a globally accepted method to make continuous nonwoven nanofiber meshes (Xue et al., 2019). This process consists of three main components: (Fig. 4.2) 1. High supply of voltage 2. Spinneret 3. A fiber collector

The drug molecules are loaded on electrospun fibers by mixing them in the polymeric solution, followed by the application of an electric field. The high voltage is applied between the latter two, where the positive end is connected to a needle charging the polymeric solution and another to the reverse polymer collector. When the potential is applied, it beats the droplet surface tension, and the formation of nanofibers can take place by solvent evaporation after the needle tip is taken out. Electrospun nanofibers have emerged as promising materials due to their large surface area, more porosity (having a greater number of tiny pores), high drug loading

Figure 4.2 Schematic representation of electrospinning assembly. Source: Adapted with permission from Wsoo, M.A., Shahir, S., Bohari, S.P., Nayan, N.H., AbdRazak, S.I., 2020. A review on the properties of electrospun cellulose acetate and its application in drug delivery systems: A new perspective. Carbohydrate Research 491, 107978.

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capacity, biocompatibility, and flexibility to form different shapes, etc., enabling them to be efficient carriers for controlled therapeutic delivery systems. Other electrospinning methods are employed for various polymers and drugs, such as co-electro-spinning, adsorption/immobilization, coaxial/multi-axial electrospinning, and emulsion electrospinning. In addition the drug delivery system, electrospinning has its applications in food engineering (Liu et al., 2019).

4.2.5 Other methods Other methods of fiber production are rotary spinning and wet spinning, which are not used much in fiber fabrication for therapeutic delivery. In rotary spinning, the microfiber solution is rotated at high speed, which evaporates the solvent resulting in the production of microfibers. Here, rotary speed, size of wall orifices, and composition of polymeric solutions are maintained (Szabo´ et al., 2015). Hydroxypropyl cellulose fibers were prepared by Szabo et al. using rotary spinning. At this point, a drug’s chemical and morphological properties can be characterized. The orodispersible tablets consisting of the drug carvedilol were developed. In the wet-spinning process, a solution of biomaterial in deionized water is stirred at high values of angular velocities to make a solution of suitable viscosity. After that, this solution is forced into a coagulation bath, and fibers of use are obtained after drying. The process is simple; however, cells can be exposed to cytotoxic chemicals for a long time that are used during fiber production. The method was used to make PLGA [poly (lactic-co-glycolic acid)] and PLLA [poly(L-lactic acid)] microfibers loaded with lysozyme, insulin, and Bovine Serum Albumin (BSA) using cryogenic emulsion strategy. Anti-inflammatory medicine, dexamethasone, was also loaded in PLLA wet-spun fibers. The study said that smaller drug molecules are better for tissue regeneration and drug delivery applications because their delivery is sustained for the long term.

4.3

Biomaterials-based drug delivery

Biomaterials have been used in the pharmaceutical field for decades. Biomaterials have enhanced the delivery system and increased the efficacy of drugs, antibodies, vaccines, peptides, and enzymes (Varanko et al., 2020). Biomaterials aid therapeutic molecules in easily reaching the target site and remain there for a long time; hence, the amount of drug intake can be reduced, leading to reduced cost and toxicity. The chemical and physical properties of biomaterials have enhanced the benefits obtained by a drug. Every dosage form of drug, whether oral, injectable, nasal, or ocular, has become easy through biomaterials. All these methods have pros and cons; hence, a suitable structure of biomaterial must be figured out for drug delivery (Petersen and Narasimhan, 2008). Recent research has led to novel antibodies, protein, and nucleic acid-based drugs that need a new set of biomaterial-based vehicles for better biocompatibility

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(Gupta et al., 2021; Ye et al., 2021). This requires efforts from scientists, engineers, clinicians, and biologists. The development is based on several facts such as drug development may show its efficacy for an extended period, protection of drug molecules, non-toxicity after degradation inside the body, cost of the drug and materials used in manufacture, and more.

4.3.1 Biomaterials for small molecules Silicon rubber was the first biomaterial studied for controlled molecular release (Henstock et al., 2015). It was noted that lipophilic-hydrophobic dyes got diffused through silicon tubing walls. Later, silicone rubbers, because of biocompatibility and usefulness in medical science, were used in the controlled release of various therapeutics like antimalarial agents, steroids, histamine, anesthetics, etc. Implanted silicone rubber-based drugs tested in certain animals showed controlled drug release, followed by ALZA Corporation’s establishment in 1968. Another example is Norplant, which is now available under the name Jadelle and comprises silicone rubber tubes that release a drug, levonorgestrel, for up to 5 years when injected into forearm (Li et al., 2018a,b). Later, research in the biomaterials field contributed to developing osmotic pumps for delivering drugs orally in dogs, drug-loaded hydrogels for eyes, and more. Hydrogels are crosslinked networks of polymeric chains that are insoluble in water and have high water-absorbing capacity. They are highly used in therapeutic delivery systems and tissue engineering because of their adjustable properties. For example, polyethylene glycol (PEG) is very useful as a biocompatible material (Narayanaswamy and Torchilin, 2019).

4.3.2 Biomaterials for bigger molecules Just like small molecules are required for controlled release in the body, large molecules such as proteins and enzymes are required to be accumulated similarly to protect them from decomposition. Silicones and polymers, as discussed in the case of small molecules, were not compatible with proteins and other macromolecules in terms of permeability. Later, to make it freely permeable in water, the lyophilized protein was mixed with the solution of polymer in its solvent. The solvent was then evaporated to produce phase separation of proteins from polymers that formed interconnected pores in the polymer matrix. Proteins and other macromolecules in the polymer diffused from these pores on getting an aqueous environment. Proteins retained their biological properties within these polymers. Such progress has created a new era in the field of biomaterials-based drug delivery (Nair and Laurencin., 2005).

4.3.3 How biomaterials have evolved for drug delivery? The transdermal delivery system made use of biomaterials instead of pills and injections to prepare drug-carrying biodegradable microneedle patches that cause less pain while piercing the skin, have high drug permeability, and do not leave any

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sharp waste after use (Dhiman et al., 2011; Yang et al. 2021). Recently, sensitive biomaterials have been developed that respond according to environmental conditions like temperature, pH, enzymes, biological signals, etc., for drug accumulation (Zhuo et al., 2020). On the other hand, biomaterials responsive to light, ultraviolet radiations, and electric and magnetic fields were also developed (Alvarez-Lorenzo et al., 2009). For treating advanced prostate cancer, a hormone called leuprolide was introduced on poly(lactic-co-glycolic) acid (PLGA) microstructure, which is collectively known as Lupron Depot, and has also been considered suitable for endometriosis. PLGA and PGA produce glycolic acid and lactic acid on degradation, which are biocompatible, and hence, they are used in many microparticle depot systems (Ding and Zhu, 2018). Gliadel wafers are small-sized implantable biomaterials that consist of carmustine, a chemotherapeutic agent, and poly (carboxyphenoxy-propane/ sebacic acid), a polymer matrix used during brain post-tumor surgery. It showed patient survival chances for up to six months in some cases (Bregy et al., 2013).

4.3.4 RNA delivery Certain diseases are caused due to incorrect protein structures because of genetic issues. A large number of patients every year present diseases like diabetes, cancer, and cystic fibrosis caused by the abnormality of proteins. For such diseases, small molecule drugs were used to target defected cells that could inhibit defected proteins, but they were also showing non-specific accumulation and insolubility. It was observed that only 2% 5% of proteins could be affected by these drugs and the rest of the human genes were unaffected. Protein drugs have the advantage that they are specific to attack target sites but it is hard to transport exogenous proteins into the target cells. In addition, sometimes, the stability and size of protein drugs can limit their use. To counter this problem, RNAs have been used as a good alternatives to drug molecules, as they help in regulating protein concentrations within the target cells. There are a variety of RNAs that are used, for example, short interference RNA (siRNAs), messenger RNA (mRNA), microRNAs, and some hybrid RNAs that can bring changes in DNA to repair defective genes at the molecular level. Hence, RNAs have helped address the problems of responsive and inert genes that were being faced in the case of protein therapeutics (Crooke et al., 2018). Despite the usefulness of RNA therapeutics, there exist only a few. The reason behind that is barriers to RNA drug delivery. Also, there are chances of RNA degradation in the bloodstream because of their instability and the presence of circulating nucleases. When they go out of the bloodstream, they have to reach the extracellular matrix discussed above and from there toward the cytoplasm. However, they again face barriers in crossing the cell membrane and get trapped within the endosomal compartments. Hence, all such difficulties one by one have reduced the usefulness of RNA therapeutics. Hence, there comes the need for a proper drug delivery system for RNA-based therapeutic molecules.

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RNAs possess anionic property, hence using a positively charged drug vehicle can be considered compatible for creating an overall drug delivery system. This can be a good strategy for preventing their degradation and enhancing circulation halflife inside the body. Viruses have also been used so far to create RNA drug delivery systems but discussing that would be beyond the scope of this chapter. Herein, we focus on biomaterials-based RNA drug delivery systems. Cationic lipids have proved to be a good option for RNA-based drug delivery. They were initially employed for DNA delivery. They have polar amine moieties with non-polar hydrophobic tails. The polar amino moiety can either have a forever positive charge, such as ammonium salts, or they can be reversibly ionizable, such as ionizable amines. There are many cationic lipids available on a commercial scale that are used for RNA-based drug delivery, such as lipofectamine, TransIT, etc., and 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) are some other lipids used for carrying RNAs (Xin et al., 2017). There are several polymers like chitosan that have been proven efficient carriers for RNA. Chitosan is a polymeric unit of N-acetyl-D-glucosamine and Dglucosamine. Then we have poly-aspartamide (monomeric unit is aspartamide), poly-L-lysine (monomeric unit is Lysine), etc. These subunits can undergo protonation in an acidic environment, which serves as a key tool for RNA binding. Products made from polyethyleneimine (PEI), such as JetPEI, have been used for transporting nucleic acids but it is toxic and non-degradable for long-term use. To overcome this situation, poly(beta-amino esters) were developed by condensing small polyamine molecules with diacrylates. Polymer-based scaffold hydrogels were also discovered for nucleic acid delivery. For example, recently, it was found that for delivery of siRNA, a polyethyleneimine/poly(ethylene glycol) host-guest hydrogel can be used. Endogenous miRNA in cancer models can be modulated by RNA triple helix hydrogels. There are a lot of applications of biomaterials-based RNA delivery systems in bone regeneration and repair compiled in a review by Tsekoura et al. Hence, it can be concluded that such hybridization strategies can be used to increase potency, stability, and cellular uptake of RNA therapeutic. Scientists are still engaged in conducting further research in the same and in making oral RNA delivery systems (Iacob et al., 2021; Ragelle et al., 2013).

4.3.5 Polymers as responsive biomaterials There are several materials used in the biomedical field due to their versatile characteristics. For example, metals are used in making pacemakers, joint replacements, etc., and ceramics are used in dental restoration. Although they have high utilizations, they are not useful when a question is raised for “responsive” materials (material that can respond to the disturbances taking place in its surroundings like temperature, pH, enzymes, electric and magnetic field, etc.). It is because it is indeed difficult to alter their fundamental properties. Hence, polymers have overcome these shortcomings by proving themselves to be “responsive” materials. Their properties can be easily tuned as per circumstances, for instance, the molecular

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weight can be altered by adjusting the number of monomeric units, the melting point can be changed by incorporation of several endogenous monomers in the polymer mixture, and functional groups can also be transformed. Most importantly, a feature relevant to the scope of our chapter is their ability to bind with drug molecules (Fig. 4.3). In Table 4.1, we have discussed some polymers that respond to chemical, biological (inside the body), and physical (outside the body) stimuli (Badeau and DeForest, 2019; Wells et al., 2010). In addition, there are magnetically responsive polymers. Magnetic resonance imaging (MRI) can be used to pinpoint the location of drugs in the body that is loaded with a magnetically responsive polymeric material. Examples include the delivery of insulin, the release of dopamine from alginate, the use of chitosan NPs for plasmid delivery to the lungs, etc. There is a great advantage of magnetically responsive material as it can be easily removed from the body in case there is an unwanted immune response, which is a great addition to the use of magnetic-based drug-polymer design. There are sound-responsive polymeric materials that make use of megahertz-range ultrasound responsive polymer. To release the drug from the polymer, a two-layered emulsion was developed via a sonosensitive emulsion by use of a microfluidic device (Medeiros et al., 2011).

Figure 4.3 Different types of stimuli-responsive polymers in drug delivery.

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Table 4.1 Comprehensive data of sensitive polymers with its advantages (Crooke et al., 2018). S. no.

Type of sensitive polymers

Situation

Materials for use

Applications

1

Redox sensitive polymers

There is difference in redox potential across between the cells (or tissues) and its surroundings.

Show response to either one or to both oxidation and reduction; triggered release of proteins; gene delivery

2

pH responsive polymers

3

Hydrolysis responsive polymers

1. Gliadel wafer (discussed above)

Chemotherapy for malignant gliomas

4

Enzyme responsive polymers

4

Temperature responsive polymers

5

Light responsive polymers

Various components of the body have dissimilar pH values. Many disease cells have different pH than normal cells. Nucleophilic water can degrade electrophilic functional groups in polymers like esters and anhydrides. Certain enzyme concentrations are affected by diseased cells/species such as metalloproteins, phospholipases, etc. There is difference between body temperature (37 C) and ambient temperature (25 C). Hence, polymers that flow at RT and gel inside the body are used. A new invasive and painless approach. Technique provides an off-distance approach in which patient contact is not required.

1. Disulfides (responds to reduction) 2. Sulfur-based materials like block copolymers 3. Soronic acid/esters (oxidation responsive) 4. Diselenides 1. Nanocomposites 2. Diaminoketal cross links 3. PEG derivatives

Treatment of tumor and other anticancer drug delivery

Tumor imaging, doxorubicin delivery

poly(Nalkylacrylamides), Poloxamers, poly (Nvinylcaprolactams), cellulose, chitosan, and xyloglucan

Local drug delivery

Azobenzene modified amphiphilic block copolymer

A photo responsive azobenzene modified amphiphilic block copolymer was used to target melanoma cells by releasing therapeutics

(Continued)

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Table 4.1 (Continued) S. no.

Type of sensitive polymers

Situation

Materials for use

Applications

6

Electrically responsive polymers

Polypyrrole

7

Swelling and contraction

Human body is full of electric stimuli for example, neurons pass information through electric signals. Some polymers are made for contracting and swelling responding to external environment.

Controlled drug release and used with temperature responsive materials to form dual systems VEG was released to increase vascularization and stimulate lymphatic vessel growth

Alginate (extracted from seaweed)

There are several hybrid-type polymers developed that are responsive to more than one stimulus, such as magnetically responsive polymers combined with pH ones to make a dual responsive system. For example, the magnetic material can be made in such a way that it can be located using MRI whether it has been delivered in an acidic environment (such as the stomach). Another example of dual responsive polymers is electrically responsive combined with temperature-responsive polymers (Fu et al., 2021). pH-sensitive polymers are mainly utilized because of the presence of ionizable, weak basic or acidic groups that stick to a hydrophobic backbone, like polyelectrolytes that may be utilized in the development of drug delivery therapeutics to pH-sensitive fibrous materials (Cabane et al., 2012). The magnetic polymers, sound-responsive polymers, and pH-sensitive polymers are now being used in production of smart textile that could respond to various stimuli, thus providing multiple functionalities. At times, biomaterials may face certain challenges in drug delivery. For instance, extracellular vesicles are majorly known for possessing a challenge in lacking standardized, low cost, and efficient isolation methods. Moreover, there are obstacles in scalable production of EV and good loading processes are not easily available, which ruins the integrity of EV (Lu et al., 2017). On the other hand, challenges faced by polymeric micelles in si-RNA delivery include immune stimulation and off-target results. The use of poly-cations is necessary for micelle blocks but it may wrongly affect the safety of micelle. Multifunctional micelle is although efficient in carrying multiple drug loads but their structures are very complex, which may result in problems in reproducible synthesis and scale-up for production (Ghezzi et al., 2021). Even nanoparticles which have been considered a great tool in medical science have several issues in drug delivery, such as toxicity, high manufacturing costs, etc. (Pasut, 2019). Such shortcomings of nanoparticle-based drug delivery for tumor cells have been mentioned in a review by Wilhelm et al. (2016).

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4.4.1 Electrospun cellulose acetate in the therapeutic delivery system Here, we discuss an example of a biomaterial electrospun material, cellulose acetate (CA). CA fibers can be used in delivering a number of drugs like antimicrobials, anticancer, vitamins, and more (Fig. 4.4). Cellulose acetate is a biodegradable, biocompatible, and non-toxic substance. It is easily degraded by microorganisms using acetyl esterase and cellulase enzymes. However, its degradation is indeed a challenge in the human body because of the absence of these enzymes. Moreover, it is cheap, heat resistant, and less hygroscopic. This makes it the most important derivative of cellulose. It is prepared by first extracting cellulose from raw materials like sugarcane straw, newspaper, cotton, rice husk, etc., and then acetylating it with acetic acid and acetic anhydride using sulfuric acid as a catalyst (Wsoo et al., 2020) (Fig. 4.5). There are other methods reported as well. Its applications in biomedical science including therapeutic delivery systems, wound dressing, tissue engineering, and antibacterial applications will be discussed. It also has good electrical conductivity, so, it can be easily removed from a syringe needle using electrostatic forces and can be settled on the collector as nanofibers. These nanofibers can be reliably used in therapeutic delivery. Several shortcomings such as drug loading efficiency, low solubility, short circulation, drug half-life, etc. have been overcome by drug-loaded electrospun (Torres-Martı´nez et al., 2018). Non-steroidal anti-inflammatory (NSAIDs) and antioxidant drugs are given to reduce the inflammation and swelling problems. However, they may lead to certain problems such as gastrointestinal problems. They also have poor solubility in water and hence require good strategic methods for their delivery. One of the common examples of NSAIDs used to reduce pain is ibuprofen. Other examples include

Figure 4.4 Application of cellulose acetate nanofibers based drug delivery.

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Figure 4.5 Process involved in the conversion of cellulose to cellulose acetate.

naproxen, sulindac, indomethacin, etc. These drugs show high effectiveness when loaded upon electrospun CA nanofibers (Tungprapa et al., 2007). Ketoprofen was incorporated into CA nanofibers because when taken orally for a longer period it causes ulcers, holes, or bleeding in the stomach or intestine (Qu et al., 2013; Yu et al., 2013). Benzocaine (a pain killer) and a pH indicator dye, bromocrezole green upon CA nanofibers, were prepared by needleless electrospinning method. This formula was employed as a new multifunctional nanofibrous material with the drug fully trapped in the nanofiber with the lowest fiber diameter. Nanofibers also have high adsorption capacity despite hydrophobic behavior (Kureˇciˇc et al., 2018). Modified CA was used in the transportation of capsaicin and sodium diclofenac, which are anti-inflammatory drugs. Before the drugs were loaded, azidation of CA was done and after loading, it was cross-linked with propargylated maltose. These processes helped in the controlled release of drug molecules from CA. Besides sesamol, a natural organic compound was delivered using nanofiber membranes consisting of zein and CA. This hybrid drug was shown to accelerate the wound healing process in diabetic mice. Cisplatin, a very famous organometallic compound and a drug used in the treatment of cancer, was loaded on PEO and CA-based fibers separately by coaxial electrospinning method (Absar et al., 2015). Electrospun CA nanofibers were also employed to deliver silymarin because its main component silibinin is a potent antioxidant and has low solubility in water. It is separated from milk thistle and utilized in treating chronic liver illness. Another similar example is gallic acid, which was limited due to its poor solubility in water, hence, fabrication with electrospun CA nanofibers solved this problem. In a similar fashion, they were also used in wound dressings. A non-steroidal anti-inflammatory drug, rosmarinic acid (RoA) when homogeneously distributed into CA nanofiber mats exhibited high drug loading tendency, prolonged release of drug in the body, and low burst release. Nanofibers carrying higher amounts of RoA have better antioxidant and anti-inflammatory properties than the ones with lower amounts of RoA. It also shows biocompatibility properties.

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Curcumin is a compound used as an antitumor, anti-inflammatory, and antioxidant agent. However, it shows poor solubility, instability, sensitivity, and low concentration in plasma. When loaded upon electrospun CA fibers showed non-toxicity to humans (Fereydouni et al., 2019). Herbal extracts such as 6-gingerol, the most important component present in ginger having several pharmacological uses like antioxidant, anticancer, and antiinflammatory benefits, were also loaded on CA nanofibers. Alkannin and shikonin are other examples in this category that have wound healing properties. Antibiotic agents have been successfully used by loading upon nanofibers to destroy or prevent the growth of bacteria. For example, N-halamines lead to cell inhibition or inactivation by getting a response from halogen exchange. BisNChloro-2,2,6,6-tetramethyl-4-piperidyl sebacate (CI-BTMP) is one example of Nhalamines. When tetracycline hydrochloride was loaded upon CA fibers, it showed an effective antibiotic effect against S. aureus and E. coli. For the same species of bacteria, rutin, a bioflavonoid substance found in vegetables and fruits was used by enclosing it into CA/poly (ethylene oxide) fiber. As observed in the case of anticancer agents, herbal compounds can be used in the current class of drugs as well. Examples include essential oils extracted from lemongrass, cinnamon, rosemary, peppermint, etc. that are combined with CA electrospun fibers. They showed immense antibacterial activity, non-cytotoxicity, and high cell compatibility. Propolis-CA/PCL mats were revealed to be a useful antibacterial tool against gram-positive and gram-negative bacteria. Silver nanoparticles have a large number of applications against microorganisms and, hence, they have been composed with CA through basic hydrolysis. An illustration is that of AgNPs loaded on cellulose/TiO2 nanofibers (produced via deacetylation of CA/TiO2 nanofibers) employed as an antibacterial agent in future bone tissue regeneration. They also showed antibacterial effects against S. aureus and E. coli. Using graphene oxide in making a similar hybrid structure by electrospinning showed antimicrobial activity against cereus and subtilis bacteria. Silver sulfadiazine functionalized upon the CA nanofibers surface and acted as an antibacterial in wound dressing against E. coli (Alven et al., 2021). More examples of antimicrobial agents have been summed up in Table 4.2. Vitamin A and vitamin E were also combined with CA nanofibers. Results revealed encapsulation capability of vitamin E to be greater than that of vitamin A and their release rates in the body gradually increased. In addition, melatonin, a hormone that controls the sleep-wake cycle is also used as a treatment for sleeping issues. So, polyvinylpyrrolidone and CA nanofibers were used to load melatonin to use it for the modified release of hormones and maintain sleep problems.

4.4.1.1 Alternative to cellulose acetate Cellulose acetate is an efficient vehicle for a therapeutic molecule due to its bioavailability and biocompatible nature, but faces challenges such as complete breakdown (of cellulose) in the human body due to the absence of cellulase. Hence, a new fiber, amylose acetate polymer, has been introduced. It is made by making

Table 4.2 Summarized data of drug delivery systems as per their applications. S. no.

Category of drugs

Name of the drug

Percent of cellulose acetate

Administration route

Description and applications of drug

References

1

Anti-inflammatory

Ketoprofen Ibuprofen Sulindac Rosmarinic acid

11 12 15 21 12

NA NA Transdermal drug delivery Transdermal delivery of NSAIDs

Yu et al. (2012) Gong et al. (2019) Chung and Kwak (2019) Vatankhah (2018)

2.

Anticancer

Cisplatin

7.5

NA

Silymarin

17

Topical or transdermal delivery

NSAIDs used as pain killer A pain killer NSAIDs used as pain killer A polyphenolic compound having strong antioxidant and antiinflammatory properties A chemotherapeutic medicine used for treating a wide range of cancers Isolated from mil thistle and used for chronic liver illness.

Gallic acid

17

Topical or transdermal delivery

Gallic acid

15

Curcumin

17

Topical or/and transdermal delivery Topical or transdermal delivery

6-gingerol

12

Asiaticoside

17

Alkannin, shikonin

20

3

Antioxidants

Topical/transdermal drug carrier Topical or transdermal delivery Topical for wound healing purpose

Natural tri-phenolic compound with excellent antioxidant property used in pharmaceuticals and other industries

Hydrophobic polyphenol compound used as antitumor, antioxidant and anti-inflammatory substance. Most potent component of ginger

Natural product that comprises of napthoquinone form. They are derived from alkannatinctoria and lithospermumerythrorhizon. Hybrid was used in wound healing

Absar et al. (2015)

Phiriyawirut and Phaechamud, (2012a, b) Phiriyawirut and Phaechamud (2012a, b) Wutticharoenmongkol et al. (2019) Suwantong et al. (2007)

Chantarodsakun et al. (2014) Suwantong et al. (2008) Kontogiannopoulos et al.(2011)

4

Antimicrobial

Amoxicillin

8

Local drug delivery

Antibiotic drug

Castillo-Ortega et al. (2012) Gouda et al. (2014)

Tetracycline hydrochloride Chlorhexidine

17

Local drug delivery

Antibiotic drug

3

Used for fabric protection

Chen et al.(2008)

15

Topical

High antibacterial effect against gram negative (like E. coli) and gram positive (like S. epidermidis) bacteria. Have intense antimicrobial activity and antibiofilm formation against bacteria and fungi. Used in wound healing

essential oils (lemongrass, cinnamon and peppermint) obtained from plants oregano and rosemary oils Silver nanoparticles

Liakos et al. (2015)

15

Topical

Used in wound healing

Liakos et al. (2017)

19

Topical

Xu et al.(2016)

Silver sulphadiazine AgNPs/TiO2

24 17

Topical Topical

AgNPs/TiO2 NPs PhyllanthusEmblica Linn (PE)- extract

12 17

Transdermal delivery

Polyhexamethylenebiguanide (PHMB) Thymol (THY)

20

topical

5.75,15

Topical

Effect micro-organisms growth inhibitors. Used in wound dressing as well. Antibacterial wound dressing Antimicrobial tendency against gram positive and gram-negative bacteria. future uses in tissue engineering Derived from fruits. Applied as antioxidant and antimicrobial. Enhances the anticancer effect of cisplatin and mitomycin C by reducing their genotoxicity against healthy cells. Wound healing therapy and useful in long-term antimicrobial effect. Antibiotic activity against S. aureus and E. coli. Their porous form revealed better antibacterial properties and cytocompatibility. Used in wound dressing

Khan et al.(2019) Jatoi et al.(2019)

Ashraf et al. (2020) Thitiwongsawet et al. (2016)

(Liu et al. (2012) Chen et al. (2020)

(Continued)

Table 4.2 (Continued) S. no.

5

Category of drugs

Vitamins, amino acids and hormones

Name of the drug

Percent of cellulose acetate

Administration route

Description and applications of drug

References

Bromelain

15

Topical

de MeloBrites et al. (2020)

Carbon nanotubes/Ag nanocomposite

17

Topical

Propolis

10

Topical

Capsaicin and sodium diclofenac Vitamin A and E

12

Topical

An enzyme found in pineapple, utilized as antibiotic, anticancer anti-edematous, fibrinolytic, antithrombotic, and anticoagulant. Also used to eliminate dead cells from burned skin, and given orally to decrease swelling and inflammation. Used in wound dressing a swell Alternatives to AgNPs alone (because prolonged use of excess Ag can be harmful). It minimizes or does not let direct contact of Ag with human cells Honeybee-produced plants and resinous mixture of buds having wound dressing applications. Used in skin wound dressing

17

Transdermal delivery

Lipid soluble substances.

Roˇsic et al. (2011)

Vitamin B2 and C L-tryptophan

18 13

Oral delivery Transdermal delivery devices

Melatonin

10

Orally as tablet

An essential amino acid soluble in water Hormone that regulates sleep-wake cycle.

Jatoi et al. (2020)

Khoshnevisan et al. (2019) Nada et al. (2019)

Agarwal et al. (2016) Ghorani et al. (2018) Vlachou et al. (2019)

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starch solution in acetic anhydride and then adding aqueous sodium hydroxide and at last stopping the reaction by adding cold water. It is similar to cellulose acetate in some aspects such as structure and degree of substitution whereas the difference lies in the glycoside bond among the glycosyl units. In addition, its semi-synthetic property can allow absorption and digestion by the human body without any toxicity. It can be decomposed into amylose and acetyl groups using esterase enzymes. Starch acetate was also introduced which has greater tensile strength. They were also used in the delivery system such as for diclofenac (Wsoo et al., 2020).

4.4.2 Silk in drug delivery system Silk is a natural biopolymer that exhibits unique drug delivery properties as it is endowed with desirable traits such as biocompatibility, biodegradability, exhibit robust mechanical strength, and easy processability that offers diverse biomedical uses. Based on the requirement for various drug delivery systems, they can be designed into different forms such as hydrogels, nanoparticles, films, microspheres, etc. (Yucel et al., 2014) (Fig. 4.6). A common way of drug delivery system using silk fibroin (SF) is by directly mixing or dissolving them in a solution of silk fibroin. These methods were advised for the preparation of drug incorporated SF hydrogels, microparticles, scaffolds, and films making sure there comes no negative effect of the method on the biological potency and integrity of the drug. Drugs can be loaded after the fabrication process as well by

Hydrogels

Nanoparcles

Silk Fibroin as a carrier

Microcapsules

Films

Figure 4.6 Applications of silk as a different drug delivery system.

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adsorption, or by covalent coupling. SF and drugs were seen to be bound by hydrophobic interactions as a result of the presence of hydrophobic blocks of heavy chain silk fibroin and corresponding moieties in drug molecules (Wenk et al., 2011).

4.4.2.1 Gene delivery Gene delivery has been used in the treatment of several genetically gained diseases, such as AIDS, cancer, cardiovascular diseases, etc. The genetic material is delivered to some particular cells to supply a gene that is similar to the infected gene that was responsible for the disease. Silk-based polymers are utilized in delivering plasmid DNA and adenovirus because of their capability to be functionalized, which is a benefit over other delivery systems such as synthetic polymers and liposomes. Genetic engineering techniques were applied to create block copolymers of poly (L-lysine) domains and spider silk consensus repeats for plasmid DNA block copolymer delivery. The gene vehicles are functionalized by using cell membrane destabilizing and cell-penetrating peptides or bioengineered as complexes or by making silk elastin-like polymers. This strategyis useful for adenoviral gene therapy in treating cancer since adenovirus-loaded silk elastin-like protein polymer hydrogels exhibited reduction in tumor as compared to injecting adenovirus in saline solution in a mouse model. In addition to efficacy, these polymers have revealed many advantages over other polymer derivatives such as aqueous compatibility for adenoviral viability. These polymers can be used to make thermosensitive hydrogels as well, which remain hydrogels at body temperature and liquid at room temperature to form an injectable system (Amreddy et al., 2018; Husseini and Pitt, 2008).

4.4.2.2 Biological therapeutic delivery The applications of biological therapeutic delivery based on silk include tissue engineering, wound healing, etc. The loading process is done either by adsorption or more preferably directly mixing with the silk fibroin solution for sustained drug delivery to maintain the medicine concentration at the action site. There are many examples of the latter approach, such as BMP-loaded silk microspheres, heparin-loaded layer-by-layer silk film coatings, dextran-, lysozyme-, or horseradish peroxidase (HRP)-loaded silk films, EGF-loaded silk films or electrospun mats and neurotrophin-loaded silk films, tubes or hydrogels or azoalbumin-loaded. The method also made use of 3D scaffolds and silk microspheres to deliver insulin-like growth factor (IGF-1) (Fig. 4.7). As observed in the case of small molecule drug delivery, silk fibroin composites have been used here as well. They can either be all silk complexes of various formats like GDNF-loaded microspheres or blends of SF with other polymers like calcium phosphate/silk fibroin/BMP-2 cement that can be injected for spinal fusion or silk-hyaluronan-based composite hydrogels. Further composite materials include silk fibroin/gelatin multi-layer films for a proper release of fluorescein isothiocyanate-labeled insulin (Pandey et al., 2020). FITC-insulin, FTIC-BSA, and silk fibroin/polyacrylamide hydrogels for FITCinulin delivery. The polymer composite strategy can be applied to control the

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Figure 4.7 Types of silk-based formulations in drug delivery system.

materialistic properties of silk-like bioactivity and biocompatibility of the structure if artificial polymers have been utilized. More complicated drug systems were prepared by a combination of synthetic and biopolymers. For instance, 3D porous silk scaffolds embedded with ITC-insulin- and BSA-supported calcium alginate or calcium alginate/SF-blended beads or IGF-1-supported PLGA microspheres.

4.4.2.3 Films/coatings Release rates of drugs are controlled by altering the amount and thickness of coating films, the crystallinity of silk, film swelling, and solubility which establishes an obstacle to diffusion. One method is to quote small molecule drug pellets by dipping them in silk fibroin solution and then drying and treating them to get crystalline form. This approach was used for adenosine and theophylline. An anticancer agent emodin showed greater retention time and efficacy when introduced with silk fibroin, an example of a reservoir-type approach. Small molecule drugs can also be homogeneously used straightforwardly into silk nanolayers or controlled drug release. Rhodamine was coated with multi silk capping layers with increased silk II, beta-sheet crystal content. Further, paclitaxel (antiproliferative) and clopidogrel (antithrombotic) were incorporated into layers of silk coatings for vascular stents. The studies showed their sustained release over 28 days. Alkali heat degumming can also be done at the time of silk fibroin purification for extra alteration of silk

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fibroin diffusive barrier. It was believed that fibroin having less than average molecular mass because of prolonged alkali heat degumming resulted in two more permeable fibroin film forms which lead to more rapid small molecule drug diffusion. The same strategies may be implemented in other silk-based techniques such as microspheres, hydrogels, or combination methods for the release of small molecules (Sun et al., 2021).

4.4.2.4 Microcapsules Silk microcapsules have proved to be excellent transporters of drugs because of their good elasticity, toughness, etc. The arrangement of multiple-layer shells is determined by supramolecular chemistry that considers various intermolecular interactions like hydrogen bonds, covalent bonds, electrostatic interactions, etc., and hence their mechanical and chemical properties can be altered by changing the shell structure. The drug molecules are confined into these microcapsules by two methods called post-loading (here, drug molecules are loaded in prefabricated microcapsules) and pre-loading (here, silica which is a porous material is used to trap the drug molecules. They are preloaded on porous silica template and get captured inside the multilayered shell) (Jastrzebska et al., 2015). Microneedles are used in transdermal drug delivery. They are pain-free and safe alternatives to hypodermic needles for skin drug delivery. Using the lithography technique, Tsioris et al., used aluminum microneedles to make microneedle negative mold based on PDMS. Recently, SF microneedles were made for the prolonged release of insulin (up to 60 hours) to give painless and effective therapy to patients suffering from diabetes (DeBari et al., 2021).

4.4.2.5 Nanoparticles Silk nanoparticles are made from silk fibroins. They are spherical, stable, and possess a negative charge. They can be produced by different methods like emulsification, organic solvent precipitation, phase separation, salting out, etc. There is a lot more research required in this field since the preparation methods are complicated and there is the involvement of organic solvents. Several modifications are done to silk nanoparticles to improve particle stability and increase blood circulation time. For instance, modifying the surface with PEG improves nanoparticles stability by reducing aggregation of particles and enhancing pH-independent doxorubicin release. Surface modifications can also be done by charge-charge interactions (Crivelli et al., 2018; Marı´n et al., 2020).

4.4.2.6 Nanofiber hydrogels Hydrogels are stable cross-linked polymers. Drug delivery using silk hydrogels is sustained and pH-responsive. Silk fibroin hydrogels are used for insulin-dependent type 1 diabetes. Delivery of doxorubicin, a cytotoxic drug used in treating breast cancer has been achieved by silk-based injectable hydrogels. Silk is also used to make thermosensitive hydrogels. The latter is a liquid at room temperature and exists as a hydrogel

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inside the body. They’ve been utilized to deliver anti-vascular endothelial growth factor as well, which is used in delivery through the eyes. Desferrioxamine-silk nanofiber hydrogels were prepared, which showed faster development of blood vessels around the wound as compared to free Desferrioxamine hence proving better healing by use of silk nanofiber hydrogels. These hydrogels were also used in tumor photothermal treatment and luminescence imaging. Hydrogels hybrid with nanoparticles revealed excellent biocompatible properties while acting with cancer cells through photothermal effect in vitro. Ciprofloxacin electrospun silk fibroin/β-cyclodextrin citrate nanofibers were also made for the controlled release of drugs. There are some miscellaneous uses of silk-like, to sustain the dental care quality. It can also be used to fix or replace the lost or infected part of the tooth. It is used for regenerating dental tissue and preparing suture materials. Hydroxyapatite is a material that is important for dentin and tooth enamel and hence, by mixing hydroxyapatite NPs with silk solutions, silk hydroxyapatite composites were prepared. DMP-1 and spider silk mixture have been employed to make biominerals that have vast applications in tissue engineering. Silver nanoparticles containing silk nanocomposites have revealed antibacterial effects. It has also proved its uses in treating dysphonia, unit-acquired pressure ulcers, cellulose wound dressing, etc. (Zhao et al., 2021; Zheng and Zuo, 2020).

4.5

Conclusion

Biomaterials and biomaterial-based fibers have proved to be efficient drug carriers and have revealed their applications in every sort of biomedical application like tissue engineering, wound healing, or oral intake of medicine because of their biodegradable and biocompatible nature. They have been employed in carrying every category of the drug-like antibacterial, anti-inflammatory, antiviral, gene delivery, etc. They have enhanced the circulation time of drugs, their solubility, and their efficacy; reduced their toxicity, and hence have proven themselves to be safe for human use when compared with synthetic drug carriers. They have now gained immense popularity among researchers and doctors all over the world. However, some of them faced degradation challenges like electrospun cellulose acetate as discussed due to the absence of degradation enzymes in the body. Silk as a biomaterial-based fiber has proved itself to be an efficient member of the list of drug carriers. Silk properties can be altered with functional groups that may modify its properties presenting it to be a flexible vehicle for delivering proteins, genes, and small and large drug molecules.

Acknowledgments Mr. Kinshuk Malik would like to thank Prof. N. D. Pradeep Singh for his support and guidance. Dr. Mallika Pathak is thankful to Principal, Miranda house for her support. Mr. Piyush

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Verma, Miss Lajpreet Kaur, and Dr. Himanshu Ojha are thankful to Director INMAS. Miss Lajpreet Kaur is thankful to CSIR for providing her fellowship.

Author contributions Kinshuk Malik: Writing original draft and editing. Mallika Pathak: Supervision, writing original draft and editing. Lajpreet Kaur: Review and editing. Piyush Verma: Review and editing. Rahul Singhal: Writing original draft and editing. Himanshu Ojha: Supervision and editing.

Compliance with ethical standard Not applicable.

Conflict of interest The authors declare no conflict of interest.

Research involving human participants and animals Not applicable.

Informed consent Not applicable.

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Biomedical applications of carbon nanotubes

5

B. Vidya1, Asha P. Johnson1, G. Hrishikesh1, S.L. Jyothi1, S. Hemanth Kumar1, K. Pramod2 and H.V. Gangadharappa1 1 Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysuru, Karnataka, India, 2College of Pharmaceutical Sciences, Govt. Medical College, Kozhikode, Kerala, India

5.1

Introduction

With the development of nanocarriers for various biological applications, nanotechnology has long attracted the scientific community’s interest (Prajapati et al., 2022). One of the most adaptable elements is carbon. Carbon nanotubes (CNTs) have diverse qualities based on the arrangement of carbon atoms. Since their discovery in 1991 (Roldo and Fatouros, 2013), CNTs have received more attention than spherical nanoparticles and other carbon-based nanocarriers because of their unique qualities, such cargo loading, intracellular bioavailability, as well as a very high aspect ratio (Kenchegowda et al., 2022). CNTs are a novel type of nanomaterial with distinct chemical, physical, and biological characteristics (Saliev, 2019). CNTs are distinguished from other nanocarriers by their unique carbon atom arrangement, ˚ with a sp2 hybridization, has a cylindrical structure with a C C spacing of 1.42 A ˚ 3.4 A interlayer structure (Prajapati et al., 2022). A graphite layer is rolled into a cylinder to create CNT. The layout of graphene cylinders varies between singlewalled carbon nanotubes (SWCNT) and multi-walled carbon nanotubes (MWCNT) (Raphey et al., 2019). SWCNTs have a smaller diameter of 0.5 to 1.5 nm, while MWCNTs have a bigger diameter of up to 100 nm. The length-to-diameter ratio of CNTs is up to 28 million to one since their diameter is in the nanometer range but their length can reach several micrometers. SWCNTs’ density might be as low as 0.6 g/cm3 due to their hollow cylindrical form (Meredith et al., 2013). Low solubility, toxicity, and biopersistance have all been problems for biomedical researchers working with CNTs. They have a high hydrophobicity, which means they are water-repellent. CNTs have a low solubility and a high tendency to cluster, limiting their use in any area. There has been a lot of study done with the goal of lowering this barrier to CNT application, particularly in physiological contexts. In the past decade, successful covalent and noncovalent surface modification techniques for obtaining homogenous dispersions of CNTs have been discovered; Kim et al. have evaluated these strategies in depth (Roldo and Fatouros, 2013). Unlike many chemical agents, CNTs don’t necessarily have a well-defined structure or purity. Depending on the preparation, purification, and functionalization process utilized to Fiber and Textile Engineering in Drug Delivery Systems. DOI: https://doi.org/10.1016/B978-0-323-96117-2.00015-7 © 2023 Elsevier Ltd. All rights reserved.

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synthesis CNTs, their size, shape, structure, and purity might vary greatly. Researchers found that the toxicity of CNTs varies based on the production method, shape, concentration, aspect ratio, functional group(s), composition, extent of oxidation, surface-to-volume ratio, and dosage. Furthermore, CNTs are extremely hydrophobic, which decreases their biocompatibility significantly. They can damage DNA as well as the cell membrane. Oxidative stress, modification of mitochondrial activity, protein synthesis, and changed metabolic processes in cells are all potential sources of damage (Alshehri et al., 2016). Surface functionalization has been used in a variety of ways to minimize the intrinsic toxicity of CNTs (Roldo and Fatouros, 2013). This review focuses on biosensing, drug transport, bio-mapping, imaging, tissue engineering, thermal therapy, dentistry, regenerative medicine, and a few additional applications of carbon nanotubes in the biomedical sector. Limitations such as their possible toxicity and characteristics, as well as their types, characterization, synthesis, and promises of biodegradability and modification, are all discussed (Me´nard-Moyon, 2018).

5.2

Properties of carbon nanotubes

5.2.1 Physical properties The hexagonal lattice of graphene is two-dimensional, and the carbon atoms are organized in a flat monolayer. Further, either single or multiple folding of graphene sheets into cylindrical shapes is possible, which helps in the development of SWCNTs and MWCNTs and carbon nanofibers (CNF) (Wang et al., 2011). SWCNTs are carbon layers that are mono-cylindrical in shape with a variety of diameters, 0.4 2.0 nm, that are structured in chiral, armchair, and zigzag patterns. Only two tubes, comparable in size to SWCNTs, make up double-walled CNTs (DWCNTs) (Lamberti et al., 2015) (Table 5.1).

5.2.2 Electrical properties CNTs loaded with metals such as Si (Wang et al., 2011) Sn, and Pd, as well as transition metal oxides (Li et al., 2017) and sulfides have better electrochemical characteristics (Poudel and Li, 2018). It was shown that abnormalities such as structural faults created during synthesis processes or physical flaws, such as those induced by intense mechanical stresses, might alter electron transport in CNTs. Semiconducting nanotubes, on the converse, have been discovered to be the most sensitive. The presence of doping chemicals has huge impact on the electrical characteristics of CNTs. Dopants can be chemically incorporated in the CNT framework or interact physically with the CNT electrical structure (Janas et al., 2017). In recent years, more production of CNTs at a fair price has been reached especially with the rise of numerous low-cost synthetic approaches for CNTs, such as laser ablation, arc discharge, and solvothermal processing, among others. Theoretical and experimental data demonstrate that CNTs have excellent electrical characteristics, with

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Table 5.1 Basic difference between single-walled carbon nanotubes (SWCNTs) and multiwalled carbon nanotubes (MWCNTs). Properties

SWCNTs

MWCNTs

References

Appearance

G

Black fluffy powder Glittering metallic look It looks like it’s made up of bundles of tubes Cylinder-shaped single layer of graphene

Black powder that is mostly granular and airy

Beg et al. (2011)

Aggregated bundles of tubes

Beg et al. (2011)

Cylinder-shaped multi-layer of graphene

Ganesh (2013)

Lower thermal conductivity (MWNT5 600 6 100 W m21 K21) than theoretically expected Multiple graphene rolled layers (concentric tubes) Lower electrical conductivity

Hone et al. (1999)

Higher mechanical strength

Maeng et al. (2007)

G

View in electron microscopy Structural differences/ Structure and symmetry Thermal properties

Number of layers Electronic properties Mechanical Properties

High thermal conductivity (from 350K to 8K) One layer of graphene Higher electrical conductivity Lower mechanical strength

Polsen et al. (2015) Maeng et al. (2007)

a carrying capacity 1000 times that of copper cable. As a result, CNTs are likely to have a significant impact as additives in improving the electrical characteristics of composite materials (Liu and Gao, 2005; Nakano et al., 2003).

5.2.3 Mechanical properties CNTs (both MWCNTs and SWCNTs) have been found to have outstanding mechanical properties (Saxena and Srivastava, 2020), since the graphene sheet with C C chemical link is probably the most powerful chemical bond in a known extensive system. Because CNTs are nothing more than flawlessly rolled-up graphene layers, it has been believed since their discovery that the properties of these nanostructures have excellent mechanical properties, and in nanotechnology, quantifying these characteristics has been a topic of discussion. Most of the potential nanotube applications, such as lubrication or composite reinforcement, are related to their mechanical characteristics in some manner, as outcome a lot of theoretical and experimental research has gone into describing them (Lebedeva et al., 2020).

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The mechanical properties of these nanoscale structures, however, can be determined directly. The application of macroscopic notions, like elastic moduli, to nanoscopic particles’ mechanical properties, instance nanotubes, must be done with cautiously, and specific rules must be followed. Young’s modulus is an example of such a concept (Yu, 2004). CNTs have a Young’s modulus of .1 Tera Pascal, diamond-like rigidity, and have a stiffness of over 200 GPa (Yamashita et al., 2004).

5.2.4 Thermal properties Thermoelectricity and thermal expansion of CNTs are both fundamentally intriguing and technologically significant characteristics. Pyrolytic graphite has a very high inplane thermal conductivity, second only to type 11-a diamond, which has the maximum heat conductivity of any material documented. Because calculating thermal conductivity directly is difficult, experimental investigations on composites with nanotubes aligned in the matrix could be a first step toward understanding carbon nanotube thermal conductivity (Ruoff and Lorents, 1995). The influence of CNTs on the heat conductivity of glass fiber/composites of polymers was researched by Wang and Qiu. They discovered that adding 3 wt.% MWCNTs to a glass fiber/polymer composite increases thermal conductivity by 1.5 times as much as the original. With a weight percentage of CNT of 1.0 wt., some SWCNT/epoxy composites showed a 125% or higher increase in thermal conductivity at air temperature, while others, such as SWCNT, MWCNT, and functionalized CNTs, showed very minor gains in heat conductivity as CNT weight fraction increased (Gardea and Lagoudas, 2014).

5.2.5 Optical properties Spectroscopy via advanced lasers (time-resolved spectroscopy and single-nanotube spectroscopy) is used to reveal novel optical characteristics of CNTs. The optically produced electron-hole pair creates a highly bonded state generating excitation, similar to CNTs having a hydrogen-like state, due to the strengthened Coulomb interaction. Here, the unique properties of excitons in CNTs, for instance singlet-dark states and triplet states, have a strong impact on the optical properties. CNTs’ optical properties are strongly intertwined to their electrical and structural qualities, in addition they are entirely controlled by a single parameter, the chiral vector, which defines the structure of the carbon-atom honeycomb in reference to the CNT axis. Optical ellipsometry, electron energy loss spectroscopy, reflectivity studies, and absorption tests have all been used to determine the optical properties of CNTs (Guo et al., 2004).

5.3

Types of carbon nanotubes

5.3.1 Single-walled carbon nanotubes SWCNTs are one-dimensional carbon materials. They are made up of graphene sheets that have been wrapped into hollow tubes with one-atom thick walls.

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SWCNTs have a lower diameter of 0.5 to 1.5 nm (Meredith et al., 2013). By esterification and amination of nanotube-bound carboxylic acids, CNTs can be functionalized. For SWCNTs, several research groups have reported effective functionalization reactions (Sun et al., 2002). SWCNTs are shown to have enormous potential in the physical science of light waves photonics. Potential wells in the area for capturing mobile excitability are created by covalent attachment to the SWCNT side-wall by alkyl/aryl groups or oxygen species. Consequently, light that was given off by SWCNTs is substantially brighter, and up to 20% quantum yields are achievable. In addition, the spectra show signatures that have been redshifted, expanding their application possibilities (Janas, 2020). SWCNTs can operate as a blueprint for conducting backbones, sensing and carrying guests spin crossover (SCO) state molecules and overcoming their natural insulating properties. SCO compounds encapsulated within the SWCNT cavities, in particular, appears to be a promising strategy, as SWCNTs can operate as rigid mechanical shells that preserve SCO molecules safe from the contaminants while simultaneously serving as containers for precisely placing them in nanoscale devices. Despite the potential appeal, as far as for our knowledge, a few of other magnetic compounds enclosed in SWCNTs have been documented in the literature (Villalva et al., 2021).

5.3.2 Double-walled carbon nanotubes DWCNTs are a novel type of carbon nanostructures. They are made up of two CNTs that are concentric. DWCNTs are used as gas dielectric devices, gas sensors, nanoelectronic devices, emitters, nanocomposites, and other applications because they have superior thermal and chemical stability than SWCNTs. Because they’re a synthetic combination of SWCNTs and MWCNTs, they have the latter’s electrical and stability in the heat while maintaining the former’s adaptability (Saxena and Srivastava, 2020).

5.3.3 Multi-walled carbon nanotubes Numerous tens of graphene sheets in cylindrical form make up MWCNTs. Individual MWNTs were found to be substantially stiffer than currently available fibers when the Young’s modules were examined. direct current (DC) arc discharge with inert gas and CH4 gas and graphite electrodes is commonly used to prepare MWNTs on the cathode. Ebbesen et al. examined individual MWNTs’ electrical conductivity generated by graphite evaporation with a DC arc discharge in He gas and then Ar gas to remove MWNT flaws (Ando et al., 1999). It has been demonstrated that sonication in mixed acids can cut raw MWCNTs into lengths of several hundred nanometers. Without the use of surfactants, the shorter MWCNTs formed a strong dispersion state within a polar solvent. The condensation reaction of shorter MWCNTs and different alkyl diamine was carried out to chemically modify MWCNTs, and the products were analyzed using Fourier transform infrared spectroscopy (FTIR) and also scanning electron microscopy (SEM) measurements (Saito et al., 2002).

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5.3.4 Carbon nanotubes justified on the basis of chirality A hexagonal graphene sheet in two dimensions was chosen as the geometric model of chiral CNTs. A piece of graphene crystal structure with chiral vector Ch 5 na1 1 ma2, the angle formed by the principal primary translation vectors a1 and a2 (a1 5 a2 5 a), and vectors of interatomic distance. The Oy-axis is parallel with the CNT axis acquired after forming a cylinder out of graphene ribbon, and the axis Ox is in line with vector Ch, which determines the ribbon’s width and specifies the diameter of the tube. The piezoresistive features of chiral CNTs with various forms of emission, at the same time, both doped and ideal with point flaws caused by substitution at various concentrations, appropriately dispersed in the crystal lattice, are studied theoretically. The piezoresistive effect is at the core of straintronics, a new field of study concentrated on solid-state effects generated by deformations that change the structure of the energy bands and conductivity and magnetization of materials. Such outcomes enable the development of new information and sensing devices generations. The deformation of CNTs is determined by the presence of contaminates in the crystal structure. Their concentration is also a factor, which may be changed to modify the piezoresistive capabilities of the nanoparticles under investigation (Lebedeva et al., 2020) (Fig. 5.1).

Figure 5.1 SWCNTs, DWCNTs, and MWCNTs with their diameter. DWCNTs, Doublewalled carbon nanotubes; SWCNTs, single-walled carbon nanotubes; MWCNTs, multi-walled carbon nanotubes.

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Characterization techniques

5.4.1 Raman spectroscopy Raman spectroscopy turned out to be an effective technique in determining carbon compounds’ structure (Jorio and Canc¸ado, 2012). It is ideal for quickly and accurately detecting the presence of SWCNT. The Raman experiment is a characterization method that is quick, simple, noninvasive, and non-destructive (McMillan et al., 2008). It is often used to detect amorphous impurities and faults in structured carbon materials for example graphite, graphene, and CNTs, as well as the quantity of each CNT. This method is particularly sensitive for studying alterations in the characteristics of nanotubes produced under diverse processes and settings (Herrera-Ramirez et al., 2018; Jha et al., 2020). The bands seen in this technique are caused by a modification in the molecules’ polarizability caused by means of light contact. As a result, when these molecules interact with light, they emit unique vibrations that can be screened. The distribution of diameters and quality of SWCNTs and MWCNTs may all be identified via Raman spectroscopy thanks to a distinctive pattern (Herrera-Ramirez et al., 2018).

5.4.2 Transmission electron microscopy The evaluation of nanostructures in nanoparticles, graphene, CNTs, and slender films is greatly aided by transmission electron microscopy (TEM). It is possible to assess the 3D shape and chemistry of nanoparticles, which finds major applications, such as the characterization of nanoparticles and catalysts being produced for the administration of drugs. The electrostatic lenses, electron gun to concentrate the electrons prior to and post the specimen, and a system for detecting transmitted electrons are the main components of a TEM microscope. The advantage of TEM is that it can be used in structural and chemical studies on the same material at length scales ranging from atoms to 100 mm (Inkson, 2016). In biological, material science, and engineering sciences, TEM has been widely used. It is being used more in the membrane separation to explore the micro- and nanoscale properties of membranes (e.g., consider the structure of a reverse osmosis (RO) membrane made of thin film composite or a membrane foulant layer) as well as the components that make them up (e.g., nanoparticle shape and/or crystalline structure incorporated in membranes) (Tang and Yang, 2017).

5.4.3 Scanning electron microscopy Scanning electron microscopy (SEM) is a technique for observing and characterizing CNT surfaces that uses electrons to create high-resolution visuals with highly comprehensive information on the morphology of the sample, surface flaws, depth of field, and distribution of phases, far beyond the optical microscopy’s capabilities (Herrera-Ramirez et al., 2018). It gives an overview of sample contents, although it is less subject to sample preparation and homogeneity than TEM. This is frequently utilized in the preliminary evaluation of CNT morphology. SEM is apparently the

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only tool capable of revealing both the content and shape of CNT metallic impurities (Dresselhaus et al., 2004). Researchers may now capture biological specimens in three dimensions using novel volume imaging technologies based on SEM. Recent advancements have enhanced capture reliability and speed, improved image quality, and reduced the amount of manual labor necessary. Volume SEM offers the potential to transform ultrastructural studies of cells and tissues in volumes spanning tens or even hundreds of microns (Titze and Genoud, 2016).

5.4.4 Proton nuclear magnetic resonance This is being adopted to determine the progress of CNT functionalization. The presence of functional groups could also be reported by the appearance of unique peaks following a change in the magnetic environment. Hydrogen nuclear magnetic resonance (NMR) is being utilized to investigate synthesis and the attachment of the functional group to CNTs. Water adsorption isotherms in cut-SWCNTs and activated carbon were assessed with NMR of H in ambient temperature (AC) (Abdulkareem et al., 2007). The isotherm of adsorption indicates the lack of dampness on the inside cut-SWNTs, despite the fact that water adsorption inside SWNTs is as high as any AC. Quantitative studies and varied impacts of deposited D2O on gas adsorption within cut-SWNTs show that the water molecules that have been adsorbed are primarily found around tube ends and flaws. NMR detects SWCNTs in solution (Yinghuai et al., 2005).

5.4.5 Thermogravimetric analysis Thermogravimetric analysis (TGA) is a method of analysis that keeps track of the changes in weight that occur as the sample is heated at a steady pace to assess a material’s thermal stability and volatile component proportion of a material (Sezer and Koc¸, 2019). TGA oxidation of nanotubes has proven to be a vital method for characterizing CNTs. Flaws in nanotube walls boost reactivity on a local scale, resulting in carbon oxidation and gasification at lower temperatures and a TGA profile of mass-loss (Bom et al., 2002). Nanotubes oxidation has been tested for a number of applications, including raw CNT characterization and oxidative purification, for nanowire production, the cap is removed and then the nanotubes are filled, and removal of CNT templates utilized in various architectures. Partial oxidation can be used to refine nanotubes by removing carbon impurities other than nanotubes such as other fullerenes, amorphous carbon, and graphite, but because it occurs in a consistently competitive way among the many forms, only those that are less stable than nanotubes can be efficiently eliminated (McKee and Vecchio, 2006; Rinzler et al., 1998).

5.4.6 Atomic force microscopy Atomic force microscopy (AFM) is a useful method for single nanotube characterization, as evidenced by the rapid advancement of carbon nanotube research

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(Zdrojek et al., 2004). CNT radial deformability has recently been quantified using AFM, and radial deformation has been discovered to have a big impact on NT electrical characteristics (Yu et al., 2001). The AFM’s extensive use can be due to its ability to accurately rebuild sample topography with atomic resolution at a low cost and in a very less amount of time. Another major reason to use this characterization is that the sample to be evaluated is almost unrestricted. AFM is used by many researchers in different fields (Bellucci et al., 2007; Kim et al., 2003). Manipulation of CNT has been studied using the point of an AFM as a miniature plow to explore their tribological and electrical or mechanical properties (Decossas et al., 2003).

5.4.7 Fourier transform infrared spectroscopy Fourier transform infrared spectroscopy (FTIR) spectroscopy is the primary method of infrared (IR) spectroscopy (Dutta, 2017). The adhesion of contaminants on CNTs was studied using FTIR in the range of 400 4000 cm21. Main peaks in the FTIR spectra of grown MWCNTs are recognized as Si O, C N, N CH3, CNT, C O, and C Hx, in much the same, at 1026, 1250, 1372, 1445, 1736, 2362, 2851, 2925 cm21 (Misra et al., 2006). FTIR can detect the graphitic nature of carbon composites, and is sensitive to heteronuclear functional group vibrations and polar bonds, making it a useful supplement to Raman spectroscopy. To avoid saturation, the FTIR method imposes restrictions on the thickness, consistency, and homogeneity of the sample (Varga et al., 2017) (Table 5.2).

5.5

Synthesis of carbon nanotubes

5.5.1 Arc discharge One of the oldest types of synthesis is arc discharge and it is the most effective method for producing high-quality CNTs (Arora and Sharma, 2014). Interest in CNTs has been sparked by their unusual mechanical, electrical, and thermal capabilities, as well as prospective applications that exploit these qualities, since their discovery by arc discharge and create high-quality CNTs with fewer structural flaws (Keidar and Waas, 2004). Iijima discovered CNTs after evaluating pure graphite rods with an arc plasma. The chamber is made up of two electrodes, one (anode) is loaded with the catalyst and powdered carbon precursor, and while the other (cathode) is normally a rod made entirely of graphite. The chamber is either submerged in a liquid or filled with gas. To generate an arc, the electrodes are brought together after turning on the electricity supply (alternating current or direct current) and 1 2 mm spacing was maintained to achieve a constant discharge. To achieve a non-fluctuating arc, a steady current is maintained by means of electrodes, and automation in a closed loop is used to automatically change the void. A flickering arc causes plasma in a state of flux, which affects the standards of the produced product. The arc current produces plasma with a temperature of 4000K 6000K, within the anode, which elevates the carbon precursor. In the gas

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Table 5.2 Instrumental method of analysis. Characterization methods

Analysis

References

Raman spectroscopy

Dresselhaus et al. (2002)

Thermogravimetric analysis

Characterization and evaluation of SWNTs using a novel approach Provides detailed about nanotubes’ radial breathing mode (RBM) The morphology is determined by this variable Purity evaluation in terms of quality The structural organization of CNT drug composites is being investigated Cellular uptake has been identified The most extensively used method for estimating the metallic content of CNT on a regular basis Assigns distinctive peaks to detect the presence of the functional groups on CNTs The diameter of nanotubes is determined Calculates the amount of carbon and noncarbon stuff in a carbon nanotube (CNT)

Atomic force microscopy

To figure out the surface topology of carbon nanotubes

Fourier transform infrared spectroscopy

A qualitative approach for identifying functional groups that also aids in evaluating the influence of functionalization on CNT characteristics

G

G

Transmission electron microscopy

G

G

Hasnain et al. (2018)

G

G

Scanning electron microscopy Nuclear magnetic resonance

G

G

Hasnain et al. (2018) Hasnain et al. (2018) Hasnain et al. (2018) Hasnain et al. (2018) Hasnain et al. (2018)

phase, carbon vapor condenses and drifts toward the cathode, where the temperature gradient causes it to cool. After a few minutes of arc application, the discharge is interrupted, and a cathodic protection of CNTs and soot is obtained from the chamber walls. To explore their morphology, the deposit is purified and viewed through an electron microscope (Arora and Sharma, 2014).

5.5.2 Laser ablation Laser ablation is a technique for ablating solid target materials that employs a laser (light amplification through radiation emission that has been stimulated). To vanish light-absorbing material, a considerable amount of energy is concentrated at a single point on a solid foundation. Ablation is the process of removing surface atoms that includes not just a single photon process (a chemical connection is broken) as well as multiphoton stimulation (heat evaporation). As the purity of particles is mostly governed by the target and ambient media’s purity (gas or liquid) without

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being contaminated by the reactor, laser ablation technique can be used to create high-purity nanoparticles (Kim et al., 2017). The reactor for CNT synthesis at the Institute of Fundamental Technological Research is an example of a common horizontal laser-furnace system. The objective was to ablate in an argon background with gas flowing slowly (5 mm/s) through a quartz tube 25 mm in diameter fitted into a 50 mm outer tube at a pressure of 6.6 104 Pa. The graphite target is made up of raw natural graphite that has been adorned with cobalt (Co) and nickel (Ni) nanoparticles, which were used at a concentration of 1% for each. Nickel chloride and cobalt chloride were reduced with NaBH4 to form metal particles. The quartz tube on the outside is housed in a 42 cm furnace with split tubes that runs at 1000 C. The target is located in the furnace’s center. The material vaporized because of laser pulse was taken away by the argon stream and deposited on a brass plate that has been cooled collection at the furnace’s exit. A two-beat pulse Nd: YAG Ekspla 303 D laser is used to irradiate the graphite target. This is a two-laser set up that produces two identical-wavelength pulses with a variable inter-pulse delay duration. The laser has the ability to be used at wavelengths of 355, 532, and 1064 nm, with pulse durations of 8 ns and a 20 Hz repetition rate. The nanotubes made of carbon soot were scraped away from the collection surface and evaluated once the experiment was finished (Chrzanowska et al., 2015).

5.5.3 Chemical vapor deposition Due to the comparatively low growing temperature, with high yield and purity that may be attained, chemical vapor deposition (CVD) appear to be the most promising approach for possible commercial scale-up. CVD can create MWCNTs and SWCNTs (Dai et al., 1996; Singh et al., 2003). Thermal chemical vapor deposition is used to manufacture SWCNTs using a methane source. MWCNTs and fibers that are thicker are the main products of an ethylene hydrogen plasma created in a plasma reactor with inductively coupled plasma. Sputtering with an ion beam is used to deposit a silicon wafers with an aluminum underlayer and an iron catalyst layer for the development of CNTs in both situations. A mat of SWNT ropes is generated via thermal CVD, whereas plasma produces well-aligned nanofibers with multiple walls that can be used to make electrodes and sensors as well as subsequent tip functionalization (Delzeit et al., 2002) (Table 5.3).

5.5.4 Catalytic chemical vapor deposition Any transition metal catalyst can benefit from the inclusion of a catalytic species with its performance, and the addition of liquids water, alcohol, and other substances during the catalytic chemical vapor deposition (CCVD) process can boost the catalyst’s lifetime and activity while also increasing CNT synthesis (Shah and Tali, 2016). Some of the common gases like ethane, ethylene, carbon monoxide, acetylene, methane, and ethanol are just a few of the hydrocarbons that can be employed as carbon sources in the CCVD process. Organic substances, for instance polymers and carbon sources, which are natural, have also been utilized to generate

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Table 5.3 Preparation methods and their outcome. Method

Outcome

References

Arc discharge

CNTs of good quality and yield are obtained Obtaining a variety of threedimensional nanocarbon structures MWCNT purity has been improved MWCNTs that are fairly straight and to obtain defect-free product Controlling the nanostructures SWCNTs have a quick and powerful photoresponse (up to 1350% at 405 nm) MWCNTs have a fine crystalline structure that can be obtained Single-walled CNTs with a diameter of 0.8 1.5 nm can be made vertically oriented MWCNTs have a high yield

Jain (2013), Joseph Berkmans et al. (2013), Singhal et al. (2013), Vasu et al. (2014)

Laser ablation

CVD

Al-Hamaoy et al. (2014), Jedrzejewska et al. (2013), Ka et al. (2012)

Chandrakishore and Pandurangan (2012), Kumar et al. (2014), Toboonsung and Singjai (2013)

CNTs using the CVD process with success. However, it is necessary to remember that such carbon precursors in gaseous form not only have carbon, but also other ones such as a mixture of hydrogen and/or oxygen, and the fact that they are present may affect CNT formation. Bimetallic catalysts have shown increased activity when a metallic-catalysts have a promoter added to them like vanadium or molybdenum, they perform better than monometallic catalysts, as the participation of a promoter causes a stabilizing effect, limiting the active phase of the catalyst from agglomerating and boosting CNT graphitization and yield (Esteves et al., 2018; Mubarak et al., 2014). The catalyst is put on the substrate and then nucleated by etching with chemicals (as ammonia) or annealing at a high temperature in the CVD production of CNTs. After that, the pre-prepared supporting material is positioned in a tabular reactor to grow. After heating the furnace/reactor to the required temperature of the reaction (600 C 1200 C), a gaseous combination of hydrocarbons (methane, ethylene, acetylene, etc.) as well as a process gas (hydrogen, argon, nitrogen) is induced to react across the surface of metal catalysts in a reaction chamber for a specified time period (usually 15 60 minutes), and when the carbon precursor decomposes, in the reactor, CNTs develop on the catalyst particle and are gathered from the walls of reactor. When compared to laser ablation and arc discharge technologies, CCVD is seen as the preferred path for large scale and for purest 1 CNT manufacturing (Dai et al., 1996; Shah and Tali, 2016).

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Biocompatibility, biodistribution, and biodegradability of carbon nanotubes

5.6.1 Biocompatibility The topic of biological materials and devices is one of the most important areas of CNT research. Vaccine and drug delivery vehicles, biosensors, and new biomaterials are only a few of the applications for CNTs that have been proposed. CNTs can be employed as nanofillers in already available polymeric materials to increase mechanical characteristics and produce extremely anisotropic nanocomposites. They have also been utilized to make polymers that are electrically conducting as well as tissue engineering structures that can deliver regulated electrical stimulation. However, biocompatibility of CNTs and their toxicity must be researched before such materials may be included into biomedical devices, both new and existing. Biocompatibility will be described as “the capacity of a material that can be used in a performance adequate host response in a certain application” for the purposes of this evaluation (Lin et al., 2004; Smart et al., 2006). CNTs have the ability to be used in unique ways in nanomedicine, for instance substrates that are biocompatible and supportive, as well as excipients used in pharmaceuticals in the creation of flexible drug delivery systems (Foldvari and Bagonluri, 2008). The fundamental criteria that govern the biological reactions produced upon interaction with biological matter are clearly the physicochemical features of any nanomaterial. Covalent bonding can modify the chemical constitution of a nanomaterial, resulting in drastic changes in its physical and biological properties. In terms of biocompatibility, it is now widely believed that chemical functionalization of CNTs can result in a drastically better biocompatibility profile, based on findings from a few laboratories over the previous decade. We have used this improved profile to look at several elements of f-CNTs in biological science (Bianco et al., 2011).

5.6.2 Biodistribution Pure and functionalized SWCNTs and MWCNTs in vivo biodistribution following pulmonary deposition, pristine CNT can be found in the lungs for months, even years. The mucociliary escalator transports the vast majority of carbon nanotube to the gastrointestinal (GI) tract if it is cleared. Possibly with the exception of the tiniest functionalized SWCNT, however, it appears that there is no CNT uptake from the GI tract. CNT translocate from the alveolar space to the near-pulmonary region, lymph nodes included, sub-pleura, and pleura (Jacobsen et al., 2017). The process by which CNTs are dispersed in living beings is currently unknown. This is because to the variety of the materials, the underlying cellular heterogeneity at the target site, and the wide range of the biological reaction in response to carrier structural change. As a result, defining guidelines to predict CNT biodistribution a priori is difficult. When functionalization is added to the material, the analysis becomes even more challenging because every decorating of the CNTs has the ability to change the interaction with living beings (Biagiotti et al., 2019).

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5.6.3 Biodegradability It is vital to look into the possibility that CNTs could be degraded under specific conditions, for as by bacteria or at the cellular level. Although the design of their biocompatibility is being actively researched as discussed above, little is known about how CNTs degrade once administered to or exposed to living organisms. Nanomaterials that are not biodegradable can build up in tissues and cause serious side effects. Furthermore, the breakdown products of nanomaterials may cause severe reactions. Here “controlled biodegradation” is a critical and difficult goal, because nanomaterials that are being developed for biomedical applications is dependent on their controlled disintegration and clearance from the body. Mesoporous silica nanoparticles, for example, are destroyed intracellularly and the resulting compounds (mostly Orth silicic acid) are excreted through the kidney without causing harm. Enzymatic degradation of MWCNTs produced from several commercial sources is the subject of a new study. In a comparative study, the HRP and PSF induced degradation of carboxylated MWCNTs is evaluated (ox-MWNTs). ox-MWNTs were dramatically altered structurally and definitely destroyed after two months in both biological oxidative settings, though not totally. Alternatively, SWCNTs have been shown to be biodegraded in fluids that simulate the phagolysosome environment (Bianco et al., 2011; Kagan et al., 2010).

5.7

Toxicity

5.7.1 Neurotoxicity Nanotechnology, which involves the characterization, design, production, and their application of nanoparticles, is rapidly gaining traction in a variety of disciplines, including energy, cosmetics, environmental science, food and agriculture, electronics, and medicine. Bioimaging, drug delivery, cancer, and gene therapy are the most prevalent biological applications of nanomaterials. Because they have unique features that distinguish them from materials in large quantities, impact of toxicity and long-term repercussions on living things are unknown (Teleanu et al., 2019). Potential dangers of CNTs utilized in biological applications, particularly neurotoxicity, must be carefully analyzed and substantial toxicology studies conducted (Shi et al., 2017). When it comes to CNT uses in the central nervous system, neurotoxicity remains one among the most popular significant challenges. CNT toxicity has been linked to a variety of parameters in both in vivo and in vitro investigations, concentration, type of functionalization, including, length of exposure, mode of exposure, and even the surfactant employed to solubilize the nanotubes. Many research, however, appear to demonstrate that such claims about CNT toxicity are unfounded (Firme and Bandaru, 2010). When examining toxicity in vivo, it is important to remember that toxicity data from small animals may not be indicative of human reactions. The percentage of effective animal model translation to human trials in cancer research, for example, is claimed to be less than 8%, owing to the high complexities of carcinogenesis and tumor growth that animal models fail to match (Shi et al., 2017).

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5.7.2 Cytotoxicity CNTs have a diverse set of applications that go beyond material science and engineering, necessitating urgent toxicological research. One of the most serious challenges in nanotechnology is identifying the cytotoxicity of CNTs. Metal impurities, dispersion and aggregation status, surface area, length and size distribution, immobilization, coating or functionalization, internalization or cellular uptake, and cytotoxic reaction of different cell types to CNTs, among other factors, can all contribute to CNT cytotoxicity (Hussain et al., 2009). Nanomaterials cytotoxicity assessments are largely based on classic toxicology testing techniques. In the past few years, there have been a great number of studies that have been dedicated to CNT cytotoxicity investigations, and the cytotoxicity testing findings have revealed that cytotoxicity is highly reliant on CNT properties. The greater the particular surface area, the more toxicological impacts of nanotechnology. SWNTs have a larger specific surface area than other nanomaterials. SWNTs frequently build bundles due to the increased Van der Waals pressures between their sidewalls, reducing their effective specific surface areas. The specific surface areas of MWNTs, which are made up of a number of coaxial SWNTs, are slightly lower. Functionalized CNTs have been used to lower the cytotoxicity of CNTs (Zhu and Li, 2008). Zhang et al., for example, demonstrated that PEG-coated CNTs are less hazardous to mitochondrial function and membrane integrity than pure CNTs (Shi et al., 2017).

5.8

Carbon nanotube modification: toward reduction of its toxicity issues

High cytotoxicity of CNTs hinders their usage in humans and a variety of biological systems. The dose, duration, size, testing methodologies, as well as CNT surface functionalization are all factors in their biocompatibility and minimal cytotoxicity. CNTs that have been functionalized have improved solubility and biocompatibility, as well as altered cellular contact routes, resulting in significantly reduced cytotoxicity. Functionalized CNTs are a potential new material for use in a variety of biomedical applications. These applications’ potential is boosted because of their ability to pass through biological membranes while causing minimal cytotoxicity. Oligonucleotides, biomolecules, surfactants, and polymers can all be used to make CNTs functional (Liao and Zhang, 2012; Vardharajula et al., 2012; Zheng et al., 2003).

5.8.1 PEGylation PEGylated phospholipids and PEG (polyethylene glycol), for example, are well-known for their exceptional dispersibility and biocompatibility, as a result, they are among the most effective noncovalent surface enhancers for CNTs. CNTs functionalized with phospholipid (PL)-PEG for adsorption have been reported to not be cytotoxic in several recent experiments. SWCNT-PEGs showed decreased cytotoxicity in PC12 neuronal

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cells than SWCNTs that have not been coated and exhibited a lower oxygen reactive species—toxicological response that has been mediated in vitro—indicating that they had less contact with cell membranes than uncoated SWCNTs (Yan et al., 2011). As a result, SWCNT-PEGs are expected to be used in nanomedicine in the near future. SWCNT-PEGs are ideal for the development of multifunctional pharmaceuticals as well as imaging instruments (Song et al., 2011). When PEG-modified SWCNTs are placed onto them, the anticancer medication doxorubicin (DOX) showed better therapeutic capability and significantly reduced effects of cytotoxicity in comparison to the free drug. In mice, SWCNT-PEGs with noncovalent functionalization were given intravenously and showed no toxicity (Vardharajula et al., 2012).

5.8.2 Folate-anchored carbon nanotubes Vitamin B9 is known as folic acid (FA). FA is a water-soluble pteroyl-L-glutamic acid that has been discovered to have a better binding capability with the body’s folate receptors (Bano et al., 2016). Convenient availability, small ligand size, less cost, and 25 conjugation chemistry that is well-defined are all advantages. The folate receptor is a 38-kD glycosylphosphatidylinositol glycoprotein that has been conjugated and has modest levels of normal cells (healthy cells) but is greatly expressed in cancer cells to fulfill the growing requirement in cancer cells for folate (Krasnopevtsev, 2017). Because nanoparticles conjugated with folate via the g-carboxyl group have a same preference for binding to free folate, they are commonly employed for targeting. Yet another investigation by Lu et al. involved the functionalization of MWCNTs that has been loaded with DOX via hydrogen bonding and stacking, followed by free radical polymerization of poly (acrylic acid). After that it was conjugated with folic 26 acid to acquire the ability of targeting. On U87 human glioma cells, the cytotoxicity of the nanoparticle system was assessed and compared to free DOX. DOX-FA-MNMWCNT (IC50 15g) was discovered to have an IC50 value of 30% of free DOX (IC50 50g) (Mahajan et al., 2018).

5.8.3 Chitosan-layered carbon nanotube Chitosan is a biodegradable polysaccharide composed of N-acetyl-D-glucosamine and b (1 4)-linked D-glucosamine, nontoxic (Chanphai et al., 2017) produced by deacetylation of chitin. Its biomedical value stems from its capacity to forming a polyelectrolyte complexes, as a result of which it is suitable for pharmaceutics and pharmacological use. It has the ability to create polyelectrolyte complexes that have pharmacological features like compatibility, degradability, and relative non-toxicity. Chitosan has a higher entrapment efficiency, and the ratio of chitosan to sodium tripolyphosphate can be adjusted to change the time it takes for it to degrade. Hydrophobic forces and electrostatic interactions wrap them around CNTs (Khan et al., 2017). The vitality of cells in vitro was discovered to be 75% at 250 L for MWCNTs, which had been surface altered with chitosan and FA (CHI-FA) nanoparticles via a gelation inotropic technique. The improved green fluorescent protein plasmid DNA was delivered into HeLa and MCF-7 cell lines using customized nanoparticles (size 30 80 nm).

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Exogenous GFP was discovered to be expressed; also, short MWCNTs have stronger transfection capacity and cytotoxicity than longer ones; nevertheless, cytotoxicity was reduced after surface modification (Mahajan et al., 2018).

5.8.4 Peptide conjugation Multiple amino acids are joined by peptide bonds to form peptides. A peptide might be anything between 2 and 50 amino acids long. In comparison to alternative targeting ligands like as antibodies, peptides must have several benefits, including ease of synthesis, small size, appropriate tumor-penetrating capacity, and superior biocompatibility. Since in cancer cells, peptide receptors are overexpressed as compared to other types of human cells, peptides have become popular ligands (Thundimadathil, 2012). SWCNTs with noncovalent functionalization with new aromatic and surfactant’s hydrophobic stacking interaction improves solubility and biocompatibility. For the treatment of glioma in the brain, Kafa et al. produced oxidized MWCNT functionalized with DOXloaded PEG-modified with angiopep-2 (ANG) (O-MWNT-PEG-ANG). ANG binds specifically to glioma cells and overexpression of the lipoprotein receptor-related protein receptor in the blood-brain barrier. Glioma-bearing mice with C6 cytotoxicity and a median survival time, hematological analysis, and immunohistochemical evaluation of CD68, DOX OMWNT-PEG-ANG was found to have better biocompatibility, less toxicity, and antiglicoma effect than free DOX (Mahajan et al., 2018).

5.9

Biomedical applications of carbon nanotubes

5.9.1 Carbon nanotubes in biosensing In the field of biosensors, CNTs have been considered as a sensing element for detecting and monitoring a variety of ailments, including diabetes and

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bacterial infection. Punbusayakul et al., for example, used electrochemical monitoring of immune complexes to detect salmonella, lowering detection time and simplifying sample preparation compared to conventional approaches. In general, having CNT on the electrode surface allows for quicker electron transfer and increased sensitivity for electrochemical detection (Chen et al., 2016; Mansouri Majd and Salimi, 2018). According to Ramnani et al., field-effect transistor (FET)-based sensors offer exceptional sensitivity, sometimes as low as attomole (Simon et al., 2019). Enzyme, glucose, protein, antigen and antibody molecules, hormone molecules, bacterium, and DNA molecules have all been detected using the CNTFET biosensor. Fig. 5.2B explains the mechanism of CNTFET biosensor. Specific antibodies can be covered with CNTs, and antigen-antibody specificity adsorption can generate an electrical impulse that can be viewed and recorded (Yang et al., 2015). New nanomaterial techniques for surface modification have the ability to bring a new range of biosensors and bioelectronic devices to biomedical applications (Yang et al., 2007). CNTs have been discovered to look promising in the design and advancements of various biosensors, such as glucose biosensors, H 2 O 2 metal ion biosensors, biosensors, immunosensors, gas sensors, choline sensors, and so on. In addition, it was also shown that the use of CNTs encouraged direct electron transfer from redox proteins’ active sites or to the electrode surface with enzymes, which is a significant issue in the creation of biosensors. In addition, using CNTs in various forms or combining them with other materials improved the biosensor’s sensitivity, selectivity, and stability when employed (Alim et al., 2018).

Figure 5.2 (A) Displaying a structural model, carbon nanotubes operated as a conductive channel between the two electrodes (with distance 3 µm) to absorb biomolecules. (B) The working principle of CNTFET is depicted schematically (Yang et al., 2015). Source: Reprinted with permission with copyright (2015) Elsevier.

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5.9.2 Carbon nanotubes in drug delivery (Fig. 5.3)

5.9.2.1 Delivery of anticancer agents The insolubility of CNTs in aqueous solutions is a significant hindrance to their use in biomedicine; however, this can be overcome via functionalization (Kesharwani et al., 2012). Aptamers (20 80 nucleotide single-stranded DNA/RNA materials) are being used right now to functionalize CNTs as well as to target them. Owing to their potential in overcoming a number of obstacles experienced during the course

Figure 5.3 Various drug delivery techniques using CNTs as nanocarrier. CNTs- Carbon nanotubes.

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of cancer treatment, like non-specificity, low permeation ability into cancerous tissues, and low consistency of bioactives with anticancer properties, CNTs are increasingly being preferred as viable drug delivery vehicles, mainly in cancer treatment. CNTs have established themselves as a distinct type of nanomaterials for cancer treatment due to their ability to protect antitumor agents via encapsulation from extrinsic deactivation agents, drug mobility capacities of suitably modified surfaces of CNTs, and their distinct physicochemical characteristics (Kesharwani et al., 2015; Zhang et al., 2010). Several studies have looked into using CNTs to target cancer cells and tissues. By collecting pharmaceuticals primarily on sick tissues and increasing drug action on abnormal cells while healthy cells are protected, this will result in fewer side effects. Passive diffusion has allowed CNTs to flow across cellular membranes and include transport processes that are active adenosine triphosphate, for example, endocytosis and phagocytosis in several investigations (Caoduro et al., 2017; Li et al., 2017). Additionally, the ability to fabricate legends as a target on the surface of CNTs allows for the most effective and anticancer drugs are delivered to cancer cells by targeted delivery (Abdallah et al., 2020). When compared to spherical nanocarriers, nonspherical nanocarriers (CNTs) have been shown to be kept in lymph nodes for longer period of time (e.g., liposomes). CNTs could thus be utilized to target lymph node tumors. CNTs should be chemically or physically functionalized to make them responsive. As mentioned in Fig. 5.4, contrast agent, antibody, drug payload, drug inclusion, targeting agents, PEG help in functionalization of CNTs for improved targeting of cancerous cells (Ahmed et al., 2018).

5.9.2.2 Delivery of antibacterial or antiviral agents The utilization of CNT nanocomposite films with antibacterial properties has progressed significantly during the past 10 years. Karajanagi et al., who studied nanoscale’s impact environments on the structure and function of proteins, published among

Figure 5.4 Schematic representation of multifunctional nanotubes.

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the very first publications on nanotube-protein interactions. SWNTs, according to Asuri and collaborators, can reduce undesirable protein protein interactions that occur at the lateral end of the protein chain and improve the adsorbed proteins’ stability in the context of tough conditions of denaturation because of their surface curvature. By integrating protease within a paint/polymer matrix, nanotubes are conjugated. Asuri et al. generated strong and effective antifouling nanocomposite films. CNTs have a high aspect ratio assisted to keep the conjugates inside a polymer matrix very less leaching, while the simple to use functionalization and CNTs’ large surface area allowed for greater enzyme loadings (Asuri et al., 2007; Mundra et al., 2014). CNTs have received a great deal of interest in the field of antiviral medicine, and they have lately been investigated as anti-HIV drugs using design based on structure. Highly hydrophilic compounds have antiviral properties and degradable carboxylated MWCNTs (ox-MWCNT) as well as the activity exerted by the same nanoparticle carrying antiviral drugs as well as hydrophilic properties were studied in vitro to investigate their capacity to bind to viral enzymes and suppress HIV (Iannazzo et al., 2015).

5.9.2.3 Delivery of proteins and peptides Proteins with a higher molecular weight could not really cross biological barriers in the parenteral delivery method. In vitro, CNTs have already been used as a protein delivery molecular carrier. Through hydrophobic interactions, proteins are adsorbed on the sidewalls of acid-oxidized SWCNTs for this function. The biotin-SWNTstrepavidin combination transported strepavidin within the cells and was harmful to HL60 cells in a research by Kam et al. CNTs were found to transport proteins, such as cytochrome C (12 kDa), protein A (SpA 42 kDa) protein A (SpA 42 kDa), and fluorescein isothiocyanate-labeled human IgG (150 kDa) into diverse mammalian cells in a comparable investigation. Peptide carbon nanotube complexes have been shown in several investigations to improve the immunological (antibody) response to peptides. In comparison to the free peptide, BALB/c mice immunized using peptide-SWCNT constructs generated strong reaction to antibodies (Blackmore et al., 2005; Patel et al., 2014).

5.9.2.4 Vaccine delivery Functionalized CNTs have been used to deliver cancer vaccines (de Temmerman et al., 2011). A number of processes have been proposed to explain the efficacy of particle vaccinations. Antigen and adjuvant in many copies can be accommodated in a particle delivery system. As a result, antigen-presenting cells (APCs) may take up particle vaccine delivery methods, increasing intracellular concentrations of antigen and adjuvant and hence density of antigens displayed. Identifying the correct antigen, adjuvant combination, and delivery vehicle is critical to the success or failure of any cancer vaccination. CNTs have demonstrated impressive antigen transport capabilities to APCs (Hassan et al., 2019; Krishnamachari et al., 2011).

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5.9.2.5 Gene delivery The capability of a bioengineered peptide and gene delivery to intact tobacco (Nicotiana tabacum var. Virginia) root cells using arginine functionalized SWCNTs was assessed after some biological and synthetic nanoparticles success, such as peptides that penetrate cells and CNTs in transferring macromolecules (nucleic acid and proteins) into mammalian cells. Fluorescence microscopy as well as western blotting analyses verified the effectiveness of gene transfer to the root cells of tobacco. SWCNTs have received a lot of attention because they have been shown to penetrate through cell membrane nanopores and also the plasma membrane. Gene transfer that is not transmitted by a virus to animal cells has been achieved using cationic (Canine and Hatefi, 2010) and hydrophobic CPPs. Plasmids that express for GFP were supplied to tobacco root cells that are still alive via a recombinant peptide fusion with hydrophobic and cationic domains. SWCNTs with arginine functionalization were also employed to deliver the same plasmid to the cells of tobacco roots. CNTs can penetrate membrane of a cell directly or via endocytosis (Yaron et al., 2011). By creating electrostatic interactions, arginine functionalization of CNTs boosts solubility and also DNA absorption (Golestanipour et al., 2018).

5.9.2.6 Lymphatic targeting The lymphatic targeting of therapeutic molecules to the reticuloendothelial system (RES) is used to treat a variety of lymphatic illnesses (liver, spleen, kidney, etc.). To deliver medications to the targeted lymphatic system, a variety of methods are used (Li et al., 2005). Researchers have recently developed magnetic nanotubes that can be used to direct medicinal molecules to the lymphatic system through selective surface functionalization (Beg et al., 2018; Schwengber et al., 2015). The regulated size of CNTs, according to Yang et al., can make drug uptake into the lymphatic system more effective. Functionalized CNTs, in combination with FA (folic acid) and its encapsulation in nanoparticles that are magnetic, offer a high level of targeting potential for malignant cells in lymph nodes (Hasnain et al., 2018).

5.9.2.7 Brain-targeting drug delivery Because there are few medications that penetrate the blood-brain barrier, many disorders go untreated (dementia, Alzheimer’s disease, mood disorders, Parkinsonism, AIDS, and both bacterial and viral infections) (Hasnain et al., 2018). CNTs have been utilized to transport medicinal molecules to the brain because of their capacity to pass the bloodbrain barrier. MWCNTs are more effective than SWCNTs at delivering neuropharmaceutical drugs to brain microglial cells. Because of their magnetic properties, CNTs are also beneficial in the treatment of neurological illnesses (Beg et al., 2018).

5.9.2.8 Ocular drug targeting Several methods have been used to generate a safe, biocompatible, and pleasant nanovehicle for controlled ocular medication administration with improved patient

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compliance and lower toxicity (Mehra et al., 2015). CNT-based drug delivery has been shown to improve the bioavailability of a limited number of ocular drugs, surpassing the limitations of standard ophthalmic drug delivery methods. CNTs might also be used to target different therapeutic drugs to distinct eye locations using ocular targeting. However, very few studies have been undertaken in this domain so far, thus, advocating for additional exploration of CNTs for the uses in ocular administration (Hasnain et al., 2018).

5.9.2.9 Transdermal delivery CNTs aid in the efficient transport of medications via the skin through transdermal electrophoretic and iontophoretic methods. Because of their extraordinarily high density of charges and modest small size, f-CNT membranes allow medicines to flow quickly utilizing CNT cores (Dasgupta et al., 2011). By combining a drug molecule with CNT membranes, a transdermal drug delivery system (TDDS) can be created. CNT membranes cause the least skin irritation and do not damage the skin barrier. The concept was used to build MWNTs-based transdermal nicotine delivery utilizing a CVD technique with xylene as the feeding gas. As a result of reduced drug release from the matrix and lower drug permeability through the skin, TDDSs have been limited to low drug amounts (Hasnain et al., 2018). The use of indomethacin, doxorubin, and clonidine for transdermal medication administration has also been confirmed in recent literature publications. Nanotube membranes have lately gained popularity for their use in transdermal nicotine administration for smoking cessation and opioid withdrawal symptoms (Beg et al., 2018; Schwengber et al., 2015).

5.9.3 Carbon nanotubes in imaging Nanocarriers are used in the field of organ imaging and aid in the identification of medication sites of action in systems of targeted delivery, both of which are important in diagnostic imaging. CNTs have been proven to have a higher potential for acting as a means of comparison in cancer cell identification and imaging. When methotrexate (an anticancer medicine) was supplied with nanotubes that have been functionalized with a fluorescein probe, the fluorescence formed on its surface by the drug-carrying probe improved visibility in the body. CNTs with fluorescent compounds that are functionalized are employed as a radio-opaque material that generate images of the organs of interest in vivo (Ghanghoria et al., 2016; Tekade et al., 2017).

5.9.3.1 Optical and nonoptical imaging Optical-based imaging approaches rely heavily on optical probe capability. Excitation by a single photon needs ongoing low laser power wavelength, whereas excitation with two photons requires a laser with a high output energy beam, commonly from a femtosecond laser. For imaging cells, cubic boron nitride (CBN) has

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emerged as a novel high-performance fluorescence agent with one and two photons (Patel et al., 2019). CBN as well been created for imaging modalities that are not optical (nonoptical) such as computer tomographic imaging, magnetic resonance, and photoacoustic, which has the ability to compensate for or help boost CBN’s optical imaging capabilities for improved theranostic outcomes (Patel et al., 2019).

5.9.3.2 Photoluminescence imaging The luminosity law of Stokes implies that the production of the wavelength (energy) of light is generally longer (lower) than its equivalent in excitement, and governs most photoluminescence processes. In recent years, its potential use in a variety of applications like photovoltaic energy conversion (Baluschev et al., 2006), photoluminescence bioimaging (Dou et al., 2015), displays, lasers, and the optical cooling of solids has sparked attention. CNTs (as single-walled carbon nanotubes) are made up of sheets of graphene folded into tubular constructions that are quasione-dimensional and have diameters on the process of one nanometer. Nanotubes serve as semiconductors with a direct band gap of the process of 1 eV and exhibit near-infrared photoluminescence optical range due to recombination of excitons, depending on how they are rolled up and diameter specified by means of two indexes (n, m) (attractive Coulomb interactions bind electron and hole pairs). Over the past decade, various unique luminescence features of CNTs and their applications have been discovered, starting with the first detection of effective Stokes photoluminescence from SWCNTs (Akizuki et al., 2015; Kruss et al., 2013).

5.9.3.3 Fluorescence imaging For biological in vivo and in vitro imaging, a variety of spectroscopic techniques can be used. Fluorescence imaging is among the most common approaches. CNTs can be labeled with fluorescent compounds or exploited for their intrinsic fluorescence capabilities. Photo-excitation causes certain carbon nanomaterials to release fluorescence light. Semiconducting SWCNTs are one of the most well-studied examples, as they exhibit structure-dependent fluorescence in the biologically essential NIR-II window (Welsher et al., 2011). As a result, the purity and chirality of the SWCNTs used are crucial. SWNTs have low fluorescence quantum yields, generally 0.01 for macroscopic samples of SWCNT, and are highly dependent on ambient conditions (Shukla et al., 2007; Stan et al., 2007; Bartelmess et al., 2015) (Fig. 5.5).

5.9.3.4 Magnetic resonance imaging Because it is noninvasive and provides great spatial resolution as well as the ability to image soft tissues, magnetic resonance imaging (MRI) is a helpful and effective tool in medical diagnostics. Around 60 million MRIs are performed each year throughout the world (Deshmukh et al., 2020). Covalent connection and layer-bylayer assembly approach were employed for identifying kidney of a human embryo

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Figure 5.5 Imaging with the help of fluorescent dye-loaded carbon nanotubes.

(HEK) 293T cells by confoncal and MRI fluorescence imaging. Gd13, Mn12, etc. are used as shortening agents and T2 (transverse relaxation time) shorten agents (Fe2O3 nanoparticles) are the most common types of contrast agents (Gong et al., 2013). Cancer cells are visualized using T2-weighted MR imaging, MWCNTs/ cobalt ferrite composite showed a considerable increase of negative contrast (Wu et al., 2011). CNTs have also been reported to be utilized for tracking and labeling stem cells. Stem cells have demonstrated tremendous regenerative potential therapy as well as drawn attention (Vittorio et al., 2011). Furthermore, MRI differs from previous imaging techniques in that it allows for without a depth limit, full body imaging, making it a lot more clinically useful imaging technology (Merum et al., 2017).

5.9.3.5 Photoacoustic imaging When light-absorbing molecules absorb laser pulses, heat is generated, which results in ultrasonic emission with a wide frequency range, which may be discovered using an ultrasound device and used to create two-dimensional or threedimensional images. Instead of detecting light, photoacoustic imaging detects sound. Because of their significant NIR absorbance, MWCNTs and SWCNTs, both, have been employed as agents with photothermal properties. This approach can map, discover, and trace measurement levels of SWCNTs in a range of histological sample of tissue for cell imaging (Merum et al., 2017). RGD peptide attached to SWCNTs were utilized as agent of photoacoustic contrast for in vivo imaging, and substantial photoacoustic signals were checked through the tumor in the SWCNTRGD group that was injected, but only faint signals were noticed in plain SWCNTs administered group, an Au layer or certain organic compounds were linked with SWCNTs to boost their absorbance in the near-infrared range to further enhance signal sensitivity (Wu et al., 2013).

5.9.4 Carbon nanotubes in tissue engineering Tissue engineering is a newer branch of biomaterials research that was initially defined by Sandor (2013) as a multidisciplinary field of life sciences and

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engineering that deals with the biological alternatives being developed that preserve, restore, or increase the function of damaged tissue in a living patient. Composites made of polymers and bio ceramics have been developed explored extensively and used in the form of scaffolds in a variety of applications in medical, one of which is tissue engineering. Important parameters must be met when developing a material for usage on scaffolds to deal with the critical possibilities: biodegradability, biocompatibility, favorable cellular response, as well as the ability to tolerate diverse physiological circumstances. The scaffold should be able to function as an integral part of the tissue after implantation, as well as in the scenario of biodegradable biomaterial, and live tissue has totally replaced without the creation of scars (Lorite et al., 2019; Sohier et al., 1742).

5.9.4.1 Bone engineering CNTs can be used to make composites, thought of as collagen nanocomposites, that are biomimetic on the level of the cell hierarchy for bone tissue regeneration and engineering. Because of their preference for cell binding, they have the potential to exhibit positivity not only on increasing cell adhesion by interacting well with cellbinding proteins (Anthony et al., 2018; Kaiser et al., 2013), but also on cell morphology regulation and accelerating the development of stem cells; thus, for osteoblast difference and to encourage new bone production, apatite mineralization was generated. MWCNTs have a higher capacity for adsorption and concentration of proteins (such as rhBMP-2), activate the expression of the cbfa1 and COL1A1 genes, alkaline phosphatase and enhance osteogenic development of human adipose-derived mesenchymal stem cells (MSCs) in vitro. According to Li et al. (2012), cell morphology regulation and accelerating the development of stem cells will lead to generating osteoblast difference, new bone production, apatite mineralization. MWCNTs have a higher capacity for adsorption and concentration of proteins (such as rhBMP-2), activate the expression of the cbfa1 and COLIA1 and alkaline phosphatase (ALP), and promote human adipose-derived MSCs osteogenic differentiation in vitro, according to Li et al. (Pei et al., 2019).

5.9.4.2 Neural engineering Carbon-based nanomaterials have already been investigated for biomedical applications and are potential materials for neuro-engineering (Elinav and Peer, 2013). CNTs are widely used in biological applications as a result of their distinct chemical and physical properties. The interaction of CNTs with the brain has sparked interest in developing CNT-based gadgets. CNTs are a viable material for triggering and recording neural activity due to their unique electrical properties. Neurons with a CNT substrate have increased electrical activity (Cellot et al., 2009). CNTs shorten electrical connectivity between somatic and dendritic neuronal compartments, resulting in increased neuronal electrical activity. Neurite outgrowth, biocompatibility, neuron development, and neurite/axonal elongation were all improved by surface modified MWCNTs (Ottman et al., 2019). CNTs may readily

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be included into a variety of bio/nanomaterials and can produce nanocomposites with a variety of materials (Kumar et al., 2020).

5.9.5 Thermal therapy 5.9.5.1 Photothermal Photothermal therapy has sparked enough interest as a cancer treatment option. The creation of highly efficient and safe photothermal agents, on the other hand, has proven to be a difficult task (Debnath and Srivastava, 2021). Many investigations on the efficacy of CNTs for photodynamic and thermal therapy on the cancerous cell lines and mice with tumors have yielded encouraging results for future human studies. Photothermal treatment (PTT) is a cancer-ablation technique that uses heat created by absorbed NIR light energy (Xue, 2017). Due to the attached catalyst metals in SWCNTs, using PEGylated SWCNTs, researchers applied a multimodal imaging-guided photothermal therapy, NIRII fluorescence imaging (1000 1400 nm) with a low-power 808 nm laser, as well as for T2-weighted magnetic resonance imaging (Li et al., 2009). These SWCNT-PEG complexes had been disseminated from the primary tumor to the lymph nodes that serve as sentinels, allowing for the ablation of the main tumor and cancer cells that have spread, as well as the suppression of breast cancer metastases to the lungs from afar, resulting in much longer survival times. MWCNTs were also used in the development of other novel materials for cancer ablation using PTT (Stan et al., 2018).

5.9.5.2 Photodynamic SWNTs have also been shown to have a lot of promise in the field of PDT (photodynamic therapy). Wang et al. created two SWCNTs, one with which it has been covalently functionalized PEI (SWNT-PEI) and the other with a noncovalent functionalization PVPk30 (SWNT-PVPk30), and employed them in photodynamic therapy (Wang et al., 2014). In presence of visible light, both in vivo and in vitro, the photodynamic effects of such two functionalized SWNTs were found. They discovered that the photodynamic effect was influenced not only by the duration of illumination, but also by the mechanism used to modify the SWNTs. In vivo and in vitro SWNT-PEI showed substantially higher photodynamic impact than SWNT-PVPk30. In addition, there is useful information on the efficacy of MWCNTs in thermal and photodynamic therapy (Xue, 2017).

5.9.6 Carbon nanotubes in dentistry Oral infections have been treated with nanotechnological techniques, and scaffolds for tissue regeneration have been developed. CNTs are a promising material for developing multifunctional dental platforms. Nanotechnology in dentistry, often known as “Nano dentistry”, aims to attain near-optimal oral health by incorporating nanoparticles (such as those used in tissue engineering and medication delivery systems) into dental restorations (Castro-Rojas et al., 2021).

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5.9.6.1 Dental restorative materials In restorative dentistry, glass ionomer solidifies and resin-based composites are emerging as promising. CNTs have been incorporated to methacrylate-based resin composites in dentistry that are used to fill cavity in the teeth (Castro-Rojas et al., 2021). These materials for dental fillings are tooth-colored, making them quite appealing and popular with patients. The vast majority of studies have focused on adding tooth-colored or add white nanoparticles, such as titanium dioxide, colloidal silica, nano-hydroxyapatite, or aluminum oxide nanoparticles in the mix (Jandt and Sigusch, 2009). While these have resulted in some performance gains, one of the groups has incorporated dental resin composites with SWCNTs, claiming their Young’s modulus and high tensile strength as the motivation in exchange for their use. The researchers described a method for depositing a thin layer of nano-silica on the oxidized surface of SWCNTs with a thin 3-aminopropyltriethoxysilane adlayer, accompanied by use of layer alteration with another organ silane with allyl terminated groupings of functions to achieve excellent dispersion and nanotubes are incorporated into a polymer matrix. The flexural strength of the resulting dental resin composites improved significantly (Dunne and Mitchell, 2011).

5.9.6.2 Bony defect replacement therapy Supplemental enhancing treatment with synthetic materials and biomaterials made from cadaveric bone is becoming more popular as a remedy for dental implants for missing teeth replacement becomes more predictable. Tooth loss, periodontal disease, and trauma can all result in insufficient volume or structural abnormalities in the alveolar bone. Biomaterials ranging from bone fillings to composite materials with tissue engineering, such as calcium sulfate, polymers, HA, calcium phosphate, and CNTs have all been investigated as potential possibilities for bony defect repair that is predictable. When MWCNTs were submerged in a solution of calcium phosphate at 37 C for nearly 2 weeks, nanoscale HA was produced surface-level, demonstrating CNTs’ ability for bone tissue engineering. To facilitate directed bone regeneration, researchers constructed electrospinning a suspension of poly (L-lactic acid), HA, and MWCNTs to create a bio membrane. The membrane showed 30% increase in periodontal ligament cell adhesion and production while suppressing proliferation of unfavorable epithelial cells, according to the authors (Bhattacharya and Seong, 2019).

5.9.7 Carbon nanotubes in regenerative medicines CNTs have proven significant promise in biomedical applications (Bianco et al., 2005). Due to CNTs’ nanoscale nature, CNTs have been used in vivo for regenerative medicine impeded by problems connected with the manufacture of threedimensional CNT scaffolds. CNTs were hybridized in situ with bacterial cellulose (BC), which has an architecture appropriate scaffolds for tissue engineering, a new approach for the biosynthesis of CNT-based 3D scaffolds has been developed. This

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was accomplished by cultivating bacteria that synthesize BC gluconacetobacter xylinus in media containing CNTs (Henriksson and Berglund, 2007). However, pure CNTs were collected in the media, preventing uniform CNT-BC scaffold hybridization, as well as the energy of binding between hydrophobic pure CNTs and hydrophilic BC was very low for hybridization to take place. APCLP (amphiphilic comb-like polymer) was adsorbed on the CNTs surface to solve these issues. The APCLP-adsorbed carbon nanotube-BC hybrid scaffold (CNT-BC-Syn) homogeneously displayed dispersed CNTs, which were found throughout BC’s threedimensional microporous structure, CNT-coated BC scaffolds (CNT-BC-Imm), on the other hand, were generated by submerging 3D BC scaffolds in carbon nanotube solution (Jiang et al., 2003). In comparison to CNT-BC-Imm scaffolds, CNT-BCSyn scaffolds demonstrated superior osteoinductivity and osteoconductivity, resulting in great bone regeneration efficacy. This approach could pave the way for the development of three-dimensional biofunctional scaffolds in regenerative medicine (Park et al., 2015).

5.9.8 Other application 5.9.8.1 Carbon nanotube-based nanohybrid application Due to CNTs intriguing and improving mechanical, electrical, optical, and thermal capabilities, carbon nanotube and carbon nanotube-based nanohybrid materials are attracting large number attention in the biological domains (Bennett et al., 2013).

Superior oil sorbents Oil spills have frequently occurred in recent decades when it comes to oil extraction, storage, and transportation. Oil-contaminated saltwater has a major impact on marine vegetation and animals. CNT-based sorbents may have applications in the separation of oil and water as well as gas adsorption, according to reports (Guo et al., 1995). However, functionalized CNTs (f-CNTs) that have been treated with p-phenylenediamine have a higher surface roughness, making them better absorbents.

Heavy metal toxicity remediation The accumulation of heavy metals in drinking water is an increasing problem around the world these days. Several researchers looked at the hazardous heavy metal’s side effects like arsenic (As), chromium (Cr), cadmium (Cd), lead (Pb), mercury (Hg), and zinc (Zn). Heavy metal contamination was removed from water using a CNT-based superabsorbent mess on a large scale. The metal absorption capacity varied with increasing pH in the majority of CNT-based nanohybrid nanomaterials. The adsorption capability of heavy metals has been found to be enhanced by surface modification of CNT. Metal oxide treatment of CNTs is a good way to improve their properties. The absorption of cadmium ions from wastewater was improved by modifying SWCNTs with alumina (Al2O3) (Dutta et al., 2020).

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5.9.8.2 Agricultural applications Nanomaterials’ unique qualities, like their huge surface area, small size, and reactivity, make them ideal for agricultural applications. Insecticides, early plant growth, seed germination, biosensor monitoring, and analysis are among the most common uses of CNTs in agriculture. Nanomaterials’ potential toxicity has yet to be thoroughly investigated (Juganson et al., 2015; Lin and Xing, 2007; Zaytseva and Neumann, 2016).

Carbon nanotubes in plant growth The usage of nanoparticles as a plant and crop growth promoter has attracted the scientific community’s interest. CNTs have been shown to pierce the seed coat and stimulate the procedure for absorbing water, which could explain why seeds germinate quickly and grow quickly (Dutta et al., 2020; Spillmann et al., 2009).

5.10

Future aspects

For a long time, CNTs have had an influence on commercial products. CNTs are already employed in anti-static packaging and to control or increase conductivity in polymers. Because of their high electrical conductivity, CNTs have the potential to be a costeffective alternative to metal wires. Because of their semiconducting qualities, they could potentially replace present computer chips. For high-end applications, CNTs will most likely compete with carbon fiber, especially in applications that are weight-sensitive like Kevlar. Researchers from North Carolina State University claim that their nanotubebased imaging technology could produce sharper, quicker images than current X-rays or CT scans. CNTs are even being used in medicine. A tailored and customizable drug delivery system with CNTs is a huge task in itself.

5.11

Conclusion

The electrical and physical features of CNTs have piqued people’s interest. They are made using a variety of synthesis techniques, including arc discharge and laser ablation, to achieve the desired physical qualities, such as diameter and length. The modification of CNT physical properties, together with correct functionalization processes, will be able to overcome CNT toxicity. To effectively leverage CNT, it must be handled safely and modified appropriately. CNTs are a new class of nanomaterials with a wide range of uses in biomedical systems, including therapeutic delivery, biomedical imaging, biosensors, tissue engineering scaffolds, thermal therapy, and dentistry. Because of their vast surface area, they have proven to be effective drug delivery vehicles for vaccines, anticancer drugs, and gene delivery. They have been utilized to detect a wide spectrum of biomolecules in the field of biosensors. In tissue engineering, CNTs have been employed to improve the characteristics of traditional biomaterials. CNTs outperform carbon fibers in terms of characteristics, making them ideal fillers for composite dentistry. CNTs have

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been shown to have a greater ability to serve as a comparative tool in cancer cell identification and imaging. Despite extensive research, biomedical applications of CNT composites are still limited to the laboratory, as well as the unfavorable effects of nanostructured material CNT, particularly in vitro investigations, CNT may still have a number of notable and helpful roles in future biomedical applications.

Acknowledgment Authors thank JSS College of Pharmacy and JSS Academy of Higher Education and Research, Mysuru for providing the facility.

Individual authors’ contributions B. Vidya: Conceptualization, Writing—Original Draft Asha P. Johnson: Writing—Review & Editing, Supervision G. Hrishikesh1: Writing—Review & Editing S.L. Jyothi: Writing—Review & Editing S. Hemanth Kumar: Writing—Review K. Pramod: Review & Editing, Supervision H.V. Gangadharappa: Conceptualization, Writing—Review & Editing, Supervision.

Compliance with ethical standards NA.

Conflict of interest We have no conflicts of interest.

Research involving human participants and animals Not applicable.

Informed consent Not applicable.

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Titze, B., Genoud, C., 2016. Volume scanning electron microscopy for imaging biological ultrastructure. Biology of the Cell . Toboonsung, B., Singjai, P., 2013. Growth of CNTs using liquefied petroleum gas as carbon source by chemical vapor deposition method. Advanced Materials Research. pp. 116 119. Vardharajula, S., Ali, S.Z., Tiwari, P.M., Erogˇlu, E., Vig, K., Dennis, V.A., et al., 2012. Functionalized carbon nanotubes: biomedical applications. International Journal of Nanomedicine. Varga, M., Izak, T., Vretenar, V., Kozak, H., Holovsky, J., Artemenko, A., et al., 2017. Diamond/carbon nanotube composites: Raman, FTIR and XPS spectroscopic studies. Carbon 111, 54 61. Vasu, K., Pramoda, K., Moses, K., Govindaraj, A., Rao, C.N.R., 2014. Single-walled nanohorns and other nanocarbons generated by submerged arc discharge between carbon electrodes in liquid argon and other media. Materials Research Express 1. Villalva, J., Develioglu, A., Montenegro-Pohlhammer, N., Sa´nchez-de-Armas, R., Gamonal, A., Rial, E., et al., 2021. Spin-state-dependent electrical conductivity in single-walled carbon nanotubes encapsulating spin-crossover molecules. Nature Communications 12. Vittorio, O., Duce, S.L., Pietrabissa, A., Cuschieri, A., 2011. Multiwall carbon nanotubes as MRI contrast agents for tracking stem cells. Nanotechnology 22. Wang, J., Sun, P., Bao, Y., Liu, J., An, L., 2011. Cytotoxicity of single-walled carbon nanotubes on PC12 cells. Toxicology In Vitro 25, 242 250. Wang, W., Zhu, Y., Liao, S., Li, J., 2014. Carbon nanotubes reinforced composites for biomedical applications. BioMed Research International. Welsher, K., Sherlock, S.P., Dai, H., 2011. Deep-tissue anatomical imaging of mice using carbon nanotube fluorophores in the second near-infrared window. Proceedings of the National Academy of Sciences of the United States of America 108 (22). Wu, H., Liu, G., Wang, X., Zhang, J., Chen, Y., Shi, J., et al., 2011. Solvothermal synthesis of cobalt ferrite nanoparticles loaded on multiwalled carbon nanotubes for magnetic resonance imaging and drug delivery. Acta Biomaterialia 7, 3496 3504. Wu, Y., Lin, X., Zhang, M., 2013. Carbon nanotubes for thin film transistor: fabrication, properties, and applications. Journal of Nanomaterials. Xue, Y., 2017. Carbon nanotubes for biomedical applications. Industrial Applications of Carbon Nanotubes. Elsevier Inc, pp. 323 346. Yamashita, S., Inoue, Y., Maruyama, S., Murakami, Y., Yaguchi, H., Jablonski, M., et al., 2004. Saturable absorbers incorporating carbon nanotubes directly synthesized onto substrates and fibers and their application to mode-locked fiber lasers. Optics Letters . Yan, L., Zhao, F., Li, S., Hu, Z., Zhao, Y., 2011. Low-toxic and safe nanomaterials by surface-chemical design, carbon nanotubes, fullerenes, metallofullerenes, and graphenes. Nanoscale 3, 362 382. Yang, N., Chen, X., Ren, T., Zhang, P., Yang, D., 2015. Carbon nanotube based biosensors. Sensors and Actuators, B: Chemical. Yang, W., Thordarson, P., Gooding, J.J., Ringer, S.P., Braet, F., 2007. Carbon nanotubes for biological and biomedical applications. Nanotechnology. Yaron, P.N., Holt, B.D., Short, P.A., Lo¨sche, M., Islam, M.F., Dahl, K.N., 2011. Single wall carbon nanotubes enter cells by endocytosis and not membrane penetration. Journal of Nanobiotechnology 9. Yinghuai, Z., Peng, A.T., Carpenter, K., Maguire, J.A., Hosmane, N.S., Takagaki, M., 2005. Substituted carborane-appended water-soluble single-wall carbon nanotubes: new approach to boron neutron capture therapy drug delivery. Journal of the American Chemical Society 127, 9875 9880.

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Ateev Vohra1,*, Prateek Raturi2,* and Emran Hussain2 1 School of Biosciences, The University of Melbourne, VIC, Australia, 2School of Science, Royal Melbourne Institute of Technology, VIC, Australia

6.1

Introduction

Since its existence, at every level, humans have evolved and tried to improve the living standards, which has enhanced the quality of life directly. The earliest documented evidence of humans exploring textiles was for mere protection from the weather, which provided a barrier between the direct skin and the external environmental conditions. This evidence dates back to thousands of years (Adovasio et al., 1996; Gilligan, 2007; Kvavadze et al., 2009; Soffer et al., 2000). From the initial application in clothing, fiber got its focus throughout the period and got a chance to evolve and thus gained popularity as a fiber technology. Natural fibers like wool, silk, cotton, hemp, etc. remained the only natural fibers used in the textile and clothing industry until DuPont invented the first synthetic fiber, nylon (Carothers, 1935). Synthetic fibers are synthesized from chemical compounds. Later, many synthetic fibers were discovered, such as rayon, olefin, acrylic, Dacron, etc., which became a part of textile industry (Heckert, 1953; Houck and Siegel, 2015). After invention, it did not take much time for synthetic fibers to enter the medical and healthcare technology realms, which was earlier dominated by natural fibers. Since then, natural and synthetic fibers have become a key component in medical and healthcare technology. Fibers have been an integral part of medicine and healthcare for various applications like wound healing, dressings, sutures, and bandages (Azam Ali and Shavandi, 2016). Extensive research in medical application paved way for textilebased fibers into drug delivery (Rostamitabar et al., 2021). With modern advancements, scientists have been able to make a special category of drug delivery systems (DDS)—hollow fibers. Hollow fibers are hollow cylindrical tubular structures having the capacity to carry drugs and act as a DDS. Hollow fibers provide a high surface area-to-volume ratio and high drug-loading capacity. This chapter entails the scope of using hollow fibers for drug delivery.

6.2

Drug delivery systems

Drug delivery system refers to the engineered technology with the aim of targeted delivery or controlled release of pharmaceuticals. Drugs have been in use for a long


Authors Ateev Vohra and Prateek Raturi will share equal authorship.

Fiber and Textile Engineering in Drug Delivery Systems. DOI: https://doi.org/10.1016/B978-0-323-96117-2.00013-3 © 2023 Elsevier Ltd. All rights reserved.

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time, the earliest records of the usage of drugs dates back to 1500 BCE in Egypt, where pills were used as DDS. These pills consisted of certain medicinal compounds mixed with multiple additives like sugars and starches to protect the stability of medicine or pills (Lavik et al., 2013). The mode of drug delivery evolved rapidly in the past few decades and is key to revolutionizing the medical industry in the future. In general, DDS refers to the method, procedures, or techniques that are utilized to produce novel materials or carrier systems intended to bring a therapeutic effect (Nayak et al., 2018; Tiwari et al., 2012). The key idea behind making an efficient DDS is to be able to deliver the desired pharmaceutical drug at the desired location with the desired efficiency. Exploring novel methods and modes is the key to an effective ailment or treatment of diseases and disorders. Pharmacokinetics and pharmacodynamics have been hot topics among researchers, which can be evidenced from the vast literature from Asia, Africa, Europe, and the United States (Nayak et al., 2018). Conventional DDS that have been used to administer certain pharmaceutical products to the desired site in the body presents multiple drawbacks, which inhibit the maximum efficacy of drugs (Alagga and Gupta, 2020; King et al., 2012). The constant race to bring an effective DDS based upon the drug intended to be delivered has been one of the prime sectors for major investments around the globe. It can be identified that the conventional modes for drug delivery include lotions, sprays, a mixture of compounds, ointments, creams, paste, syrups, injectables, pills, capsules, tablets, suspensions, etc. (Nayak and Sen, 2016). The pharmaceutical sector has

Figure 6.1 This image portrays the concentration of the administered drug in the plasma over a period for three different drug delivery system (DDS). The blue line shows the concentration of drug in plasma when administered via tablet or pill, the green line shows the curve for a sustained release DDS while the dotted black line shows the curve for controlled release DDS.

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been blessed by a better understanding in the biotechnology sector, which has impacted the drug delivery sector directly (Park, 1997). This has enabled researchers to develop advanced DDS that have the capability of providing controlled drug release system, specific site targeting approaches, liposome-based DDS, dosage forms with fast dispersing action, and controlled release of drug over-controlled period of time (Fig. 6.1) (Allen and Cullis, 2013; Martı´n del Valle et al., 2009).

6.3

Hollow fibers

Hollow fibers are hollow tubular filaments with axial empty cores that can be singular or multiple. They have been an area of interest due to the advantages they offer as DDS. These fibers offer the advantage of their flexible structure, which is controlled during its synthesis or fabrication process. The structure shows a clear distinction between the rigid walls and the pores (Figs. 6.2 and 6.3). The internal hollow structure has been referred to as core while the outer rigid structure has been referred to as shell in articles (Fig. 6.3A) (Tian et al., 2021). Hollow fibers have been actively used in the field of tissue culture, bioreactor, biosensors, extraction of substances at the micro level and gas extraction (Tian et al., 2021). Using the techniques of fabrication and spinning the diameter of fiber, the thickness of fiber, its elasticity, and the thickness of pore can be altered (Ismail et al., 2006). In comparison to a usual fiber, they are 20% light in weight when calculated per unit volume (Cheung and Li, 2017). One of the initial hollow fibers was invented by DuPont, which were made from polyamide and was used in the application of

Figure 6.2 SEM images of uniaxially aligned ceramic hollow fibers. The fibers were fabricated using the process of electrospinning. The fibers were collected between the gap of two electrodes forming an array. With the help of a sharp razor blade, the horizontal section was cut to reveal its cross-section shown on the top-left side (Li & Xia, 2004a,b). Source: Reprinted with permission from Ref. Li, D., Xia, Y., 2004a. Direct fabrication of composite and ceramic hollow nanofibers by electrospinning. Nano Letters 4 (5), 933938. Li, D., Xia, Y., 2004b. Electrospinning of nanofibers: reinventing the wheel? Advanced Materials 16 (14), 11511170. Copyright © 2004 American Chemical Society.

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Figure 6.3 SEM images of different sections of hollow fiber. (A) Cross-section of wet spun hollow fiber at magnification X100. (B) Inner surface of hollow fiber at magnification X500. (C) Outer surface of hollow fiber at X10,000. (D) Cross-section of the hollow fiber at X1000. Source: Reprinted from Qin, J.-J., Gu, J., Chung, T.-S., 2001. Effect of wet and dry-jet wet spinning on the shear-induced orientation during the formation of ultrafiltration hollow fiber membranes. Journal of Membrane Science 18 2(1), 5775, Copyright (2001), with permission from Elsevier.

desalination of the water from the sea (Loeb, 2010). After many studies and research, hollow fibers entered the field of medicine as DDS due to their drugloading capacity and efficiency.

6.4

Types of hollow fibers

There are four categories in which the hollow fibers can be grouped based on their morphological structure. The four categories are one-layered, multi-layered, multihollow fiber, and branched hollow fiber. In the case of one-layered hollow fiber, there is a single shell and a single core. Most of the hollow fibers used in drug delivery make use of this kind of hollow fiber. By altering the rate of flow of the core solution and the solution for shell, the diameter for core and core-shell can be adjusted (Qin et al., 2001). Bringing strategic alterations in the core solution can also result in different shapes. The most common hollow fiber used is the cylindrical. In case of two-layered hollow fiber, using the spinning technique of coextrusion or electrospinning, different shell solutions are utilized. Whereas, if multiple solutions for core are used during the spinning process, multihollow fibers can be produced. Using 3-D printing fabrication, branched Y-shaped hollow fiber can be produced (Tian et al., 2021).

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Pharmaceutical drugs refer to the drugs that aid in diagnosis, prognosis, and prevention of diseases. Pharmacology refers to the study of these drugs. The Food and Drug Administration (FDA) website defines the term “drug” as a substance that provides a therapeutic effect, has the capacity to activate a biological effect on the function of the body system and biological products, such as proteins and hormones. The study of molecular information of the drug, its biochemical behavior, and its physiological effects are coined together as pharmacodynamics (Marino et al., 2021). When the drugs are administered into a biological system, they tend to bring certain biological effects. To bring these effects, drug needs to bind or interact with the biological system or target which further brings on molecular changes via intramolecular and intermolecular interactions. Common drug targets in biological systems include G-protein coupled receptors, ion channels, enzymes, and nuclear receptors. These interactions can be categorized into binding of drug with the receptor, chemical interactions between the drug and target, and post binding interactions (Sachdev and Gupta, 2019). The study of drug absorption, its distribution and metabolism across the body and its eventual excretion from the body are termed together as pharmacokinetics (Alagga and Gupta, 2020). Bioavailability is referred to the extent to which the desired drug is fully available for its desired biological location (Price and Patel, 2020). Conventional medicines like capsules, pills, and tablets depend upon the absorption of drugs via the alimentary canal. Once they are taken up orally, they can be absorbed through passive diffusion or carrier-mediated membrane transporters. The drawback for this mode of drug delivery is that they need to pass through the digestive system where they need to get metabolized first, in some cases this might lead to an inappropriate quantity of drugs being available for absorption (Alagga and Gupta, 2020) (Fig. 6.1). To overcome this, a high dosage of the drug is needed or multiple dosage at regular intervals of time, which also poses a drawback that it might lead to side effects due to toxicity in certain scenarios (Nierstrasz, 2007). Thus, it is often seen that when the conventions systems for drug delivery are used, they might bring certain side effects in the body that might be due to non-specific activity of the drug or when the intended drug gets released in the system in uncontrollable quantities. For the fibers to be used as an implant or as a DDS, there are certain factors that need to be taken care of while choosing the fiber. The fiber needs to exhibit the properties of being non-toxic, nonallergenic, and noncarcinogenic. The fiber needs to be compatible with the biological systems intended as targets, and provide an efficient system for the delivery of the intended drug (Belino et al., 2019). When the morphology of hollow fibers is compared with other candidates for drug delivery, the cylindrical shape offers an advantage due to its ability to cover a large surface area to release the intended drug. When compared with spherical candidates like liposomes, the volume of drugs that can be loaded is determined by the

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radius of the sphere, whereas in the case of hollow fiber, there is a control over the length and the internal radius of the fiber (Sharifi et al., 2016). Conventional medicines depend upon the physical and chemical property of drug itself for example solubility of the drug, charge on the surface of the drug, size of the molecule, and the site at which that drug has been administered, for example pH, surface area of the drug administered site, enzymes presence, subcutaneous blood flow, etc. (Gradel et al., 2018). Hollow fibers have been utilized to deliver controlled release of drug over a period of time (Polacco et al., 2002). For a DDS to have controlled drug release, it needs to fulfill certain conditions, namely the system needs to be able to sustain an optimum level of drug concentration in the blood with minimum alterations, the period in which the drug shows its effects should be enhanced for the drugs that have a short half-life, the side-effect needs to be minimized as much possible, dosing frequency needs to be short with the least wastage of drug, the drug delivery needs to be optimized as per patients compliance (Martı´n del Valle et al., 2009). Using the advantages of hollow fibers, they have been extensively researched as DDS. One such research was done with vascular grafts (Tu et al., 1991) and patented in 1988. Vascular grafts are biocompatible and mechanically durable biomaterials that are used as a mode of bypassing a blocked artery or vein. The process to implant the graft is called vascular grafting. The graft is implanted to provide blood supply to the partially or completely blocked organ of the body (Leon and Greisler, 2003). The biomaterials that have been used in the fabrication process of synthetic vascular grafts are expanded polytetrafluoroethylene, polyethylene terephthalate (Dacron), polyurethane, polycaprolactone, polylactide-coglycolide, etc. (Ravi and Chaikof, 2010; Kannan et al., 2005). In the study by Tu, Chen, and Mathewson in their US patent 5024671, they used porous vascular graft for drug delivery where the hollow fiber formed the innermost surface. This graft provided favorable conditions for tissue regeneration and recovery while preventing any kind of bleeding during the process. Another application that was patented in the year 1989 for sustained release of drugs used hollow fibers made of polyethylene terephthalate. They were used in conjunction with plaster as an advantage over conventional plaster or tapes for drug delivery (Hidaka et al., 1989). The conventional plaster has a drawback in that it displays an initial high concentration of the released drug if the plaster is layered with the drug on the side exposed toward the skin. This hollow fiber-based plaster was able to successfully deliver the sustained desired release of the drug over a period.

6.6

Ion exchange hollow fiber membranes

Ion exchange membranes (IEMs) have shown significant results as a drug delivery device in several studies (Bonvin and de Bertorello, 1994; Burns et al., 2010). IEMs can be categorized into two types. First one is the cation-exchange membranes consisting of negatively charged molecules set to the backbone of membrane

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allowing passage of cations, and the second one is anion exchange membranes, consisting of positively charged molecules attached to the backbone of membrane, thus, allowing the passage of anions through the membrane (Xu et al., 2009). In the initial studies of IEMs, they have been used to capture ionic drugs via electrostatic exchange of molecules. Hence, resulting in the ability of the membrane to differentiate between the anions and cations from the surrounding environment during the process of drug delivery (Schwendeman et al., 1992, 1993, 1994). The principle of IEMs has been utilized to create ion exchange hollow fiber membranes (IEHFMs) expressing significant results concerned with controlled release of drugs compared to application of ion exchange flat membranes (Abetz et al., 2006). The preparations of IEHFMs varies with its applicability. Wang et al. proposed an anion exchange hollow fiber membrane (AEHFMs) and hybrid anion exchange hollow fiber membrane, which were produced via sol-gel process, expressed compelling observations in regards to the controlled release of traditional therapeutic. The studies also shed light on the controlled release of ionic drugs showing the future potential of IEHFMs in biomedical applications acting as scaffolds in tissue engineering, wound healing, and organ or tissue specific drug delivery (Wang et al., 2010, 2011, 2012).

6.7

Fabrication techniques for hollow fibers

6.7.1 Solution-based technique Solution-based spinning technique is the earliest technique introduced in the initial expansion of textile industry to produce fibers. The solution-based spinning technique comprises wet and dry spinning techniques. Initially, rayon fibers were produced via wet spinning, and then dry spinning was introduced later to produce acetate fibers (Preston, 2016). The basic principle that both the techniques follow requires a viscous solution consisting of a solvent that is extruded through an extruder with the help of pressurized pump. Following this it passes through the spinneret, then the solvent is removed, leaving a fiber. The solution spinning techniques are differentiated based on the volatility of the solvent, that is, if the polymer solution is highly volatile and the formation of fiber is via solvent evaporation, then the process is called dry spinning. If the polymer solution is less volatile, the fiber must pass through a non-solvent bath to draw out the spinning solvent, enabling the fiber to coagulate; this process is known as wet spinning (Imura et al., 2014).

6.7.1.1 Wet spinning The first fiber produced using wet spinning method was chardonnet silk commonly referred to as rayon. Rayon was produced by ejecting a solution of alcohol and cellulose nitrate through the ejecting nozzle or spinneret dipped in cold water (Ozipek and Karakas, 2014). Then roller blades were used to continuously stretch and roll to

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form spindle. Wet spinning is based on the principle of precipitation where the precipitant is the synthesized fiber. There are three stages to produce a fiber using this method, a polymer solution consisting of lyophilized polymer and its suitable solvent is formed. This solution is ejected through the desired diameter of orifice of spinneret; this stage is called extrusion, preferably the diameter of the orifice should be as fine as possible, allowing the production of fine fiber. This solution is immediately released into a coagulating bath consisting of a non-solvent liquid, this stage is called the coagulating stage. This bath eradicates the solvent into which the polymer was dissolved leaving a solidified polymer fiber initiating the drawing stage. This polymer is stretched continuously using mechanical take up rollers forming a continuous fine filament of the polymer. In this stage, using the rollers desired diameter and lengths can be achieved (Shang et al., 2019).

6.7.1.2 Dry spinning In this technique, the choice of polymer is essential, as the polymer must be heated close or equal to its degradation point for it to dissolve in the solvent, which is used to produce the polymer solution. The three factors that are crucial in this process are the viscosity of the polymer solution, temperature at which the dope is created and evaporation rate of the solvents to form the filament (Imura et al., 2014). In this process the polymers are required to be soluble when mixed with organic solvents like acetone or ether. The process initiates by dissolving the intended polymer in an organic solvent of interest. Then, additives for delustering such as titanium dioxide and carbon black for pigmentation are added to the solution. This is followed by filtration. This process creates a highly viscous polymer solution called dope. The dope goes through a series of processes; where it is filtered, the air is removed and heated again. Then to achieve its right consistency, a pump maintains a steady flow to the filter; the filtered dope undergoes the extrusion process in which the dope passes through the spinneret. At a constant rate, dope is extruded, which turns into filaments. As it enters the evaporation chamber, the hot airflow of inert gas like nitrogen allows the solvent to vaporize; as a result, concentration of the polymer increases in the filaments, which solidifies the filament immediately, thereby eliminating the process of drying. In the evaporation chamber, first, the outer layer of the filament dries, creating a solid skin-like outer layer. As the filament passes downward, all the solvents evaporate. As a result, dumbbell or dog bone-shaped fibers are produced, which are finally taken up by rotating rolls and are collected onto bobbins. The fibers can be stretched more or treated with different chemicals if any desired characteristics are required before collection (Online Textile Academy, 2017). Risk factors in the process include viscosity, temperature, and evaporation rate. If the viscosity of the polymer solution is either high or low, it can lead to a defective fiber. This can also be caused by high polymer solution temperature. If the evaporation rate is high, then the formation of air pockets increases, reducing the fiber strength (Imura et al., 2014).

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6.7.1.3 Dry-jet wet spinning Dry-jet wet spinning technique utilizes the concept of both dry spinning and wet spinning (Park and Farris, 2001). One of the methods invented by H Blade, for which currently the patent is held by Du Pont showed the initial process of this spinning method (Blades, 1972). Using this there are applications where the authors utilized this spinning method to produce hollow fibers (Park and Farris, 2001). To produce a hollow fiber using this method two solutions are used—dope solution and bore solution. Viscous solution of the polymer known as dope is poured into a spinneret, while a bore fluid is fed into the inner tube of the spinneret. After filtering both the solutions to prevent any blockage during the spinning process, both the fluids are degassed under vacuum before pouring, this ensures removal of air bubbles allowing the production of continuous fibers. This whole setup is like a piston-type setup. This piston has an extruder. The movement of piston is controlled by nonreactive gasses like nitrogen. After both the solutions have reached the tip, this piston is activated at a pressure of 150 psi, the fiber that emerges from the extruder enters coagulating bath after falling through the air, the fiber is not directly extruded into the bath. As this fiber is extruded into the air, the first roller takes up this fiber and pulls it into the coagulating bath acting like wet spinning setup. This facilitates the reduction of internal diameter of the fiber. Followed by this, second roller pulls it out of the air. Then the first winder is used, which is connected to a second winder in conjunction with the coagulating bath, having same content as that of first bath. The fiber gets pulled from second roller to second winder. The second winder used in conjunction with the coagulating bath solidifies the filament. This filament is then taken out of the bath, washed in water, and stored under dry condition at room temp (Fig. 6.4) (Blades, 1972; Park and Farris, 2001; Qin, 1999; Qin et al., 2001; Zhu et al., 2008). Fibers produced via dry wet spinning method use the combination of the wet spinning and dry spinning, thus the principle remains same, while the different studies can have modified setup of the winders and take-up roller’s locations based upon the applicability.

6.7.2 Melt spinning Melt spinning is a process that is generally used for the synthetic fabrication of various forms of polymer fibers, amorphous metals, and glassy metals (Klement et al., 1960; Qin, 2016a,b). This process is used in the textile industry. In this process, dried polymer pellets or granules are inserted into a chamber to create a polymer melt, and a suitable viscosity is achieved for its extrusion through the spinneret designed with numerous pores. A metering pump maintains the pressure, allowing controlled extrusion through the spinneret. This leads to the steady production of threads of polymer filaments, which are then passed through a cold air chamber that allows them to cool and solidify into continuous long fibers. This helps retain the shape and the structure of the filaments. These polymer filaments are then spun by a series of polymer yarn, which help increase the fiber’s elasticity.

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Figure 6.4 Experimental setup for dry jet wet spinning-based fabrication of hollow fiber. The bore fluid and polymer fluid are extruded from the spinneret together into the air. After passing through air, it passes through a setup of two coagulation baths to produce the hollow fiber.

A take-up wheel finally spins the fiber for the final production of polymer fiber roll; this process is termed quenching. The spinning rate of this process is reasonably high and does not require any solvent, which makes this process highly economical (Qu and Skorobogatiy, 2015). Hollow fibers using this mechanism are produced using spinnerets of specific designs. The spinnerets used to create hollow fiber have a design, which consists of a system that blows air or liquid into the inner core creating a hollow portion within the fiber (de Rove`re and Shambaugh, 2000). Other types of spinnerets use segmented arc-type spinnerets (Oh et al., 1998). The arcs in the spinnerets may vary from 1, 2, 3, and 4 creating 2C, 3C, and 4C segmented arcs, respectively, in the spinnerets design. In these spinnerets, inflow of air between the segmented arcs are induced to create hollow inner core, thus creating hollow fibers. Some examples of hollow fiber spun via these spinnerets are polypropylene hollow fiber (Ruckdashel and Shim, 2020) and polyethylene terephthalate fibers (Oh, 2006).

6.7.3 Electrospinning Electrospinning is based on an electrohydrodynamic mechanism, during which an ultra-fine jet is generated by the liquid droplet of a polymer solution or a polymer

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melt using the application of an electric field, that stretches, elongates, and solidifies to generate fiber (Reznik et al., 2004; Robb and Lennox, 2011). In electrospinning, a pendant droplet of the polymer solution is released from the spinneret and under the influence of a strong electric field, the repulsive electric force between the surface charges that have the same polarity causes the deformation of the droplet into a conical shape (Taylor cone), from which a charged jet is released. Initially, the jet extends linearly and then, due to whipping instabilities, it undergoes rigorous circular motions. Because of the evaporation and elongation of the solvent, the charged jet thins and solidifies rapidly, until it is deposited as solid fiber on the conductive collector (Fig. 6.5) (Hohman et al., 2001; Li and Xia, 2004b; Yarin et al., 2001). The electric conductivity, concentration, and feeding rate of the solution or melt are the major factors responsible for controlling the diameter of the fiber. The fiber thickness increases with the increase in the concentration and feeding rate of the solution, whereas it can reduce significantly if the electric conductivity is increased (Dersch et al., 2007). Hollow fibers can be synthesized by using the conventionally electrospun fiber as a “template,” then coating or depositing a second material or polymer or metals upon the template using chemical vapor deposition method (Hou et al., 2002) or layer-by-layer techniques and, finally, dissolving the template by calcination or drying with centrifugal rotation dryers (Cui et al., 2008; Ge et al., 2007; Li et al., 2008; Rahmathullah et al., 2007).

Figure 6.5 Schematic diagram of electrospinning setup. The major components of an electrospinning set up include a high voltage AC or DC supply, a spinneret, a syringe pump, and a collector which collects the electrospun nanofibers.

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However, another method, called co-axial electrospinning (or co-electrospinning) is more regarded by researchers for fabrication of hollow fibers. It is a modification of traditional electrospinning in which a coaxial spinneret is used, and two different solutions are released simultaneously, from inner and outer capillaries that are arranged in a concentric configuration. A high voltage is supplied to both the capillaries and the nanofibers are fused when the solvent is evaporated and stretched (Agarwal et al., 2008). To obtain hollow nanofibers, the core material is dissolved by biodegradation, thermal decomposition, or selective solvents, when the process is completed (Dersch et al., 2007; Zhan et al., 2006, 2007).

6.7.4 Microfluidic spinning This type of spinning has the capacity to generate hollow fibers with high precision as it can be made from very small quantities of polymeric liquids. For this type of spinning capillary based microfluidic devices are used. These devices can have varying number of capillaries ranging from two or more capillaries. These capillaries are set in such manner that with the help of micro-pipette-based puller enables injecting capabilities to the orifice. The capillaries are aligned on glass slide with syringes ranging from two or more. These capillaries are arranged in co-axial manner. This assembly can be referred as microfluidic chip. In one of the studies published by Meng et al. (2016) (Fig. 6.6), they generated hollow calcium alginate microfibers. To produce these fibers, four solutions were obtained. The first solution (sol.) had distilled water and sodium carboxymethyl cellulose, sol. 2 consisted of sodium alginate and bromeosin, sol. 3 had water and polyethylene glycol, and sol. 4 had anhydrous calcium chloride. The assembly consisted of three cylindrical glass capillaries with two glass tube fixed on a glass slide. Two other capillaries were used to functions as injector. With the help of capillary puller, one end of the injector capillary was fixed into the orifice. To this, two capillaries were used to function as outlet tubes. These capillaries were fixed in an epoxy resin leaving the inlet ends open.

Figure 6.6 Experimental setup to produce hollow fiber using microfluidic spinning. This setup utilizes four different solutions that facilitate the production of precise and continuous hollow fibers which are collected on a rotor in plate with capillary tubes.

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All the aqueous solutions were loaded into a microfluidic device via their respective capillaries Here sol. 1 ends up as the core phase for the inside of the tubular microfiber. Sol. 2 forms the sheath for the fiber, sol. 4 aids in crosslinking of the alginate with the sheath, and the role of sol. 3 is to provide as a buffer for the gelation process. The hollow fiber that was created via this setup were collected in a rotating rotor with protruding capillaries serving bi-function of spool and providing a continuous pull. These hollow fibers need to be washed after formation and can be stored (Meng et al., 2016). By altering the capillary assembly, the composition of fiber can be altered. By altering the flow rate of the solutions from capillaries, the diameter of the hollow fiber can be modified (Tian et al., 2021).

6.7.5 Other fabrication techniques In addition to the aforementioned fabrication techniques, various other methods have been used to produce hollow fibers. In the template method, there are further three categories—videlicet template coating method, hard template coating, and soft template coating. These methods are prone to barriers in the development of a continuous fiber, thus limiting the length of fibers (Liu et al., 2014; Zhou et al., 2014a). In three dimensional (3D)-based fabrication technique, the inks are developed and are deposited via extruder tip directly. This method is restricted due to its inability to generate hollow fiber quickly. The other factor for its restricted usability is that there is a very high cost involved for setup (Gao et al., 2017; Wang et al., 2021). Another fabrication method utilizes the self-crimping method. In this technique, the properties of certain polymer materials to exhibit varied physical changes in their structure with the alterations in temperature is used. When these materials are exposed to certain temperatures, they end up swelling and get deformed (Tian et al., 2021).

6.8

Drug-loading in hollow fiber

One of the prominent ways to load a hollow fiber with drug involves the use of a vacuum chamber. In this setup, hollow fibers are placed in a petri plate or a relevant container containing the desired liquid. This liquid consists of the desired concentration of drug dissolved in the corresponding solution. This container is placed inside an airtight vacuum chamber with a controllable vacuum pump attached. As this vacuum pump is started, partial negative pressure is built in the chamber making the air within the hollow fiber to escape in the form of minute bubbles into the chamber and eventually get sucked out. As the fiber is surrounded by the drug solution, when the pump is turned off and the air is allowed to go in, the air pressure is back to normal pushing the leftover air to escape from the fiber and this gushes the drug solution into the fiber. As the fiber still has a negative pressure and when the chamber pressure is allowed to return to its original state, the pressure inside the hollow fiber brings the drug solution inside the fiber (Fig. 6.7). The rate of time

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Figure 6.7 Drug-loading in hollow fiber. This image shows the drug-loading procedure by developing negative pressure via a vacuum pump. When the negative pressure is developed, the air from hollow fiber gets released in the form of air bubbles. When the pump is turned off, the pressure tries to stabilize, as the pressure inside hollow fiber stabilizes, it gushes the drug solution from the vicinity into the fiber.

for drug delivery by the fiber is inversely proportional to the length of fiber. Thus, the longer the fiber, the greater would be the time needed to empty the hollow fiber. The rate of drug delivery is directly proportional to the cross-sectional area of the hollow fiber. Thus, greater the hollowness, the greater would be the rate of drug delivery. The concentration of drugs being loaded in the fiber also plays a key role in the delivery of drugs. Higher the concentration of drug in the hollow fiber, there would be a higher rate of diffusion. When cutting the fibers from the end, if a blunt tool is utilized, the ends would be pinched, which would impact the cross-section of hollow fiber by reducing the internal radius, thus, for effective delivery, sharp tools need to be used (Ahn, 1994). Another method where drug was loaded into the hollow fiber was used by Cheung et al. (2017). In this method, a vacuum beaker with drug solution was taken. To load the drug into the solution, one end of the fiber was dipped in the drug solution and the other end was connected to the vacuum pump. This was done such that when the pump was turned on, due to negative pressure build-up, the drug got sucked into the

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fiber (Cheung et al., 2017). This setup is similar to the application of a straw to draw the drink into the buccal cavity to drink. There is an ongoing commitment by researchers to develop methods that can be utilized to load the drug efficiently, which is cost-effective and does not hinder the structure of hollow fibers. Another method to load the drug in the fiber is done simultaneously while the fiber is being fabricated. In the coaxial electrospinning, the core and shell are fabricated simultaneously. In this method, the intended drug is mixed with the desired polymer solution having the eventual fate to form the core loaded with the drug. After the drug-polymer material is produced via the process of co-extrusion, the hollow fiber is formed altogether with the core and outer membrane of the fiber (Agarwal et al., 2008; Qin, 2016a,b).

6.9

Mechanism of drug release via hollow fiber

One of the major advantages offered by fiber-based DDS is ability to efficiently deliver the desired drug with the targeted accuracy for defined period. The method or way the drug gets released or transported from its delivery system is called as drug release mechanism (Shah and Halacheva, 2016). In case of hollow fibers, the morphology of the fiber plays a key role in how the drug gets released, for example the length of the fiber, release duration, hydrophobicity of drug loaded, and the fiber used, chemical properties of drug used, etc. In case of drug release via a hollow fiber, generally, there are three mechanisms that are utilized. In scenarios where there is an immediate necessity for drug release, the preferred mechanism is immediate release. In this case, there is a quick release of the intended drug into the target site. For example, in case of research where there is implant being implanted in a bio site, there are chances for infection (Chu, 2001), to overcome such scenarios, fibers that can undergo immediate mechanism are loaded with antibiotics, release of these antibiotics can prevent infections from happening at the implantation site (He et al., 2009). Another release mechanism follows extended release. In this type of release mechanism, the drug release is dependent on the rate of degradation, which leads to drug release and is influenced by the phenomena like diffusion, exchange of ions, degradation, swelling, dissolution, and decomplexation. Here, the release of drug can be controlled by defining the parameters for these phenomena, which are dependent on the rate of diffusion, thus, controlling these phenomena for different fibers gives an even greater control over the release of drug, hence the release could be made constant for a period of time or slow rate release distributed over a period (Shah and Halacheva, 2016), (Fig. 6.1). When the release is controlled by controlling the phenomena of dissolution, diffusion, and osmosis, they are called temporally controlled release. Whereas, in case where the implant is directly implanted at the intended drug release site, it is called distribution-controlled release (Chu, 2001; Shah and Halacheva, 2016). The third method for the release mechanism is called delayed release also referred as triggered release. This type of release gives a greater control, thus depending upon

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the type of material used for fabrication of fiber and loading the fiber, the release could be immediate or delayed. The stimulus that can trigger the release drug can be pH (Zou et al., 2010), light like near-infrared (Choi et al., 2019) and laser (Kurochkin et al., 2020), temperature (Park et al., 2019), sound (Lin et al., 2010; Sirsi et al., 2013), dissolution (Dukhin and Labib, 2017), magnetism (Jiao et al., 2021; Wang et al., 2016, 2021), ionic strength (Li et al., 2015; Zeng et al., 2011), erosion (Maleki et al., 2014; Sundararaj et al., 2013), etc. (Tuzlakoglu et al., 2004). Due to this broad range of control over the release of drug, this mechanism of release has been used in the applications of smart fiber-based drug delivery (Dry, 1992; Perera et al., 2018).

6.10

Drug release kinetics

Evolution in the material design and engineering research revolving around such materials has brought about significant developments in modern materials, which provides improved functionality due to improvement in complexities of designs. As novel materials are being implemented in the field of drug delivery, information about drug release gives a better picture of the functionality of fiber as a mode of delivery (Fu and Kao, 2010). There is detailed research being done for various types of fiber at an individual level to enable scientists and researchers build a better picture of the DDS (Fu and Kao, 2010). The kinetics for drug release is influenced by the physiochemical properties of the fiber, its polymer and the loaded drug together forming a system. These physicochemical properties that influence this polymer-drug system include the method of spinning used to make the fiber, method used to load the drug, drug solubility in the medium used for DDS and the interactions between the drug, fiber, and the target biological site. Mechanisms that entail the systems for mass transport include diffusion, dissolution, swelling, etc., which directly influence the release of drug onto the target site. It is often seen that hydrophilic drugs are released into the target system by mode of simple diffusion, whereas in case of hydrophobic drugs it happens by the method of swelling or the wearing off the layers of macromolecular matrix (Agnes and Ortega, 2003). Various mathematical models have been built around these mechanisms to study and predict, describe, and quantify the drug release kinetics. The key toward understanding the drug release kinetics is to be able to group and consider as much variables as possible. These variables include the dosage of drug, rate of release, time taken for the release, etc. (Rostamitabar et al., 2021). Drug dissolution refers to the speed at which the desired drug dissolves in the targeted medium (Shaikh et al., 2018). This plays a significant role in the bioavailability of desired drug (Pattnaik and Swain, 2018). In a medium, the rate of drug dissolution can be explained by, dC=dt 5 Dah Cs 2 CðtÞ




dC/dt is the rate of dissolving, diffusion coefficient of the drug is D, width of diffusion is represented by h, surface area of the polymer which is subjected to the

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medium is represented by A, Cs corresponds to the amount of dissolvable drug in its saturated state, and C(t) corresponds to the release of the concentration of drug at time “t”. Plotting a graph for drug release fraction against time gives the drug release profile. QðtÞ 5 Mt =Mtot The cumulative fraction of drug is represented as Q(t), Mt represents the amount of drug at the time “t”, and the Mtot represents the total amount of drug that has been loaded into the fiber (Rostamitabar et al., 2021). Using these equations there are various mathematical models that have been built to study the drug release kinetics via a fiber, namely zero-order (Mo¨ckel and Lippold, 1993), first-order (Mulye and Turco, 1995), Peppas and Sahlin (1989), Higuchi (Higuchi, 1961), Hixon-Crowell (Pisani et al., 2019), and Korsmeyer-Peppas (Korsmeyer et al., 1983). Understanding the drug release profile by implementing the right mathematical model for drug release kinetics aids in effective drug delivery to the target site (Rostamitabar et al., 2021).

6.11

Drug delivery applications of hollow fibers associated with different organ systems

Hollow fibers have been widely used for the delivery of a wide range of drugs. This chapter provides a brief overview of how hollow fibers have been used to bring a therapeutic effect with respect to the targeted organ system.

6.11.1 Nervous system Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease in which voluntary muscle movement is impaired due to progressive loss of motor neurons (National Institute of Neurological Disorders and Stroke, 2013). Hollow fibers were used by Aebischer et al. (1996) for treatment of ALS. The hollow fibers were 5 cm long, with 500 μm inner diameter, and 50 μm wall thickness, and their fabrication was done from poly-ether-sulfone (PES). Hollow fibers loaded with baby hamster kidney cells (Hernandez and Brown, 2010) that were genetically engineered to release ciliary neurotrophic factor (known to cause reduction in motor neuron cell death) (Middaugh and Pearlman, 1999; Richardson, 1994) were place in the cerebrospinal fluid and the results showed that this approach can be used for controlled delivery of neurotrophic factor and other proteins or peptides across the blood-brain barrier. A method was developed for treatment of Alzheimer’s disease, which involved the use of an implanted catheter, with a porous tip composed of polysulfone hollow fiber, for delivering anti-inflammatory agents, such as indomethacin (PubChem CID 3715, 2022),

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directly into the lateral ventricle (Gupta, 2017) and the hippocampus (Dhikav and Anand, 2012; Elsberry, 2007). Oh et al. (2007) constructed a 3 mm long, porous hollow fiber catheter, which was made up of polysulfone and had a sealed distal tip. Evans blue dye was introduced into the mouse brain through convection-enhanced delivery (Hall, 2009) and it was observed that, in comparison with needle-mediated infusion, the volume of the brain tissue was increased by 2.7 times when dye was infused through the catheter. Thus, for infusion of drugs into a brain tissue, its surface area can be significantly increased by using this hollow fiber catheter. Catheter-like devices were also used by Eriksdotter-Jo¨nhagen et al. (2012), Fjord-Larsen (2012), and Eyjolfsdottir et al. (2016) for delivery of nerve growth factor (NGF) into the basal forebrain. NGF is an insulin-like protein that plays a significant role in the growth and survival of forebrain, sympathetic, and sensory neurons (Aloe et al., 2015; Andres and Bradshaw, 1980; Middaugh and Pearlman, 1999). Eriksdotter-Jo¨nhagen et al. (2012) and Eyjolfsdottir et al. (2016) conducted their studies on Alzheimer’s disease patients whereas Fjord-Larsen (2012) tested the device on Go¨ttingen minipigs. The device used in all the three studies had its tips made up of 11 mm long, semipermeable, polyethersulfone (PES) hollow fiber membrane (Akzo Membrana, Wuppertal, Germany). The membrane protected the NGF-secreting cells from rejection by the host immune system while the nutrients and NGF could diffuse across the device. Fransson et al. (2018) used a similar, neurotrophic factors releasing, encapsulated cell device with a porous hollow fiber membrane for protecting spiral ganglion neurons (SGNs) in deafened guinea pigs (Nayagam et al., 2011; Scheper et al., 2019). Cochlear implant is the only option available for treating patients suffering from hearing impairment and the functioning of this implant is dependent on the survival and functioning of remaining SGNs. This device can be employed for preventing the degeneration of SGNs and maintaining their electrical responsiveness. Thus, making it a feasible cure for progressive deafness. Jiao et al. (2021) used hollow fiber for treatment of peripheral nerve injury (Qian et al., 2020). Peripheral nerve is a part of the peripheral nervous system, which is responsible for exchange of information between the central nervous system and other parts of the body (Menorca et al., 2013). The hollow fibers, with tunable elasticity, and improved conductivity and mechanical strength, were fabricated with coaxial microfluidic technology, by using sodium alginate and calcium chloride, polypyrrole, and polyacrylamide. Through in vitro experiments it was found that the PC 12 cells (Wiatrak et al., 2020), which were undifferentiated, underwent neuronal differentiation when they were treated with NGF-7S (Bax et al., 1997)loaded hollow fibers, and NGF secretion, migration, and proliferation of Schwann cells (Fallon and Tadi, 2020) was enhanced through electromotive forces generated by a pulsed magnetic field. The schwann cells were isolated from the sciatic nerve (a peripheral nerve) of male Sprague Dawley rats and it is believed that their migration promotes regeneration of the injured peripheral nerve. For in vivo studies, incisions were made into the leg of the rats to introduce injury into the sciatic nerve. Then, NGF-7S containing hollow fibers were grafted into the injured sciatic nerve after which the nerve, muscle, and skin were sutured, and the leg was subjected to magnetic pulses. It was found that by applying the NGF along with the pulsed magnetic field, the injured nerve could be regenerated, and both the nerve and muscle

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could be functionally repaired. Such applications have paved the pathway for the advancement of this concept of smart drug delivery using improved textile and fiber materials.

6.11.2 Circulatory system Extensive studies were done by Comfort and his team in 1989 for analyzing the application of hollow fibers in clinical hemodialysis; the first study conducted (Comfort et al., 1989a) used immobilized enzyme cellulose hollow fiber. These hollow cellulose fibers were loaded with heparinase to reduce anticoagulation during blood purification. Heparinase (Singh et al., 2019) immobilized to tresyl-chlorideactivated cellulose hollow fibers were used for blood purification, as the enzyme helps in eliminating heparin’s anticoagulant activity from blood. A system was created on a lab setting using various manufactured devices necessary for the circulation of the solutions and administration of the flow rates. The second study demonstrated kinetic analysis of the technique in the fiber lumen; when the mass transfer coefficient of heparin increases, the apparent Michaelis constant decreases. At the same time, an increase in Michaelis constant (Johnson and Goody, 2011) was observed when enzyme activity, which immobilized the fiber lumen, increased (Comfort et al., 1989b). The third study (Comfort et al., 1989c) illustrated that urea and creatinine clearance in cellulose-heparinase hollow fiber hemodialysis device system inhibits the elimination of passing albumins even at an increased flow rate. The in vitro analysis of above studies showed the biocompatibility of cellulose with bound heparinase with no significant change. Similarly, when celluloseheparinase hollow fiber device was used for blood perfusion, anticoagulation with no change in blood cell components levels was observed. Wound healing is also considered a crucial part of the circulatory system (Anderson and Hamm, 2012). A study published in 2011 (Hoefer, 2011) used a drug delivery system of needle webs in which cellulosic hollow fibers for wound dressing were medicated using two sets of biodegradable hollow fibers produced by the dry-wet spinning technique. These were loaded by drug solution: the first set of hollow fiber was loaded with enzyme cellulase, and the second set contained Krillase (Hellgren, 2009) and Pseudomonas-specific bacteriophages, which was used to create a hollow fiber- needle web that was self-dissolved in the presence of aqueous solutions. In vitro experiments of the study analyzed the needle web when exposed to a wet solution and an immediate release of bacteriophages and a constant release of Krillase with a high burst effect (Bhattacharjee, 2021) were observed. This novel technique can be used for certain tissue wound dressings by loading the hollow fiber needle webs therapeutic agents and drugs. When a patient goes through an open-heart surgery, artificial lungs are used to mimic the functioning of natural lungs. Salehi-Nik et al. (2016) conducted a study to improve the biocompatibility of artificial lungs via the endothelialization of the hollow fiber. The study used collagen-coated silicone hollow fibers (SiHF) patches loaded with nanoliposomal growth-inducing hormone (nGH) and antithrombotic sodium nitrite(nNitrite). This patch was subjected to finite element modeling to

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virtualize nitrite transport enclosed by a parallel-plate flow chamber, for bioavailability of nitrite on the fiber-blood interface. A closed loop system was used to expose the endothelial cells to fluid shear stress flow. The results expressed a decrease in thrombus deposition and increase in nitrate concentration; the SiHF was coated with nitrite-nGH-collagen conjugate when subjected to shear stress, which displayed an increase in endothelialization of SiHF in biohybrid artificial lungs. An increase in nitrite bioavailability on the surface of parallel plate flow chamber inhibits thrombus deposition when exposed to increased shear stress.

6.11.3 Digestive system Hollow fibers have been used for treatment of periodontal disease. In a study conducted by Lindhe et al. (1979), the fibers of length 15 mm, made up of cellulose acetate, with inner and outer diameter of 200 and 250 μm, respectively, consisting of approximately 450 μg of tetracycline HCl, were used. The amount of supragingival plaque and percentage distribution of different types of bacteria present on the tooth surfaces adjacent to the diseased sites, and the degree of inflammation of the tissue sites (gingival inflammation) were the parameters used in this study of 37 days. Through the study it was determined that the composition of the subgingival flora of diseased periodontal sites can be significantly changed, and the symptoms of periodontal pathology can be eliminated or reduced by using tetracycline filled hollow fibers. Moreover, for untreated sites, the subgingival flora remained unchanged, which shows that the hollow fiber devices had a restricted effect, which means that there was no “carryover” effect to other sites. Tetracycline-loaded hollow fibers as controlled drug delivery devices were also used by Goodson et al. (1979, 1985) for periodontal therapy. Hollow fibers, when used for oral administration, can also act as a sustainedrelease delivery system. The wet spinning technique was used to spin these fibers with 36% (w/w) polyurethane and 50% (w/w) propranolol hydrochloride (model drug) containing 2% (w/w) Klucel HF as sheath and core, respectively. For in vitro studies, the drug was released into 0.1 N HCl and for in vivo evaluation, fibers enclosed in gelatin capsules were administered to female dogs. The results were compared to those of Inderal LA (Mishriki & Weidler 1983), which is a commercial product for propranolol sustained-release, and it was found that the propranolol sustained-release profiles for hollow fiber delivery system was like those of Inderal LA (Hussain et al., 1989). In 2003, Ahuja et al. (2003) developed amoxycillin trihydrate-loaded fibers made up of a biocompatible polymer, ethylene vinyl acetate, using the melt spinning technique, for treating oro-dental infections. For in vitro studies, a container filled with an alkaline borate buffer of pH 8.1 containing 2.25% glycoproteins was used and it was found that fibers with 2% drug-loading maintained their flexibility and elasticity and the drug was released for up to 192 hours by. The drug release followed the Fickian diffusion mechanism (Ritger and Peppas, 1987). In situ studies were conducted by constructing a continuous flow through apparatus in such a way that it could mimic the conditions of the periodontal pocket. The results obtained

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from in situ studies showed that the drug-loaded fibers could efficiently inhibit the growth of microbes (Bacteroides cereus, S. mutans, and S. aureus) that are usually associated with oro-dental infections.

6.11.4 Respiratory system In case of severe improper functioning of the cardiac and respiratory system, an extracorporeal membrane oxygenator (ECMO) device is used. Its function is to facilitate oxygenation of the blood (Lindstrom et al., 2009). During the interconnection of humans with ECMO, in certain cases, coagulation and inflammatory response can be observed. To prevent this, biomaterials loaded with anticoagulation therapeutic agents can be used (Maul et al., 2016) to reduce the complications in the body that can arise from the coagulation of blood. ECMO coupled with a Levitronix CentriMag ventricular assist device (VAD) (Shuhaiber et al., 2008), consisting of Rheoparin [a commercial anticoagulant (Maul et al., 2016)]-loaded hollow fiber-based membrane oxygenator can be used for patients undergoing surgeries or suffering from conditions which require the use of an ECMO machine (Khan et al., 2008). Other types of drugs that have shown to function as anticoagulants are warfarin and enoxaparin, which can be loaded in the hollow fiber-based membrane for VAD-coupled ECMO devices (Harter et al., 2015). Tuberculosis is a pulmonary lung disease and can manifest itself in bones, central nervous systems, and other organs (Smith, 2003). Post infection, the body produces an immune response. This immune response leads to the formation of a cluster of allocated cells in an organized fashion to produce granuloma. The key role for this granuloma is to constrict the infectious bacteria within the cluster and prevent it from spreading in the body (Silva Miranda et al., 2012). There are various articles debating whether granuloma serves the function of a savior or satan (Rubin, 2009; Silva Miranda et al., 2012). Concentrating on its savior part, the immune response plays a crucial role. When the bacillus infects the respiratory tract, they affect the alveolar macrophages. These macrophages release cytokines and other chemotactic factors. Cytokines initiate a cascade of events recruiting various populations of cells. These populations of cells include more macrophages. Another category of cells called dendritic cells take up these antigens and stimulate T lymphocytes (The´ry and Amigorena, 2001). These signaling events lead to the formation of granuloma. This granuloma gets surrounded by activated macrophages and lymphocytes (Gonzalez-Juarrero et al., 2001). Exosomes are extracellular vesicles responsible for intercellular cell signaling. One of the functions performed by them is to help in T cell activation in both in vivo and in vitro models. In a study by Singh et al. (2012), in vivo model was created to study the effects brought by exosomes during pathogenesis of infection. To study this, mice were infected with TB using hollow fiber-based implants. The implants were loaded with macrophages which were pre-treated with exosomes. Their model showed that, when the mice were infected, the exosomes further stimulated the recruitment of macrophages. These macrophages also act as chemoattractants for

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leukocytes, suggesting the functioning of exosomes during the process of infection to help in the recruitment process of various cells. The exosome-containing hollow fibers were implanted subcutaneously in the mice. The study showed that these hollow fibers enhanced the recruitment of immune cells (Singh et al., 2012). Thus, by utilizing macrophages treated with exosomes and loading them in hollow fiber, implants can be used as a treatment for TB due to their property to generate a stronger immune response.

6.11.5 Endocrine system Eenink et al. (1987) conducted a study utilizing the dry-wet spinning technique, and a range of hollow fibers was produced using dope components mixed with poly (Llactide) (PLLA), and other compounds such as N-methyl-2-pyrrolidone (NMP), dioxane, chloroform (CHCl3), and polyvinylpyrrolidone (PVP). Various drug release mechanisms of each type of hollow fibers were discussed. The hollow fiber samples in this study were loaded with micronized 3H-levonorgestrel suspendedcastor oil. Levonorgestrel is a drug which inhibits egg release from the ovary and mimics the functioning of progesterone (PubChem CID, 13109, 2022). The drugloaded samples were implanted subcutaneously in the scapular region of rabbits, and the hormone level was analyzed via radioimmunoassay, which demonstrated that a constant levonorgestrel blood plasma level could be maintained, and a collagen capsule was formed around the implant. Analysis of each type of hollow fiber implant was done in both, in vivo and in vitro, to observe the drug release; two polymer H-1467(PPLA/PVP/dioxane) and H-1485(PLLA/PVP/CHCl3) had a zero-order release. In 1988, a similar study (Schakenraad et al., 1988) was conducted using poly-Llactic acid (PLLA), a biodegradable hollow fiber spun via dry-wet spinning technique consisting of contraceptive hormone levonorgestrel. The hormone suspended in castor oil was loaded in the hollow fiber for the subcutaneous implant; the hollow fiber implant used was 1 cm long and had a diameter of 0.7 mm, which was implanted in rats. The fiber used had a shell and core diameter of 0.72 and 0.4 mm, respectively. This study determined the tensile strength and molecular weight of PLLA followed by the amount of drug released over a period, by harvesting the hollow fiber from rats. The obtained result was compared with the in vitro model, and the result demonstrated a zero-order release rate in vitro and in vivo. The molecular weight of PLLA decreased over four months due to biodegrading with no significant changes in drug release. The implantation in the above studies (Eenink et al., 1987; Schakenraad et al., 1988) induced mild foreign body reaction. Moreover, a collagen capsule was formed around the implantation, which in turn increased the tensile strength of the hollow fiber. These studies provide evidence that hollow fibers can be used as long-term drug-reservoir devices for delivery of contraceptives or hormones. Diabetes mellitus causes deficiency in insulin secretion causing diabetes type 1 and type 2. This condition can affect various organs due to hyperglycemia or hypoglycemia depending on the patient’s lifestyle, which may lead to severe chronic

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diseases; hence, it is crucial to maintain and achieve near-normoglycemic glucose levels (Kharroubi, 2015). Skrzypek et al. (2020) used non-degradable multi-bore hollow fibers (MBHF) consisting of 7 cores (El-Zanati et al., 2020), which were produced by dry-wet spinning technique. The hollow fiber dope was made of PES (Ultrason E6020) and PVP dissolved in NMP. Microencapsulation of islets of Langerhans was done via cell seeding in six bores of the MBHF and a small section of encapsulated islets MBHF was implanted in mice. The formation of new blood vessels next to the implant showed that the implant was highly biocompatible. The blood vessels played an important role in exchange of glucose and insulin (Skrzypek et al., 2020). Matsumoto et al. (2020) combined hemodialysis hollow fiber with boronate gel to create a device for insulin-diffusion control. A hollow fiber dialyzer was disassembled to create this device, that was connected to a reservoir made up of silicon, which contained recombinant human insulin, a tube was used which had a catheter to load the reservoir with insulin and the other arm extruded from the device contained hollow fibers which was installed to boronate gel. Finally, the gel-installed fiber was covered with cellulose membrane for insulin-diffusions. This device was implanted subcutaneously inside a rat and insulin was released via cellulose membrane from the device. The study observed blood glucose concentrations and HbA1c over a period, the device maintained constant control over normoglycemic blood glucose levels. This study expresses the potential of this device to overcome the drawbacks of current closed-loop insulin delivery devices as it does not require any form of external source of energy, but one of the limitations of this device is that the reservoir needs to be refilled by injecting insulin into the reservoir. This study and the study conducted by Skrzypek et al. (2020) shows that hollow fibers can be used to create therapeutic devices which can be used for the treatment of diabetes.

6.11.6 Integumentary system It forms the largest organ system of the body, which includes skin (epidermis, dermis and hypodermis), associated glands, nails, and hair (Kim and Dao, 2021). Acyclovir is an antiviral drug that is used for treating herpes viruses. Acyclovir containing hollow fibers, made up of polymer polyacrylonitrile (PAN), having a diameter of 300 μm, were prepared by Zhu et al. (2008) using the dry-wet spinning process. The fibers were spread on the skin of mice, but only 8.07% of the drug released from hollow fibers was able to permeate the skin, which shows that acyclovir permeation was limited by the skin. Griseofulvin nanocrystals were produced by Zhou et al. (2018) using a hollow fiber antisolvent crystallizer. Polacco et al. (2002) created biodegradable hollow fibers and loaded them with dexamethasone nanoparticles with controlled drug release. Both griseofulvin (PubChem CID 441140, 2022) and dexamethasone (RxList, 2019) can be used to treat skin conditions. Studies have shown that topical drug delivery can also be done through drug nanocrystals to overcome the dermal barriers (Patel et al., 2018).

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Thus, hollow fibers loaded with drug nanocrystals or nanoparticles might be able to improve the bioavailability and permeability of the drug, so that they can be used in topical applications. Wound healing is a complex process involving various organ systems of the body like circulatory system (Rodrigues et al., 2019) and immune system (Guo and DiPietro, 2010). By targeting the inflammatory phase, there is a scope of utilizing hollow fiber to aid the wound healing process by targeting the skin, termed as drugloaded hollow fiber-based cutaneous wound healing. Drug delivery to the skin aids in the process of wound healing (Gainza et al., 2015; Kim et al., 2019). The wound healing process has been broadly categorized into four phases having their own individual and crucial role. The four phases are coagulation and hemostasis, inflammation of the site, proliferation, and remodeling of the wound with the help of scar tissue (Velnar, Bailey and Smrkolj, 2009). Cutaneous healing of the wound provides a bifunction of restoration of the epidermal layer of the skin and homeostasis and prevents the chances of infections. Drugs derived from chitin itself accelerate the process of wound healing (Prudden et al., 1970). This chitin and its derivatives have shown that these drugs aid in the process of migration of macrophages and inflammatory cells to the wound site. Macrophages engulf the chitosan particles and help in the promotion of an immune response. Inflammatory cells promote the release of pro-inflammatory protein-based products along with some growth factors (Ueno et al., 2001). Using a hollow fibers fabrication technique of spinning the fibers and loading them with chitin and its derived products, medical membranes, or patches can be constructed for targeted drug delivery at the wound site. One of the fabrication techniques, namely microfluidic spinning provides the scope of producing drug-loaded patches for targeted delivery of an intended drug (He et al., 2014; Plettig et al., 2015). These patches can be used at the topical surface by themselves or in conjunction with the dressing material for the epidermal layer of the skin. Another study by Zhu et al. (2019) portrayed the utilization of electrospun membranes for the delivery of tazarotene. However, further research is required to assess the efficacy of hollow fibers as potential topical agents for drug delivery and wound healing.

6.11.7 Immune system and lymphatic system Rheumatoid arthritis (RA) is a chronic, inflammatory autoimmune disease, which majorly affects the joints and cartilage, and can lead to bone erosion and physical disabilities. It can also affect other areas such as eyes, lungs, kidney, heart, blood vessels, and bone marrow (Chauhan et al., 2020; Mayo Clinic, 2019). An animal model of collagen-induced arthritis (CIA) is an animal-based model, which is widely used to perform RA studies (Pietrosimone et al., 2015). A study by Bessis et al. (1999) involved the use of hydrogel based hollow fibers (Honiger et al., 1994) that were used to encapsulate IL-4 or IL-13 (Chomarat and Banchereau, 1998) gene transfected Chinese hamster ovary fibroblasts. These modified hollow fibers were then implanted in the peritoneum of CIA mice, which were monitored for indications of arthritis. The findings of this experiment indicated that the

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severity of the disease, including the cartilage destruction, inflammatory infiltration, and hypertrophy, could be significantly reduced through this gene therapy approach. The results imply that gene transfected cells can be encapsulated in hollow fibers, which in turn can be used as therapeutic agents for treatment of rheumatoid arthritis, as well as other autoimmune diseases. Another approach of antitumor immunotherapy was brought to light by Schwenter et al. (2011). Human erythroleukemic cells (K562) (Andersson et al., 1979) were transfected to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF), which is a growth factor with a cytokine effect (Lotfi et al., 2019). The cells were encapsulated inside macrocapsules which were created with polyether sulfone hollow fibers. High levels and stable secretion of cytokines were observed upon the encapsulation of the transfected cells in hollow fiber capsules. Moreover, for applications in humans, reinforced capsules were designed, which were cryopreserved and showed adequate secretion even after one week of thawing. Stable cytokine secretion and local inflammatory reaction was observed when the capsules were implanted extra-peritoneally and subcutaneously inside mice for in vivo studies. Inflammation around the implanted area clearly indicated biological activity and potent secretion of GM-CSF. It has been stated that cytokine secretion can be modified by changing the capsule design and cell density, that is, controlled production can be achieved. The results from this study indicate that this approach of cytokine secreting hollow fiber macrocapsules has the potential to be used in anti-tumor immunotherapy. Marroquin Belaunzaran et al. (2011) showed that semi permeable polysulfone (PS) hollow fiber capsules can also be used as antibodies secreting devices for treatment of Alzheimer’s disease. Mouse myoblasts cells, in this study, were genetically engineered to secrete single-chain fragment variable (scFv) antibodies (Paganetti et al., 2005), which were encapsulated inside the hollow fibers and implanted into the cortex of the APP23 mice (Van Dam et al., 2005). These antibodies were targeted against Aβ peptide, which is a major molecule associated with Alzheimer’s disease (Verdile, 2004). Aβ production and accumulation was reduced in mice, following a six-month immunotherapy. Moreover, significant reduction in anxiety and recovery of memory traits were also observed. According to a theory, hollow fibers of high permeability can also be used to deliver drugs to the lymphatic system, by overcoming the drawbacks of currently available diffusion-based devices which can only attain a low release rate. This can be achieved by using drug-loaded hollow fiber membrane, that is implanted near lymphatics, whose hydrodynamic permeability is considerably higher than the adjacent tissue, because of which the interstitial flow would penetrate the membrane with a much greater velocity as compared to the surrounding tissue. The interstitial liquid would take up the drug before it enters the lymphatics. The successful application of this theory is largely dependent on appropriate study of physio-chemical hydrodynamics of the interstitial fluid flow and the characteristics of the hollow fibers used. Practical application of this approach could have a breakthrough in treatment of lymphatic metastasis via delivery of immunosuppressant or anticancer drugs (Dukhin and Labib, 2017).

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6.11.8 Renal system Renal system is also referred to as the urinary system and constitutes the organs responsible for purification of blood by removing waste, excess salts, and excess fluid from the body in the form of urine. The applications of renal system targeting drugs have found a hard time reaching from lab to life. One of the reasons for such limitation is the requirement of high dose concentration to bring any physiological effects, the adverse effects associated with high drug dosage corresponds to sideeffects of those drugs, for example, certain anti-inflammatory drugs. In certain disorders, for example pathological conditions, where the filtration capability of the glomerulus is affected, the accessibility of drugs is affected due to improper functioning of the kidney, thus making it difficult for the drug to reach its intended bio site (Zhou et al., 2014b). Cell-based therapy has been one of the modern techniques to provide therapeutic effects for pathological disorders. “The first broad-based application of cell therapy may be the delivery of biologic compounds as drugs” (Humes, 2005). By understanding the effects of certain cells and their biological functions, cells such as renal proximal tubule can be utilized for conditions like renal failure (Manzoli et al., 2017). Encapsulating certain cells can be utilised for the treatment of renal disease (Farina et al., 2018). Positive results for renal cell carcinoma were shown by a macro encapsulation-based device, designed to release granulocyte-macrophage colony-stimulating factors (Lathuilie`re et al., 2015). Similarly, a renal tubule assist device bearing hollow fibers fabricated from polysulfone encapsulated with renal proximal tubule cells has been studied for acute kidney injury (Humes, 2005; Tumlin et al., 2008).

6.11.9 Reproductive system Ostad (1998) studied the effects of norethisterone (PubChem CID 6230, 2022) and levonorgestrel (PubChem CID, 13109, 2022) on cytotoxicity and teratogenicity (Ele´fant et al., 2020), in vitro. Both the drugs showed toxicity to endometrial cells and potential teratogenicity at B5 and B10 μg/mL, respectively. However, when hollow nylon fibers were used for their delivery, a significant reduction in the effects on fetal and endometrial cells was observed with norethisterone. Based on the results of this study, it was suggested that hollow nylon fibers can be used for delivering norethisterone into the uterus. Another study by Gard et al. (2000) showed that hollow nylon fibers can also be used as chlorhexidine (an antimicrobial agent) (PubChem CID 9552079, 2022) releasing devices. The chlorhexidine-loaded hollow fibers were implanted into the uterus of guinea pig and the results showed that they have the potential to reduce the bacterial infections in the uterus which are caused by intrauterine devices. Experiments conducted by Ostad and Gard (2000) also demonstrated that chlorhexidine releasing hollow fibers can be considered as a safe option for treatment of intra-uterine infections, but the drug might have some adverse effects on the fetal cells. Prostate is a small gland in the male reproductive system which produces the seminal fluid that nourishes and provides a medium for the transport of the sperms.

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In a study conducted by King et al. (2012), a solution was injected into the canine prostate using a microporous hollow fiber catheter and distribution of solution was studied. Results showed better distribution with the catheter in comparison to a standard needle. These findings supported the use of this hollow fiber catheter for treatment of prostate disease. Hollow fiber’s advantage of being able to provide a large surface area and the flexibility to design its inner surface opens up possibilities for various applications. One such application that can be implemented in the field of male reproductive health is the utilisation of these fibers to treat male hypogonadism—a medical condition in males caused by abnormally low levels of testosterone hormone. In males, Leydig cells are the interstitial cells that are located next to the seminiferous tubules in the testes. These cells are responsible for producing testosterone in males. The testosterone is produced post response to luteinizing hormone (LH). This LH is secreted from the pituitary glands (Vasta et al., 2006). Low testosterone levels were conventionally thought to be due to ageism, in contrast, there have been reported incidents of impairment in the release of this hormone in young adults as well (Cohen et al., 2020). The current treatments include delivery of this hormone externally throughout the lifespan. Based upon the four different studies by Li et al. (2019), Lamb (2019), Machluf et al. (2003) and Skrzypek et al. (2020), we propose a possible approach of testosterone delivery via hollow fibers. The study by Li et al. (2019) presents a method to direct human embryonic stem cells and human-induced pluripotent stem cells populations that have the development origin from the same human pluripotent stem cells having the capacity to differentiate into any kind of somatic cells (the cells that have diploid chromosomes, all cells except male or female gametes), thus, paving a pathway to treat male hypogonadism by directing these cells to differentiate into Leydig like cells to produce testosterone. The study by Lamb (2019) provides an approach to direct these Leydig cells to get differentiated from human pluripotent stem cells. The study published by Machluf et al. presents a method of microencapsulation of these Leydig cells. In this study, the researchers isolated Leydig cells from male Sprague Dawley rats, cultured these cells in vitro and encapsulated them in calcium alginate microspheres. Then the researchers implanted these microspheres into castrated male Sprague Dawley rats. Though this study revealed the release of low levels of testosterone in rats, the ones with microsphere implants showed that the testosterone levels were sustained for a longer duration in comparison to the rats with ip injection of unencapsulated Leydig cells showing the testosterone release for a shorter duration of time. In this study, they also showed that no level of testosterone was detected in the castrated rats who were not given these Leydig cells via implantation or injection. The study by Skrzypek et al. (2020) portrays a microdevice created using high cell capacity bearing multi-bore hollow fiber for microencapsulation of the islet of Langerhans to produce insulin in diabetic patients. The study published by Lamb (2019) sheds light on the need to understand the ultrastructure and genetics of these Leydig cells and pathways to differentiate these cells from stem cells. As we are advancing toward having a better understanding of these cells, one of the possible applications to treat hypogonadism is to utilise a

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high cell bearing capacity multi-bore hollow fiber-based system to make a device similar to catheter-based systems as shown by Eriksdotter-Jo¨nhagen et al. (2012) and Eyjolfsdottir et al. (2016). This device can be utilised for macroencapsulation of Leydig cells into the multi-bore and can be implemented to treat hypogonadism after researching a suitable location for the implantation of this device for testosterone delivery via hollow fibers.

6.11.10 Skeletal system Tetracycline is an antibiotic that portrays its therapeutic effects in periodontal defects by regeneration of the periodontal tissues (Panwar and Gupta, 2009). Moreover, it prevents the progression of alveolar bone loss in dogs (Jeffcoat et al., 1982). In studies conducted by Goodson et al. (1979) and Lindhe et al. (1979), tetracycline hydrochloride-loaded cellulose acetate HF were used for periodontal therapy. Though the studies done by Goodson and Lindhe using tetracycline-loaded hollow fibers did not include its application in bone grafting and bone regeneration, studies by Kang et al. (2015) and Jeffcoat et al. (1982) express the future potential of tetracycline-loaded hollow fibers for regeneration of bone and prevention of the progression of alveolar bone loss. Various studies state that bone marrow stromal cells are mesenchymal stem cells that can be used as “stem cell drugs” (de Girolamo et al., 2013; Polymeri et al., 2016; Van Pham, 2016). In combination with human bone marrow stromal cells (HBMSC), the hollow fiber can be used as stem cell therapeutics/drugs to reconstruct skeletal tissue (Morgan et al., 2007). In the study conducted by Morgan, HBMSC were cultured for mesenchymal stem cells expansion, which were loaded in biodegradable porous poly DL-lactide-co-glycolide HF via cell seeding. The perforated acrylic graft chamber was combined with HBMSC-loaded HF which prevented its displacement from the implantation site. The graft chamber was implanted in the flank of SCID mice. Evidence of type I collagen deposition, mineralized bone, osteoid formation, collagenous proteins within a bone matrix, and evidence of new woven bone was confirmed from the study. Jin et al. (2020) proposed pH-sensitive anti-inflammatory therapy against knee osteoarthritis. The study used chitosan packaged hollow mesoporous silica nanoparticles loaded with celastrol (PubChem, CID 122724, 2022) which were injected via the intra-articular pathway. As a result, a decrease in cartilage damage and relieving inflammation, in vitro and in vivo, was observed (Jin et al., 2020). Nonsteroidal antiinflammatory drugs such as sodium salicylate (NaSA) (PubChem, CID 16760658, 2022) can be used in the treatment of arthritis. Wang et al. (2011) used brominated poly(2,6-dimethyl-1,4-phenylene oxide) to create AEHFMs and loaded them with NaSA. In vitro studies provided proves for high loading capacity and prolonged drug retention of the membrane. Thus, it can be said that there is a scope of using such hollow fiber membranes loaded with nonsteroidal anti-inflammatory drugs for treatment of pain and inflammation associated with chronic and osteoarthritis. Bone regeneration ability was observed via a drug delivery device designed by Kang et al. (2015). The device used a nanofibrous scaffold consisting of

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mesoporous bioactive nanospheres (MBNs) (Kang et al., 2015). The MBNs were used as a bioactive carrier, for long-term delivery of an osteogenic enhancer fibroblast growth factor (FGF18). The MBNs containing FGF18 were loaded into the hollow fibers made up of polyethylene oxide and another set of hollow fibers made up of polycaprolactone was loaded with FGF2. FGF2 is a cell proliferative and angiogenic growth factor. Rat mesenchymal stem cells, on exposure to FGF2FGF18 hollow fibers, demonstrated cell proliferation, initiation of alkaline phosphate activity, and skeletal cellular mineralization. For in vivo studies, the nanofibrous scaffold was implanted in a rat calvarium. The results exhibited significant bone-forming ability of fibroblast growth factor-loaded hollow fibers. These devices (Kang et al., 2015; Wang et al., 2011) have the potential to improve the symptoms and therapeutic progression of osteoarthritis. Such approaches of drug delivery via hollow fiber technology might be helpful for improvement of severe symptoms of osteoarthritis, bone fractures in various joints, induce bone tissue regeneration and inhibit cartilage damage.

6.12

Other drug delivery applications of hollow fibers

There are various drug delivery applications of hollow fibers which have been extensively studied in vitro, in cell cultures and animal models. Some of these studies are elucidated below in Table 6.1.

Table 6.1 Studies conducted for drug delivery using hollow fibers indicating the polymer used for the fabrication process and the loaded drug. HF/HF polymer used

Drug/therapeutic agent/chemical compound/s used

Application/purpose of study

Poly-L-lactic acid

Levonorgestrel

Poly(L-lactide), (PLLA)

Adriamycin

Bromomethylated poly (2,6dimethyl-1,4-phenylene oxide)

Sodium salicylate, sodium methotrexate, and Congo red

To analyze the potential of poly-L-lactic acid hollow fiber as a drug delivery device (Schakenraad et al., 1988) Anti tumor activity (Esselbrugge, 1994) To analyse the potential of HF dendronized with Poly (amidoamine) for drug delivery and tissue engineering (Zhang et al., 2012) (Continued)

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Table 6.1 (Continued) HF/HF polymer used

Drug/therapeutic agent/chemical compound/s used

Application/purpose of study

Sodium alginate (mixed with Fe3O4 nanoparticles)

Doxorubicin hydrochloride

Calcium nitrate, triethyl phosphate with a phaseseparation-induced agent, poly (ethylene oxide) Polypropylene or Polysulfone (with calcium alginate gels)

Gentamicin sulfate for drug loading and release studies

To synthesize magnetically driven hollow fibers for controlled released of drugs (Wang et al., 2021) Wound healing and hard tissue repair (Hong et al., 2010)

Nylon 6 or polyamide 6 (PA 6)

Antibiotic penicillinstreptomycin solution

Hydroxyapatite

Bovine serum albumin

Polycaprolactone (with added Fe3O4 NPs)

Ketoconazole

Polyethylene

Fibroblast growth factor

Cellulose

In vitro studies performed using PEG

Polysulfone

differentiated islets and porcine islets (derived from mesenchymal stem cells)

Poly(L-lactide), PLLA

3-ketodesogestrel, cisplatin and Adriamycin

Endothelial cell growth supplement (ECGS)

To assess neovascularization potential of ECGS delivered through HF (Tilakaratne et al., 2007) To develop textile-based devices or clothing with antibacterial action (Cheung et al., 2017) Potential application as bone defect repair treatment (Yi et al., 2016) Potential application as antimicrobial or for treating fungal infections (Wang et al., 2016) Aneurysm healing (Kawakami et al., 2006) Drug delivery pump was designed using hollow fibers that can be useful for infusion-therapy of diabetic and hypertensive patients (Tanaka et al., 1986) HFM developed can be used as implantable pancreas as a therapy for type 1 diabetes (Teotia et al., 2017) Synthesis of porous membranes of Hollow fiber for drug delivery system (van de Witte et al., 1993)

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6.13

199

Prospects

Hollow fibers hold immense potential for becoming efficient carriers for targeted drug delivery inside the body. They have shown to increase efficacy of drugs by increasing the surface area for drug absorption. Their ability to act as smart DDS and deliver the drug, based upon an external or internal stimulus opens the possibilities of a plethora of applications in medicine. The key for utilizing the hollow fibers to their extent lies in the exploratory studies to understand the properties of hollow fibers and determining how certain cells and tissue react to them or to the drug delivered by them. One such field where they can be of great advantage is organ transplantation. Using the hollow fibers and macroencapsulation of certain cells within the lumens of fibers, they can be designed to release hormones or biological components. This can prove to be helpful in patients who need an immediate organ transplant. This setup can also be used as a therapeutic treatment in people who are unable to produce certain biological components in their body. As discussed above, these fibers can also help in production of testosterone in people having certain medical conditions affecting this release. Similarly, they can be applied in wound healing to fasten up the process. Similar studies to facilitate a fast immune response, targeting the granuloma are in the clinical trials where hollow fibers are being used to deliver certain drugs that can facilitate the recruitment of macrophages. These studies are being done to explore the use of hollow fibers for treatment of tuberculosis. The goal for using such strategies is to prevent the requirement of organ transplant, the complications that can arise due to inaccessibility of organs at the right time and organ rejection by the host’s body. Moreover, hollow fiber devices might be modified for fast action of delivered drugs and with least side effects. As indicated, there is a great gap between research being done in a lab and their practical application in life. It might be a giant leap for mankind but based upon the level of advanced scientific tools that are now available, it won’t be long enough that studies like these will become the building blocks for the next era of medicine.

Acknowledgments The authors would like to thank the publishers of this book, Dr. Navneet Sharma and Dr BS Batola, for giving us the opportunity and the guidance to write this chapter in their book. We would also like to thank Mr. Chung Tai-Shung Neal for allowing us to use the picture from their article titled “Effect of wet and dry-jet wet spinning on the shear-induced orientation during the formation of ultrafiltration hollow fiber membranes”. The Figs. 6.4, 6.5, 6.6, and 6.7 were created using BioRender.

Authors’ contributions Ateev Vohra made Figs. 6.1, 6.4, 6.6, and 6.7, and collected information about hollow fibers, their types, their use for drug delivery and the drug loading, drug release

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mechanism and drug release kinetics of hollow fibers. All the authors contributed towards the fabrication techniques. Prateek Raturi made Fig. 6.5, collected data for Table 6.1 and was also the corresponding author. Prateek Raturi and Emran Hussain collected information about the drug delivery applications of hollow fibers. All the authors wrote, reviewed, and contributed to the final manuscript.

Compliance with ethical standards Not applicable.

Conflict of interest The authors declare that there is no conflict of interest.

Research involving human participants and animals Not applicable.

Informed consent Not applicable.

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Anju Singh1,2, Shoaib Khan2,*, Nishu Nain2,* and Shrikant Kukreti2 1 Department of Chemistry, Ramjas College, University of Delhi, Delhi, India, 2 Nucleic Acids Research Lab, Department of Chemistry, University of Delhi, Delhi, India

7.1

Introduction

Nanoscience focuses on observing and studying the unique phenomena and properties exhibited by structures and materials at the nanoscale, whereas nanotechnology deals with the utilization of nanoscience in designing and producing nanomaterials and devices for their real-world applications. The word ‘nano’ comes from a Greek root which means DWARF or something super small or one billionth of a meter. Fig. 7.1 represents a brief integration of various objects and species on a nanoscale (comparison of macro, micro, and nanometer). So, now we have the idea of how super-duper tiny nano is. Since the size is a material property, with the change in the size, various material properties change. With the size down to the nanoscale, the surface to volume ratio increases so does the number of atoms or molecules at the surface which changes the surface forces of any material. Thus, nanomaterials have a relatively greater surface area to volume ratio that leads to their unique properties compared to macrosized materials. Nanomaterials exhibit different physical, chemical, electrical, mechanical, and optical properties than bulk materials i.e. can be lighter, faster, more energy-efficient, and can get into small target sites. Nanomaterials can be categorized into three types based on dimension: G

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One-dimensional (1D)—it has only one dimension within the nanoscale. Examples are nanofilms, layers, coatings, etc. Two-dimensional (2D)—it has two dimensions within the nanoscale. Examples are nanowires, nanofibers, nanotubes, etc. Three-dimensional (3D)—all the three dimensions at the nanoscale. Examples are nanoparticles and nanoshells etc.

7.2

Evolution of nanoscience

The scientific community had long debated whether the matter is continuous or particulate, which has taken us to what we consider as an indivisible particle of an atom (1021 nm). So, nanoscience is not new, the evolution may take us back to as


Shoaib and Nishu have contributed equally to writing this chapter.

Fiber and Textile Engineering in Drug Delivery Systems. DOI: https://doi.org/10.1016/B978-0-323-96117-2.00011-X © 2023 Elsevier Ltd. All rights reserved.

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Figure 7.1 Brief representation of objects and species on the nanoscale.

much as the 5th century BC when a famous Greek philosopher “Democritus” gave the theoretical concept of the indivisible fundamental particle (https://www.britannica.com/science/atom/Development-of-atomic-theory). Nanomaterials were already found to exist even long before the modern scientific era (Kokarneswaran et al., 2020; Sharma et al., 2017; Sciau, 2012). Ancient and medieval artisans had been using nanomaterials for their unique properties. However, they were not aware of the cause of these unique properties. Modern research has recognized their existence which has given nanoscience significant validation. In the era of modern science, Michael Faraday’s colloidal suspensions of ruby gold arguably present the first study which demonstrated how nanoparticles exhibit unique optical and electronic properties (Faraday, 1857). While scientists started to observe unique phenomena in the early 20th century, the visualization of nanomaterials was still a distant place. However, by the end of the 1930s researchers were able to break through to the nanoscale with the discovery of electron microscopes (Von Ardenne and Beischer, 1940; Knoll and Ruska, 1932; Mu¨ller, 1936). These microscopes were capable of providing images of far greater magnifications than what was possible with optical microscopes. The resolution could get down to one million times compared to 1500 times of optical ones. The scientific world eventually got to see atoms in real for the first time with the invention of the field-ion microscope (Mu¨ller and Bahadur, 1956).

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The conceptual origin of nanoscience or nanotechnology is widely believed to be inspired by the talk of the famous American physicist and Nobel laureate Richard Feynman. In his lecture (1959) entitled “There’s Plenty of Room at the Bottom,” he talked about the concept and possibilities of manipulating materials at the atomic level (Feynman, 2011). The ideas were very promising for a new scientific world, but somewhat too early to be accepted, thus this talk did not get much coverage. However, Nanoscience continued to progress gradually for another few decades with multiple developments. In the meantime, a Japanese scientist “Norio Taniguchi” coined the term “nanotechnology” in 1974. He described nanotechnology as the science of processing materials atom-by-atom (Taniguchi, 1974). The early 1980s gave it a boost when a scanning tunneling microscope (STM) was invented (Binnig et al., 1982). The development proved such a milestone for the entire science that the inventors were awarded the Nobel Prize in 1986. This invention inspired the further developments of the atomic force microscope (AFM) (Binnig et al., 1986) and scanning probe microscope (SPM) (Binnig, 1990) which allowed to image nanomaterials in three-dimension and thus made it possible to manipulate atoms and fabricate nanomaterials for the first time. These inventions became so popular and useful that they are still extensively used in the scientific community. The table consists of a list of a few remarkable developments in nanoscience. In a very short time, a large number of nanomaterials are now being used for their unique properties in the development of various research fields such as chemistry, physics, material sciences, computational science, and biomedical sciences. Nanoscience or nanotechnology has begun to be treated as fundamentally applicable to creating materials for industrial production.

7.3

Nano-bio interface

In particular, nanoscience or nanotechnology has done wonders with its exponential growth in biomedical applications, that is, in the diagnostic, control, or treatment of various diseases. Owing to their small size, bio-nano materials fall in the typical size range of biological components. Thus, they can interact more effectively with functional entities of biological systems both on the surface as well as inside the cells. By gaining access to various physiological targets inside the body, they show the potential to diagnose diseases and offer treatment. Several studies have featured the potential of nanomaterials in nanomedicine. Nanotechnology offers multiple advancements in bioimaging, biosensing, and targeted drug delivery systems (McNamara and Tofail, 2013). Few other noteworthy biomedical applications include tissue and implant engineering, 3D printed bionic organs, artificial cells, prostheses, etc. (Zheng et al., 2021; Di Marzio et al., 2020; Ramos et al., 2017). The interaction of nanomaterials and biosystems has led to the advent of the most dynamic areas of research, that is, nanobiotechnology and bionanotechnology. Moreover, both fields can be referred to as the convergence of nanotechnology and

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biology. However, there is a small distinction. Nanobiotechnology works on applying the fundamentals of nanotechnology to develop nanomaterials or devices that have physicochemical and biological applications. These nanomaterials may or may not have any biomolecule involved and might include other material-based structures for the advancements in biological research from diagnosing disease to treating or eventually curing it. “Lab on a chip” and “real-time sensors” are two excellent examples of efficient diagnostics. Other examples of nanobiotechnology include the development of matrices for targeted and controlled drug delivery, tissue engineering, and so on. On the other hand, bionanotechnology refers to the study of biological nanostructures and their potential applications. Bionanotechnology is more focused on applying biochemical ideas to create nanodevices for various fields (technological applications of biomolecular nanomaterials). This approach might not be confined to biological applications but rather in practice offers a much broader scope. Bionanotechnology utilizes biomolecules like nucleic acids and proteins to build nanostructures that could have various technological applications. Fig. 7.2 gives a schematic representation of the convergence of nanotechnology and biology. One of the primary research areas in bionanotechnology is DNA nanotechnology which itself has emerged as a novel field of research. This chapter will focus more on the DNA nanotechnology field and its applications in drug delivery systems.

Figure 7.2 Schematic representation of nanotechnology-biology interface.

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DNA nanotechnology

DNA, besides being a carrier of genetic information in all living things on earth, has also evolved as an inarguably preferred structural component for designing and fabricating a wide range of nanomaterials. DNA offers various advantages over other biomolecules because of its Watson-Crick self-assembling nature. DNA structures are very appropriate to construct nanomaterials because the DNA selfassemblies are easy to produce, predictable and programmable since they depend on simple Watson-Crick base pairing. These features can virtually empower the synthesis and assembly of DNA strands into any desired architecture. DNA nanotechnology presents an extended class of self-assembled structures posing unparalleled opportunities. This field involves the designing and development of programmable molecular assemblies of nucleic acids of controlled size, geometry, and functions for technological use. Since, the last three decades, the use of nucleic acids has exponentially improved in medical therapies because of their inherent properties of biocompatibility and structural programmability. Though nanostructures have a variety of applications, most importantly they are used for biomedical purposes such as biosensing, bioimaging, biomedicines, smart therapeutics, and drug delivery (Bujold et al., 2018).

7.4.1 Advantages of DNA in nanotechnology G

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Basic properties like thermodynamics and geometry are already well known. A variety of bioinformatics tools help in predicting functional and structural features of DNA. The helical structure of DNA contributes to the framework to work with. The self-assembly properties of DNA make it simple to fabricate a wide range of structures. DNA sequences can be modified and controlled using commercially available enzymes. Synthesis of single-stranded DNA is quite economical. DNA macromolecular structures can easily be visualized by various imaging techniques like Atomic Force Microscopy (AFM), Transmission Electron Microscopy (TEM), etc.

7.5

DNA nanostructures

The architectural properties of DNA help in the construction of nanoscale DNA materials. In general, the self-assembly of ssDNA sequences with predefined Watson-Crick base pairing complementarity produces DNA nanostructures. The main idea of engineering DNA nanostructures is to design distinct domains (or subsequences) in ssDNA complementary to other domains so that ssDNAs can rationally hybridize to create complex structures. DNA nanostructures can be categorized into two types on the basis of their design: scaffolded DNA nanostructures and tile-based DNA nanostructures. In scaffolded DNA nanostructures, the long ssDNA (typically a long strand of bacteriophage

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Figure 7.3 A glimpse of DNA nanostructures.

genome) folds into the desired structures with the help of staple strands. These staple strands are short ssDNA which interact with long ssDNA and regulate their folding. Paul Rothemund invented the notion of DNA origami in 2006 (Rothemund, 2006a,b), which has now evolved into a wide range of techniques for creating scaffolded DNA structures (Dietz et al., 2009; Veneziano et al., 2016; Han et al., 2011, 2013a,b; Marchi et al., 2014; Yang et al., 2012; Zhang et al., 2013; Zhao et al., 2010, 2011a,b). On the other hand, tile-based DNA nanostructures are constructed from a collection of short ssDNA strands but unlike scaffold structures do not have long folding strand (Ke et al., 2012; Wei et al., 2012a,b). Currently, both the designing techniques are used in order to create DNA nanostructures (Nummelin et al., 2018; Zhang et al., 2014a,b; Pinheiro et al., 2011; Feldkamp and Niemeyer, 2006; Wang et al., 2017). Fig. 7.3 consists of a glimpse of DNA nanostructures.

7.5.1 Driving forces of self-assembly of DNA nanostructures DNA strands as building blocks self-assemble to form multiple ordered assemblies. These biomolecular assemblies are formed based on geometrical and chemical recognition. The driving forces that are involved in these formations are generally noncovalent interactions (Lee et al., 2010). Noncovalent interactions, unlike covalent

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bonds, are generally considered much weaker since they are more dispersed within a molecule (Anslyn and Dougherty, 2006). However, they have a prominent impact on self-assemblies individually or synergistically. G

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Hydrophobic effect—Among all the noncovalent interactions, the hydrophobic interactions are the most important for self-association. Biomolecules are amphiphilic and contain polar and nonpolar regions. These molecules are self-assembled in aqueous solutions through the microphase separation technique. In this process, the nonpolar parts of the molecules collide with each other and form clusters, while the polar parts are attracted to water (Lee et al., 2010). These hydrophobic clusters then self-assemble into a core with a hydrophilic shell surrounding it. Amphiphilic diblock copolymers are examples of this technique. Electrostatic interactions—Another important interaction in the self-assembly process is electrostatic interaction. Cationic polymers can interact with anionic regions of proteins or nucleic acids via electrostatic interactions to produce stable nanoparticles in aqueous solutions (Li et al., 2013). The conjugated polymers show different binding affinities with different forms of nucleic acids. Thus, hydrophobic and electrostatic interactions play important roles in designing various biosensors (Xia et al., 2010). Hydrogen bonding—This again is a kind of an electrostatic attraction that takes place between molecules having H-atoms and electronegative atoms. Biomolecules for example nucleic acids and proteins exhibit enormous Hydrogen bonding patterns. In addition to other interactions, Hydrogen bonding helps with the stability of self-assembly (Ulijn and Smith, 2008). ππ staking—Similar to Hydrogen bonding, ππ interactions also play supporting roles in stabilizing the self-assembled nanostructures. In the case of multi-ordered self-assembled polymeric aromatic peptides, the ππ interactions along with hydrogen bonding hold the structures together (Silva et al., 2013). The other examples where ππ interactions play significant roles are folic acid and methotrexate nanostructures (Gottarelli et al., 1996; Kamikawa et al., 2004; Lock et al., 2013).

In brief, noncovalent interactions play a significant role in the construction of nanostructures, either separately or synergistically. Controlling these interactions can be critical for the design and development of multiple ordered self-assembled nanostructures. Thus, these interactions should be implemented rationally in strategies to functionalize nanostructures, especially in drug distribution.

7.5.2 Formulation of DNA nanostructures The design and creation of DNA nanostructures begin with the modeling of the structures. There are plenty of online tools available that can help in optimizing the structures based on thermodynamic parameters with their smart algorithms. CaDNAno (Douglas et al., 2009a,b), CanDo (Castro et al., 2011; Kim et al., 2012), and Daedalus (Veneziano et al., 2016) are some examples of such software tools. These software provide the interface to generate 2D and 3D molecular coordinates of the desired DNA origami structures as well as allow their computational analysis (Li et al., 2014). The experimental approach for preparing DNA nanostructures involves mixing of scaffold and staple strands in slight alkaline conditions. The mixture then

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undergoes structure-specific annealing. The staple strands are used in excess amount to favor thermodynamics of the reaction (Ke et al., 2012). The product is then purified and excess or unbound reactants are eliminated. Finally, the target DNA nanostructure formed is characterized to ensure structural accuracy using different characterization techniques such as gel electrophoresis, fluorescence, atomic force microscopy, transmission electron microscopy, chromatography, etc. (Mathur and Medintz, 2017).

7.6

Holliday junction in designing DNA nanostructures

Holliday Junction is a four-way DNA junction that is formed as an intermediate in the DNA recombination process. It mainly contains a cross-shaped structure formed between two double-stranded DNA molecules when they undergo segment exchange during recombination. The two ds-DNA start to unwind and interact with complementary strands of another ds-DNA molecule. The strands of ds-DNA molecules get separated into four double-stranded arms to form a cross-shaped structure (Holliday junction). This structure was first proposed in 1964 by Rabin Holiday (Holliday, 1964). Even before the basic concept of DNA nanotechnology given by Nadrian Seeman in 1982 (Seeman, 1982), a variety of natural branched DNA Holliday junctions were already in existence. These structures proved to be fundamentally key components to generating various DNA nanoformulations. Seeman had proposed that these junctions could be built into crystalline lattices. The formation of the first DNA cube was demonstrated in 1991 and further 2D-lattices were built, made up of double crossovers providing rigidity to the structure (Chen and Seeman, 1991). Another breakthrough in DNA nanotechnology came in 2006 when Paul Rothemund invented a new formulation technique to build much more creative DNA nanostructures (2D-DNA origami) of any arbitrary design (Rothemund, 2006a,b). Just after three years, Seeman finally demonstrated the formation of a 3D-DNA origami that made it possible to create much bigger nanostructures (Seeman, 2010). Fig. 7.4 represents a brief history of DNA nanotechnology. These inventions were followed by the formation of more advanced DNA nanostructures such as DNA polyhedral, DNA networks, DNA nanorobots, DNA nanowires, etc. Four-way junctions may form conformational isomers based on various factors (Nain et al., 2021).

7.7

DNA aptamers in functionalizing DNA nanostructures

In addition to the well-celebrated double-helical structure, DNA/RNA oligonucleotides can form either through the folding of a single strand or association of two, three, or four strands, giving rise to several exotic multistranded nucleic acid structures involving W-C, Hoogsteen, and reverse-Hoogsteen hydrogen bonding

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Figure 7.4 Emergence of DNA nanotechnology.

(Kukreti et al., 2010; Kaushik et al., 2011a,b, 2016, 2017; Singh and Kukreti, 2018a,b; Khan et al., 2021). Aptamers are not a particular class or type of structures but rather defined by their functionality as nucleic acids; ds-DNA, ss-DNA, RNA, etc. which form secondary structures due to intermolecular interactions and thus can bind with an analyte of interest via noncovalent forces such as hydrogen bonds, electrostatic attraction, Vander Waals forces, etc. This analyte of interest can be anything from single large molecules, biomolecules, nanoparticles, cell receptors, organelles, to entire cells. systematic evolution of ligands by exponential enrichment (SELEX) is used to isolate aptamers, which is a process of exposure of potential DNA or RNA library containing millions of unique sequences to an analyte, followed by coincubation and washing to isolate sequences based on binding affinity. This process is repeated several times to obtain pure sequences (aptamer) with high binding affinity. The selection and binding process of aptamers have been compared to antibodies, that is why they have also been termed as chemical antibodies, with many advantages over the same. Aptamers can be identified, isolated, and synthesized in vitro and thus do not require cell cultures. They can be mass-produced quite inexpensively because they are mostly prepared by using the PCR technique. They are more tolerant to denaturation across a wide range of pH, temperature, and humidity, making them potential candidates in realistic environmental conditions. Owing to their specific structural properties, they have been combined with various other materials, particularly nanomaterials for the fabrication of nanosensors, and aptamer functionalized drug-containing nanocarrier which is of great use in the specific delivery of drugs to their required site as well as accurate detection of pathogens and other pollutants for quick countermeasures. DNA nanotechnology may be differentiated into two parts depending on structural behavior i.e. Structural DNA nanotechnology and Dynamic DNA nanotechnology.

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Structural DNA nanotechnology

Structural DNA nanotechnology deals with the construction of desired nucleic acid assemblies by using DNA motifs. These motifs are rendered through mutual exchange of strands via sticky ends, edge-sharing, or other coiling interactions. These nanostructures may be further divided based on geometry into 2D- and 3D-DNA nanostructures.

7.8.1 2D-DNA nanostructures 7.8.1.1 DNA tiles and lattices DNA strands having sticky ends form various complex structures by DNA crossovers. Here, the two different strands of DNA are joined by the sticky ends and form a programmable DNA lattice structure known as DNA tiles. There are three major strategies for the formation of DNA tiling lattice: (1) unmodified self-assembly for 2D pattern in a predictable manner. However, in the case of complex structures, it requires sophisticated control of parameters like crystal growth rates, nucleation rates, and spontaneous nucleation and error rates. (2) Second is the sequential stepwise assembly by using molecular building blocks with solid support. It removes the excessive reactant present in every step. This kind of assembly is mostly used in complex structure formation. (3) The third strategy is “directed nucleation assembly” in which the already assembled DNA encodes the pattern information and arranges the other oligonucleotide around its input scaffold strand for the formation of the desired pattern of DNA tiles (Sharma et al., 2018). Various simple and complex DNA crossovers are designed and optimized. The formation of long one-dimensional and two-dimensional structures has been reported by the use of DNA tiles with sticky ends (Li et al., 1996; Malo et al., 2009; Mao et al., 1999). Also, well documented are the other structures, like double- and triple-crossover DNA tiles, tensegrity triangles (Liu et al., 2004a,b) four by four DNA tiles (Yan et al., 2003), and six-helix tube (Mathieu et al., 2005), etc. The general rule for designing a structure is to avoid sequence symmetry to circumvent the undesirable pairing (He et al., 2005). The same ensures the perfect geometry to grow larger without any distortion in the DNA nanostructure. However, there are a few major drawbacks of this method: G

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First, designing complex structures is very challenging one should have to check the new sequence at every time-consuming step. Second, for high order nanostructure, it is very hard to control the production. The available sticky strands have no control over oversize. The third drawback is to obtain the predicted structure, the strands are quantitatively controlled.

7.8.2 3D-DNA nanostructures 7.8.2.1 DNA polyhedral DNA polyhedral are formed via interlinkage of DNA with DNA junctions to construct a cage-like structure (Sadowski et al., 2014). Seeman and coworkers designed

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the earliest DNA polyhedral in the form of the cube by using six DNA strands. For the synthesis of DNA cube and octahedron, solution-phase synthesis is used and a covalent ligation method is utilized for connecting all the components. After the formation of DNA polyhedral, the restriction enzyme method and Polyacrylamidegel electrophoresis was used to analyze the structure. Later they also reported the truncated octahedron (Chen and Seeman, 1991). In 2004, Goodman and his group developed a single-step technique for DNA tetrahedron formation by self-assembly technique and reported a high yield of around 95% (Goodman et al., 2004). Later on, various nanostructures such as tetrahedron, icosahedron, dodecahedron, and nanoprisms were designed by the DNA self-assembly technique (Aldaye et al., 2008; Aldaye and Sleiman, 2007). The DNA polyhedral structures have a nanocapsule cavity and functionalized surface which make them useful in drug delivery, biomaterials, diagnostics, and carrying payloads like organic polymers, gold nanoparticles, etc. (Aldaye and Sleiman, 2006, 2007). Erben et al. reported the encapsulation of cytochrome C protein conjugated with the oligonucleotide of DNA tetrahedron (Erben et al., 2006). In a separate study, Bhatia et al. showed the efficient uptake of the FITC-dextran loaded DNA icosahedron in vivo model of Caenorhabditis elegans cell lines (Bhatia et al., 2011). In an animal model study, the streptavidin-antigenencapsulated CpG-functionalized DNA tetrahedron showed enhanced immune response in comparison to streptavidin alone (Schuller et al., 2011).

7.8.2.2 DNA origami The nanoscale folding of DNA to produce arbitrary 2D and 3D shapes at the nanoscale is known as “DNA origami”. An approach to constructing DNA structures under DNA origami has emerged in the last decade, (Chandrasekaran and Zhuo, 2016). It folds the long-stranded bacteriophage using more than 200 complementary staple strands to twist the backbone (Angell et al., 2016). The variety of 2D and 3D nanostructures, include tetrahedrons, smiling faces, DNA barrels, DNA nanotubes, and “DNA dolphins” (Chandrasekaran and Zhuo, 2016; Smith et al., 2011; Zhao et al., 2012; Andersen et al., 2008; Rothemund, 2006a,b; Zhang et al., 2014a,b). As mentioned above, the first DNA origami was proposed by Paul W. K. Rothemund in 2006 (Rothemund, 2006a,b). This method uses the annealing of short oligonucleotides for the creation of 2D- and 3D-DNA nanostructures. A diverse DNA origami was constructed by varying the number, arrangement, and DNA helix length. This method involves the use of short chemically synthesized DNA strands (staple strands) for the folding of large naturally occurring DNA (scaffold). The DNA base pairing has the self-assemble feature which forms a definite structure. In this process, the staple strand is mixed with the scaffold strand, heated, and annealed. The staple strand gets attached to the long DNA and gives it a specific architecture. These origami structures are rigid, condensed, and more stable as compared to DNA polyhedrons. DNA origami requires a long DNA which is mostly taken from M13 bacteriophage, however the DNA extraction and purification process face endotoxin contamination issues. In the early development phase, Rothermund

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constructed various arbitrary structures such as squares, triangles, rectangles, stars, smiley faces, and many more structures. Interestingly, later using this method, a Chinese group reported and designed a map of china. With the improving involvement of bioinformatics tools, several software have been developed to design DNA origami (Andersen et al., 2008; Douglas et al., 2009a,b). Recently, the software canDo was developed by the Dietz group to predict the properties such as the final shape and flexibility of structures (Castro et al., 2011). DNA origami has various applications in photonics, memory storage, drug delivery, and many more applications currently at the testing stage (Douglas et al., 2009a,b). Du and coworkers have recently reported the use of 2D triangular and 3D-DNA origami tubes for doxorubicin delivery. Doxorubicin is a DNA intercalating anticancer drug. These origami structures showed the enhancement in the drug loading efficiency, enhanced cellular uptake, and enhanced properties in regular human breast adenocarcinoma cancer cells (MCF 7) (Zhang et al., 2014a,b).

7.8.2.3 DNA nanotubes DNA nanotubes are cylinder-like structures molded from DNA double-helical domains whose helix axes are linked to each other by at least two crossovers resulting in DNA double-crossover (DX) molecules (Holliday, 1964). The two helix axes are coplanar such that the unit can be considered as a box-like unit (two-dimensional array) that can be tailed into sticky ends to form a cylindrical structure (Fu and Seeman, 1993). As reported in the literature DNA nanotubes are of two different types (Rothemund et al., 2004a,b; Mitchell et al., 2004). One type is made up of the DNA double-crossover (DX) molecules and the second type of DNA nanotube is formed to contain the precise numbers of helices, which are applied to the molecule by sequence design. DX molecules are quite stiff (Sa-Ardyen et al., 2003) and have found applications in algorithmic (Rothemund et al., 2004a,b) and periodic assemblies’ formation (Winfree et al., 1998), translation systems (Liao and Seeman, 2004), and in nanomechanical devices (Mao et al., 1999). Strand switching between helices to be at positions leading to particular structures enforces the bend angle between DX components. For example, for DNA with 10.5 base pairs per turn, strand switching at 7 or 14 base separations results in 240- or 120-degree angles, respectively, resulting in a six-helix bundle (Mathieu et al., 2005; Constantinou et al., 2006). Recently, the most common method for producing low-stress DNA nanotubes with precise numbers of helices and with specifically designed enclosed cavities has been reported (Sherman and Seeman, 2006). Despite the widespread interest in constructing cavities of certain shape and size, DNA nanotubes seem very fascinating to sheathe specific rod-like species seen either in nanotechnological or biological systems such as amyloid fibrils, microtubules, and actin filaments (Garibotti et al., 2006; Zheng et al., 2006). Molecular dynamics (MD) simulations have been used extensively to deduce the structure and properties of DNA nanotubes (Yoo and Aksimentiev, 2013; Snodin et al., 2016; Joshi et al., 2015). Aksimentiev et al. using MD simulations revealed that DNA nanotubes undergo substantial structural fluctuations in nanometers (Yoo and Aksimentiev, 2013).

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Furthermore, in most cases, tube opening has been reported where DNA nanotubes are formed via cyclization of 2D arrays. To prevent the tube opening, enzymatic ligation can also be employed in some nanotube designs (O’Neill et al., 2006). Alternatively, intrinsically cyclic species such as the six-helix bundle (6HB) motif, can be produced possibly. Kuzuya et al. demonstrated the three ways to make specific DNA nanotubes corresponding to the half circumference of components (Kuzuya et al., 2007). The first one is to make particular six-helix bundle (6HB) molecules by joining couple of distinct bent triple-crossover (BTX) molecules to form a 6HB where their terminals are phased together. The 6HB molecules are linked by sticky-ended cohesion at their tips and centers to form nanotubes. Second is forming 6HB nanotubes by combining two different BTX molecules phasing half a length to each other. Here the molecules are joined only by cohesion at their centers and in the complete absence of sticky ends on their tips. Thirdly, 8HB formation from arched 4HB molecules. These 8HB molecules are combined to produce 8HB nanotubes. Because of their chemical and structural features, DNA nanotubes have become an intriguing material with potential uses in engineering and biology. They can be functionalized by adding nanoparticles and/or biomolecules to them. Moreover, stiffer nanotubes have the potential to replace the actin filaments and other cytoskeletal components, for both technological and biological applications. It is crucial to characterize the physical properties to implement those applications. A large number of DNA nanotubes have been documented to be synthesized so far, either by assembling designed closed species of DNA helix bundles or by folding 2D arrays into cyclic species (Douglas et al., 2007; Ke et al., 2006; Liu et al., 2004a,b, 2006; Mathieu et al., 2005; Mitchell et al., 2004; O’Neill et al., 2006; Park et al., 2005; Rothemund et al., 2004a,b; Yan et al., 2003; Yin et al., 2008). Also, a few nanotubes are metalized that might be used to create DNA nanowires or as templates for the 3D geometrical nanoparticle arrangements (Sharma et al., 2009). In only some cases, the persistence lengths of nanotubes have been assessed and evaluated (Rothemund et al., 2004a,b; O’Neill et al., 2006).

7.9

Dynamic DNA nanotechnology

This subfield focuses on developing nanostructures that have useful dynamic features. These disequilibrium dynamics allow complexes to reorganize and be autonomous based on chemical or physical changes. One of the simple methods of designing dynamic DNA nanostructures is DNA strand displacement which works on thermodynamics and allows the construction of various autonomous nanomachines.

7.9.1 DNA tweezers DNA tweezers are one of the recent DNA nano complex formed by DNA hybridization technology (Yurke et al., 2000). These were designed by taking three strands

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namely A, B, and C, where strand A partially hybridized with the other two strands B and C to get linked with each other to form a V-type structure that has the flexibility to move and twist. These tweezers can be dynamically open or closed depending on the appropriate stimuli, that is, the sequential addition of fuel or antifuel strands. This open or closed state of tweezers can be determined by FRET using fluorophore and quencher on the arms of tweezers. Further, the researchers developed more tweezers and use them for the cyclic processes as a biocatalyst (Chen and Mao, 2004). The DNA tweezers have various applications such as cell repairing, drug delivery, and nanoscale devices.

7.9.2 DNA walkers As the term indicates DNA walkers are the DNA nanostructure having legs like two oligonucleotides attached with the single-stranded DNA linkers. This structure consists of basically four content; a track, walker, fuel strands, and antifuel strand. The foot of the DNA walker is a duplex with a single-stranded extension which tends to be paired with its complementary strands. Various research approaches have been carried out over the past few years for the development of fully autonomous walkers and their movement with the help of DNAzymes, enzymatic stimuli, photolysis, and restriction enzymes. This structure has various functional properties such as picking up and dropping off cargo and can be performed as DNA-templated synthesis (Yin et al., 2004).

7.10

Why are DNA nanostructures suitable for drug delivery?

DNA nanostructures are good candidates for drug delivery possessing a combination of exceptional features, summarized below. G

G

Predictable and well-defined structure: It is well established that the shape and size of objects have an impact on cellular internalization pathways. Given the ease and flexibility in designing and synthesizing DNA nanostructures with various sizes and shapes ranging from several nanometers to micrometers. This versatility provides us with a good opportunity to try out different architectures as drug carriers with plenty of room to adapt to different parameters for cellular internalization (Gratton et al., 2008; Huang et al., 2012). High capacity for cargo loading: There are several methods that can be used to bind DNA with functional molecules. These include covalent modification, nucleic acids hybridization, biotin-avidin interactions, and DNA duplex intercalation (Bandy et al., 2011; Sacca` and Niemeyer, 2012). It is feasible to accurately control the valence and the position of cargo molecules due to the well-defined and highly addressable properties of DNA nanostructures, a property that is barely achieved with organic or inorganic nanomaterials. For example, Streptavidin (STV) binding at predefined sites of a DNA nanostructure can be achieved by chemical modification of DNA strands with biotin (Sacca` and Niemeyer, 2012; Sacca` et al., 2010; Voigt et al., 2010). The hybridization of cargo-bearing nucleic acids provides an alternative method for loading cargo molecules at particular locations

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G

G

G

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(Lee et al., 2012). In addition to such specific binding methods, payloads can also be directly incorporated within container-like nanostructures assembled with DNA (Bhatia et al., 2011; Zhao et al., 2011a,b). Capability to be internalized by cells: While nucleic acids are notoriously difficult to enter the cellular membrane, Mao and colleagues discovered that DNA nanotubes tagged with folic acid may bind receptors on the surface of cancer cells, resulting in internalization (Ko et al., 2008). Turberfield’s and coworker’s findings in 2011 that tetrahedral DNA nanostructures could easily enter into live cultured cells without the use of any ligand or transfection agent, implying that pure DNA nanostructures of specific geometries can be internalized by mammalian cells regardless of their surface charges (Li et al., 2011; Walsh et al., 2011). Sleiman et al. also found that a tubular-shaped DNA nanostructure assembled with rolling circle amplification (RCA) was effective in cellular uptake (Hamblin et al., 2012). Although the mechanism of such internalization is not yet clear, there has been evidence that these DNA nanostructures are actively taken up by cells, maybe through microtubule-mediated endocytic pathways. Structural stability under physiological conditions: Stability and integrity of DNA nanostructures’ in the intracellular environment are crucial for their functions in vivo. However, it is challenging to directly characterize DNA nanostructures in living cells through conventional nanoscale characterization techniques, such as AFM. In the presence of specific and nonspecific nucleases, Keum et al. investigated the resistance of DNA nanostructures using electrophoresis (Keum and Bermudez, 2009). In their demonstration, they showed that tetrahedral nanostructures were substantially more stable than linear DNA strands. In another study, Yan and coworkers examined the stability of several DNA origami constructed in lysate from different cell types (Mei et al., 2011). Agarose gel electrophoresis is used to separate the origami-lysate mixtures, and complete DNA structures were retrieved for functional assays and further microscopic examination, demonstrating that artificial DNA origami nanostructures, unlike natural single- and double-stranded DNA, are stable in cell lysate. The stability of DNA nanostructures was further investigated in mammalian cells by FRET using fluorophore tags on DNA nanostructures (Li et al., 2011; Walsh et al., 2011). The structures remained mostly unchanged inside the cells for about 48 hours showing their potential as delivery carriers. Excellent Biocompatibility: Being a natural material present in all living things, there should be minimal concerns over the biocompatibility or toxicity of DNA molecules. Several studies have demonstrated that DNA nanostructures do not exhibit obvious toxicity in intracellular or in vivo applications. (Ko et al., 2008). They are also good biodegradable materials due to their biological nature. However, this is also evident in some studies that nanostructures of particular shapes and sizes may have a certain degree of immunity (Schuller et al., 2011).

DNA nanostructures are mostly negatively charged and hydrophilic molecules that make it hard for them to penetrate cells directly through the cell membrane (Mishra et al., 2020). As a result, transfection agents, mainly cationic polymers such as endocytosis, doxorubicin, and lipofectamine are frequently used to compensate for the charge to ensure efficient cellular uptake of DNA nanostructures. It has been documented that such DNA nanostructures have better uptake efficiency when combined with cationic and hydrophobic molecules (Lv et al., 2006; Zhdanov et al., 2002). Nevertheless, the new findings demonstrate that DNA nanostructures that can easily pass across the membrane barrier are of high interest in examining the delivery potential of these biological vehicles.

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Modes of drug delivery

7.11.1 Passive delivery Typically, drugs are often allied in nanostructures with the help of nanocarriers via chemical interaction or physical encapsulation and are supplied passively (referred to as “cargos”). In the past, nanocarriers have incorporated the drugs physically into their interior cavity via noncovalent bondings, particularly the hydrophobic interactions (Keith and Cui, 2015; Liu and Fre´chet, 1999). For example, several nanobased carriers (nanocapsules, nano micelles, etc.) encapsulate drugs through hydrophobicity and carry drugs to target sites where nanostructures disassemble to release drugs (Chung et al., 2014). One of the major disadvantages associated with physical encapsulation is its low drug loading capacity (Lin et al., 2013). On the other hand, chemical conjugation involves the direct bonding of drugs with nanocarriers. The interaction between drugs and nanocarriers must be controlled in such a way that drug release triggers only at target sites to achieve optimal bioactivity. Further, if drugs dissociate rapidly from their nanocarriers, they will not be able to reach the action target sites in the required dose. This phenomenon is known as burst release which can result in faster removal of drugs (Keith and Cui, 2015). Thus, designing rational strategies can prove to be very crucial for efficient drug delivery.

7.11.2 Self-delivery The general methodologies outlined above simply treat drugs as active substances that must be delivered. In recent years, many utmost important features like selfassembly as well as solubility are neglected. There has been an increasing trend to make building units of well-defined nanostructures with drug molecules. Such a strategy in nanostructures is required to precisely control the delivery and constituents of drugs. Through rational analysis, nanostructures have been designed and formulated with high and definite drug content (Allen and Cullis, 2013). One of the prime challenges for nanotechnology is effective drug delivery. The idea is that nanoparticles can provide many advantages over conventional drug delivery, that is, more efficient drug delivery to target sites, thus reducing dosage and adverse side effects. Various nanomaterials have been explored for this purpose such as polymeric particles (Markovsky et al., 2012), liposomes (Torchilin, 2005), carbon nanotubes (Bianco et al., 2005), quantum dots (Christine et al., 2012; Probst et al., 2013), extracellular vesicles (Johnsen et al., 2014), solid-lipid nanoparticles (Mu¨ller et al., 2000), engineered viruses (Lu et al., 2015), spherical nucleic acids (Zheng et al., 2012), and RNA nanoparticles (Shu et al., 2011). Despite tremendous efforts, however, the goal of the accomplishment of effective drug delivery has not been achieved. Very few nanoparticle drug delivery systems were translated to clinic purposes from the laboratory, yet dominated by tiny molecules and protein-based biologics (Petros and DeSimone, 2010). The biological barriers in the body are often accounted for a low success rate for therapeutic nanoparticles

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(Blanco et al., 2015). The biological barriers mainly comprise of organs (spleen, liver, and kidney) that filter or take up nanoparticles, scavenger cells from the innate immune system that phagocytize nanoparticles, and also the physical cell boundaries of the targeted cells including the endosomal and plasma membranes that eliminate nanoparticles from the cell interior. These multidimensional challenges impose strict stringent criteria for nanoparticle design in terms of shape, size, and surface modifications (Okholm and Kjems, 2016).

7.12

Recent advances in DNA nanostructure-mediated drug delivery

With millions of different cases reported every year, cancer is one of the foremost grounds of death and disease all over the world (Cong et al., 2016). There are various approaches to treating cancer, each with its own set of benefits and drawbacks. Cisplatin (CPT), a platinum-based medicine, is commonly employed to treat several malignancies (Jung and Lippard, 2007; Kang et al., 2015). CPT suppresses cancer cell proliferation by interfering with the transcription process of the cell. Apoptosis, commonly known as cellular death, is caused by the suppression of cellular DNA transcription (Zhou et al., 2015). CPT is frequently used for the treatment of various malignancies such as testicular, lung, bladder, ovarian, and cervical as a first- or second-line treatment (Dhar et al., 2008; Jamieson and Lippard, 1999; Rosenberg et al., 1969). However, systemic toxicity, primarily owing to kidney injury, severely limits its use (Leong et al., 2007). Since CPT is employed to cure many types of cancer, it is efficacious to improve its effectiveness while reducing its noxious side effects (Latcha et al., 2016). The majority of clinically recommended dosages lack an effective response to the targeted sites, resulting in a passive mode of transport of active components into tumor cells leading in decreased efficacy and increased toxicity. In modern medicine, developing effective and safest carriers to a targeted site for cytotoxic drug delivery still remains a serious issue. The nanoparticle-based delivery system has gained popularity over the past 20 years, and materials made up of liposomes and inorganic and organic polymers are utilized to make nanoparticles (Baig et al., 2019; Kumar et al., 2016). Improving the pathways of drug delivery to the targeted sites is one strategy to enable active transportation and reduce systemic toxicity. When the body is exposed to the minimal and the tumor site excessively, both the drug efficacy and toxicity are improved. DNA is an excellent material owing to its complementary base pairs and ease of production to achieve the appropriate morphology of nanoparticles. Multiple DNA strands can be mixed and self-assembled into predetermined forms (Tørring and Gothelf, 2013). Consequently, DNA-based materials might be created to have precise features for a variety of applications, such as biosensing, drug delivery to specific areas, and nano- and microelectronics (Kallenbach et al., 1983; Seeman, 1982). Many nanoscale systems have been explored to produce drug delivery

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systems, but the DNA nano thread (DNA-NT) based architecture has many advantages over other approaches. Each of the particles in the DNA-NT-based structure possesses similar physical properties, such as size, shape, and charge (Andersen et al., 2009; Dietz et al., 2009; Douglas et al., 2009a,b, 2012; Ho¨gberg et al., 2009; Kang et al., 2015; Liedl et al., 2010; Rothemund et al., 2004a,b, 2006a,b; Zhao et al., 2012). The DNA-NTs have been used to bound the drug and safeguard it from the surrounding environment in the cell culture medium, making it longer for the drug to reach cancer cells (Dhar et al., 2008; Wang et al., 2018). A recent report has shown the delivery of CPT via DNA-NT technology by utilizing base pairing to design the delivery carrier. DNA-NT as a polyanionic ligand stimulates scavenger receptors on the cell surface, causing DNA-NT to be endocytosis via the clathrin/ caveolin endocytic pathway, as shown in Fig. 7.5 (Abbas et al., 2021). Doxorubicin (Dox) is a type of chemotherapy drug that can be embedded into the duplexes of DNA origami resulting in lower drug resistance and higher cytotoxicity in cancer cells. Recently, Zhao and coworkers demonstrated that doxorubicin-loaded DNA origami nanostructure tends to provide an efficacious delivery system in breast cancer cells, with a high level of internalization and excessive programmed cell death as shown in Fig. 7.6 (Zhao et al., 2012). Instead of utilizing straight nanotubes, Hc¸gberg et al. designed 18HB nanotubes having different degrees of global twist.

Figure 7.5 Schematic representation displaying the cellular uptake of cisplatin-loaded DNA nano thread (CPT-DNA-NT) toward the tumor cells (HeLa) in vitro; (A) binding on the cell surface of DNA-NT. (B) Internalization by scavenger receptors of CPT-DNA-NT. (C) Intracellular CPT delivery.

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Figure 7.6 Schematic depiction for doxorubicin delivery by DNA origami systems.

They have the potential to boost cytotoxicity and decrease the elimination rate of drugs in cancer cells. Intriguingly, twisted nanotubes exhibited a 33% greater loading capacity and slower release kinetics than straight nanotubes. As a result, twisted nanotubes may serve as a promising platform for drug delivery. In recent years, self-assembled DNA nanotubes have emerged as one of the most promising drug delivery vehicles (Chao et al., 2014; Jiang et al., 2012; Kim et al., 2013; Niemeyer, 2000; Rinker et al., 2008; Xie et al., 2016; Zhang et al., 2014a,b). Mao and coworkers reported that DNA nanotubes tagged with folate acid may target receptors present at the surface of cancer cells, causing internalization as shown in Fig. 7.7 (Ko et al., 2008). Sleman et al. demonstrated that DNA nanotubes can load cargo along the tube’s length and trigger the release of this cargo during specific external stimuli responses (Lo et al., 2010). Lichteneggar et al. reported the cellular uptake of DNA nanotubes carriers along with siRNA molecules (Kocabey et al., 2015). Rehberg et al. showed that DNA nanotubes were a promising targeted delivery vehicle for tissue macrophages (Sellner et al., 2015). These findings have considerably enriched the understanding of the role of DNA nanotubes as a drug delivery vehicle. However, the molecular level interaction mechanism between DNA nanotubes and drugs is seldom researched and remains unknown. Particularly, the effect of structure of DNA nanotubes on drug distribution is yet to be examined, which obstructs the molecular design and modification of DNA nanotubes as drug carriers. Liang et al. investigated the clinically popular anticancer drugs such as daunorubicin (ADR), doxorubicin, vinblastine (VIN), and taxol (TAX) tend to adsorb strongly on the DNA nanotubes (tetramer, hexamer, and octamer). Moreover, the stability of DNA nanotubes also improved with the absorption of anticancer drugs. Their studies proposed that DNA nanotubes were promising delivery vehicles as shown by the strong adsorption of drugs (Liang et al., 2017). Often, there has been

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Figure 7.7 Overall strategy: (A) self-assembled DNA nanotubes include both a fluorescence dye (Cy3) and a targeting agent (folate); (B) dual-functionalized DNA-NTs specifically bind to cancer cells via folate-folate receptor (FR) interaction.

a challenge to thread a potential target species via the cavity of the DNA nanotube at the center. To overcome this, DNA half tubes are designed to cover one side of a rod-like species that can form full nanotubes, so producing the complete cavity and possibly sheathing its contents. DNA nanotubes can transport a variety of functional agents through intercalation into dsDNA grooves, base pairing, and other interactions. Toll-like receptor 9 (TLR9), a specialized receptor of the innate immune system, recognizes CpG sequences, triggering an immunological response (Li et al., 2011). Liedl et al. deliver 62 CpG sequence using a 30HB into spleen cells via base pairing. This combination could stimulate the immune system more than traditional carriers like Lipofectamine (Schuller et al., 2011). They also created 8HBs in vivo as CpG delivery vehicles (Sellner et al., 2015). Sprengel et al. tailored DegP protein by conjugating the DNA strand and protein inside a hexagonal DNA prism (Sprengel et al., 2017). Stupp and coworkers made bioactive DNA-peptide nanotubes that directed the differentiation of neural stem cells into neurons (Stephanopoulos et al., 2015). Richert et al. reported that the internal cavities of 4HBs can specifically bind pyrimidine nucleotides with micromolar affinity (Schwarz and Richert, 2017). Sleiman and coworkers deployed PEG- and polystyrene-DNA copolymers onto rung-like DNA nanotubes via sequence-specific hybridization, which might be used as a cargo carrier (Carneiro et al., 2012). Ke et al. investigated the different stages of the intracellular trafficking of DNA nanotubes in cancer cells by using the localized AuNPs on the nanotubes (Wang et al., 2018). Developing artificial carriers capable of delivering functional agents into cells is important for disease diagnosis and treatment. Several carriers have been reported, such as dendritic polymers, (Shukla et al., 2005) viral capsids, (Brown et al., 2002)

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inorganic nanoparticles, (Rosi et al., 2006; Wei et al., 2012a,b) carbon nanotubes, (Kam et al., 2006) and DNA nanostructures (Jiang et al., 2012; Pei et al., 2012). DNA nanostructures are a viable candidate among them for their low toxicity, biocompatibility, and high programmability. The cellular absorption (uptake) efficiency of DNA nanostructure was impacted by shape, size, and cell line. Remarkably, most of the studies manifested that DNA nanotubes had a greater cellular absorption efficiency when compared to ring-shaped, spherical, and other DNA nanostructures, especially for larger rigid nanotubes (Bastings et al., 2018; Liu et al., 2019; Rahman et al., 2017; Wang et al., 2018). DNA nanostructure-based vaccines are potent carriers for immunizing against numerous human diseases, including tuberculosis (Tang et al., 2015), malaria parasites (Tyagi et al., 2012), hepatitis B (Huang et al., 2017), and Alzheimer’s disease (Matsumoto et al., 2013). Without eliciting vector immunity, DNA-based vaccination is found to be effective in triggering humoral and other cellular immune responses (King et al., 2015). Some advantages of DNA-based vaccinations are reported where Lyse´n et al. found that T cells can be easily polarized and activate a Th1 immunological response. High stable and long shelf life of DNA vaccines than protein-based vaccinations, making them more convenient in terms of manufacturing, storage, and transport (Stenler et al., 2014). Besides, DNA tetrahedra (wireframe nanostructure) fabricated from DNA-lipid micellar nanoparticles have the potential to assemble more CpG ligands. DNA tetrahedra is also used as a nanocarrier for the targeted CpGs delivery that penetrates the cell without any transfection agent and efficiently triggers a robust immune response. They can also mimic the complex structure of Virus-like particles, providing an ideal multifunctional platform for the manufacturing of DNA vaccines. Here, the antigen and adjuvant immediacy is quite advantageous to improving the immunogenicity of the vaccine. DNA tetrahedrons were used for the first time as a scaffold for the construction of synthetic vaccine complexes comprising streptavidin (STV), a model antigen, and CpG (Liu et al., 2012). Significantly, DNA tetrahedrons can uphold the delivery of CpG and antigens together to cancer cells which is a vital prerequisite for immune response (Chi et al., 2020).

7.13

Pros and cons of DNA nanostructures in drug delivery

Applications of DNA nanostructures have been limited for quite a time, but recently these allusive structures are referred to as molecular vehicles or DNA nano vehicles, used to deliver cargo to the target cell. The permissible shape and size of nanoparticles are spherical below 25 nm, which is efficient to get filtered in the kidney as well as absorbed in the liver, whereas particles having size 150 nm or above, are shown to have more propensity for filtration in the spleen and attacked by macrophages, ultimately undergoes phagocytosis (Petros and DeSimone, 2010). This advisable size and shape of nanoparticles play a pivotal role in vivo also

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(Blanco et al., 2015). DNA nanostructures are found to be a superior nano vehicle above all owing to their property of being molded in any desired shape and getting functional with varied molecules in any stochiometric control. Undeniably, owing to distinctive properties DNA can be fabricated for creating nano vehicles to deliver cargo in the biological system. Being polymorphic and dynamic molecules, programming of DNA nanostructures can be done skillfully to respond against external stimuli like markers for molecular ailments as well as pH with very high specificity. This facilitates DNA nano vehicles to monitor changes in their surrounding solution environment and plans their action accordingly at the target organs. It is easy to identify specific nucleic acid strands using strand displacement reactions. For example, these studies can lead to induce conformational changes to occur in dynamic DNA origami structure which in turn releases the loaded cargo at the particular target (Andersen et al., 2009). It was established that proteins and small molecules can activate DNA origami structures in vitro as well as in vivo via binding to DNA aptamers which engrossed in-network with DNA nano vehicles (Amir et al., 2014; Douglas et al., 2012; Modi et al., 2009). These fascinating DNA nanostructures can be programmed to use for sensing pH change in the surrounding environment by incorporating them with I-switches. Various nucleic acid modules can be used in hybridization with DNA nanostructures such as short interfering RNAs (siRNAs) and antisense oligonucleotides as these are more efficient for drug delivery owing to their capability to regulate gene expression in the cellular environment.

7.13.1 In vitro and in vivo structural stability of DNA nanostructures/DNA origami structures Several challenges are faced by a biological system, which raises questions about the integrity of DNA nanostructures. Almost every DNA nanostructure is found to be stable with appropriate physiological buffer and salt conditions at room temperature, but the scenario is completely changed in the complex solution condition inside the cell. In vivo DNA nanostructures have to deal with DNases, elevated temperature, varying salt concentration (e.g., Mg21 concentration less than 1 mM in blood as well as within cells), many DNA binding proteins, etc. A plethora of reports are available in which scientists studied the stability of DNA nanostructures by mimicking the intracellular or intravenous solution condition. Bermudez and Keum were the first who demonstrated the stability of DNA nanostructures in the presence of DNase 1 as well as fetal bovine serum (FBS) (Keum and Bermudez, 2009). They reported that DNA tetrahedron decay is three times slower than DNA double-stranded linear structures in the presence of DNase 1 whereas interestingly DNA tetrahedron displayed wonderful results with FBS, that is, it shows 50-fold enhanced stability than DNase. Sleiman and coworkers also supported this result, as triangular prism assembled DNA was found to give the decay pattern. They also demonstrated that tagging the oligonucleotides (DNA prism) with hexamethylene glycol improved the decay time by fivefold (Conway et al., 2013). Forster

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resonance energy transfer (FRET) is also implemented by the Tuberfield group to see the stability and retention in the integrity of DNA tetrahedron inside HEK cells. They found that the viability of DNA tetrahedron was for up to 48 hours inside the cells. Interestingly, DNA origami structures have also been depicted to have tremendous stability toward degradation by DNase 1 in comparison to linear DNA double-helical structures (Walsh et al., 2011). The main challenge in drug delivery via DNA nanostructures as well as DNA origami structures is their viability in cellular solution conditions. Extensive studies have been made by Perrault and coworkers to demonstrate the structural persistence of DNA nanostructures at varied solution conditions. It was demonstrated that owing to nuclease activity in serum, DNA origami structures have been found to degrade completely after 24 hours (Castro et al., 2011). The structural integrity of DNA origami is also tested in presence of a low concentration of Mg21 ion concentration simulating the physiological condition and it was observed that only sixhelix bundle retained their structure after incubation in media (Hahn et al., 2014). The structural integrity of DNA nanostructures in a cellular environment is also discovered in vivo experiments in many organisms such as C. elegans, cockroaches, and mice (Amir et al., 2014; Bhatia et al., 2011; Lee et al., 2012; Liu et al., 2012; Perrault and Shih, 2014; Zhang et al., 2014a,b). Lee and colleagues have established that DNA tetrahedrons have a blood half-life of B24 minutes in mice. In a similar line, Perrault and Shih have shown that DNA origami has B38 minutes blood half-life, which is enhanced ten-fold on encapsulation of DNA origami structure with PEGylated lipid bilayer (Perrault and Shih, 2014). Pharmacokinetics and biodistribution experiments have shown that unmodified DNA origami structures are prone to filtration through the kidneys into the urine. Fig. 7.8 depicted a PEGylated lipid bilayer having inside it DNA Origami octahedron used for drug delivery.

7.13.2 DNA origami in the immune system (stability and viability) The promising role of the immune system is undeniable to combat foreign particles but it plays a crucial role as a challenge for DNA nanovesicles in a biological system. While entering blood circulation, DNA nano vehicles and nanostructures must have traveled under the surveillance of the mononuclear phagocyte system (MPS). MPS system has resident scavenger cells which are actively involved in sequestering the foreign bodies. On sequestering nanoparticles, various plasma proteins such as opsonin get attached to nanoparticles (Juliano and Stamp, 1975). Being positively charged, opsonin has a great affinity for negatively charged DNA; therefore, DNA nano vehicles are more susceptible to binding with opsonin. Opsonin binding enhances the degradation of DNA nano vehicles by MPS as well as obstructs/hinders the interaction of surface proteins/ligands with their target molecules (Salvati et al., 2013). Apart from MPS, many endogenous receptors are also present in the cellular system and are involved in locating foreign DNA. DNA nano vehicles

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Figure 7.8 DNA origami octahedron encapsulated with a PEGylated lipid bilayer.

while entering inside the cell may also trigger these receptors which induce interferon production thus leading to undesired symptoms (Surana et al., 2015). It is not clear yet how the innate immune system gets affected by unmodified DNA nanostructures, therefore further investigation is required to gain insight into the exact mechanism as well as to uncover this mystery.

7.14

Outlook and future perspective

Unquestionably, being a dynamic biomolecule with robust properties DNA provides new horizons to exploit it for the drug delivery purpose. Owing to the selfassociation property of DNA, it can be molded and programmed into various shapes and sizes, such as DNA nanostructures and DNA origami structures. Conventional and novel drug delivery systems, for example, hydrogel, liposomes, etc. are usually employed for drug delivery in any biological system; however, DNA origami and DNA nanostructures have advantages over other systems due to their smaller size, biocompatibility, functionalization with other molecules (proteins), etc. This chapter is a modest attempt to give a glance at DNA nanostructures and DNA origami as well as their promising role in drug delivery. The advantage of using these structures for drug delivery is owing to their unique properties in vivo, like improving drug solubility, reducing side effects, enhancing the effectiveness of drugs, and so

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on. The possibility of diverse structures in every size and shape makes it tremendously significant nano vehicles for drug delivery. It is evident in various studies that DNA origami structures are capable to survive in an extreme cellular milieu as well as against nucleases. The stability and cell viability of these macrostructures can be improved by coating them with proteins or lipid membranes (Castro et al., 2011; Mei et al., 2011; Mikkil¨a et al., 2014; Perrault and Shih, 2014). DNA nanostructures, besides being efficiently used to complete the predefined task in a classy manner, have many obstacles to face while entering the biological system. The main challenge for DNA nano vehicles is to cross those barriers efficiently to reach their target organs and deliver the cargo, that is, drug molecule. Though the major advantage of using DNA nanostructure is its intrinsic biocompatibility and biodegradability, still these structures have to enter the cell under the radar of the immune system, specific endonucleases, etc. Therefore, some challenges that remain unexplored are scaling up, cost issues, and safety concerns. Though the preparation of DNA nanostructures/nano vehicles consumes fewer materials as compared to other delivery materials, the process of production is very much uneconomic. Besides drug delivery, other promising uses of DNA-based nanostructures are as biosensors as well as gene delivery systems. Extensive research is going on worldwide to overcome the problems and impediments in the way of drug delivery via DNA nanostructures. Wide-ranging research has recognized molecular modules that aid in efficient uptake and endosomal escape of DNA nanoparticles (Yameen et al., 2014). Undeniably, current knowledge of the functionalization of DNA nano vehicles has been exploited based on studies that included varied sizes and shapes of DNA nanostructures. The promising role of DNA nano vehicles needs to be addressed by combining each unique structural and functional module of DNA and the main hindrance/biological barriers in the cellular system. So, the crucial challenge for these structures is stability, crossing biological barriers, and maintaining their structural integrity along with effective delivery of the drug to the targeted organ (Mathur and Medintz, 2019). These structures can be fabricated as theranostic material to treat malicious diseases such as cancer etc. It is anticipated that more DNA-based nanostructures, as well as DNA origami structures, would emerge as potential nano vehicles, in near future. Thus, it can be hypothesized that the day is not very far when DNA nanostructures will become the major instrumental module to be exploited for therapeutic purposes. In nutshell, more strategies are needed to be adopted and manipulated to achieve the desired results with DNA nanostructures as well as DNA origami structures.

Authors’ contribution Conceptualization and supervision by A.S. and S.K., A.S., Nishu, Shoaib performed the literature review, drafting and writing the Ms., S.K. gave valuable input in the writing of the paper, A.S. and S.K. reviewed the Ms.

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Compliance with ethical standards Not applicable.

Conflict of interest The authors declare no conflict of interest.

Research involving human participants and animals Not applicable.

Informed consent Not applicable.

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Multifaceted approach for nanofiber fabrication

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Thareja Rakhi1, Malik Pragati 2, Bansal Prerna3 and Singh Jyoti 4 1 Department of Chemistry, St. Stephen’s College, University of Delhi, Delhi, New Delhi, India, 2Department of Chemistry, Acharya Narendra Dev College, University of Delhi, Delhi, New Delhi, India, 3Department of Chemistry, Rajdhani College, University of Delhi, Delhi, New Delhi, India, 4Department of Chemistry, Hansraj College, University of Delhi, Delhi, New Delhi, India

8.1

Introduction

Nanofibers are looked upon as exciting materials because of their unique properties like large surface area-to-weight ratio, small pore size, low density, and high porosity, which makes them useful in numerous areas. Nanofibers, with diameter ranging from 50 to 100 nm, can be natural or synthetic or hybrid. Applications include areas of environment, renewable energy, biomedical engineering, wound healing, drug delivery, cosmetics, lithium-ion batteries (LIBs), metal ion adsorptions, and many more. Nanofibers can be synthesized with the help of different methods available like template synthesis, electrospinning, melt blowing, self-assembly, drawing, chemical, and physical vapor deposition. These methods are used for designing a variety of nanofibers like discontinuous fibers, continuous fibers, and atypical nanofibers. Discontinuous fibers are fabricated using the drawing process. Fibers of a particular diameter are synthesized via template synthesis, and phase separation is used only for some specific polymers. However, the electrospinning technique (Kumar et al., 2012; Luo et al., 2012) is the only method through which continuous polymeric nanofibers can be synthesized, as this method allows manipulation to control not only the diameter but also the parameters like porosity, surface area, and basis weight (fiber weight per area). This technique applies high electrostatic voltage on the polymer solution. Application of such high electrostatic voltage helps in the fabrication of nanofiber of desired diameter and length. Hence, both can be varied from a few nanometers to several micrometers. Modified electrospinning methods such as coaxial nanofiber preparation (Kamperman et al., 2010; Lee et al., 2010) or side-by-side nanofiber preparation lead to the synthesis of atypical nanofibers, such as the production of nano-coils or nano-springs structures (Chen et al., 2009a,b). Nanofibers can be clubbed under four categories based on chemical composition. These are inorganic-based nanofibers, organic-based nanofibers, composite nanofibers, and carbon nanofibers. The availability of a large number of techniques allows one to synthesize nanofibers using different fibrous materials ranging from natural polymers, synthetic polymers, nanofibers of metals, metal oxides, ceramics, and Fiber and Textile Engineering in Drug Delivery Systems. DOI: https://doi.org/10.1016/B978-0-323-96117-2.00012-1 © 2023 Elsevier Ltd. All rights reserved.

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Figure 8.1 Techniques used for fabrication of nanofibers.

more. Some of the widely used techniques adopted for the fabrication of these nanofibers are summarized in Fig. 8.1.

8.2

Fabrication techniques

8.2.1 Template synthesis This method is used for the synthesis of nanofibers that have well-defined shape, size, and configuration. This is possible because of the availability of the template used for their synthesis. Template synthesis generally proceeds via three steps. Step 1: Preparation of the template Step 2: Synthesis of nanofiber on/using the template Step 3: Separating nanofiber from template (if required).

Templates with nanostructure features are either of natural origin (nanostructured minerals, biological molecular assemblies, and organs) or synthesized using synthetic nanostructures (both direct synthesis and template synthesis) (Ikegame et al., 2003). Nanofibers are produced when polymer solutions pass through the pores (having nanoscale diameter) of the template used under the force of pressurized water from one side. From the other side of the template pores, fine nanofibers of the desired diameter are formed as polymer solution comes in contact with the solution used for solidification (Fig. 8.2). One can fabricate nanofibers having varying diameters by using templates of different diameters. Template synthesis is mainly used to fabricate carbon nanotubes/nanofibers (inorganic nanofibers), conductive polyaniline, and polypyrrole nanofibers. It cannot produce one-by-one continuous fibers. Hence, the nanofibers produced are only a few micrometers long. It is used to produce nanofibers using nonporous membranes having numerous cylindrical pores of typically 5
50 nm thickness. This method suffers a significant disadvantage that includes high cost due to the unique process required to make templates. Also, the template removal from the nanofiber synthesized adds to the total cost. Sometimes a template in itself is pretty costly due to the kind of metal involved for template synthesis. Some specific templates are cheaper, such as silica beads, but then they possess environmental issues as their removal requires harsh chemicals (corrosive acid/bases) (Liu et al., 2013). Eco-friendly and biodegradable polymer poly(ε 2 caprolactone) nanofibers are generally synthesized via the template method (Tao and Desai, 2007). A precursor material, that is, 6,60 -(CH2)6(B10H13)2

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Figure 8.2 Synthesis of nanofiber using template synthesis method.

is used for the fabrication of boron carbide (BC) nanofibers using membranes made up of alumina (Pender and Sneddon, 2000).

8.2.2 Phase separation One can synthesize microporous nanofibers using this method. It is a unique method due to the simple protocol followed for the generation of the highly porous nanofibers having narrow pore diameter distribution. It does not require specialized equipment. It is reproducible, and one can achieve batch-to-batch consistency. There are two ways by which the phase separation of the solution is carried out. The first is induced by changing the temperature of the polymer solution known as temperature-induced phase separation, and the other is called nonsolvent induced phase separation, initiated by adding a nonsolvent to the solution. This method is usually planned through a five-step process, as shown in Fig. 8.3. Polymer gel of known concentration is prepared by preparing a homogeneous polymer solution and then keeping it in the refrigerator at the gelation temperature (induced thermally) (Ma and Zhang, 1999). The other way is by adding a suitable nonsolvent to the polymer solution. In both ways, the polymer solution will be converted to an unstable polymer gel. This is followed by immersing the polymer gel in distilled water, for solvent extraction, and then it is removed from distilled water followed by blotting done with filter paper. In the last step, it is transferred to a freeze-drying vessel that leads to the generation of a porous nanofiber matrix. Morphology of the nanofiber can be controlled by varying parameters like using different types of porogen, the concentration of polymer solution, changing the freezing temperature, etc. This method has been used successfully for the fabrication of nanofiber matrices of poly-L-lactic acid, and blends of poly-L-Lactic acid-polycaprolactone (Mo et al., 2002). Scaffolds of a polymer prepared using this method have nanoscale pores preferably with sponge-like porous morphology (Hua et al., 2002; Nam and Park, 1999).

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Figure 8.3 Steps followed in temperature-induced phase separation.

The phase separation method is best suited for selected polymers like polylactide, polyglycolide as it requires gelation which is not possible with all polymers. This can also be used for the generation of one-by-one continuous nanofiber but the process in itself is time-consuming and is strictly a laboratory-scale method, which is a major limitation of this process. Also, the nanofibers generated lack structural stability and porosity. Although the synthesis of porous structures using this method is time-expensive, it is proven to be successful in making potential candidates for drug delivery applications (Ashammakhi et al., 2009).

8.2.3 Drawing process A small drop (preferably a millimeter) of polymer solution is deposited or taken into the substrate. A micropipette is moved slowly towards the circumference of the drop. The moment the pipette makes contact with the polymer solution it is quickly pulled back at a specified rate. When this micropipette is pulled out, nanofiber starts forming due to the solidification because of the cooling/evaporation of the solvent. The cross-section of the nanofiber depends on the parameters like the exact composition of the polymer solution, the rate at which evaporation of the solvent takes place, and the drawing velocity. Instead of the micropipette, a micromanipulator is used to produce nanofiber. Although the process seems simple, the polymer solution used for the production of nanofiber plays a significant role. It requires a viscoelastic material, which can hold strong deformations and tensions during the drawing of the nanofiber. In other words, polymer material should have adequate cohesion to survive external stress caused due to pulling of the nanofiber. The evaporation of the solvent also changes the viscosity of the polymer solution as time progresses. It affects the dimension of the nanofiber being drawn from the solution as one can draw a single nanofiber using a drawing method that cannot be achieved using an electrospinning technique (discussed in Section 8.2.6). Xie and coworkers have used electrospinning followed by the drawing method to prepare carbon

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Figure 8.4 Illustration showing fabrication of nanofiber using drawing method.

nanofiber precursors in nanofiber yarn. These nanofibers can be drawn or pulled six times their original length without causing any damage, which was not possible when one employed only electrospinning techniques (Xie et al., 2015). In a study by Sehaqui et al. (2012), they used an eco-friendly cold drawing process to align the nanofibrillated cellulose, that is, TEMPO-NFC (2,2,6,6-tetramethylpiperidine-1oxyl-nanofibrillated cellulose) into nanopaper for different applications. The fabricated nanofibers possessed remarkable mechanical and structural features. No harmful solvents were used. The same method was also applied to prepare TEMPO-NFC/hydroxyethyl cellulose nanocomposites that allowed tailoring of mechanical properties of nanocomposites. Fig. 8.4 illustrates the drawing method for practical synthesis of nanofibers. This method does not suffer any major limitations except that it is limited to the availability of viscoelastic polymer and one cannot fabricate nanofibers with a diameter lower than 100 nm.

8.2.4 Self-assembly It is a process through which the complicated three-dimensional nanofiber can be fabricated from smaller or nano-units. It is a simple bottom-up process in which smaller units organize themselves into nanofibers through various noncovalent interactions which are usually difficult to obtain through various top-down approaches (Beachley and Wen, 2010). Hence, it is a promising technology for organizing randomly oriented components into defined ordered nanostructures (Hartgerink et al., 2002; Zhang et al., 2005a). It is frequently used for fabricating very small nanofibers and the length of these nanofibers can be varied up to several micrometers. This is possible because of the formation of supramolecular hydrogels in which small molecules are held together by hydrogen bonding and hydrophobic interactions (weaker forces). The overall shape of the nanofibers is based on the shape of smaller units of molecules used in the fabrication process. The various disadvantages of this method are: complexity of the technique, long length, low productivity, and inability to control the nanofiber diameter and length. Also, it is

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limited to some specific active small molecules such as amino acids, and monosaccharides which can orient themselves on their own or under an external stimulus (Zhang and Lua, 2014). Just like the phase separation technique, it is also a timeconsuming technique.

8.2.5 Melt blowing The discovery of this method can be dedicated to Van A. Wente of the naval research group who used it for the first time for development of nanofibers (Wente et al., 1954, 1956). It is a simple and a single-step process where polymer melt is fed through the orifice die holes. The polymer web structure is formed due to the elongation of the polymer melt coming out of the orifice under the influence of a high-velocity hot stream. The hot air temperature is set according to the melting point of the polymer used. The ultrafine fibers coming out of the orifice are deposited on the collector plate. The average diameter of the fibers depends on melt temperature, a viscosity of polymer melt, air temperature, air velocity, and speed of throughput. The process prefers low molecular weight polymers. The main disadvantage of this method is to design a very small orifice of the die. A basic diagrammatic illustration of the process is given in Fig. 8.5. Ellison and coworkers have demonstrated that the morphology of the nanofibers can be varied by bringing a

Figure 8.5 Illustration of melt blowing process.

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suitable modification in melt blown set up such as special die designs with a small orifice and reducing the viscosity of the polymeric melt (Ellison et al., 2007). A slight modification in the rheology of polymer solution is used for the fabrication of nanofibers (Bodaghi and Sinangil, 2006). Hence, this technique allows the fabrication of graded short fiber of diameter in the range of 5
10 μm. One can scale up the process by increasing the number of orifice die holes like the multineedle electrospinning method but here the melt-blown fibers are randomly deposited generating a nonwoven sheet (Uppal et al., 2013). The nanofibers generated via this process are free of solvent and one need not invest in solvent recovery like phase separation, template synthesis, and other methods. However, this method largely depends on the type of polymer used. Controlling the thermal degradation of polymer melt during synthesis is also a major concern.

8.2.6 Electrospinning The evolution of the most popular technique for the synthesis of nanofibers, electrospinning, gives us deeper insights to understand its role in the scientific world today. A summary of chronology is shown in Table 8.1 for better understanding. The use of high electric fields for the generation of filaments (Formhal’s patent in 1934) marks the origin of the electrospinning technique. The principle involves the effects produced due to electrostatic force on liquids. The charged substance is brought closer to a fine capillary end holding a liquid drop. This results in a cone shaped drop and from the tip of the cone small jets of nanofibers are ejected when charge density increases. Based on the steps followed for the preparation of polymer, this method can be of two types: solution technique and melt technique of electrospinning. The former has been extensively studied based on features affecting properties and characteristic features of nanofibers of prime importance. The limitations of electrospinning include lower yields and the need for innovative solvent extraction techniques. Another limitation is that it causes environmental damage due to the usage of toxic solvents for synthesis. Melt electrospinning helps in overcoming the damage to the environment. Solution electrospinning enhances productivity by increasing jets’ number by making use of variable techniques like multijets from the single needle, multiple needles, and needleless systems (Xue et al., 2019). A diagrammatic representation of the electrospinning technique is shown in Fig. 8.6. Specific instruments are required for the electrospinning technique that includes a metallic collector plate, high voltage power, and a fabricated capillary cylinder with a metal syringe with a spinneret. The two electrodes are bonded such that one is attached to the collection plate while the other is put into the polymer solution. A capillary cylinder holds the polymer solution to which an electric field is applied for the generation of charge on the solution surface. As observed in nanofiber fabrication, the impact of an increase in an electric field is that the hemispherical surface of the liquid gets converted into a Taylor cone. At the electric field’s critical value, the electrostatic power disables the surface tension and a liquid jet emerges from the cone’s tip. The highly stretched jet becomes thin due to the

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Table 8.1 Genesis and development of electrospinning (Islam et al., 2019). Year

Researchers

Work

References

1900, 1902, 1903 1902

John Francis Cooley

Patent on electrospinning

Tucker et al. (2012)

W. J. Morton Antonio Formahal

Patented the method of preparing fibers for textile or another purpose Patent filed in subsequent years for textile yarns from cellulose acetate

Morton (1902)

1964

Charles L. Norton Vonnegut and Newbauer Taylor

1969

Taylor

1971

Baumgarten

1987

Hayati and group

Invented the electric current and air stream
assisted melt spinning process Preparation of nanofibers with uniform drops of 0.1 mm diameter by electrical disintegration method for liquids Modeling of the fluid droplet to obtain the desired shape of the cone Polymer droplet’s shape examined at the tip of the spinneret during electrospinning process Invented the procedure of fabricating acrylic fibers Liquid conductivity’s effect was displayed based on electrospinning which proved that semiconducting and insulating liquids produced relatively stable jets

1934

1936 1952

Formhals (1934, 1937, 1940) Norton (1936) Vonnegut and Neubauer (1952) Taylor (1964) Taylor (1969)

Baumgarten (1971) Hayati et al. (1987)

discharged and unstable solution. 6 kV voltage is required for initiating the electrospinning process (Taylor, 1964) and it can be carried out at a lower voltage when the grounded target is brought near to the spinneret (Taylor, 1969) or by using a multijet spinneret (Zhang and Yu, 2014). Although the type of spinneret has very little effect on surface chemistry and stability of the nanofiber, they help in the diameter and mechanical stabilities of the nanofibers. For example, Clip spinneret, coaxial spinneret, heating spinneret, and tube-less spinneret are some of the commonly employed spinnerets. Along with these, the latter minimizes the changeover time and reduces the wastage of polymer solutions (Williams et al., 2018). The uniformity in size and morphology of nanofiber depend on the concentration of polymer along with the movement of the jet stream. Electrospinning can transform different types of polymer solutions into nanofibers. The nanofibers, thus produced, resemble the extracellular matrix (ECM) that simulates the ECM associated with the porosity and mechanical features. Hence, it is employed for the massive generation of continuous nanofibers. This method is not only cheap but additionally has a flexible approach. It is simple with several advantages such as uncomplicated and inexpensive equipment, the possibility to monitor the morphology of nanofiber, the probability of ascending the procedure, and practically employing a majority of

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Figure 8.6 Illustration of electrospinning technique (Williams et al., 2018).

polymers including the one with high molecular masses. It also suffers a few limitations such as changing solution conductivity, high-voltage electrical fields, risk of employing toxic solvents, imprecise control over fiber orientation, difficult 3D formations, lower yields, as well as appropriate pore diameters spinneret are required. Hence, the electrospinning of nanofiber depends on several parameters, which can be clubbed under three variable categories, that is, polymer solution, processing conditions, and environmental parameters as shown in Fig. 8.7. We will be briefly discussing the effects of these parameters in the coming sections.

8.2.6.1 Polymer solution Polymer viscosity depends upon the molecular chain entanglement in the polymer solution which plays a primary role in deciding the nanofibers’ diameter. The viscosity of the solution not only depends on the polymer’s mass or solution concentration but also on the solvent properties (Williams et al., 2018). Usually, the viscosity of polymer solution ranges from 1 to 200 poise (Bhardwaj and Kundu, 2010). He and coworkers predicted a linear relationship between concentration and diameter of polyacrylonitrile nanofiber (He et al., 2008). For polymer solutions with the same concentration, the decrease in the molecular weight leads to the formation of smooth nanofibers. The increase in molecular weight leads to the formation of micro-ribbon (Gupta et al., 2005). Polymers with low concentrations have a low coefficient of viscosity along with high surface tension and these aid in the loss of intermolecular attractions by the charged jets, thereby producing the Taylor cone droplets (Greiner and Wendorff, 2007). At higher concentrations, a combination of

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1. POLYMER SOLUTION

2. PROCESSING CONDITION

Viscosity

Flow rate of the solution

Molecular weight

Applied voltage

Concentration Atomic radii

3. ENVIRONMENTAL PARAMETER Temperature

Humidity

Diameter of the needle

Type of the collector

Electrical conductivity Surface charge density

Gap between the collector and needle

Surface tension

Gravitational force

Dielectric constant

Figure 8.7 Different parameters affecting the electrospinning process.

the beads’ mixture and nanofibers is acquired. Tarus and group have demonstrated the effect of polymer concentration on the morphology of poly (vinyl chloride) nanofiber and cellulose acetate (Tarus et al., 2016). The salts or surfactants in addition to the polymer solution also impact the morphology, and nanofiber diameter. For example, when the effect of NaH2PO4, NaCl, KH2PO4 on poly (d,l-lactic acid) was studied, it was predicted that the nanofibers from NaCl solution have the shortest diameter. In contrast, the presence of KH2PO4 increases the diameter of the nanofiber (Zong et al., 2002). The atomic radii of chloride and sodium ions are smaller than phosphate and potassium ions, thereby possessing higher mobility at the applied voltage. Therefore, sodium ion jets face greater elongation forces that lead to the formation of nanofiber with the reduced diameter (Jiang et al., 2004). Nanofibers formation is not observed in the solution with zero surface charge density due to the absence of dipole moment (Angammana and Jayaram, 2011). Beaded nanofibers are formed from solutions with low surface charge density. These solutions have lower mobility responsible for lower elongation force applied during the fabrication (Hayati et al., 1987; Jarusuwannapoom et al., 2005). The next parameter is the surface tension of the polymer solution. The lower the surface tension, the higher the chances of formation of beadless nanofibers. The surface tension is effectively reduced by adding a surfactant to the polymer solution such as the addition of lauryl sulfate surfactant decreases the surface tension of the polyurethane (PU) polymer solution, which resulted in the formation of uniform

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nanofibers (Hu et al., 2011). The last parameter under this category is the dielectric constant, a temperature-dependent property. The high dielectric constant means high net charge density which is responsible for applying higher elongation forces during synthesis. This decreases the diameter of nanofiber during synthesis (Williams et al., 2018). Addition of solvents like acetonitrile, acetic acid, tetrahydrofuran, m-cresol, toluene, acetone, ethyl acetate, chloroform (Berkland et al., 2004), dichloromethane, dimethylformamide, ethanol (Yang et al., 2004a) to polymer solution leads to improvement in the dielectric constant of the polymer solution.

8.2.6.2 Processing conditions In this category, the effect of flow rate, diameter of needle, applied voltage, collector-needle gap, and type of collector are discussed. The polymer solution’s flow rate influences diameter, porosity, and nanofiber geometry to a great extent. To have the beadless nanofiber, the polymer solution must get sufficient time for polarization. Therefore, it is suggested that a slow flow rate should be used for the same (Yang et al., 2004a). The diameter of nonporous polylactide fibers increases as the flow rate varies from 1 to 2.5 mL/h and 0.1 to 0.5 mL/h, respectively (Ghelich et al., 2015; Tang et al., 2014). Another influencing factor, the applied voltage, affects the morphology and diameter of nanofibers. The studies have reported that when one uses a high voltage polymer solution gets ejected rapidly resulting in the development of larger nanofibers with big diameters (Zhang et al., 2005a). Researchers have also reported that the diameter of the nanofiber decreases on increasing the applied voltage (Beachley and Wen, 2009; Katti et al., 2004). In a study by Hu et al. (2011) the diameter of nanofiber increases significantly by changing the applied voltage from 20 to 40 kV. Higher voltages result in electrostatic attenuation that makes the polymers molecules to have more order, thereby improving the crystallinity. However, the latter, that is, a jet’s crystallinity has chances of getting reduced beyond a specific voltage that is induced owing to a shorter flight period. Collectors’ plates consist of a plate with protrusions array, pin-type collectors, wire mesh, liquid nonsolvent, series of parallel ridges, grids, parallel bars, and a rotating wheel (Ki et al., 2007). To maintain a constant difference in potential, between the collector and the source, a conducting collector is used. The usage of a collector with no/less conducting material assembles the charged jets quickly in the collector thereby reducing the yield of beaded nanofiber (Wang et al., 2005). Nonconducting collectors produce three-dimensional nanofiber, due to repulsive charged forces. The presence of sufficient charge density on the fiber mesh causes repulsion, especially between the fibers that leads to the formation of structures resembling honeycomb (Deitzel et al., 2001). Rotating collectors are used for preparing aligned dry nanofiber as it provides more time for evaporation. Aligned type I collagen fibers and poly (glycolic acid) were obtained using the same (Kilic et al., 2008). One needs to control the alignment speed of the rotating collector as the charged jet travels at high speed during electrospinning. Below the specified value

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of alignment speed, the nanofibers collected are more but less oriented due to repulsion from the incoming nanofibers. Another critical feature is the gap between the collector and needle tip. Beaded nanofibers are formed when a short collector lead is used. This causes the jet to move through a shorter distance because of some inter/intralayer between the junctions nanofibers giving a shorter time for nanofiber solidification (Buchko et al., 1999). An enhancement in the needle tip-collector gap will lead to increasing the average nanofiber diameter (Geng et al., 2005). Despite the exceptions, polyvinyl alcohol (PVA) nanofibers are prepared with longer diameters by application of decreased electrostatic force and more considerable length (Ghelich et al., 2015). Hence, one must keep in mind that an optimum distance is always required to have nonbeaded nanofiber. The last parameter in this category is the gravitational force which influences the Taylor cone and polymer droplets’ shape. To have beadless continuous nanofiber, the requirement of a higher flow rate in horizontal arrangement than the vertical arrangement is mandatory (Rodoplu and Mutlu, 2012). Suresh et al. (2020) also talked about the preference given to horizontal arrangement over vertical arrangement when the electrospinning of nanofibers is not stable.

8.2.6.3 Environmental parameters Environmental parameters like temperature, humidity, and pressure play a prominent role in the production of nanofibers. Temperature increase results in an increase in the rate of evaporation of the solvent and hence, the viscosity of the polymer solution decreases. This helps in producing nanofiber with smaller diameters with an increase in chain orientation (Wang et al., 2007). In another study, the change in temperature led to a change in morphology and texture of silk nanofibers. They obtained flat fibers at 50 C and 75 C whereas circular fibers were obtained at lower temperatures (Amiraliyan et al., 2009). Vrieze et al. (2009) researched the influence of humidity and temperature on the nanofibers of poly (vinylpyrrolidone) and cellulose acetate. They observed that for cellulose acetate nanofiber, diameter increases, whereas for polyacetate it decreases with increase in humidity. However, the use of higher temperatures leads to a loss in functionality of nanofiber of biological substances like enzymes and proteins (Fujihara et al., 2005). In another study, nanofiber formed from a polymer solution made using a volatile solvent had condensed water on its surface (Megelski et al., 2002). Low humidity was preferred for fabrication of poly(m-phenylene isophthalamide) (PMIA) membranes embedded in a nanonet structure used in air filtration (Zhang et al., 2017). In a study by Baumgarten (1971), the electrospinning process stopped because of maintaining low humidity. This reduced the removal of solvent from the tip of the needle because of a slower rate of evaporation (Baumgarten, 1971). The three parameters discussed so far are responsible for bringing variation in the morphology, diameters, and surface of the produced nanofibers through the electrospinning technique. Table 8.2 highlights the various advantages and limitations of the methods discussed so far. It also summarizes the typical production

Table 8.2 Comparison of various methods used for fabrication of nanofibers. Method used

Type of production

Diameter of nanofiber

Set up requirement

Advantage

Limitation

Template synthesis

Laboratory

1
100 nm

Suitable templates

Special templates, cannot synthesize continuous nanofibers

Phase separation

Laboratory

50
500 nm

Small

Drawing

Laboratory

2
100 nm

Small

Self-assembly

Laboratory

Middle

Melt blowing

Industrial

Few nm
100 nm .than 250 nm

Diameter of nanofibers can be varied using different templates Production of continuous nanofiber, controlled pore size and shape Very fine long nanofibers Very fine nanofibers

Huge

High-quality nanofiber

Electrospinning

Industrial

50
500 nm

Depends on the volume of production

Tailorable, costeffective, long continuous nanofibers

Only limited to few polymers, cannot synthesize long continuous nanofibers

Discontinuous process, limited to viscoelastic polymers limited to biomolecules Designing very small orifice, only some polymer, expensive machinery, difficult to maintain uniformity, difficult to dissipate heat High voltage, toxic solvents

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setup requirements and the diameter of the nanofibers synthesized using these methods. Innovations are constantly happening in this field and newer methods are getting developed to get nanofibers with desirable characteristics for suitable applications. Some broad areas of applications of nanofibers are discussed in Section 8.3. The methods of synthesis discussed above are successful in yielding nanofibers which are of great importance in modern-day research. However, the electrospinning technique of synthesis is explored the most among all and hence, finds its applications suitably in a wide range of fields. The next section deals with applications of nanofibers that help in smarter living in the day-to-day world.

8.3

Application of nanofibers

Nanofibers and their other counterparts display excellent tunable properties despite being at a nanoscale level due to the presence of more atoms at the surface. They cover a wide range of applications starting from tissue engineering to water remediation in addition to being an outstanding candidate material for energy devices like LIBs, catalysis and fuel cells (Fig. 8.8). These applications are largely due to their high surface area-to-volume ratio, scalable porosity, and low density.

8.3.1 Water treatment Due to their flexible pore size and large surface area, nanofibers find a number of applications in water treatment. All these properties when clubbed together make them attractive to be used in water treatment. Waste water treatment is a matter of global concern. Hence, exploring efficient and innovative nanofibers for water remediation becomes primordial. Owing to the need of the hour, the use of nanofibers for water treatments such as heavy metal remediation or contaminants is of great concern (Agarwal et al., 2021). In studies done by Bhaumik et al. (2014), the group designed composite nanofibers consisting of metallic iron nanoparticles supported on polyaniline nanofibers that were used to remove As(V), Cr(VI), and congo red dye from aqueous solution. In a similar study by Wang et al. (2014), Manganese dioxide (MnO2)/cellulose nanofibers hybrids were investigated for application in methylene blue dye wastewater treatment. Bahmani and coworkers found that a thin film composite membrane composed of polyethylene terephthalate as scaffold substrate for support with Polyacrylonitrile as a coating layer is much more efficient in the removal of arsenate ions from contaminated water (Bahmani et al., 2017). Nanofibers are also used in water desalination which was demonstrated by Fan and coworkers by designing super hydrophobic titania nanofibrous ceramic membranes and further modifying them by using fluorination (Fan et al., 2016). Hydrophilic surface nanofibers efficient in water filtration were prepared by dissolving polyvinyl chloride (PVC) in N, N-dimethylacetamide along with polyvinylpyrrolidone (PVP) (Alarifi et al., 2018). Recent advances also show the

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Water treatment Catalysis & Energy storage

Cosmetics

Wound Healing

Applications of nanofibers

Electrodes in Fuel cells

Lithium ion batteries

Drug delivery Tissue Engineering

Figure 8.8 Applications of nanofibers.

fabrication of antibacterial and antiviral nanofibers (Fahimirad et al., 2021). This proves to be highly efficient for the removal of pathogenic contamination of water, which is a matter of global concern.

8.3.2 Catalysis and energy storage Electrospun nanofibers have found wide utility in use as catalyst support materials owing to the increased surface area-to-volume ratio. In fact, metal oxides and metallic nanoparticles loaded nanofibers demonstrated promising catalytic activities. The advantage of using nanofiber-based catalysis also comes from its good recyclability and reusability (Ogunlaja et al., 2016). Carbonized nanofibers have swelling resistance and insolubility in solvents which makes them the most favored metal catalyst support materials. Carbonizing metal-organic frameworks (MOFs) functionalized nanofibers help in the construction of metal catalysts that work for the reduction and oxidation of oxygen. Zn(II) phthalocyanine-gold doped electrospun polystyrene (PS) nanofibers are potential photocatalysts for the degradation of 4-chlorophenol and Orange G (Tombe et al., 2013). In fact, TiO2 nanofibers have attracted considerable attention recently since apart from being biologically and chemically inert, they can be modified to be photocatalytically selective by altering surface functionality (Ogunlaja et al., 2016). A TiO2/SiO2 nanofiber composite selectively dissociates methylene blue in presence of disperse red dye in water

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which shows its selective photocatalytic activity (Zhan et al., 2007). The internal channels of mesoporous SiO2 allows smaller methylene blue molecules to enter, but did not allow the entry of larger disperse red dye molecules. Water stable Au/Ag nanoparticles immobilized within electrospun polyvinyl alcohol (PVA)/polyethylenimine (PEI) exhibit excellent catalytic efficiency for transforming 4-nitrophenol to 4-aminophenol. TiO2 nanofibers embedded with graphene oxide (GO) sheets were synthesized and show improved photocatalytic production of hydrogen and generation of photocurrent (Kim et al., 2014). Cerium oxide materials are widely used as luminescent materials, catalysts, gas sensors, and oxygen storage owing to their excellent redox ability. When a suitable metal oxide like copper(I) oxide is added to it, the catalytic activity is greatly enhanced for oxidation of methylene blue under the same condition when it was used without metal oxide which is due to the increased surface area and large absorption effect. Also, there is improved separation of electron/hole pairs by Cu2O (Raees et al., 2021).

8.3.3 Electrodes in fuel cells The electrochemical reactions form the basis of fuel cells and their high power efficiency makes them suitable for their wider use. They create electricity by reacting oxygen and hydrogen to form water. Fuel cells are often classified based on electrolytes as Alkaline, phosphoric acid, solid oxide, proton exchange fuel cells, etc. In case of proton exchange fuel cells at high current densities, the water generated at the cathode results in water flooding as it is not transported properly which may lead to carbon electrode corrosion. The electrospun nanofibers can be used as cathode, anode, or membranes by tailoring for their porosity, surface area, and other chemical properties to achieve the desired application (Banitaba and Ehrmann, 2021). The large surface area of electrodes results in an enhanced utilization rate and improved capacity of the fuel cell. Chung et al. (2018) introduced hydrophobic graphitized carbon nanofibers in the Pt/C cathode via annealing at different temperatures to tackle the water management problem. They found enhanced power performance at high current densities which insinuates that graphitized carbon nanofibers can act as a gas transport pathway. Wei et al. (2016) found high conductivity and enhanced porosity of graphenedoped electrospun nanofiber mats when used as both cathode and anode, making them well-suitable for fuel cells after Pt loading. Nanofibers mats are also used as anodes in microbial fuel cells in which anodes decide the performance of the fuel cells. These cells oxidize biodegradable organic matter like glucose or proteins in presence of microorganisms to generate electricity. Jung and Roh employed electrospun nanofiber mats as anodes in microbial cells and found that the power density almost doubled as compared to commercial graphic felt (Jung and Roh, 2017). Nitrogen-doped carbon nanofibers were used as anodes by Massaglia et al. (2020) for microbial fuel cells while Karra et al. (2013) used activated carbon nanofibers and found their performance better than anodes from granular activated carbon or carbon cloth. Electrospun nanofiber mats of Nafion/polyphenylsulfone showed

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good water swelling and mechanical performance as well as proton conductivity (Ballengee and Pintauro, 2013). The porosity of nanofibers accelerates ion and electron conduction, thereby improving the fuel cell performance. The exchange membranes (both cation and anion) play an important role in fuel cells (Shang et al., 2021). Choi et al. (2010) developed a membrane with high water retention properties and proton conductivity by adding sulfonic acid ion exchange groups that are found to have high proton conductivity. Nanofiber electrode catalysts are explored to improve the power density and durability of fuel cell electrodes. Zhang and Pintauro (2011) successfully fabricated Pt/C/Nafion/Polyacrylic acid nanofiber structured electrodes and tested them as the cathode in proton exchange membrane H2/air and H2/O2 fuel cell MEAs (membrane-electrode-assemblies). The proton and oxygen transport to catalyst sites increases due to the uniform distribution of Pt/C particles, and Nafion binder in a nanofiber mat increases the electrochemically active catalyst surface area making them exhibit improved stability and durability.

8.3.4 Lithium-ion batteries Lithium-ion batteries (LIBs) have attracted great attention owing to their high power storage, high operational voltage, use in hybrid vehicles, and low selfdischarge rate. The electrospun nanofibers which have a high specific area, high interconnected porosity, and controllable nanofiber diameter, are promising candidates for use in LIBs to increase the electronic and ionic conductivity, thereby improving their cyclability and rate capability. Not only this, the nanofibers can be functionalized to control properties like electrolyte affinity, pore size, and thermal stability, that further improve the battery performance. Despite great advances in LIBs, the conventional LIB still uses graphite electrodes which have a low theoretical capacity and poor rate capabilities. Electrospun nanofibers are increasingly finding applications in LIBs in cathodes, separators, and interlayers. The active anode and cathode materials are loaded onto these electrospun nanofibers and are found to be robust platforms for greater electrochemical performance (Weng et al., 2019). In the studies conducted by Cavaliere et al. (2011) LiCoO2/MgO composite nanofiber is found to retain its initial charge capacity (90%) after 40 cycles as compared to typical LiCoO2 cathode material (52%) without MgO. MgO protects the surface of the cathode material from surface passivation during cycling. Besides LiCoO2, V2O5 and LiFePO4 have also been extensively studied as cathode materials (Cheah et al., 2011; Mai et al., 2010; Toprakci et al., 2011; Zhu et al., 2011). Carbon nanofibers are considered promising candidates for anode materials in LIBs due to their long life cycle and low cost, yet their low specific capacity and rate capability is their drawback. In this regard, several composite nanofibers like C/Si, C/Sn, and C/MnOx nanofibers have been synthesized to achieve cycling stability and electrical conductivity (Li et al., 2013; Zhang et al., 2013). Commercial separators have low porosity, thermal instability, and poor wettability in the liquid electrolyte (Lee et al., 2013). Liang et al. (2013) and many other groups

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(Jayaraman et al., 2004; Lee et al., 2010) in their experiments demonstrated that polyvinylidene fluoride (PVDF), PVDF-CTFE (Polyvinylidenefluoride-co-chlorotrifluoroethylene) and gelled electrospun PVDF-HFP nanofibers membranes can overcome these shortcomings and showed excellent cyclability, high conductivity and high rate capability due to faster ionic transport.

8.3.5 Tissue engineering Nanofibers owing to the high surface area, pore size, porosity, and high mechanical strength have the potential for enhanced cell adhesion, and their similarity to ECM in 3D architecture, they are excellent sources for cells to grow and perform their routine function (Vasita and Katti, 2006). There are natural polymeric materials for nanofibers like collagen, hyaluronic acid, gelatin, chitosan, elastin, etc (Yannas, 2004) which aid in tissue engineering due to their similarity with macromolecular substances present in the human body so that they can interact favorably with the natural polymers. For instance collagen nanofibers (Matthews et al., 2002) are found to be compatible with a large variety of cell types. In a study conducted by Huang et al. (2001) they blended collagen type 1 nanofibers with polyethylene oxide (PEO) which demonstrated high mechanical strength due to high intermolecular interactions between collagen and PEO. This trait of natural nanofibers makes them the most sought materials in tissue engineering. Chitosan/PEO nanofibers synthesized using electrospinning possess greater structural stability in water and enhanced lingering of cell types onto the nanofibers without changing their morphology indicating high cytocompatibility (Bhattarai et al., 2005). Likewise gelatin/ PCL composites from electrospinning and silk fibroin have been reported to have improved mechanical strength, and good attachment with the cell lines (keratinocytes, fibroblasts) making them a suitable candidate for scaffolding technology (Jin et al., 2002; Min et al., 2004; Zhang et al., 2005b). Hence a large number of natural polymers have been explored as scaffolds for the synthesis of nanofibers to be used in tissue engineering. Apart from natural polymers, synthetic polymers like polylactic acid (PLA), PET-Poly(ethylene terephthalate), PCL, PLLA-CL, poly lactic-coglycolic acid (PLGA), polyethylene-co-vinyl acetate (PEVA), PLGA-poly(ethylene glycol)(PLGA-PEG) nanofibers scaffolds developed through electrospinning have been used in various tissue engineering applications, including blood vessel, bone, and cartilage tissue engineering (Table 8.3). In a study conducted on neonatal rats, Mesenchymal stem cells derived from bone marrow seeded on nanofibrous scaffolds produced abundant ECM in the scaffold which insinuates their potential use in bone tissue engineering (Yoshimoto et al., 2003). Articular cartilage tissue, which has limited ability to regenerate due to reduced availability of chondrocytes and absence of progenitor cells in the vicinity of the wound to mediate the repair process, is embedded in dense ECM to limit their mobility and availability for wound healing (McPherson and Tubo, 2000). Mo and Weber (2004) in their studies fabricated tubular scaffolds of biodegradable PLLA-CL (75:25) for engineering blood vessels and found that they mimic natural ECM that provides mechanical properties comparable to a human artery and

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Table 8.3 Synthetic polymeric materials for nanofibers. Scaffold

Application

References

Polylactic acid

Blood vessel tissue engineering

Poly(ethylene terephthalate) Polycaprolactone

Blood vessel tissue engineering

Tu et al. (2003), Yang et al. (2004b) Ma et al. (2005)

Poly lactic-co-glycolic acid Poly (ethylene-vinyl acetate) Poly(ethylene glycol)polyethylene glycol Poly(L-lactic acid-coepsilon-caprolactone Carbon and alumina nanofibers

Neural and cartilage tissue engineering Bone & cartilage and controlled drug delivery

Li et al. (2005)

Controlled drug delivery

Katti et al. (2004), Uematsu et al. (2005) Kenawy et al. (2002)

DNA delivery

Luu et al. (2003)

Biomimetic ECM for smooth muscle and endothelial cells Dental and orthopedic implants

Mo et al. (2004), Mo and Weber (2004) Price et al. (2003a,b)

provides an architecture for smooth muscle adhesion and proliferation (Mo and Weber, 2004; Xu et al., 2004). These fibers needed mechanical strength to sustain high blood pressure and maintain vasoactivity. Nanofibers have found extensive applications in musculoskeletal, bone regeneration, cartilage, ligament, skeletal muscle, skin, blood vessel, and neural tissue engineering (Vasita and Katti, 2006).

8.3.6 Drug delivery Nanofibers are often used for specific drug delivery to improve the therapeutic efficacy of drugs. The nanofibers should have certain characteristics like a high surface-to-volume ratio and high porosity to achieve controlled drug release. Usually, swellable or degradable polymers are employed for this purpose. They are formulated at desired time and location. The drug loading techniques are crucial in the drug release process. Its solubility in the polymer solution is also critical for determining the suitable loading technique. The drug loading mechanism involves encapsulation which involves single phase electrospinning of a blend of polymer solution and drug. Sometimes, chemical immobilization is employed via surface treatment which makes adhesion relevant for further immobilization using suitable functional groups. The other mode of drug loading involves physical adsorption, which involves the formation of weak bonds that can lead to a large explosion release of drugs. The rapid release of drugs from nanofibers allows easy therapeutic treatment (Singh et al., 2021; Vasita and Katti, 2006). The nanofibers can be used to deliver both hydrophilic and hydrophobic drugs depending upon their scaffold morphology which can be tailored for porosity and composition.

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In a study by Kim et al. (2003, 2004), the group demonstrated the use of PLG nanofibers due to the sustained release of antibiotics where the drug was incorporated into the nanofibers during electrospinning itself. The bioactivity of the drug (cefotoxin sodium) was not altered due to electrospinning. In another study by Verreck et al. (2003), the group used nonbiodegradable polymer, PU nanofibers, by electrospinning to deliver water insoluble drugs (intraconazole and ketanserin). For fast drug delivery, a polymer with high porosity and large surface-to-volume ratio is required. Usually degradable polymers are used for stimulus activation and prolonged drug release (Kajdiˇc et al., 2019). Electrospun nanofibers are designed with mucoadhesive properties that release drugs at sites like oral, gastroenteritis, vaginal and nasal passage (Pe´rez-Gonza´lez et al., 2019). The widespread applications of nanofibers including drug delivery, has the advantage in being used for wound healing. In the studies conducted by Kenawy et al. (2002), the drug tetracycline hydrochloride is delivered through electrospun nanofibers (PEVA and PLA) in periodontal applications. They observed that the rate of release of drug was varied when the ratio of polymers were varied or used in pure form when used for the same duration (Kenawy et al., 2002). Nanofibers are often used to close the wound and also to stimulate the regeneration of dermis. Skin tissues often regenerate themselves but in absence of reduced ability to heal, collagen and many other natural and synthetic polymers are used for skin tissue engineering. PU electrospun nanofiber allows for oxygen exchange, and hence, facilitates the fluid from wound to exude out while keeping the wound hydrated. Also ultrafine porosity prevents invasion of exogenous microorganisms (Khil et al., 2003).

8.3.7 Wound healing Nanofibers have shown great potential in promoting wound healing. The microstructure of nanofibers makes them suitable for ECM which is necessary for cell growth, proliferation, and adhesion. Due to the high permeability and absorption rate, it can absorb exudes from wounds while keeping the wound moist for healing. Both natural and synthetic polymers are used in wound dressing materials. Natural polymers (like chitosan, gelatin, collagen, silk fibroin, hyaluronic acid) are nontoxic, biocompatible, and biodegradable making them more advantageous over synthetic polymers (like PCL, PVP, PVA, PEO, PLGA, nylon). Chitosan, for instance, is often used in pharmacy, food packaging, and wound treatment owing to its amino activity and ductility of a hydroxyl group. Natural polymers in combination with synthetic polymers show better performance in wound healing (Liu et al., 2021). Nanofibers have accelerated healing effects on wounds as compared to gauze. In similar studies conducted by Vargas and coworkers, the group evaluated the calendula-loaded electrospun hyperbranched polyglycerol nanofibers (Vargas et al., 2010) and found that due to high swelling and porosity properties, rapid release of calendula was observed from the nanofibers that aided in wound healing. Likewise, nanoparticle (Ag) loaded and gelatin-loaded electrospun nanofibers have been found to significantly increase the wound healing ability of nanofibers (Nguyen et al., 2011; Rujitanaroj et al., 2008). Not only this, the nanofibers have been found

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to have antibacterial properties but are an excellent healer of burn wounds. MohitiAsli et al. (2013) fabricated silver ions releasing poly(L-lactic acid) nanofibers to check for their antimicrobial activity, when used as transdermal bandages due to their resemblance with ECM of skin. Hadisi et al. (2020), prepared hyaluronic acid and silk fibroin/ZnO core-sheath type nanofibers and the resultant nanofibers had antibacterial properties because of ZnO which aided in healing burn wounds. Despite many advantages of natural polymers, synthetic polymers have more utility owing to excellent mechanical properties, thermal stability, and spinability. For instance, PVP is a hydrophilic polymer that is biocompatible and is widely used in wound dressing (Kurakula and Rao, 2020). Chinatangkul et al. (2019) mixed shellac with PVP and Monolaurin to prepare electrospun nanofibers that displayed inhibitory activity against Staphylococcus aureus and Candida albicans which helped in wound healing. Ramalingam et al. (2021) combined natural and synthetic polymer PCL/gelatin to prepare an electrospun core-sheath nanofiber membrane containing antibiotic minocycline and herbal extracts for treating secondary burns. The resultant polymer showed promising antibacterial activity and promoted the proliferation and diffusion of skin cells.

8.3.8 Cosmetics and skin treatment Undoubtedly nanotechnology gives value-added products which have gained considerable interest in the cosmetic industry. The nanomaterials are often used in cosmetic industries with liposomes in moisturizers being the first. Besides personal care, skin wound healing, antiageing, antiwrinkle, and artificial skin applications are currently gaining importance. A large surface-to-volume ratio allows nanofibers to acquire greater liquid absorption capacity and also increased retention of functional groups. The large contact surface area of nanofiber with skin leads to deeper penetration of cosmetic products. High porosities and low pore diameters help in producing more breathable cosmetics including moisturizers and sunscreens (Dreno et al., 2014). Nanofibers are highly molecular-oriented and possess great mechanical strength and low basis weight which makes them suitable candidates for artificial skin material and templates for artificial skin applications (Agarwal et al., 2008). Skin health and renewal products like facial masks and skin cleansing and healing therapy are a new sensation in this industry (Khayet and Matsuura, 2011; Ramakrishna et al., 2006). Fathi-Azarbayjani et al. (2010) fabricated an antioxidant and antiwrinkle nanofiber face mask by adding ascorbic acid, retinoic acid, and collagen and gold nanoparticles during electrospinning to the solution for sustained release of active agents when wetted for deeper penetration into the skin. Smith et al. (2002) designed a nanofiber facial mask to remove accumulated oil on the skin. Various skin revitalizing agents can be added to nanofibers to achieve skin therapeutic effects (Ramakrishna et al., 2006). Taepaiboon et al. (2007) made comparative studies of nanofibers and cast films loaded with vitamins (A and E) while electrospinning and found that as compared to nanofibers (cellulose acetate in this case), which had sustained and gradual release of

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vitamins (24 hours for vitamin E and 6 hours for vitamin A), the cast films had burst of vitamins when in contact with skin. This gradual increase in drug use is attributed to the increased surface area as compared to cast films (Ramakrishna et al., 2006). Similar studies made by Sheng and coworkers (Sheng et al., 2013) showed that vitamin E-loaded silk fibroin nanofibers could be used as skin care products as they increase the survival rate of fibroblast cells (in mouse). It is expected that the use of nanofibers will soon find more prevalent use in cosmetics.

8.4

Conclusions

Nanofibers are nanomaterials that exhibit significantly improved novel properties in terms of physicochemical and biochemical applications owing to the porous structure and large surface area. The desired nanofibers can be obtained depending upon the type of method used for its fabrication. The properties can, thus, be modified accordingly. The fabrication can be carried out on a small scale as well as on an industrial level depending upon the type of method employed for fabrication. Electrospinning is used for the generation of continuous nanofibers with different biological and physicochemical properties. Electrospun nanofibers are employed for a wide range of applications as they can be fabricated by altering the properties like surface tension, viscosity, concentration, voltage, syringe to collector distance, molecular weight, etc. during their fabrication. Hence, one can fabricate nanofiber of desired diameter and length by focusing on the type of application ranging from water treatment, fuel cells, energy storage, drug delivery, tissue engineering, and cosmetics. In totality, nanofibrous scaffolds have gained interest as they show excellent potential to be used in tissue engineering, for example, bone, skeletal muscle and cartilage repair. Despite multiple challenges, the area of nanofibers’ generation appears to be exciting, enabling researchers across various disciplines to innovate and fabricate nanofibers with desirable features.

Individual authors’ contributions All Authors have contributed equally to this manuscript.

Compliance with ethical standards Not applicable.

Conflict of interest No conflicts of interest.

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Research involving human participants and animals Not applicable.

Informed consent Not applicable.

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4412.

Electrospun nanofiber a smart drug carriers: production methods, problems, solutions, and applications

9

Chandan Bhogendra Jha1,2, Sanusha Santhosh3, Chitrangda Singh1, Sujit Bose3, Kuntal Manna2, Raunak Varshney1 and Rashi Mathur1 1 Division of Radiological, Nuclear and Imaging Sciences, Institute of Nuclear Medicine and Allied Sciences, DRDO, Timarpur, Delhi, India, 2Department of Chemistry, Indian Institute of Technology, Delhi, India, 3School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, India

9.1

Introduction

The global population is rapidly aging because of sedentary lifestyle, which leads to major health-related complications. As the population grows older, these health-related problems lead to chronic disorders (Nune et al., 2017). This enthuses biomedical researchers to develop effective strategies to address health issues. Increased rates of chronic illness and age-related conditions, such as obesity, diabetes, arthritis, osteoporosis, cancer, and cardiovascular diseases, lead to a slew of consequences. In 2008, there were 57 million deaths worldwide, with 63 million deaths related to diabetes, cancer, cardiovascular illnesses, and chronic respiratory disorders (Fig. 9.1). Around 80% of all fatalities, or 29 million people, live in poor and medium-income nations (Alwan et al., 2010).

Cardiovascular Disease

Cancers

Other noncommunicable disease Chronic respiratory diseases Digestive diseases

Diabetes

Figure 9.1 Proportion of global deaths due to the chronic disease under the age of 70. Source: Adapted with permission from WHO report-2008 on global burden of disease. Fiber and Textile Engineering in Drug Delivery Systems. DOI: https://doi.org/10.1016/B978-0-323-96117-2.00002-9 © 2023 Elsevier Ltd. All rights reserved.

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The abovementioned diseases are the primary causes of mortality in the majority of countries in the Americas, the Eastern Mediterranean, Europe, South-East Asia, and the Western Pacific. Infectious diseases continue to kill more people in Africa than chronic illnesses (Alwan et al., 2010). Nevertheless, chronic diseases are on the rise, and by 2022 chronic diseases are expected to account for about three-quarters of all fatalities, surpassing communicable, maternal, perinatal, and nutritional disorders as the leading causes of mortality (Parkin, 2006).To overcome these problems, we need to modify or improve our existing treatment strategies and develop new molecules, which must have the ability to address the issues. However, developing new molecules is a time-consuming and costly process, therefore, it is the need of the hour to improve the pharmacokinetics and pharmacodynamics behavior of existing drug candidates. This needs the development of drug delivery systems that must have the potential ability to overcome these issues currently, multiple techniques or delivery systems have been in use, such as nanoparticles, liposomes, nucleosomes, niosomes, self-nano-emulsifying drug delivery systems and more. Among the various nanomaterials, electrospun nanofibers have garnered much attention as a construction material for drug delivery systems because of their larger surface area, controllable surface conformation, better surface modification, complex pore structure, and biocompatibility (Nune et al., 2017; Sun et al., 2019). Electrospun nanofibers are superior to other drug carriers because of their high drug loading efficiency and increased surface-to-volume area, which allows for drug administration through a variety of pathways (Sun et al., 2019). Electrospun nanofiber can be administered via common routes, such as oral, buccal, sublingual, rectal, vaginal, transdermal, ocular, and inhalation and can be implanted locally or in the vicinity of a certain location (Cleeton et al., 2019). Electrospun nanofibers allow controlled release of drugs, making them suitable for different therapies. In addition, electrospun nanofibers should be biocompatible and have superior in vitro and in vivo performances because of their nano size and improvement in the mass transport limiting membrane (Teixeira et al., 2020). Antiemetic coating by electrospinning can improve patient compliance and the lifetime of electrospun nanofiber (Asia et al., 2010). These nanofibers are manufactured by electrospinning, which is a simple, variable, and successful method of synthesis for preparing and controlling nanofiber production (Fig. 9.2). The modification/functionalization of these nanofibers customizes their applications according to the desired target site (Parkin, 2006).

9.2

Advantages of electrospun nanofiber

Electrospun nanofiber has multiple advantages; a few of them are listed below (Fig. 9.3). We have also discussed these advantages in details with some examples for better understanding.

9.2.1 High surface area-to-volume ratio Nanofiber possesses a high surface area-to-volume ratio because of its nano size. This characteristic makes it suitable for biomedical use that needs a better surface

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Figure 9.2 Overview of Electrospinning (Toriello et al., 2020). (A) Process of electrospinning. (B) SEM image of electrospun nanofiber Source: Adapted with permission from Toriello, M. et al., 2020. Progress on the fabrication and application of electrospun nanofiber composites. Membranes 10 (9), 1 35.

High Surface Area to Volume Ratio

Commercial Applications

Advantages (Electrospun)

Ease of fiber functionalization

Ease of Fiber deposition onto other substrate

Figure 9.3 Different advantages of electrospun nanofiber.

area, such as the development of affinity-based membranes and sensors. Keeping an eye on these properties of electrospun nanofiber in 2019, Feng et al. described in their publication that nanofiber membranes had much better zone inhibition of Gram-negative (Escherichia coli) and Gram-positive (Staphylococcus aureus) bacteria than cast film made of the same materials, polylactic acid, and loaded with the same number of TiO2 nanoparticles (Feng et al., 2019). Nanofiber membranes have a larger surface area than cast film, which has certain advantages when it comes to

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antibacterial membranes and films whereas this nanofiber’s greater surface area allows for fast disintegration in circumstances where rapid medication release is desirable. Whereas just before this publication in the year 2017, Kwak et al. observed that electrospun fish gelatin (FG)/caffeine membrane decomposed in 1.5 seconds in water but needed 40 seconds in the form of a solvent cast film. The electrospun FG/caffeine membrane dissolved fully in 5 seconds on the wet sponge, but the solvent cast remained gel for three minutes owing to insufficient water absorption for ultimate disintegration (Kwak et al., 2017).

9.2.2 Nanofibers can be synthesized from a variety of polymers and materials All important types of materials, such as chitin, polyvinyl alcohol, and chitosan, have been electrospun to form nanofibers. These materials may be employed directly or indirectly in a variety of ways. Although the approach is most often employed to make polymeric nanofibers, it has also been utilized to electrospin ceramic and metal nanofiber precursor materials (Feng et al., 2019).

9.2.3 Ease of fiber functionalization This benefit of electrospun nanofiber originates from the large choice of polymers that may be used to create electrospun nanofibers. The functionalization of electrospun nanofibers can be done by simple mixing of polymer solution in different ways, such as before its blending, post spinning surface functionalization, or by core-shell electrospinning arrangements (Kwak et al., 2017).

9.3

Methods of electrospinning

A few procedures have been proposed for the manufacturing of nanofibers: phase separation technique, self-assembly fibers, template synthesis, and electrospinning. The electrospinning method is utilized for the polymeric arrangement that can be changed and improved with bioactive atoms. Nanofiber is one of the electrospinning tools used as a drug carrier. This strategy utilizes a few methods, for example, mixing, coaxial method, and surface alteration, that allows the inclusion of any medication (Mohammadian and Eatemadi, 2017).The production of pharmaceutical electrospinnable emulsions is a multi-faceted and difficult task. A systematic design of trials would be more effective in achieving electrospinnability quality features (DoE). Quality by design is a proactive risk-based approach aimed at achieving a given predictable level of quality with predefined criteria. The approach requires an in-depth understanding of the primary and interaction impacts of many factors on a product’s critical quality attributes, as well as the use of statistical procedures to minimize experimental trials (Badawi and El-Khordagui, 2014). Quality by design has been effectively applied to the formulation and process development of

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pharmaceuticals. The ICH Q8 guideline mentions the concept of quality by design, stating that “Quality should be tested into the product, i.e., quality should be built in by design.” ICH Q8 guidelines says that “quality by design” is a method for making things that starts with clear goals and puts a lot of emphasis on understanding and controlling the product and process. It is based on good science and quality risk management (Patil and Pethe, 2013). Quality by design is the process of developing and improving formulations and manufacturing processes to guarantee that stated product requirements are satisfied. In 2002, the FDA revealed a new initiative “cGMP for the 21st Century: A risk-based approach”. This program was sought to reform the FDA’s regulatory framework governing pharmaceutical quality and performance (Charoo et al., 2012; Patil and Pethe, 2013). A critical component of quality by design is understanding how process and formulation parameters affect product qualities and then optimizing these parameters to monitor them online during the manufacturing process (Patil and Pethe, 2013).

9.3.1 Blending electrospinning The utilization of a mixture of polymers upgrades the balance among the physical, chemical, and mechanical nature of the drug-stacked nanofibers. Likewise, this adequately builds the detailing plan for drug delivery, where the delivery speed can be controlled with modified polymer concentration in the mixing solution. This is a single-step technique, where drug incorporation is accomplished by electrospinning since drugs are diffused or distributed in the polymer solution. Both drug and polymer solutions are mixed and loaded into needles having specific sizes. The stream of mixed solution is electrostatically collected by the collector. At that point, the solvent vanishes, and dry filaments are gathered on the collector. In this technique, both hydrophilic and hydrophobic polymers can be used for drug loading. Hydrophilic polymers like polyethylene glycol, polyvinyl alcohol, and amphiphilic copolymers like PEG-b-PLA may improve drug loading efficiency (Cornejo Bravo et al., 2016).

9.3.2 Coaxial electrospinning The filaments with center shell form are acquired due to the coaxial electrospinning. This strategy is utilized to get certain drug strands captured within the middle of the filaments, which results in a continued and controlled medication discharge. The benefits of this technique are the upgrading of biomolecule functionality, into the innermost stream, while the electrospinning technique is working and the polymer solution is into the outermost stream offering assurance to the biomolecule. The polymeric shell assists with staying away from the immediate exposure of the biomolecule to the outer environment (Pant et al., 2019). The overall arrangement and the fiber-producing process are adroitly like that of ordinary electrospinning. In this technique, the spinneret is changed by embedding a smaller coaxially inside the larger capillary to acquire a coaxial arrangement. The external needle consists of sheath preparation while the inward one consists of a central preparation.

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A core-shell droplet is produced due to simultaneous pumping of two die rent spinning solutions by the inner and outer nozzles. The gathering of charge happens overwhelmingly on a superficial level of the sheath solutions emerging from the coaxial capillary, while the polymer preparations are delivered with high voltage. The pendant drop of the sheath extends because of the charge-charge repulsion, framing a cone-like form. When the charged gathering arrives at a limit, a stream rises out of the tip of the twisted drop coordinated toward the counter cathode. At last, a center shell fiber is kept on the substrate (Ghafoor et al., 2018).

9.3.3 Emulsion electrospinning This is an adaptable and likely procedure for the entrapment of drugs into nanofibers. It is one of the main techniques for the preparation of core-shell electrospun nanofibers in a savvy and efficacious way. In this technique, the oil phase is made due to the emulsification of the drug or the polymer solution containing aqueous protein preparation, trailed by electrospinning. When the medication to be loaded has an adequate low atomic weight, the biomolecule-load stage may be disseminated inside the fiber or a central shell fiber could be designed as macromolecules blend in the aqueous part (Mohammadian and Eatemadi, 2017). When contrasted with the blending procedure, the primary promising benefit of this method is that the polymer and drugs are solvated in appropriate solvents, rather than using a common solvent. Various hydrophilic drugs and hydrophobic polymers are utilized. Emulsion electrospinning leads to degradation of macromolecules like pDNA as compared to coaxial electrospinning (Ghafoor et al., 2018).

9.3.4 Surface modification electrospinning In this system-specific method, the conductive surface is synthetically modified and altered to change the outer properties of the covered device, by fusing specific atoms that disguise the surface by offering the same surroundings as the tissue, which will encompass the embedded material. Typically, it is applied to prevent quick initial rupture release and reduce the pace of fixation of the organic particles on a specific surface. It is conceivable to cover 3D exteriors with nanomaterials or to cover homogeneous surfaces with a decent electrospinning framework and by a normalized technique that makes an electric field inside a camera (Cornejo Bravo et al., 2016).

9.3.5 Electrospray This method includes spraying the fluid through the nozzle into the electrical field that shapes the Taylor cone due to the surface tension. The Taylor cone splinters into profoundly charged beads, making reasonable situations to develop nanomaterials, as the electric field expands. The solvent evaporates to give shape to the solid particles. The variables like the needle gauge breadth, voltage and gap from the

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Figure 9.4 Different techniques of drug loading in electrospun nanofiber.

needle to the conductive collector, and flow rate should be considered to correctly encapsulate the drug (Cornejo Bravo et al., 2016).

9.3.6 Coaxial electrospray This technique creates multifilm materials with sizes ranging from 10 and 100 μm with the help of a high electric field within a coaxial slim needle and ground. The developed electrical shear pressure lengthens the core and menisci the shell fluid at the needle source to shape the “Taylor cone”; after this process, the stream of the fluid is elongated till it is broken into multifilm beads attributable to the electrohydrodynamic powers (Cornejo Bravo et al., 2016) (Fig. 9.4).

9.4

Applications of electrospinning

In this section, we discussed some recent advancements in their applications (Fig. 9.5) as drug carriers.

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Figure 9.5 Visual presentation for application of electrospun nanofibers.

9.4.1 Ocular delivery Nanofibrous materials in the shape of small patches or sheets, similar to therapeutic contact lenses, may be easily positioned near the desired site of administration. Some of the significant advantages are these materials that do not cover the whole conjunctiva, which in turn allows the easy penetration of fresh oxygen present in air and useful components to the eye surface. These nanofibrous materials have adequate mucoadhesive characteristics, since adherence to the cornea is not ensured by other features, such as a lens curvature similar to that of the cornea. Consequently, they can remain on the cornea throughout the length of application. If the materials are made from biodegradable polymers, then the nanofibrous material need not be removed even after the drug is released. As a result of all these, the electrospun nanofiber allows for the local maintenance of therapeutic activity for a long duration of time, increased effectiveness, a reduced dose of the drug, and increased patient compliance. The in vitro drug release studies are generally performed in simulated tear fluid via cellulose dialysis membranes (Cegielska and Sajkiewicz, 2019).

9.4.2 Transdermal delivery Electrospun naonofibers reduce the systemic absorption of topical drugs, resulting in less drug dose usage and minimizing unwanted side effects. These nanofibrous materials are applied locally for drug and growth factor delivery, siRNA or DNA distribution, and cancer treatment. Hydrophobic drugs (like paclitaxel and rifampicin), hydrophilic drugs (like doxorubicin hydrochloride and tetracycline hydrochloride), and biomacromolecules (like DNAs and proteins) can be easily loaded in electrospun nanofibers (Table 9.1). For delivering the drug-using electrospun

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Table 9.1 List of drugs used for transdermal application in electrospun nanofibers. Sr. no.

Drug category

Drug name

Polymers used

References

1

Vitamin

Vit B12

Poly-caprolactone

2

Vitamin

Vitamin E

Cellulose acetate

3

Topical dosinfectant

Chlorhexidine

Cellulose acetate

4

Antimicrobial agent

Cellulose acetate

5

Cellulose acetate

Naproxen

Cellulose acetate

Indomethacine

Cellulose acetate

8

Nonsteroidal antiinflammatory drug Nonsteroidal antiinflammatory drug Nonsteroidal antiinflammatory drug Antibiotic

N-halamin (CIBTMP) Ibuprofen

Tetracycline hydrochloride

9

Antibiotic

Amoxicillin

Poly (ethylene-covinyl-acetate)/Poly (lactic acid) Cellulose acetate/ Polyvinyl pyrrolidone

10

Anibiotic

Ornidazole

Madhaiyan et al. (2013) Taepaiboon et al. (2007) Chen et al. (2008) Sun et al. (2010) Tungprapa et al. (2007) Tungprapa et al. (2007) Tungprapa et al. (2007) Kenawy et al. (2002) CastilloOrtega et al. (2011) Meinel et al. (2012)

6

7

Cellulose acetate/ polyvinyl pyrrolidone

nanofibers, the drug should be in the form of nonionic or amorphous form and should be taken on a patch. In comparison to other drug carriers like hydrogels and liposomes, electrospun nanofibers are more efficacious in encapsulating drugs and other macromolecules and decreasing the burst effect of the drug. Moreover, electrospun dressings over films are generally prepared by the casting method, which helps in the easier distribution of active ingredients in the surrounding environment (Rahmani et al., 2017)

9.4.3 Cancer treatment Electrospun nanofibrous materials have been extensively used for cancer therapy by maintaining the release of anticancer drugs (Table 9.2), controlling the movement

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Table 9.2 List of anticancer drugs used for electrospunnanofiber-based drug delivery. Sr. no.

Drug used

Polymers used

Type of cancer

References

1

Gallic acid

Poly (ethylene oxide)/ Zein

Xue et al. (2019)

2

Doxorubicin

Poly (l-lactic acid)

3

4

Camptothecin-11 and 7-ethyl-10hydroxycamptothecin Paclitaxel

PCL and poly (glycerol monostearatecoε-caprolactone) Poly lactic-co-glycolic acid

Gall bladder cancer Hepatic cancer Colorectal cancer Malignant glioma

5

Green tea polyphenols

Hepatic cancer

6

Titanocene dichloride

Poly (ε-caprolactone)/ multiwalled carbon nanotube Poly (l-lactic acid)

Ranganath and Wang (2008) Shao et al. (2011)

Lung cancer

Chen et al. (2010)

Liu et al. (2013) Xue et al. (2019)

of tumor cells, and/or producing a synergistic action of tumor cell proliferation, angiogenesis, and invasion. By controlling alignment and morphology, nanofibrous materials are used for cancer treatment by inducing apoptosis and regulating the migration of tumor cells. These strategies inhibit the growth of primary tumor cells. These materials are generally conjugated with multifunctional nanoparticles to produce a long-term locally releasing implantable device (Contreras-Ca´ceres et al., 2019). Kamasani et al. explored all of these aspects in depth in their minireview, with particular emphasis on the use of smart electrospun pH-responsive nanofibers in new biomedical advancements, such as cancer treatment targeting, oral controlled release, wound healing, and vaginal drug administration (Kamsani et al., 2021).

9.4.4 Enzyme immobilization The electrospun nanofibers’ maximal porosity and larger total surface area efficiently minimize the diffusion resistance of the film matrix and significantly improve the catalytic activity of the encapsulated enzyme (Table 9.3). Surface loading approaches are the most often used way of immobilizing enzymes in these materials since various loading techniques might result in variable binding capabilities between fibers and enzymes (Sun et al., 2019).

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Table 9.3 List of enzymes immobilized in electrospun nanofiber. Sr. no.

Enzyme name

Polymer name

Inference

1

α-Amylase

Polyvinyl alcohol and polyacrylic acid The immobilized α -amylase was more resistant to temperature inactivation than free α-amylase.

Bastu¨rk et al. (2013)

2

Protease

Polyvinyl alcohol

Sarathi et al. (2019)

3

Lipase

Polyvinyl alcohol

4

Glucose oxidase

Polyethylene oxide and chitosan

5

β-Galactosidase

Polyvinyl alcohol/ chitosan

The keratinolytic enzyme loaded on the electrospunnanofiber enhanced the stability and activity even at a wider pH range and higher temperature. Enzyme-loaded nanofiber showed increased enzymatic stability. The formulation had the potency to retain 90% activity at 70 C after 40 min, whereas the free lipase lost all its activity just at the same time. The spun membranes demonstrated high overall porosity, homogenous pore size distribution, and high specific surface area, being key properties to a successful functionalization as well as to the activity of the immobilized enzyme. Immobilized β-galactosidase exhibited more temperature stability than free enzyme at 50 C. Improved temperature and storage stability.

References

Sun et al. (2019)

Bo¨siger et al. (2018)

Haghju et al. (2018)

9.4.5 Controlled release To achieve a long-term therapeutic activity, controlled and sustained release of drugs is significantly used in the biomedical field. The drug release characteristics from these electrospun nanofibrous scaffolds are greatly affected by the diameter of the fiber and the microstructure of the single nanofiber (Sun et al., 2019).

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Weng et al., in their review article, discussed the mechanisms of various environmental parameters functioning as stimuli to tailor the release rates of smart electrospun nanofibers. They also illustrate several typical examples in specific applications (Weng and Xie, 2015).Various classes of drugs are delivered by electrospun nanofiber, which is summarized in Table 9.4. However, pharmacokinetics and release mechanisms of drug-loaded electrospun nanofibrous scaffolds are still very few, which in turn limit the practical applications in the biomedical field (Sun et al., 2019).

9.4.6 Filtration Electrospun nanofibers can be used as a filtration membrane to be widely used in biomedical applications like the separation of white blood cells and bacteria (Xue et al., 2019). In engineering, fiber filtration is considered to be one of the most applicable fields. These materials are widely used for the removal of small unfriendly particles. Oil droplets of sizes as small as 0.3 μm can be entrapped by the electrospun nanofibers, which is an important attribute in the filtration industry. Media filters have properties like small air repellent and high filtration performance (Mirjalili and Zohoori, 2016). For example, white blood cells were successfully filtered from poly (butylene terephthalate) electrospun nanofibers, which were coated on a traditional poly (butylene terephthalate) nonwoven fabric. When comparing the results, it was observed that pristine fabric had the potential to reduce the number of cells from 109 to 105 L21 while the poly (butylene terephthalate) nonwoven fabric reduced the number of cells from 109 to 104 L21. In another study, PAN nanofibers containing silver nanoparticles exhibited 99% filtration efficiency against Gram-negative E. coli bacteria and Gram-positive S. aureus bacteria in addition to significant antibacterial activity (Selvam and Nallathambi, 2015).

9.4.7 Tissue regeneration Tissue regeneration or tissue repair comprises combining the scaffolding tissue or cell to assist tissue growth by providing biochemical instruction to tissues, topographic guidance, and mechanical support. During the formation of a scaffold material, it is of utmost importance to mimic the native extracellular matrix (ECM) so that it can resemble its architecture, composition, and other properties. ECM’s function can be easily imitated by the electrospun nanofibers due to their architecture, length scale, and unique ability to recapitulate the composition. The electrospun nanofibers can be easily coated with adhesive glycoprotein in ECM via physical adsorption, covalent grafting, and/or electrostatic interaction. Considering the microscopic level, it is easier to engineer the surface structure of a scaffold by changing the topographic cues including the alignment, diameter, and porosity of the nanofiber, thus manipulating the fate and behavior of tissue regeneration. At the macroscopic level, engineering the bulk structure of a scaffold-like matching the morphology of the target tissue, changing from 2D to 3D, or from a single layer to multilayers can altogether affect tissue repair. In the process of tissue regeneration,

Table 9.4 List of different class of drugs used for electrospun nanofiber. Sr. no.

Drug category

Drug name

Polymer name

Inference

References

1

Antineoplastic drug

Dichloro acetate

Polylactic acid

Liu et al. (2012)

2

Antiinflammatory drugs

Indomethacin

Ethyl cellulose and zein

3

Skin care drugs

Ferulic acid

Cellulose acetate

4

Antihyperlipidemic drug

Lovastatin

Polylactic acid

5

Antineoplastic drug

Paclitaxel

Poly-caprolactone

6

Antihypertensive drug

Carvedilol

Polyvinylpyrrolidone

Exhibited targeted delivery of therapeutic concentration of drug from electrospun matrix to minimize the cervical carcinoma in animal models. In vitro drug dissolution tests revealed that electrospun nanofibers possessed a sustained release profile with Fickian diffusion. In vitro drug release showed that electrospun nanofibers loaded with the drug could produce zeroorder release kinetics for more than 36 hours without an initial burst release of medications. In vitro release study revealed that the drug release was divided into two different stages: the first stage was the rapid release on the first day and the second stage was slower release which reached a plateau level after the seventh day. Nanofiber and nanoparticles exhibited synergistic effects, which had the potency to prevent liver tumor metastasis and inhibit the growth of liver tumors. In comparison with the direct administration of carvedilol, this new drug delivery system (composed of an adhesion layer which prolonged the residence time in the mouth, a drug-loaded electrospun fiber layer, and a support layer) had improved drug penetration and also improved its bioavailability by 154%.

Lu et al. (2017) Sun et al. (2019)

Zhu et al. (2017)

Sun et al. (2019) Chen et al. (2018)

(Continued)

Table 9.4 (Continued) Sr. no.

Drug category

Drug name

Polymer name

Inference

References

7

Antiinflammatory drugs

Ketoprofen

Poly-caprolactone and gelatin

It was observed during in vitro studies that the fiber mat prevented burst release of drug and showed controlled release capacity up to 4 days. Moreover, the fiber mat also improved the adhesion and proliferation of mouse L929 fibroblasts, which helped in active wound dressing.

Liu et al. (2019)

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the scaffold should only have functioned as a temporary matrix system to support the proliferation of cells that secret growth factors and other biomolecules into the surrounding environment, which in turn helps in the development of the permanent ECM. By combining the cellular components with bioactive materials and structural support, electrospun nanofibers can help in the repair of nerve injury, patching of myocardium defects, healing of the wound, bridging of vascular rupture, construction of interfaces between different tissues, and remodeling of musculoskeletal tissue (Ranganathan et al., 2019).

9.4.8 Barrier membranes Nonwoven mats of electrospun nanofibrous materials can be used as a barrier membrane by fighting against bacteria, enhancing osteogenesis, and preventing post-surgery adhesion. In case of tendon surgery also, a barrier membrane is required. Post-surgery adhesion between the tendon and surrounding tissues is generally caused by the chemotaxis

Figure 9.6 Multifunctional nanofibrous wound dressing. Source: Adapted with permission from Chen, S. et al., 2017. Recent advances in electrospun nanofibers for wound healing. Nanomedicine: Nanotechnology, Biology, and Medicine 12 (11), 1335 1352.

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of extrinsic fibroblastic precursor cells. Therefore, it is highly useful to develop an antiadhesion membrane using nanofiber mats with multiple activities like antiinflammation, antiinfection, and lubrication (Dong et al., 2020).

9.4.9 Wound healing Electrospining is one of the oldest but most prominent methods for the development of wound dressings. The fibers that are made from this method possess small diameter sizes ranging from micro to nanometers. Electrospun nanofibers are widely used as a fibrous wound dressing due to the unique architectural features that mimic the ECM, have a small pore size, and have a large surface area-to-volume ratio which makes them suitable for this biomedical application (Aavani et al., 2019). Electrospun nanofibrous dressings have exhibited the potential to help in cell migration and proliferation of the wound bed, gaseous exchange, provide hemostasis, and management of the wound. These dressings are biocompatible, safe, comfortable, semi-permeable, and can be easily removed from the wound site without causing any pain or trauma at the site (Haik et al., 2017). Comparing the traditional electrospun nanofiber drug delivery system with stimuli-responsive electrospun nanofibers, the latter shows more precise control of drug release and also allows less time for the response. Enhanced wound healing can be observed in the case of electrospun nanofibers with mechanical stress, pulsed magnetic field, and electrical stimulation (Chen et al., 2017). Various biological active agents and drugs like growth factors, vitamins, antibiotics, oxygen, minerals, and/or other molecules can be loaded into wound dressing (Aavani et al., 2019) (Figs. 9.6 9.8).

Figure 9.7 Wound dressing by electrospinning. Source: Adapted with permission from Mirjalili, M., Zohoori, S., 2016. Review for application of electrospinning and electrospun nanofibers technology in textile industry. Journal of Nanostructure in Chemistry 6 (3), 207 213.

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Figure 9.8 Various biological molecules that can be loaded into nanofibers. Source: Adapted with permission from Aavani, F., Khorshidi, S., Karkhaneh, A., 2019. A concise review on drug-loaded electrospun nanofibres as promising wound dressings. Journal of Medical Engineering and Technology 43 (1), 38 47.

9.5

Conclusion and outlook

The production of electrospun nanofiber or electrospinning is a technique of producing functionalized electrospun nanofibers along with its enhanced morphological properties for targeted drug delivery applications. This enthuses biomedical researchers to develop an effective strategy to understand their interactions, which particularly regulate the entire performance of these therapeutic materials and their technological advancement in the field of nano biomedicines for local or targeted treatment. Among the various nanomaterials, electrospun nanofibers have garnered much attention as a construction material for drug delivery systems because of their larger surface area, controllable surface conformation, better surface modification, complex pore structure, and biocompatibility. The better drug loading efficiency and large surface-to-volume ratio make electrospun nanofibers superior to other small drug carriers because they allow the delivery of substances via a range of different routes. Electrospun nanofibers can be administered via common routes such as oral, buccal, sublingual, rectal, vaginal, transdermal, ocular, and inhalation and in the form of local or loco-regional implants. Electrospun nanofibers allow the controlled release of drugs, making them optimal for therapy. Furthermore, electrospun nanofibers should be biocompatible and have better in vitro and in vivo performance because of nano size and improvement in the mass transport limiting membrane. Similarly, biomimetic coating by electrospinning can improve patient compliance and the lifetime of electrospun nanofiber. These nanofibers are produced by the process of electrospinning, which allows a simple, variable, and effective way of synthesis to prepare and control the production of nanofibers. The modification/functionalization of these nanofibers customizes their applications according to the desired target site.

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Acknowledgments The authors show gratitude for the constant support of Director INMAS during this work.

Authors’ contribution Chandan B Jha: Conceptualization, Writing Original Draft. Sanusha Santhosh: Visualization Chitrangda: Formal Analysis, Sujit Bose: Formal Analysis, Kuntal Manna: Supervision, Raunak Varshney: Formal Analysis, Rashi Mathur: Conceptualisation, Formal Analysis, Project Management.

Compliance with ethical standards Not Applicable

Conflict of interest We have no conflict of interest.

Research involving human participants and animals Not Applicable.

Informed consent Not Applicable.

References Aavani, F., Khorshidi, S., Karkhaneh, A., 2019. A concise review on drug-loaded electrospun nanofibres as promising wound dressings. Journal of Medical Engineering and Technology 43 (1), 38 47. Available from: https://doi.org/10.1080/03091902.2019.1606950. Alwan, A., et al., 2010. Monitoring and surveillance of chronic non-communicable diseases: progress and capacity in high-burden countries. The Lancet 376 (9755), 1861 1868. Available from: https://doi.org/10.1016/S0140-6736(10)61853-3.

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Potential of stem cells in combination with natural and synthetic polymer hydrogel for wound healing dressing

10

Subodh Kumar, Somya Chaaudhary, Ranjan Verma and Yogesh Kumar Verma Stem Cell & Tissue Engineering Research Group, Institute of Nuclear Medicine & Allied Sciences (INMAS), Defense Research and Development Organization (DRDO), Timarpur, New Delhi, India

10.1

Introduction

According to WHO, injury-related deaths have been reported in 4.4 million people all over the world. Each year, unintentional injuries claim the lives of 3.16 million people, whereas violence-related injuries claim the lives of 1.25 million people. The major cause of death due to delayed healing or tissue repair and significant blood loss (https://www.who.int/news-room/fact-sheets/detail/injuries-and-violence). Chronic wounds have also become more common as peripheral vascular disease, type 2 diabetes, and metabolic syndrome has increased. Patients with substantial burns, infected wounds, or chronic wounds confront long-term care issues; however, therapies for acute and minor wounds are effective. Skin is considered the largest organ because of its massive surface area, and it serves as the body’s outermost layer exposed to external stress, microbes, and other stimuli (Yildirimer et al., 2012). Skin serves as a barrier between the environment and the internal organs, protecting them from mechanical stress, microbial infection, and fluid imbalance while also regulating body temperature (Erika Maria et al., 2020). Wound develops when layers of skin, mucosal surfaces, or tissue lose their integrity as a result of mechanical stress (such as accidents), illness, microbial infection, and cellular damage. Microbes and foreign substances may enter the body through a wound and causes inflammation and local or systemic infection (Klein et al., 1995). This puts human organs and the body in jeopardy, and can sometimes lead to life-threatening situations. As a result, wound care and rapid wound healing have become crucial and clinically important, necessitating the development of more effective wound healing therapies. Most of the wound healing therapeutics available in the market are either biomaterials or cells based and very few are cellsincorporated biomaterials based on having regenerative potential. Fiber and Textile Engineering in Drug Delivery Systems. DOI: https://doi.org/10.1016/B978-0-323-96117-2.00016-9 © 2023 Elsevier Ltd. All rights reserved.

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Wound healing is a complex and dynamic process in which cellular and extracellular matrix (ECM) components collaborate to repair/replace the damaged tissue (Eming et al., 2014). In response to infection, our body recruits immune cells (e.g., Langerhans cells, T cells, regulatory T cells, and resident memory T cells) at the wound site (Vocanson et al., 2009 ) During inflammation, these cells and chemical factors such as stromal cell-derived factor 1 (SDF-1), epidermal growth factor (EGF), fibroblast growth factor (FGF), transforming growth factor-beta (TGF), platelet-derived growth factor (PDGF), and transforming growth factor-beta (TGF) help to maintain homeostasis (Decker et al., 2000; Lech et al., 2012; Sherwood, 2015). Wounds are majorly classified based on duration of healing (Table 10.1) and integrity of the skin (Kumar et al., 2021). Scientists have also classified wounds based on the degree of bacterial contamination and their origin (Boateng et al., 2008; Kumar et al., 2021; Patrulea et al., 2015). Given the wide range of wound types, selecting an appropriate dressing requires a methodical approach. Cleaning, dressing, and treating wounds effectively to prevent infection and promote complete healing are all part of proper wound care (Martin, 1997; Tottoli et al., 2020). The first step in wound care is determining the Table 10.1 Classification of wound. S. no.

Type of wounds

Description

On the basis of duration of wound 1.

Acute wounds Scrapes or abrasion Cut or crush wounds Contusions Laceration

2.

Radiation wounds or ulcers Chronic wounds Vascular ulcers Diabetic wounds Ischemic wounds

Knife cuts, burns, and other environmental events cause trauma to the bone structures and soft tissues. When skin rubs against rough surfaces, the resultant lead to scrapes e.g., rope burns. A forcible impact on the body breaks or pulls the bone away from the remainder of the bone, resulting in a wound. Collection of blood outside a blood vessel due to injury in blood vessels Tearing of soft tissues in the body, which can be internal or external. Ionizing radiation causes injuries to the underlying soft tissues. Caused by slow-healing tissue injuries. Stasis ulcer or dermatitis is a condition that affects the lower extremities of the legs. Usually seen in the elderly. Unable to prevent infection due to a weakened immune system, and small wounds become chronic. It helps in blood supply to the vascular beds.

Based on the integrity of skin 1. 2.

Open wound Closed Wound

Caused by skin laceration with or without tissue loss. No damage to the skin’s integrity occurs and the skin remains undamaged.

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origin of tissue injury, site of infection, and features of a wound. This is only possible if we can differentiate wounds and classify them appropriately (GhareeKermani and Pham, 2001). It is important since a healthy person’s wounds and an ill person’s wounds have different levels of bacterial infection, and ability to heal. There are several treatment options available for wound healing for example cream, bandages, hyperbaric oxygen therapy, negative pressure wound therapy, skin grafts, honey, etc. In hyperbaric oxygen therapy, the injured tissue is placed in a specific chamber with a high oxygen pressure to ensure that there is enough oxygen in the blood to enhance the wound’s blood flow. In ultrasound therapy, a sound wave is used to make tissue warmer resulting in wound healing but the therapy hasn’t been effective in all types of wounds. In negative pressure treatment, a negative pressure is applied around the injury area to suck the fluid out of the wound but same time increases the flow of blood to the wound and improves wound healing. In large wounds, skin grafts are considered the best option in which the skin taken from a bvody part is transplanted onto the wound (https://www.ncbi.nlm.nih.gov/books/NBK326436/). The marketed available wound dressing usually takes a long time for wound healing and further any delay leads to the development of complications like infection. Whereas commercially available drugs are associated with several side effects such as kidney and liver damage. To overcome these limitations novel therapeutics are required with enhanced efficiency and lesser side effects. Hydrogels, which are 3D networks made up of chemically cross-linked linkages of hydrophilic polymers, are frequently employed in skin, fat, blood vessels, and muscle tissue engineering (Al Shaibani et al., 2016). The insoluble hydrophilic structures absorb wound exudates and allow oxygen diffusion as prerequisites to accelerate healing (Kumar and Jaiswal, 2016). The hydrogel itself is not sufficient to accelerate tissue repair, therefore, we need further addition to enhance wound healing, for example, surface medication, stem cell encapsulation, etc. Stem cells (SCs) can be an option for wound healing due to their self-renewal and differentiation properties. SCs can regenerates damaged tissues and function as any type of cell under precisely regulated condition. Various types of SCs are used in the wound such as Adult stem cells, Mesenchymal stem cells (MSCs), Endothelial progenitor cells (EPCs), and Adipose tissue-derived stem cells (ADSCs). The immense advantage of SCs in wound healing is their regenerative and immunomodulatory properties (especially in MSCs). The major limitation of SCs therapy is an ineffective mode of transplantation. In this chapter, we have emphasized the use of synthesis and natural polymer hydrogel as a carrier of SCs for wound healing and tissue repair to maximize their efficiency (Ayavoo et al., 2021).

10.2

Physiology of wound healing

Despite the cause or the extent of tissue damage, under normal circumstances, the wound healing process occurs in four overlapping stages such as hemostasis, inflammation, proliferation, and remodeling (Hunt et al., 2000).

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10.2.1 Hemostasis Following injury, exsanguination occurs as a result of vascular damage, resulting blood vessels contraction and blood clotting (Golebiewska and Poole, 2015). When platelets come in contact with the vascular subendothelial matrix, they become activated to aid in hemostasis by promoting adhesion of the walls of a blood vessel via ECM proteins such as fibronectin and collagen. Coagulating factor II, thrombin, induces a conformational change via the release of dense granules of bioactive molecules that strengthen the clotting process (Fig. 10.1). Hemostasis also serves secondary functions such as protecting injured cells from bacterial invasion, forming a protective scaffold for incoming immune cells, and storing cytokines and growth factors to guide cells during the early stages of repair.

10.2.2 Inflammation Increased vascular permeability, active blood cell movement, and the transit of plasma components into wounded tissue are all signs of inflammation (Silver, 1993). It is a protective process against germs that infiltrate a wound. Damageassociated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) are released by damaged tissue and bacterial components respectively (examples of injury-induced signals). Pattern recognition receptors on resident immune cells such as mast cells, T cells, and macrophages activate PAMPs and DAMPs, triggering downstream inflammatory pathways. Circulating leukocytes are drawn to the injury site by the production of pro-inflammatory cytokines and chemokines. The inflammatory molecules have been listed in Table 10.2.

Figure 10.1 Phases of wound healing. (1) Hemostasis; Vasoconstriction and activation of platelet are induced (2) Inflammation; Recruitment of neutrophils, monocytes, and macrophages and debridement of wound is induced (3) Proliferation; Angiogenesis and extracellular matrix (ECM) deposition is induced (4) Remodeling: Scar formation and degradation of ECM takes place.

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Table 10.2 Role of inflammatory molecules in wound healing. S. no.

Inflammatory molecules

Functions

1.

Neutrophils

2. 3.

Monocytes Lymphocytes

4.

Innate Lymphocytes

5. 6.

CD8 1 T Cells CD4 1 T Cells

7.

B Cells

They release chemo-attractants at the site of injury, allowing them to capture Fc-receptors of opsonized pathogens and phagocytize them. These cells remove damaged cells via white blood cells. Lymphocytes are the cells adaptive immune system (T and B cells) that keep specific memory for a long time to combat intra and external infections. Natural killer cells are lymphoid cells belonging to the innate immune system with cytolytic activities that generate interferon-gamma and tumor necrosis factor. These cells are the initial line of defense against pathogens. T helper cells (Th cells) and regulatory cells, comprising Th1, Th2, Th17, Th22, and Th9, support host defense by secreting cytokines that encourage the production of INF, defensins, antimicrobial peptides, and protective inflammatory response. By releasing growth factors, pro-inflammatory cytokines, and anti-inflammatory cytokines, these cells produce antibodies, transfer antigens to T cells, and regulate local immune responses.

10.2.3 Proliferation Proliferation is the process of forming new collagen and ECM tissue. During this phase, the wound size decreases as new tissues form. A network of blood vessels develops to ensure that the body receives appropriate oxygen and nutrients. Myofibroblasts contract the wound in the same way as smooth muscle cells do during wound contraction by grabbing and drawing the wound edges together. During the early stages of wound healing, granulation tissue is pink in color and has an irregular texture. This resists bleeding. Dark granulation tissue can be caused by infection, ischemia, or poor perfusion. At the end of the proliferative phase, epithelial cells resurface the wound. To speed up the epithelialization process, the wound must be kept wet and moisturized (Bas et al., 2018; Lande´n et al., 2016).

10.2.4 Remodeling Remodeling is the last that starts from the 21st day and lasts up to 1 2 years of injury (Velnar et al., 2009). During this phase, maturation of wound takes place wherein components of ECM undergo certain changes, for instance, replacement of collagen type III into type I. The orientation of collagen also changes in the small parallel bundles. Collagen helps to decrease the development of a scar. During this

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process angiogenesis declines hence, the flow of blood in the wounded area reduces (Young and McNaught, 2011).

10.3

Approaches to heal wound

The process of wound healing is regulated at each phase, that is, hemostasis, inflammation, proliferation, and remodeling. During the inflammatory phase, vascularization is achieved via the activation of genes/proteins having a role in vascularization. Initially, mostly plant-based products were used in wound care, for example, viscous exudate of Euphorbiaceous. Another plant Cudrania cochinchinensis has shown fibroblast proliferation and protection of endothelial cells against oxidative damage. As time passed the development of new therapeutics resulted in efficient wound healing. Nowadays, scientists are using siRNA/miRNA (Chouhan et al., 2019) to silence genes involved in the negative regulation of cell proliferation (Table 10.3).

10.4

Biomaterial used in wound healing

Biomaterials are used in tissue regeneration, repair, and the fabrication of artificial devices. Before designing biomaterials for wound dressing it is critical to use noninflammatory materials that promote tissue synthesis while preserving its volume and shape (Chen and Liu, 2016). The most responsive biomaterials would promote wound healing and the formation of new viable tissue in vitro as well as in vivo. Biological healing does not address the physical repair of the wound. There is a significant impact of biomaterials on wound healing even though the biomaterials Table 10.3 Approaches of wound healing. S. no.

Approaches

Mechanism

1.

Immunomodulation and vascularization. siRNA-based skin therapeutics

In damaged tissue, vascularization is achieved through utilization of cellular and molecular biology. Small interfering RNA (siRNA) is a synthetic RNA with a length of 21 25 nucleotides that can silence certain genes by knocking down messenger RNA unique to that gene. Despite their comparable structures (a 25-nucleotide RNA duplex with a 2-nucleotide 3’overhang), miRNA and siRNA have different methods of action. The miRNAs are less precise in terms of complementarity to their target than siRNAs, which are developed with specificity for binding as a major goal. As a result, they can target several genes.

2.

3.

MicroRNA-based skin therapeutics

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break down mechanically and chemicallyas they are used in vitro and in vivo. Repairable biomaterials are particularly advantageous for implants that replace selfhealing tissues (Aramwit, 2016; Smith et al., 2016). An ideal biomaterial should be biocompatible, bioactive, degradable and possesses high mechanical strength (Table 10.4; Bhat and Kumar, 2012; Samavedi et al., 2014). Biomaterials are classified based on the source of origin for example, natural and synthetic biomaterials.

10.4.1 Natural biomaterials Natural biomaterials have a therapeutic advantage over synthetic biomaterials. These biomaterials are appropriate alternatives to ECM due to their natural origin. Natural ingredients with antibacterial, anti-inflammatory, and antioxidant characteristics help in wound healing. Biocompatible substrates such as chitosan, collagen, elastin, and fibrinogen are similar to macromolecules recognized by the human body (Mogo¸sanu and Grumezescu, 2014). In regenerative medicine, they are utilized to produce human epithelial SCs and regenerate epithelial tissue in vitro. The mechanical strength of natural macromolecules can be increased by cross-linking or combining them with synthetic polymers, but this comes at the cost of biocompatibility (Dan Mogosanu et al., 2014; Table 10.5).

10.4.2 Synthetic biomaterials Synthetic biomaterials (Table 10.6) act as an alternative to natural materials due to their defined chemical composition and ability to control the mechanical properties, degradation rate, and shape. However, many of the synthetic materials lack sites for cell adhesion and may have to be chemically modified to allow for cell adhesion (Willerth and Sakiyama-Elbert, 2019).

Table 10.4 Ideal characteristics of biomaterials. S. no.

Properties of biomaterials

Description

1.

Biocompatibility

2. 3.

Mechanical Property Degradability

4.

Bioactivity

The ability of a material to perform an appropriate function with human cells/tissues. The implant should match the mechanical properties of the target tissues. An ideal biomaterial should possess a regulated rate of degradation. The byproducts released from the implant are likely to be removed by metabolic processes of the body. A biomaterial feature that promotes intrinsic tissue regeneration by releasing a biochemical substance that drives Progenitor cell homing and recruitment.

Table 10.5 Source of natural biomaterials and their functions. Natural biomaterials Sources 1.

Function

Polysaccharide-based biomaterial Starch

Starch is a natural biomaterial that is granular. It is composed of amylose and amylopectin.

β-Glucans

It’s made from fungi and grains, and it’s well-known for its immunological and pharmacological characteristics. It’s made up of a polysaccharide chain made up of -(1 4)-linked Dglucosamine (deacetylated unit) and N-acetyl-D-glucosamine.

Chitosan

Cellulose

It is obtained from industrial processed wood.

Alginic acid and its salts

It is a polysaccharide found in the cell walls of brown algae such as Laminaria and Ascophyllum species.

Hyaluronic acid Pectins

Skin, cockscomb, cartilage, and vitreous humor are all rich in this biomaterial. It is obtained from fruits and vegetables.

It can be employed as bone replacement implants, drug delivery systems, and tissue scaffolds because it is renewable and biodegradable. It reduces skin irritation while also inhibiting adipogenic differentiation. It possesses antibacterial and anti-inflammatory effects. It enhances tissue regeneration in both soft and hard tissues and causes few foreign body reactions. The mechanical and swelling properties of this material are remarkable. Because of its hemostatic qualities, alginate and its salts are utilized for wound therapy in various forms such as gel or sponge. Calcium alginate can improve cellular adhesion and proliferation as well. It is suitable for wound healing because of its bacteriostatic Properties. It is a hydrophilic agent that reacts with the wound fluid and helps in wound healing.

Protein-based biomaterial Collagen

Gelatin Keratin Fibrin

Collagen is the most abundant triple helical protein in the human skin. Each collagen unit is made up mostly of the amino acids, glycine, proline, and hydroxyproline, Obtained from denatured collagen. It’s a filament-forming intermediate protein present in epithelia and corneous tissues of vertebrates. Fibrin is a nonglobular, fibrous protein.

It is used as hemostatic agents, injectable material, and wound dressings. It is used in wound dressings, and as an adhesive, absorbent pad for surgical. Keratin can help with nerve regeneration by activating Schwann cells. During hemostasis, fibrin binds to platelets and some plasma proteins together.

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Table 10.6 Some synthetic biomaterials and their applications. S. no.

Synthetic biomaterials

Application

1.

Poly (lactic-co-glycolic acid) (PLGA)

2.

Poly (ethylene glycol) (PEG)

3.

Polymethylmethacrylate (PMMA) Poly(ethylene terephthalate) (PET) Poly(tetrafluoroethylene) (PTFE),

MSC differentiation into adipocytes is aided by PLGA scaffolds (Willerth and Sakiyama-Elbert, 2019). PEG scaffolds seeded with stem cells assist in bone cartilage regeneration (Willerth and SakiyamaElbert, 2019). PMMA has been used in bone cement for bone fixation (Samavedi et al., 2014). It is commonly used in repairing large blood vessels and soft tissues (Samavedi et al., 2014). It is used for small artery replacement (Samavedi et al., 2014).

4. 5.

10.5

Wound healing dressings

Traditional wound dressings such as natural or synthetic bandages, cotton wool, and gauzes of varying absorbency (Table 10.7) are used to manage wounds. They conceal minor lesions with minimal secretions and promote healing in conditions such as minor surgical incisions and nonsevere ulcers. To protect the wound, these dressings are applied to the skin, keeping it dry by allowing the exudates to evaporate, thus, preventing the entry of microbes. These dressings do not appear to be involved in the healing process. However, gauze dressings are made from cotton, viscose, and polyester fibers. They absorb exudate and fluid from an open wound due to their fibrous structure. Xeroform is a commercially available nonocclusive wound dressing that contains 3% bismuth tribromophenate. It is used to treat mild exudative injuries (Landgraf, 2007; Sharma et al., 2003). Bandages are composed of natural cotton, cellulose, and polyester and are typically used as secondary dressings for wounds Although cotton bandages shed fibers and adhere to the wound surface, they are used to clean wounds and treat dry venous and arterial ulcers. Additionally, rayon, polyester, and polyamide bandages are nonadherent absorbents that allow liquid and water vapor to pass through but do not adhere to the wound surface, making them ideal for granulated wounds with mild to mild-moderate exudate. These dressings have the advantage of being affordable and straightforward to use. They do have several disadvantages, including the promotion of ischemia/necrosis and adhesion to the wound bed, which results in pain and mechanical trauma during removal. When saturated with exudates, the dressing it becomes ineffective at draining the wound. As a result, numerous modifications are required before their use (Barillo et al., 2017). To address these drawbacks, novel wound care technologies have been discovered resulting in the development of advanced wound dressings that actively address the protection and cure of more severe injuries involving complex healing

Table 10.7 Different types of available dressing. S. no.

Type of dressing

Type of wound

Function and composition

1.

Gauze sponge

All wounds

2.

Gauze bandage rolls

All wounds

3.

Nonadherent pads

Wounds with mild to moderate drainage; successfully applied for acute wounds and skin tears

4.

Nonadherent wet dressings

Suitable for wounds with mild to moderate drainage; applied with burns also.

5.

Foam dressings

Works effectively with pressure injuries and wounds with moderate to heavy discharge.

6.

Alginate

Works well for vascular ulcers and wounds with moderate to heavy discharge. It is safe to use on infected wounds but not on dry wounds.

Gauze sponges are 100% cotton sponges that absorb liquids like blood and other biological fluids, making them versatile wound dressing that can be used to clean, treat, pack, or prepare a wound. Additionally, it is a cost-effective option. Gauze bandage rolls are made of 100% cotton and can be used as a protective or first-layer dressing. This wound dressing is appropriate for wounds on the limbs or head, as well as wounds that are difficult to treat. The wound is protected while staying nonadherent using this form of the wound dressing. It is a simple, all-inone dressing that can be used on almost any wound and allows for minimum leakage. As the main layer, these dressings are effective at preserving moisture in the wound bed and stimulating cell migration. Wet dressings that are nonadherent fit the wound without sticking to the surface. Foam dressings are ultra-soft and absorbent because of the foam substance used in their manufacturing. This form of wound dressing covers and cushions the wound while encouraging healing. This wound dressing is extra ordinary absorbent, able to hold up to 20 times its weight of fluids. It is particularly effective in wicking moisture from deep tunneling sections of a wound.

7.

Hydrogel dressings

Cleaning of necrotic wounds by rehydrating dead tissue and stimulating autolytic debridement in dry or mostly dry wounds. Acts as a securement layer

8.

Transparent dressings

9.

Alcohol preps

Used for prepping, not for dressing the actual wound.

10.

Hydrocolloids

Suitable for light to moderately exuding noninfected wounds and for both wet and dry wounds.

11.

Films

Suitable in the later stages of wound healing where little exudate is produced as loss of water vapor can cause a wound to dry out. Not suitable for infected wounds and thin or fragile skin

Hydrogel dressings add moisture to a wound, which can help dry and break down dead tissue. It keeps the wound wet, which promotes cell development. These dressings allow moisture to pass through while providing a strong securement layer and allowing for visible wound evaluation. Although alcohol preps are not a type of wound dressing, they are required when dressing a wound. They provide a humid environment. There is no discomfort during removal. Can stay on the wound for a long time. No additional dressing is required. It also facilitates autolytic debridement and rehydration of necrotic wounds. Permeable to moisture and vapor, allowing some exudate It is impenetrable to microorganisms.

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processes (Dhivya et al., 2015). These advanced dressings contribute to the concept of promoting epithelial cell movement to treat wounds. The dressings optimally provide a moist environment surrounding the wound, adequate oxygen circulation to support regenerating cells and tissues, and a low bacterial load. Advanced dressings have a semipermeable surface and an extremely absorbent layer. Additionally, they promote granulation tissue formation and epithelial cell migration from the wound’s edges to its center. For example, semipermeable film dressings made of a porous transparent and adhesive polyurethane allow for aqueous vapor transmission, oxygen and carbon dioxide gas exchange, and scab removal via autolysis bacteria-resistant polyurethane films. As a result, they have largely displaced conventional dressings (Silva et al., 2019). These dressings take advantage of the biocompatibility of natural and synthetic materials and stimulate a healing response via interaction at a molecular level. Biomaterials used in advanced dressings are critical in wound treatment and healing stimulation, absorbing exudate and protecting the wound from external agents, thereby managing the healing process. Numerous new dressings have been developed that are aimed at managing chronic wounds. Some modern dressings emphasize the direct delivery of drugs to the affected site, as well as growth factors anti-fibrotic, anti-inflammatory agents, antimicrobial, small-molecule drugs, nucleic acids, or cells that promote wound healing. For example, PDGF, FGF, and EGF, are all being evaluated for wound repair applications in the current scenario. However, their application in wound repair is limited due to their low absorption capacity, short half-life, and high carcinogenicity. CutisorbIodosorb and Actisorb Silver 220 are two antimicrobial dressings available in the market (Morton and Phillips, 2016). The successful design of wound dressings is contingent upon several factors, including the patient’s health, environment, social circumstances, physicochemical properties of dressing materials, types of wounds (e.g., acute, chronic wounds), and wound phases. However, no single dressing is appropriate for managing all types of wounds (Table 10.8) (Frykberg Robert, 2015). Today, wound dressings are a critical component of the global medical wound care market regardless of the type of lesion. An exemplary dressing should exhibit several characteristics, (Fig. 10.2) including providing a moist, clean, and warm environment; provision of hydration in the event of a dry or desiccated wound, removal of excess exudates, prevention of desiccation (Table 10.9), protection of the wound area, gaseous exchange and impermeable to microbes (RezvaniGhomi et al., 2019; Sood et al., 2014).

10.6

Application of hydrogel in wound healing

Hydrogels are three-dimensional (3D) networks of hydrophilic polymer chains that are chemically cross-linked. The insoluble hydrophilic structures have an incredible capacity for absorbing wound exudates while allowing oxygen

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Table 10.8 Role of dressings with respect to different wound types S. no.

Wound type

Appearance

Role of dressing

1.

Necrotic

Often olive green or black and dry to touch, due to presence of necrotic tissue.

2.

Sloughy

3.

Granulating

4.

Epithelializing

Slough is generally yellow in color. Large amounts of granulation tissue, usually red or deep pink in color. It’s possible to have too much exudate. A pink margin or isolated pink islands on the surface of the wound. Generally little exudates.

Removes dead tissue. Rehydrates wound bed. Maintain moist wound bed. Prevents bacterial ingress. Maintain moist wound bed and absorb excess fluid. Assists in thermal insulation and protects from bacterial infiltration.

Mechanical and physical properties

Prevention of bacterial infection

Oxygen permeability

Keeps the wound bed wet and assists in thermal insulation.

No toxic component

Adhesiveness

Ideal wound dressing Minimal tissue trauma (pain)

Absorption of excess exudate

Thermal insulation

Cost effective Moisture

Figure 10.2 Characteristics of an ideal wound dressing.

diffusion. Hydrogel possesses a highly hydrated polymeric network, capable of binding several times to their dry weight in water, and contributes toward moisture retention at the injured site. Additionally, hydrogel act as a carrier of cells, antibacterial agents, growth factors, and a variety of other bio-macromolecules (Tavakoli and Klar, 2020).

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Table 10.9 Role of dressing with respect to clinical significance to wound healing. S. no.

Dressing functions

Clinical significance

1.

Provides or maintain a moist wound surface.

2.

Absorption. Removal of blood and excess exudate.

3.

Debridement, i.e., wound cleansing.

4.

Gaseous exchange (water vapor and air).

5.

Protects the healing wound from bacterial invasion.

6.

Provision of thermal insulation.

7.

Low adherence that protects the wound from trauma.

By rehydrating tissue, it prevents desiccation and cell death, increases angiogenesis and connective tissue development, and aids in autolysis. Increases leukocyte migration into the wound bed and makes it easier for enzymes to accumulate. Exudate from chronic wounds contains enzymes that retard wound healing by preventing cell proliferation, degrades extracellular matrix and growth factors. Removal of necrotic tissue, foreign items, and particles, which act as a medium for bacterial development. The permeability of exudate to water vapor determines how it is treated. Low oxygen levels in the tissues aid angiogenesis. Increased tissue oxygenation promotes epithelialization and fibroblast formation. The prolonged inflammatory phase is due to the infection present which reduces collagen synthesis and thus, increases tissue damage. Maintaining a normal tissue temperature promotes epidermal migration by increasing blood flow to the wound bed. Adhesive dressings can be uncomfortable and difficult to remove, resulting in additional tissue damage.

10.6.1 Natural hydrogels in market Due to their high water content, softness, flexibility, and compatibility with living organisms, hydrogels made up of natural biomaterials are frequently used as dermal skin substitutes. Integra is one of several acellular devices for dermal tissue regeneration, which is commercially available (Heimbach et al., 2003). It’s made up of a porous matrix made up of cross-linked bovine tendon, collagen, and glycosaminoglycan that’s enclosed in a semipermeable silicone layer. It is composed of a porous matrix of cross-linked bovine tendon, collagen, and glycosaminoglycan, encased in a semipermeable silicone layer. This silicone membrane prevents water vapor loss (Farokhi et al., 2018). Integra’s biodegradable collagen glycosaminoglycan matrix promotes adequate blood vessel and fibroblast ingrowth and rapid wound closure. It has been used to treat wounds of varying thickness, venous ulcers, diabetic ulcers, pressure ulcers, and chronic vascular ulcers, as well as surgical, traumatic, and draining wounds. Before adding keratinocytes, the Integra is placed on the wound

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for 3 6 weeks to allow for fibroblast invasion and vascularization. Algisite is an alginate-based hydrogel that is used in lacerations, abrasions, and minor burns. Helix3-cm is a collagen-based use in chronic and acute wound healing (Tavakoli and Klar, 2020). As of now, natural skin substitutes are thought to be more biocompatible than synthetic polymers. However, they may vary between batches, resulting in the instability of certain physical and chemical properties. Another limitation of natural wound healing hydrogel is its low mechanical properties (Aramwit, 2016).

10.6.2 Synthetic hydrogels in market Synthetic hydrogels have several advantages over naturally occurring polymers when used as skin templates. First, they exhibit predictable and controllable properties, including ease of shaping, low manufacturing costs, and consistent mechanical properties. Second, synthetic scaffolds are uniform in composition, and simple to fabricate. On the other hand, synthetic materials used in biomedical applications should be selected carefully to avoid transplant rejection. Some commercially synthesized polymers, for example, polyvinyl alcohol (Tavakoli and Klar, 2020), have been used in cutaneous wound dressings due to their lack of elasticity, membrane stiffness, and hydrophilic properties. It is frequently combined with other polysaccharide-based hydrogels such as starch, alginate, and carrageenan for wound healing (Lech et al., 2012). Inadine is a Polyethylene glycol-based synthesis hydrogel used in open wounds (Tavakoli and Klar, 2020).

10.7

Stem cells in wound healing

Cellular therapy is currently investigated for application in the treatment of cutaneous wounds. Because of their great proliferative capacity, ability to specialize in numerous cell types, and ability to release cytokines and growth factors that help wound healing (Al Shaibani et al., 2016; Herdrich et al., 2008).

10.7.1 Endothelial progenitor cells in wound healing EPC are endothelial precursor cells that assist in tissue repair and revascularization (Kawamoto and Losordo, 2008). In preclinical and clinical experiments with ischemia illnesses such as myocardial infarction, stroke, and peripheral arterial disease, EPCs revascularization abilities have been demonstrated. EPCs transplantation has shown an accelerated wound healing by increasing granulation tissue for neovascularization. Additionally intradermally injected EPCs produce a variety of growth factors and cytokines therapy, enhancing monocyte/macrophage recruitment and encouraging angiogenesis (Balaji et al., 2013). These findings suggested that EPCs transplantation could be useful in the treatment of cutaneous wounds.

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10.7.2 Mesenchymal stem cells in wound healing MSC were isolated from bone marrow for the first time. These cells can develop into adipocytes, chondrocytes, and osteocytes in vitro and in vivo. Earlier, MSCs don’t have a distinct cell surface identifier, hence they were identified through “adherent selection.” Later, surface markers such as CD105, CD73, and CD90 (expressed by .95% of the population), with just 2% expressing CD45, CD34, CD14, CD11b, CD79, or CD19, as well as HLA class II surface molecules, have been reported in the literature as additional criteria for distinguishing MSCs. These cells can differentiate into osteoblasts, adipocytes, and chondroblasts. Dermal papilla cells, which surround the hair follicle, are speculated to play an important role in wound healing by differentiating into fibroblasts in response to injury. In vivo, perivascular pericytes may serve as MSCs, and additional dermal MSCs may exist in the intermolecular dermis. In addition, cutaneous injury can promote MSCs differentiation into adipose tissue. During the proliferative phase, mature and precursor adipocytes, as well as fibroblasts, occupy the wound region. It was observed that lipoatrophic animals had a reduced ability to heal wounds, indicating that MSCs from adipose tissue are likely to play a role in fibroblast recruitment and skin restoration (Fig. 10.2). Because BMSCs are found to be recruited to injured tissue during the early phases of inflammation and remain in the repaired dermal tissue, they are expected to play a role in cutaneous wound healing (Wu et al., 2007) (Fig. 10.3).

10.7.3 Adipose tissue-derived stem cells Stem cells (SC) produced from adipose tissue are found in the vascular part of adipose tissue (ADSCs). When cultivated under proper conditions, ADSCs can develop into adipogenic, osteogenic, chondrogenic, and myogenic cells. The influence of ADSCs on neovascularization in animal models of ischemia has been studied recently. In an in vivo investigation, ADSCs were discovered to produce a range of potent angiogenic factors and integrate into blood arteries after maturing into endothelial cells. ADSCs transplantation facilitates wound closure and blood flow to

Figure 10.3 In hair follicles, the dermal papilla cells as mesenchymal stem cells play an important role in wound healing by differentiating into fibroblasts in response to injury.

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injured skin, according to a study by Ebrahimian et al. ADSCs produce five times more VEGF when cultivated in hypoxic settings than when cultured in normoxic conditions. Endothelial cell proliferation and mortality were both boosted by hypoxic conditioned media produced from ADSCs (Franck et al., 2019).

10.7.4 Application of stem cells loaded biomaterials in wound healing When SCs are used to heal wounds, the transplanted SCs must remain viable within the wound beds. Hydrogels are particularly beneficial in this regard because they enable SCs to remain in the wound for extended periods. Hydrogels are advantageous because they facilitate cell attachment and serve as a medium in which cells can maintain their phenotypic integrity. Since SCs have been shown in some studies to persist in the wound for up to 11 days after transplantation, preculturing SCs in hydrogels in vitro enhances their homing capacity. The application of SCs and biomaterials is contentious within the scientific community, with some studies focusing on stem cell differentiation into skin lineages and others on the therapeutic potential of undifferentiated SCs. Undifferentiated SCs may enhance immunoregulatory capacity (Fig. 10.4), secretome release, angiogenesis, and cell recruitment capacity. Due to the potential for the release of regenerative mediators, stem cellloaded hydrogels are a potential candidate for wound healing (Velnar et al., 2009). The animal-derived comports used in scaffolds limit the translation of the new innovation into clinics. The wood-derived nanofibrillar cellulose by Kiiskinen et al. has shown a significant increase in cell survival and thus increase wound care due to the exclusion of all the animal-derived biomaterials that hinder immune rejection (Kiiskinen et al., 2019).

Figure 10.4 Stem cell-loaded hydrogels dressing as a potential candidate for wound healing in regenerative medicine.

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Cell-based wound dressing

Dressings contain SCs and other differentiated cells for example fibroblasts and keratinocytes. Cell-based (living) wound dressings are intended to mimic the biological functional and physiological properties of human skin by forming an ECM. In the market, several cell-based wound dressing has been used such as Apligraf (keratinocytes) for chronic wounds, Dermagraft (fibroblasts) for chronic diabetic wounds, Epicel (autogenous keratinocytes), and Laserskin (autogenous keratinocytes) for burn wounds. Apligraf is an FDA-approved dressing used for chronic venous ulcers. It is a bilayered skin made up of keratinocytes and exposed to oxygen during manufacturing. During heading, it mimics the epidermis and dermis of natural skin. Apligraf creates a microenvironment that provides a physical and biological barrier against microbial infections, providing growth factors responsible for keratinocyte migration and ECM formation (Ehrenreich and Ruszczak, 2006; Zaulyanov and Kirsner, 2007). Dermagraft is a single-layered dermis substitute made from newborn fibroblasts that have been cryopreserved. It promotes the ingrowth of fibrovascular and epithelial tissue by depositing ECM components like collagen, vitronectin, and glycosaminoglycans, as well as secreting a variety of cytokines and growth factors. The fibroblasts continue to release growth factors and recruit host cells until the donor cells and tissue are gradually replaced by fibrovascular ingrowths. Dermagraft has no antigenic cells and does not appear to cause rejection (Navarro et al., 2000; Wang et al., 2006). A cultured epidermal autograft is a single-layered skin substitute manufactured from the patient’s keratinocytes and mouse fibroblasts that have been grown ex vivo to form a thin sheet of skin. It has been approved for full-thickness burns. It has also been used to treat leg ulcers with moderate effectiveness (Mulder et al., 2012).

10.9

Limitation of biomaterials dressing in wound healing

The use of synthetic and natural biomaterials has several drawbacks. For example, the porous nature of biomaterial limits the homogeneous distribution of cells. Specific cell types necessitate different pore sizes and surface modification to avoid immune rejection. In scaffolds, the soft structures, mechanical strength is limited. Microsphere sintering methods are not always compatible with cells, resulting in a reduction in cell viability. When organic matter degrades, acidic byproducts are produced resulting in toxicity to cells. To develop composite scaffolds, we need to invest a lot of time and effort into the optimization of biomaterials to avoid immune responses (Chaudhari et al., 2016).

10.10

Conclusion

In recent years, significant progress in skin replacement therapy has been made with the use of a variety of natural and synthetic biomaterials. Hydrogels are often

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used as wound dressings because they closely resemble the biological properties of human skin. Hydrogels are available in a variety of forms, including film, sprayable gels, and injectable gels. Sprayable hydrogel-based wound dressings have recently emerged as an efficient use in wound care due to their flexibility. A growing interest in the synthesis and manufacture of these hydrogels, as well as the development of new “in situ” forming “SMART” stem cell-loaded hydrogels for a variety of biological applications can be seen in a number of research studies. A deeper understanding of and control of the interactions between polymeric chains and cells will drive future research on SCs embedded in hydrogels. New manufacturing processes will also enable the development of appealing scaffolding materials with a more natural cellular milieu, akin to that of natural human skin tissue. Despite several advantages and rapid progress in evaluating the efficacy of stem cell-based transplantation, there are several questions that need to be addressed. The ideal source of SCs and mode of delivery (Dehkordi et al., 2019).

Acknowledgment We would like to thanks Nishant Tyagi for his valuable suggestion.

Authors’ contributions Manuscript was conceptualized, designed, and drafted by Subodh Kumar and Somya Chaaudhary, drafted by Ranjan Verma and supervision and editing by Dr. Yogesh Kumar Verma

Compliance with ethical standards NA.

Conflict of interest We have no conflicts of interest.

Research involving human participants and animals Not applicable.

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Informed consent Not applicable.

Funding Authors like to thanks Director, INMAS, Delhi, for the encouragement and funding.

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Kirtida Gambhir, Nishant Tyagi and Yogesh Kumar Verma Stem Cell and Tissue Engineering Research Group, Institute of Nuclear Medicine and Allied Sciences (INMAS), Defense Research and Development Organization (DRDO), Delhi, India

11.1

Introduction

A wound is created on perturbance of skin integrity and can be classified as acute or chronic based on the extent of damage (Takeo et al., 2015). Acute wounds occur as a consequence of disturbance in the local environment caused by surgical procedures, or traumatic alterations while, chronic or hard-to-heal wounds occur as a consequence of an infection or a disease (Raziyeva et al., 2021). Physiological healing is an intricate process that results in the closure of a wound usually within days or weeks, depending on the depth and diameter of the wound (Nourian Dehkordi et al., 2019). Certain immunological and/or systemic factors such as chronic stress, old age, or weakness have been attributed to prolonging the healing process from days to weeks (Guo and Dipietro, 2010). As the world population ages, the inefficiency of therapeutic intervention for hard-healing wounds has brought about a huge economic burden (Han and Ceilley, 2017). Thus, it is imperative to develop novel strategies for chronic wounds to optimize the treatment of this prospective silent pandemic. A new “smart” class of wound dressings have been developed with the ability to provide insights into the wound by assessing the wound parameters of the patients in real-time (Derakhshandeh et al., 2018). Various advanced wound care dressings including hydrogel, hydrocolloid, or naturally derived components such as alginate or collagen-based bandages have recently been introduced to augment the healing of chronic wounds (Okur et al., 2020). These dressings aim to maintain wound moisture balance by accelerating the impairment of surplus exudate and protecting the wound from contamination. Nevertheless, these dressings are expensive and require frequent changes, which often causes undue stress to the patients. Albeit effective healing can be achieved through the utilization of traditional wound dressings, they do not provide real-time feedback to alter ineffective treatments. Recent advancements in material fabrication technology have expedited the manufacture of Fiber and Textile Engineering in Drug Delivery Systems. DOI: https://doi.org/10.1016/B978-0-323-96117-2.00008-X © 2023 Elsevier Ltd. All rights reserved.

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bandages that bestow an optimum environment to spur the healing process. Tissue engineering has evolved as a potential solution to restore the function of damaged tissues, and often utilizes developmental processes. However, the lack of oxygen and vasculature often leads to the failure of a tissue-engineered implant in vivo, and thus, apprehending the relationship between the availability of oxygen and developmental processes including, angiogenesis, stem cell lineage commitment, and tissue morphogenesis, could contribute to substantial advances in improved development of tissue engineering based therapeutic approaches (Tyagi et al., 2021). Oxygen has been heavily explored over the years as a therapeutic modality to facilitate the healing process due to its involvement at several stages including—re-epithelialization, collagen synthesis, the oxidative killing of bacteria, and angiogenesis. For the development of tools to modulate oxygen microenvironments, it is important to understand the interaction of oxygen in the local environment and developmental processes. This approach holds the scope to overcome the oxygen limitation during tissue regeneration and healing (Sen, 2009). Following injury, oxygenation and wound perfusion are critical for optimal wound healing and acute inflammation. Wound oxygenation depends on, first, the oxygen supply to the wounded tissue, which is influenced by the cardiac output, the blood hemoglobin level, the capillary density, the pulmonic gas exchange, and the peripheral perfusion rate, in the wound tissue and its periphery and, second, on the oxygen consumption rate of the cells which constitute the wound tissue, namely, stromal, parenchymal, and inflammatory cells (Pittman, 2011). The healing process is initiated through a well-orchestrated series of biological events that are often abnormally regulated in hard-to-heal wounds. Although various systemic and local factors can negatively influence the healing of an injury, this includes pre-existing infections, malnutrition, chronic inflammation, poor perfusion rates, and increased local pressure (Frykberg and Banks, 2015). To stimulate the healing process, it is crucial to ensure sufficient oxygenation of the wound bed via vascularization, and delivery of nutrients at the healing site. It is also necessary that the generation of exudate and the bacterial load at the wound site is minimized (Okur et al., 2020). The hypoxic environment around chronic wounds is abundant with proteins thereby, providing suitable conditions for the bacteria to flourish. These microorganisms are responsible for stimulating the process of debridement by releasing certain proteolytic enzymes; although the wound healing process is severely impaired postcritical colonization of bacteria (Rodrigues et al., 2019). The incessant rise in the prevalence of chronic wounds signifies that the archaic strategies to treat a wound are futile, and thus require proactive preventive approaches. Recently, 3D-printed wound dressings, smart-flexible bandages, or bioactive dressings have emerged as alternative strategies to facilitate the healing process. Further, a new class of bandages, that is, next-generation bandages have been fabricated to encompass diverse micro-electronic sensors to assist with real-time monitoring and are capable of inducing the required actions to support healing (Farahani and Shafiee, 2021). The advancement in sensor manufacturing has facilitated the progress of such dressing, for the detection of physiochemical parameters within the wound microenvironment (Tan et al., 2019). Thus far, wearable and

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Figure 11.1 Types of bandages—traditional and next generation to facilitate the repair process.

sensor-integrated skin bandages have been developed by the installation of multiple electrical (impedance, potentiometry, etc.) and/or optical (colorimetry, fluorescence, etc.) sensors onto traditional dressing substrates to develop smart wound dressings which possess the ability to detect and translate the biomarkers-based data present at the site of injury into visual electrical signals for subsequent actions (Tang et al., 2021). This chapter reviews the significant developments in the field of skin wound dressing and highlights the importance of next-generation wound dressings as a developing approach for wound management and the latest progress in the manufacturing of different wound dressings to promote wound repair (Fig. 11.1).

11.2

Role of oxygen in wound healing

To initiate the process of wound healing, one of the basic requirements is the constant supply of biochemical energy or its equivalents in the form of adenosine triphosphate, essentially produced in the presence of oxygen via the citric acid cycle and/or fatty acid oxidation (Ennis et al., 2007). Hence, tissue oxygenation is a prerequisite for the proper functioning of cells, especially for healing tissues to induce restoration as the energy demand is progressively higher for restorative processes including, collagen synthesis, the proliferation of cells, and bacterial defense (Yip, 2014). NADPH-linked oxygenase is an oxygen-dependent enzyme that catalyzes the generation of reactive oxygen species (ROS) such as—hydroxyl ion (HO2), superoxide anion (O22), and peroxide anion (HO22) (Kurutas, 2016). ROS, act as cellular messengers to play a vital function in the killing of bacteria (Fig. 11.2)

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Figure 11.2 Role of reactive oxygen species (ROS) in wound healing; (A) in the inflammatory phase, ROS recruits and activates neutrophils, macrophages, and fibroblasts to the injury site along with migratory epithelial cells to actuate the initial steps of wound healing; (B) in the proliferative phase, ROS stimulates fibroblasts to induce angiogenesis via VEGF; (C) in re-epithelialization, ROS stimulates proliferation of keratinocytes to induce scar formation by a process called “proliferative burst.”

through oxidation and co-regulate prevalent wound healing processes like release of cytokines (including PDGF signal transduction), angiogenesis, and proliferation of cells (Dunnill et al., 2017). ROS production increases under hypoxic and hyperoxic environment, particularly through hypoxia-inducible transcription factor 1α (HIF1α) (Semenza, 2009). HIF-1α/β heterodimer forms a complex inside a cell with another HIF endogenous form, wherein HIF-1α acts as a regulatory subunit of the heterodimeric transcription factor (Hu et al., 2003). Hypoxic conditions induce HIF-1α to bind to the gene promoter regions of hypoxia response elements, to upregulate the expression of genes involved in the process of erythropoiesis, glucose metabolism, angiogenesis, control of vascular tone, and iron transport (Haase, 2013). It also regulates the homeostasis of oxygen at the site of injury. Hypoxia reduces the interleukin (IL)-2 and IL-8 production, thereby activating macrophages, neutrophils, endothelial cells, and even T-lymphocytes.

11.2.1 Reactive oxygen species in inflammatory phase The inflammatory phase, under physiological conditions, persists for about 4 to 6 days post-injury. Trauma causes the blood vessels to constrict followed by activation of endothelium and platelet aggregation (Schultz et al., 2011). The constriction of the blood vessels creates a hypoxic microenvironment, exacerbated by high rates of oxygen consumption in metabolically active cells (Honnegowda et al., 2015). This hypoxic microenvironment initiates the healing process via ROS by triggering

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the activation of the endothelium, platelets, and actuating the release of cytokines [tumor necrosis factor (TNF), transforming growth factor (TGF)-β, vascular endothelial growth factor (VEGF)] from monocytes, parenchymal cells and platelets (Sinno and Prakash, 2013). Although wound healing is initiated by acute hypoxia, chronic hypoxia hinders all the phases of healing thus, reoxygenation at the wound site is crucial for physiological healing (Schreml et al., 2010). The aggregation of platelets activates the coagulation cascade to initiate blood clotting, which forms a provisional barrier of extracellular matrix (ECM) (Rodrigues et al., 2019). The ECM is composed of vitronectin, fibronectin, thrombospondin, fibrin, and fibrinogen, and enables the movement and migration of cytokines and cells involved in the process of wound healing to fill in tissue defects (Tracy et al., 2016). Aside from the structural aspects, platelets control the secretion of growth factors [TGFβ1/β2, platelet-derived growth factor (PDGF), and epidermal growth factor (EGF)] to regulate the healing process. These growth factors activate and recruit neutrophils and macrophages to the site of injury to further actuate fibroblasts. However, the healing process is not just initiated by platelet-derived processes (Thiruvoth et al., 2015). The injured tissues activate epithelial and non-epithelial cells in the wounded area. Consequently, chemokines and cytokines are released to activate the complement signaling and stress pathways, both oxygen-dependent processes (Mittal et al., 2014). Subsequently, certain factors [insulin-like growth factor (IGF), keratinocyte growth factor (KGF), TGF-α/β1, PDGF, and EGF] are secreted which stimulate fibroblasts and inflammatory leukocytes to further prompt the healing process (Borena et al., 2015). Even superficial injuries with no vascular disruption can initiate the healing process. Damaged parenchymal cells release histamines, serotonin, prostaglandins, and bradykinin to enhance vascular permeability by inducing vasodilation. As a consequence, cell diapedesis and oxygen supply are increased at the site of injury (Muller, 2013). Hydrogen peroxide (H2O2) has recently been identified as a key mediator in wound-leukocyte interaction. The infiltration of leukocytes, monocytes, and macrophages is an important event during the initial repair process, they perform the indispensable function of degradation of cell detritus, counteracting phagocytosis of microorganisms, and tissue infection (Zhu et al., 2017). Metabolically, inflammatory cells lead to hypoxia, even in well-oxygenated wounds as they are extremely active and have a high rate of oxygen consumption. Throughout the inflammatory phase, ROS acts as the central product of macrophages, fibroblasts, monocytes, neutrophils, and endothelial cells (Serra et al., 2017). Platelet-activating factors and IL-1 regulates the secretion of ROS from fibroblasts, while PDGF, TNF, and thrombin influence the production of ROS from endothelial cells. ROS acts as the main factor acting against microorganisms and thus reducing infection in the wound (Lande´n et al., 2016). A major enzyme responsible for the production of ROS is nicotinamide adenine dinucleotide phosphate (NADPH)-linked oxygenase, it generates ROS via an oxygen-dependent process with Km value in the range of 40 80 mmHg, below which neutrophils lose their bactericidal activity (Nguyen et al., 2017). The loss of oxygenation results in significant colonization of bacteria specifically in hypoxic chronic wounds (Bowler et al., 2001).

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Therefore, the killing of bacteria via phagocytosis is vital for preserving wound sterility, which requires a high oxygen partial pressure. Once the pathogen is engulfed, a respiratory burst occurs by the transfer of electrons from NADPH. The NADPH-linked oxidase present in the neutrophil membrane generates O22, which further changes to produce ROS by combining with oxygen molecules. Subsequently, the ROS facilitates bactericidal killing (Nguyen et al., 2017).

11.2.2 Reactive oxygen species in the proliferative phase Both the absence and presence of oxygen has demonstrated to influence on the synthesis of collagen. A growth factor, TGF-β1 primarily regulates the transcription and expression of the procollagen-1 gene, which in turn increases fibroblast migration (Rodriguez et al., 2008). Oxygen is involved in the synthesis of collagen during the latter stages namely—cross-linking, and post-translational hydroxylation of proline and lysine (Yamauchi and Sricholpech, 2012). Fibroblasts require an oxygen tension in the range of 30 40 mmHg for proper collagen deposition since the production of collagen is proportional to oxygenation (Schreml et al., 2010). Oxygen is required as a cofactor for the crucial enzymes involved in the post-translational step of collagen synthesis namely, lysyl oxidase, prolyl hydroxylase, and lysyl hydroxylase. Prolyl hydroxylase catalyzes the synthesis of hydroxyproline, which is necessary for the formation of a triple helix (Salo and Myllyharju, 2021). In the absence of oxygen, the under-hydroxylated, pro-alpha peptide chains fail to form a triple helix and is considered to be a non-functional protein. Oxygen is also essential for cross-linking and collagen maturation. Oxygen-activated lysyl oxidase and lysyl hydroxylase enable proper collagen cross-linking (Falanga et al., 2002). Apart from oxidatively killing bacteria, ROS are capable of augmenting neutrophil chemotaxis and stimulating the process of angiogenesis. Hypoxia has the ability to trigger neovascularization, however, it cannot sustain the process (Dunnill et al., 2017). VEGF is considered to be the most influential angiogenic growth factor (Johnson and Wilgus, 2014). Under hypoxic conditions, ROS stimulates fibroblasts, keratinocytes, macrophages, and endothelial cells to synthesize VEGF (Andre´-Le´vigne et al., 2017). Hypoxia-activated HIF-1α binds to VEGF hypoxia response element at the promoter region thereby upregulating the expression levels of VEGF (Ziello et al., 2007). VEGF, stimulates the migration, and proliferation of endothelial cells to form new capillaries. The new capillaries branch out to disrupt the wound matrix and restore the ECM by depositing fibroblasts (Shibuya, 2011).

11.2.3 Reactive oxygen species in re-epithelialization Re-epithelialization covers the surface of the wound with an epithelium layer formed by epidermal keratinocytes. Certain chemokines and cytokines (TGF-α/β1, IGF, TNF, EGF, KGF, and PDGF) are released by these keratinocytes in an oxygen-dependent manner via stress pathways that are activated by injury (Pastar et al., 2014). These cytokines stimulate the epidermal cells present on the hair follicles and wound edges in an autocrine manner to re-structure their cytoskeleton, an

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oxygen-dependent process initiated within hours of injury. The processes involved in the epithelialization steps require a high metabolic activity and are thus oxygen and ROSdependent (Lande´n et al., 2016). One such process mediated by oxygen via ROS is the movement of chemokines and cytokines including, EGF, KGF, TGF-α, nerve growth factor, IL-1, IL-6, HGF, and IGF-1, by a process known as “proliferative burst” to stimulate keratinocyte proliferation to close larger wounds (Peplow and Chatterjee, 2013). Additionally, re-epithelialization is also affected by ROS and other oxygen metabolites which are essential for the functioning of growth factors. Taking all these considerations into account may assist in the subsequent development of therapies focused on a local area, such as local oxygen therapy to accelerate re-epithelialization of second-degree burns or partial-thickness wounds.

11.2.4 Reactive oxygen species in infection control Adequate oxygen during the inflammatory phase is critical to prevent infection. ROS plays a pivotal role in the inflammatory phase to maintain the sterility of the wound. After hemostasis, monocytes and neutrophils invade the site of injury to produce ROS through respiratory burst—the core defense against wound infection. ROS, specifically H2O2 and O22 are released by these macrophages and neutrophils via NADPH-linked oxygenase (Bryan et al., 2012). This enzyme ensures the optimal concentration of oxygen and thus under hypoxic conditions, it blunts oxidative killing. Oxygen levels also have predictive value to help prevent post-surgical infections as the wound infection rates are inversely proportional to the subcutaneous oxygen tension (Greif et al., 2000). Although various studies have suggested that the activity of phagosome-derived ROS is sufficient to kill pathogens, it is still being argued whether the pathogens are directly targeted by ROS derived from the host.

11.3

Conventional wound dressings

Historically, dampened gauze dressings were broadly applied to wounds which required debridement. Around 1600 BCE, strips made of linen were immersed in oil/grease, protected by plasters, were used to occlude wounds (Dhivya et al., 2015). Mesopotamians used clay tablets circa 2500 BCE to treat wounds. Water or milk was used for cleaning before dressing the wound with honey. Hippocrates of ancient Greece (c. 460 370 BCE) used vinegar/wine with oil or honey to clean wounds. They utilized wool boiled in water or wine as a bandage (Shah, 2011). Amid the 19th century, a breakthrough occurred with the introduction of antibiotics as a way to decrease mortality and control infections. Once the dressing is applied to close the wound, it is constantly exposed to complement signals, growth factors, chemotactic molecules, and proteinases which are lost in the exposed wound. They assist in healing by providing a moist environment to the injured area and have been shown to increase epithelialization, collagen synthesis, and promote angiogenesis while decreasing necrosis of ischemic skin flaps

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and scar formation (Tan et al., 2019). However, until the mid-1900s it was assumed that wounds heal quicker when kept dry and uncovered. It wasn’t until the mid1980s that the first modern wound dressing was introduced which could provide moisture and absorb fluids. Thus far, polyurethane (PU) and hydrocolloid-based dressings have been known to improve collagen synthesis and epithelialization as compared to air-exposed wounds (Maaz Arif et al., 2021). Wound dressings often induce hypoxia at the wound site which stimulates processes like reepithelialization. During the mid-1990s the synthetic wound dressings branched out into several groups, which included hydrocolloids, silicone meshes, synthetic foam dressing, hydrogels, vapor-permeable adhesive films, alginates, tissue adhesives, and collagen or silver-containing dressing (Mir et al., 2018).

11.3.1 Traditional wound dressing Traditionally wound dressing like lint, bandages (natural and synthetic), gauze, plasters, and cotton wool were used to protect the wound site from contaminations as either primary or secondary dressings. Gauze dressings composed of woven/nonwoven fibers of rayon, polyesters, or cotton protect against infections by bacteria. Certain antiseptic gauze pads are utilized for their ability to absorb exudates and fluids from an open wound through fibers present in these dressings (Dhivya et al., 2015). These dressings entail incessant replacing to impede the maceration of healthy tissues. Additionally, owing to excessive drainage at the wound site, these dressings may also cause pain upon removal as they tend to adhere to the wound. Bandages made out of cellulose, wool, synthetic bandages, or natural cotton, composed of polyamide materials perform different functions. Conventionally, they are utilized as a second layer since they are inept in providing the wound with a moist environment and thus these dressings are preferred for mild exudate-releasing dry wounds (Sood et al., 2014).

11.3.2 Modern wound dressing Modern wound dressings were invented to replace traditional wound dressing with more advanced features to facilitate wound healing rather than just providing a protective covering. These dressings prevent dehydration and assist in healing. Primarily, synthetic polymers are used to create modern dressings, and can be categorized as either bioactive, interactive, or passive products (Shi et al., 2020). Passive products, such as tulle and gauze dressings, are non-occlusive and employed for covering the injury and restoration of tissue function. On the other hand, interactive dressings are either occlusive or semi-occlusive, available in the form of hydrogel, hydrocolloid films, or foams. They act as a barrier to protect against bacterial penetration (Tan et al., 2019).

11.3.2.1 Semipermeable film dressings Transparent PU-based film dressings adhere to the wound and allow the exchange of carbon dioxide, oxygen, and water vapor. These dressings provide autolytic

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debridement of eschar nonetheless impenetrable by bacteria. Originally, film dressings were composed of adhesive polyethylene frame, for support with nylon derivates which made them occlusive. Previously, dressings made of nylon were not utilized for high exudate wounds because of their inadequate capacity to absorb leading to maceration of the wound and that of the surrounding tissue (Rahmani Del Bakhshayesh et al., 2017). However, these dressings present several advantages, including high elasticity and flexibility, thus they can uphold any shape and do not require additional tapping. The transparency of the film allows inspection of the wound without removal. Thus, these are prescribed for superficial wounds, shallow wounds, and epithelializing wound with low levels of exudates.

11.3.2.2 Semipermeable foam dressings These dressings are composed of hydrophilic and hydrophobic foam with adhesive borders. The outermost layer is hydrophobic and provides protection against liquids but allows the exchange of gases and water vapor. Foam dressings have the ability to absorb wound exudate of varying quantities depending on the thickness of the wound, and thus, are utilized as primary dressings (Weller et al., 2020).

11.3.2.3 Hydrogel dressings Hydrogels are hydrophilic and are composed of materials such as polyvinyl pyrrolidine and polymethacrylates. The elevated content of water assists in the initiation of tissue granulation and maintains a moist environment. Hydrogels possess the property of soft elastic which provides easy application and removal after healing without causing damage. Additionally, these dressings provide a cooling effect by decreasing the temperature of cutaneous wounds (Tavakoli and Klar, 2020). These dressings are utilized for burn wounds, chronic wounds with low exudate, necrotic wounds, and pressure ulcers. These are non-reactive, non-irritant and allow metabolites to permeate within the biological tissue. However, they have a low mechanical strength which makes them difficult to handle and causes accumulation of exudate which results in tissue maceration and bacterial proliferation in the injured tissue that produces a foul smell (Kamoun et al., 2017).

11.3.2.4 Hydrocolloid dressings Hydrocolloid dressings are broadly classified as interactive dressings and are composed of two layers, the innermost colloidal layer and an outer layer that is water-impermeable. The layers are formed by the amalgamation of gel-forming agents like pectin, gelatin, and carboxymethylcellulose with adhesives or elastomers. Hydrocolloids allow water vapor to permeate but are impenetrable by bacteria. These dressings help in the debridement and absorption of exudates (Thomas, 2008). They are recommended for wounds with mild exudate, namely, minor burn wounds, traumatic wounds, and pressure sore. Once the hydrocolloids encounter the exudate, a gel is formed which provides a moist environment to the wound and aims to protect granulated tissue by absorbing and retaining exudates (Kamoun et al., 2017).

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11.3.2.5 Alginate dressings Alginate is a naturally derived material obtained from seaweed, used extensively in the field of biomedical sciences, as a drug delivery system (Tyagi et al., 2022) and in the food industry (Gheorghita Puscaselu et al., 2020). Alginate dressings possess the ability to form a strong hydrophilic gel which enables it to reduce bacterial contamination by enhancing its absorption capacity for wound exudates. Once the dressing is applied, the calcium ions present in the blood replace the sodium ions from the alginate dressings to form a protective film (Aderibigbe and Buyana, 2018). Alginate dressings are prescribed for moderate to heavily draining wounds and are not suitable for third-degree burn wounds, severe wounds or dry wounds. These dressings require an additional secondary dressing as they can be dehydrating which results in delayed healing.

11.3.3 Bioactive wound dressings Bioactive wound dressings are biocompatible, biodegradable, and non-toxic as they are usually obtained from natural and/or artificial tissues. Based on the nature of the injury, these dressings are either composed of a single polymer such as elastin, hyaluronic acid (HA), chitosan, collagen, and alginate or a combination of these polymers (Schoukens, 2009). Collagen, being a major structural protein plays a vital function in the natural healing process. Upon contact with the injured tissue, collagen induces fibroblast formation and stimulates the migration of endothelial cells. Similarly, HA is a biocompatible, biodegradable glycosaminoglycan component of the ECM with unique biological and physicochemical properties. On the other hand, chitosan is known to boost the formation of granulated tissues during the proliferative stage of the wound healing process (Tottoli et al., 2020). These dressings have been reported to be superior compared to other dressings as these polymers can be embedded with antimicrobial and growth factors to enhance the healing process.

11.3.4 Tissue-engineered skin substitutes There are two tissue-engineered skin substitutes available for the human skin or dermal equivalents. The first substitute resembles the native skin layer comprising fibroblasts and keratinocytes over a collagen matrix, whereas the second substitute includes dermal elements (acellular) on a collagen matrix (Goodarzi et al., 2018). These alternatives can to adapt to the microenvironment, and to release cytokines and growth factors embedded within these dressings.

11.3.5 Medicated dressings The physiological repair process is regulated by the cellular activities heralded by growth factors that exist in our body. However, the growth factors and cells begin to accrue in the wound bed within the clots to hinder the healing process, in case of chronic wounds. Medicated dressings are developed with the incorporation of drugs

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including, enzymes, growth factors, and antimicrobial agents which play a crucial role in the process of healing either directly or indirectly by removing necrotic tissues (Kus and Ruiz, 2020). Debriding agents, antimicrobials, and growth factors are employed for the cleaning of necrotic tissues, prevention of infection, and promotion of tissue regeneration, respectively. Among different growth factors, PDGF is commonly used to promote cell proliferation, chemotactic recruitment, and enhance angiogenesis. Moreover, autologous platelet thrombin, PDGF, EGF, and fibroblast growth factor (FGF) are studied exhaustively for their utilization in the tissue repair process. However, among these only EGF and PDGF are approved by FDA for human application (Pierce et al., 1991).

11.3.6 Composite dressings These dressings are convenient and versatile for both full and partial-thickness wounds. Composite dressings, as the name suggests are composed of several layers, where each layer plays a distinct physiological role to attain homeostasis. Primarily, a three-layer approach is followed which may include a transparent firm or adhesive border of non-woven fabric tape. The outermost layer protects from infections, whereas the middle layer consists of an absorptive material such as polyacrylamide responsible for maintaining a moist environment and facilitating autolytic debridement, and the innermost layer comprises of non-adhesive material to avoid adherence to the newly formed granulating tissues (Purwar et al., 2014). These dressings can act either as primary or secondary dressings and may even be used with topical medications, however, their usage is limited due to lack of flexibility.

11.4

Limitations of conventional dressings

Despite their ability to act as either a primary or secondary dressing for various wounds, the use of traditional and modern wound dressings presents several disadvantages due to which their use has now been limited. Passive products such as gauze and tulle are dry fabrics and do not possess the ability to control moisture levels, they can, however, adhere to the wound bed resulting in mechanical trauma when removed. Additionally, they lose their dressing efficiency once saturated with exudate (Pilehvar-Soltanahmadi et al., 2018). On the other hand, interactive wound dressings, such as films that are nonabsorbent and cause excess exudate accumulation and foams may be adherent or nonadherent and thus can require a secondary film. Additionally, they can adhere to wounds if exudate dries (Weller et al., 2020). Hydrogels may result in maceration of skin around wounds because of their highwater content, and their adsorptive capacity is limited therefore are not prescribed for high exudating wounds (Tavakoli and Klar, 2020). Alginate dressings require frequent change with high exudate. Hydrofibers are inadvisable for dry eschar, nonexudating wounds, heavy bleeding, and third-degree burns. These bandages act as a support bed for the dressing, which is adhered to the wound. However, the frequent

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need for changing and adherence to the dressing to the injury presents a major challenge that has rendered it to be clinically less desirable (Aderibigbe and Buyana, 2018). Further, traditional dressings are still underdeveloped and fail to provide insights regarding the status of the wound. Therefore, SMART (sensing, monitoring, and release of therapeutics) or next-generation bandages that can provide the quintessential conditions to hasten the repair process have been developed.

11.5

Next-generation bandages

Over the last few decades, advancements in microfabrication technology have significantly contributed to the evolution of several ingenious dressings along with devices. Such dressings possess the ability to simulate the local dermal tissue microenvironment while simultaneously monitoring the repair process. Nextgeneration bandages act not only as a protective covering but also as a diagnostic sensors to observe the damage and implement the necessary treatment to accelerate the restoration process. Smart systems can monitor damaged tissue environments without the need for replacements or visits to medical facilities (Brown et al., 2018). Distinct actuators and sensors can be assimilated to form a single platform, that can efficiently maintain consistent contact with the wound to provide invaluable information about a selection of treatment strategy. These dressings are known to alter their physio-chemical properties in response to environmental change (Table 11.1). SMART bandages have been exploited to combine self-adjusting treatments into the intricate process of wound healing (Derakhshandeh et al., 2018). In this respect, various SMART materials, that is, ROS-responsive, pH-responsive, thermo-responsive, etc. have been explored for providing information about the parameters associated with the wound healing process (Fig. 11.3).

11.5.1 Wound dressings with monitoring capacity The intricate process of chronic wound healing makes them susceptible to contamination. Thus, monitoring the status of chronic wounds is a benevolent factor to ensure their management. The traditional dressings for chronic wounds under optimum conditions might passively deliver therapeutic agents and act as wound coverage. The inefficiency of contemporary dressings to treat chronic injuries has unveiled a dire need to formulate a novel class of dressings (Pang et al., 2020). The emergence of SMART dressings with the capability to simultaneously analyze and automatically or semi-automatically deliver therapeutic molecules to the site of injury would assist in better management of wounds. Smart bandages, that is, integrated with microsensors can sense and process the expressed markers present at the wound site (Table 11.2) thereby providing valuable insights regarding the wound environment (Zhang et al., 2021). It also provides the ability to measure the wound exudate levels, to determine the stage of the wound healing.

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Table 11.1 Commercially available next-generation bandages. Nextgeneration bandages

Category

Component

Function

Reference

ChitoGauze

Bandage

Bandage

Mediates localized clotting by attracting RBCs to the wound site Repair internal injuries Triggers body’s clotting cascade

Xie et al. (2010)

Gecko Bandage QuikClot

Polyester/rayon blend nonwoven coated with chitosan Nano-sized Gecko hair Kaolin clay; aluminosilicate High energy ultrasound waves Skin cells

Cauterize open wounds and stop bleeding Acts as a skin farm over the wound Anti-microbial property; drugdelivery potential

SonoBandage

Hemostatic sealing material Bandage

Scaffold Bandage Selfassembling gel

Bandage

Electric bandages

Bandage

Gel

Hydrogel containing selfassembling peptides Mild electrical current

Surface wound healing

Yanik (2009) Johnson et al. (2012) Langer et al. (2013) Bye et al. (2014) Schneider et al. (2002)

Ghatak et al. (2015)

11.5.1.1 Wound oxygenation Oxygen is a crucial regulator, whose absence results in impairment of the healing process. Acute hypoxia is one of the detrimental conditions in hard-to-heal wounds which obstructs the neovascularization in the wound microenvironment (Castilla et al., 2012). Consequently, simultaneous detection of oxygen concentration at the site of injury is crucial. Ochoa et al. (2020) have fabricated an inexpensive, paperbased, flexible, and SMART wound dressing for incessant sensing and delivery of oxygen to the damaged tissue. To mimic the structural flexibility of the basement layer, parchment paper was utilized owing to its properties of adhesiveness, fluid filtering, and flexibility. These bandages demonstrated a functional similarity to the natural skin tissue and prevented the entry of viral/pathogenic molecules into the wound.

11.5.1.2 pH responsive The pH of normal healing wounds fall in the range of 5.5 6.5, however, in nonhealing infected wounds, pH tends to reach the range of 7.15 8.90 due to

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Figure 11.3 Next-generation bandages have various application in the field of wound treatment, such as, monitoring capacity, stimuli-responsive (reactive oxygen species, temperature and pH), drug-delivery, oxygen-based therapy, and self-healing wound dressings. Table 11.2 Biomarkers and their applications in next-generation bandages. Biomarker

Function

Reference

Oxygen pH

Absence may be detrimental for hard-to-heal wounds; accelerates the repair process Possible monitoring of infection at the site of injury

Temperature

Probable indicator of bacterial infection

ROS

Oxidative bacterial killing; cellular proliferation; angiogenesis Sense the severity of wound

Castilla et al. (2012) Tang et al. (2021) Abdali et al. (2015) Dunnill et al. (2017) Fernandez et al. (2011) Okan et al. (2007)

Uric acid

Moisture

Maintains a moist environment to control wound exudate levels and hastens the process of healing

proliferating bacteria. Further, the wound pH also varies in response to the severity of the infection. Thus, pH monitoring could provide valuable information regarding the possibility of infection. These materials act via an exchange of ionization and

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hence can be utilized as drug delivery tools with the ability to respond to the environment triggering the release of their payload (Tang et al., 2021). Currently, there are various sensors available to monitor pH levels in wounds. Moreover, the rate of encapsulated antibiotics release depends on the pH of the wound environment and might be insufficient for pathogen removal. The critical pH is not easily adjustable, which limits its application for the treatment of different wounds.

11.5.1.3 Thermo responsive The wound temperature is directly dependent on inflammation, where an increase of .1.11 C is considered to be a probable indicator of bacterial infection and manifested as palpitations around the wound. Thus, it could be used for pre-screening of chronic wounds (Abdali et al., 2015). Temperature-sensitive drug carriers for ondemand release in response to temperature variation are being employed. Mostafalu et al. (2018) fabricated an alginate-based hydrogel sheet embedded with poly(N-isopropylacrylamide) (PNIPAM)-based particles. This sheet was cast directly on top of a flexible heater, and controlled with an integrated microcontroller. The construct has transparent medical tape to form a wearable platform with a thickness of ,3 mm. They demonstrated that the construct can be employed to deliver antibiotics by triggering an external temperature lower than 42 C. PNIPAM is a thermoresponsive, biocompatible material that possesses the ability to undergo hydrophobic-hydrophilic transition over its critical temperature (32 C), which makes it self-triggering. While the alginate hydrogel sheet absorbs the exudates generated by chronic wounds.

11.5.1.4 Reactive oxygen species-responsive Several ROS-responsive materials have been recently explored to reduce the unnecessary oxidative stress at the site of injury. Tang et al. (2015) have employed the use of stromal cell-derived factor-1 α (SDF-1α) encapsulated within poly-(1,4-phenyleneacetone dimethylene thioketal) (PPADT) based ROS-responsive nanoparticles. The excessive inflammation in the wound environment facilitates cleavage of the thioketal bonds resulting in depolymerization of PPADT and subsequent release of SDF-1α. The released SDF-1α promotes the migration of mesenchymal stromal cells toward the wound and its periphery, thereby enhancing vascularization.

11.5.1.5 Uric acid-based biosensors Uric acid is a principal biomarker of injury whose elevated levels are directly correlated with the severity of the wound and oxidative stress, specifically in hard-toheal wounds. Uric acids inhibit the healing process by promoting inflammation and the generation of superoxide radicals (O22), which can disturb the normal functioning of DNA, lipids, and proteins (Fernandez et al., 2011). Clinical assessment of this biomarker might contribute for the treatment of the chronic wounds through continuous detection. Kassal et al. (2015) developed a “bandage-based sensing system” with contactless, and wireless transmission. The uricase enzyme was

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immobilized onto a Prussian blue carbon electron with silver or silver chloride electrodes as a reference which was printed onto the commercial dressing. A connected potentiostat quantifies the current output of the sensor, stores the data, and transmits signals to a connected smartphone. A similar system was also developed by Pal et al. (2018) wherein they developed a sub-bandage that monitors wound parameters and electrochemically quantifies the levels of wound pH and uric acid. The uric acid-based biosensors demonstrated sensitivity to detect samples with low volumes of uric acid, however, the potential of these sensors is limited due to interference from exudate constituents, such as lactate, electrolytes, proteins, and glucose.

11.5.1.6 Moisture controlling dressings One of the cardinal parameters of the healing process is to maintain a moist microenvironment. Although several bandages provide suitable regulation of wound exudate absorption, to ensure a moist wound environment, the only approach to measure the level of moisture at the wound site is by removing the dressing. A hydrofibers-based dressing was developed by Milne et al. (2016) with an integrated moisture sensor to monitor moisture content in real-time, providing a non-invasive approach to monitoring the wound environment without causing aggravation or impairment to the healed area.

11.5.2 Self-healing wound dressings Flexible skin constructs composed of hydrogels have gained attention as a prototype for the next generation of dressings. These hydrogels have exhibited immense potential for the development of novel materials for distinct biomedical applications. The ability to imitate the biological systems to heal the wound showcases the “smartness” of these substrates. A self-healing coordinative hydrogel was developed by Chen et al. (2019) in an injectable form with angiogenic and bactericidal properties, that can be employed for the treatment of diabetic ulcers. These Ag-SH-PEG (hydrogel) anti-bacterial dressings were fabricated with the coordinative crosslinking of multi-armed polyethylene glycol thiolated (SH-PEG) with silver nitrate (AgNO3). The reversible, dynamic nature of this coordinative Ag-S bond allows the hydrogel to self-heal. This characteristic of the Ag-SH-PEG hydrogel system has helped reduce fragmentation of the gel structure and allows integration of the disrupted gels, at the target site even after external mechanical destruction. Martanto et al. (2006) have developed a multi-functional micro-needle skin patch with a hollow microneedle array for continuous administration of a precise quantity of morphine sulfate directly into the dermal layer. These microneedles can prevent the wound from bacterial infection and promote healing.

11.5.3 Drug delivery dressings Recently, efforts have been dedicated for the identification of drugs or biological factors that can stimulate a single or multiple physiological healing processes.

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Integration of restorative factors within the dressings like stimulatory bioactive molecules may prove to be an innovative strategy. Passive delivery is a commonly used delivery system wherein a drug or molecule is integrated within the wound dressing in a pre-designated dosage and embedded in the dressings (drug carrier). Such delivery strategies fail to tackle the dynamics of hard healing wounds; thus, a semipassive delivery technique has now been established for wound status-specific release of therapeutic molecules (Saghazadeh et al., 2018). In this delivery system, various responsive materials with the ability to adjust the rate of drug release by responding to the stimuli generated by the wound are being employed to design dressings. Nevertheless, inadequate control over the drug release rate has unveiled the need to develop a dressing. Recently, a variety of bioactive molecules, like anti-bacterial growth factors, nucleic acids, and drugs have been incorporated within dressings to prevent bacterial infection and amplify the regeneration of skin. An innovative drug release “ON/OFF” photocontrollable system was developed using a surface-loaded Rcyclodextrin-5-fluorouracil (R-CD-5-FU) prodrug on a PVBC-b-PGMA crosslinked nanofibers with azido groups (Fu et al., 2009). This nanofiber mesh provided a fast and photo-controllable “ON/OFF” mechanism of release to ensure quick delivery of therapeutic molecules.

11.6

Oxygen therapies

11.6.1 Hyperbaric oxygen therapy An increase in oxygen tension is a pre-requisite to ensure faster, and more efficient healing, thus, therapies based on oxygen supply have been suggested to accelerate the repair process of acute and hard-to-heal wounds. Hyperbaric oxygen therapy (HBOT) is one such strategy of additional oxygen delivery at the wound site. It can be defined as the administration of 100% oxygen at a pressure of greater than 1 ata. HBOT is a US-FDA approved treatment with some established indications (Bhutani and Vishwanath, 2012). These include necrotizing soft tissue infections, chronic, clostridial gas gangrene, non-healing wounds, and crush injuries among others. Other than the outermost layer, there is presumably no topical absorptions of O2. Hence, systematic administration is necessary for supplemental O2 delivery to hypoxic tissues. The HBOT involves exposing the whole body to a pressure exceeding 1 ata when pure O2 is inhaled, which is then circulated to all the body parts. Moreover, the local hypoxia that exists in the case of chronic wounds can be reversed after diffusion of O2 in blood plasma with a pressure of about 2.2 to 2.5 ata (Shah, 2010). The two most commonly used hyperbaric chambers for HBOT are—(1) monoplace, where the patient resides alone within small pressurized vessels filled with pure O2, and (2) multiplace, which treats several patients at the same time inside the vessel. Such sporadic reversal of local hypoxia helps in the restoration of optimal conditions for regeneration (Carney, 2013). HBOT aims to alter the ischemic

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effects, reduce edema, modulate the production of nitric oxide, and immune system response, modify the effects of cytokines and growth factors, promote proliferation of cells, accelerate the deposition of collagen, and microbial oxidative killing, stimulate capillary budding, and enhance the O2 radical scavengers (Thackham et al., 2008). When the pO2 level at the injured site surpasses the limit for the survival of facultative or obligate anaerobes, HBOT demonstrates bacteriostatic activity or bactericidal effect on anaerobic bacteria. With the rise in O2 tension, the bactericidal ability of leukocytes increases, and thus, it can be concluded that HBOT possesses an indirect anti-bacterial effect on both aerobic and anaerobic strains. Further, HBOT exhibits a strong synergistic effect with certain antibiotics including, imipenem, vancomycin, linezolid, ciprofloxacin, and teicoplanin (Memar et al., 2019). HBOT also exhibits anti-inflammatory effects by decreasing TNF-α, IL-1β, and IL8. The HBOT is generally recognized as a safe procedure, however, there are a few known contraindications including—the inability to equilibrate pressure in febrile condition, claustrophobia, and asthma among others, which could increase O2 toxicity along with rare conditions of CNS or pulmonary toxicity (Heyboer et al., 2017).

11.6.2 Topical oxygen therapy Topical oxygen therapy (TOT) is defined as the administration of oxygen over the wound by either pressurized or continuous delivery systems. The availability of high pO2 reverses localized hypoxia in the wound. It provides an impetus to the leukocyte functioning to address pathogens while directly killing anaerobic bacteria (Frykberg, 2021). Angiogenic factors like FGF-2 and VEGF, are significantly upregulated to ensure neovascularization and regulation of collagen synthesis by increasing fibroblast activity, this occurs as a result of enhanced O2 concentration, once the inflammatory signaling subsides. Altogether this results in effective granulation of the wound bed, formation of strong collagen tissue, and closure of the wound. TOT can also be used for hard-to-heal wounds by consistent delivery of non-pressurized oxygen. These devices maintain incessant delivery of nonpressurized (normobaric) oxygen via thin tubes or small cannulas to occlusive wound dressings (Dissemond et al., 2015). An incessant flow of pure oxygen is supplied to the wound through small portable, battery-powered oxygen generators. The wound dressings are typically changed weekly and the oxygen generators are replaced every two weeks. Another approach is to supply increased cyclical pressure oxygen through the topical wound oxygen (TWO2) system. It applies a high humidified oxygen pressure in the range of 5 to 50 mmHg, in a cyclical waveform. The gradient of pressure gradient allows oxygen molecules to diffuse deeper into the hypoxic wound tissue and thereby enhancing enzymatic functions and multiple molecular (Gottrup et al., 2017). The TWO2 system has been shown to create successive non-contact compression of the limb that aims to minimize peripheral edema and stimulate wound site perfusion.

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Different oxygen-releasing dressings and gels are also available, which either release pure O2 embedded into the bandage itself or release O2 that is generated via biochemical reactions in a hydrogel. Pure O2 is embedded in these dressings, for instance through vesicles, and disseminate upon liquefication of the dressing by the wound exudate (Lim and Jang, 2021). In these dressings, O2 is released continuously for up to six days, and is used as secondary dressings, whereas, the dissolved O2 in occlusive (hydrogel) dressing is obtained via biochemical reactions by employing the use of hydrogen peroxide, which breaks down to form dissolved O2 and water. This O2 diffuses into the wound bed through a permeable separator. On the contrary, certain dressings require two distinctly separate components, a hydrogel sheet embedded with low concentrations of glucose with iodide ions forms the first component, while the second constituent is a sheet containing glucose oxidase, these components must be employed in conjunction to actuate the biochemical process. The oxidation of β-D-glucose to D-gluconic acid and hydrogen peroxide is catalyzed by glucose oxidase in the presence of O2. The released hydrogen peroxide diffuses through the dressing which oxidizes the iodide ions to form free iodine and O2, or alternatively, they reach the exterior of the wound to metabolize into O2 and water. The oxidized iodide ions are known to have anti-microbial properties within the gel which helps prevent bacterial proliferation at the interface of wound and dressing while the dissolved O2 creates favorable effects within the wound (Bankar et al., 2009). Oxygen transfer is another approach wherein hemoglobin is used as an O2 carrier for topical wound treatment. O2 transport is facilitated by hemoglobin, thus, employing the use of hemoglobin spray directly onto the wound concomitantly with the standard therapy. In wound treatment, the hemoglobin spray is applied concomitantly with standard therapy. The topical application of O2 at the site of injury has emerged as a potential therapeutic strategy, based on the anti-microbial property of ROS. ROS acts as signaling molecules that support wound healing processes by effectively eliminating a wide spectrum of biofilms and pathogens (Petri et al., 2016). Their mechanism of action entails the physical destruction of a pathogen’s cell wall, and therefore curbs the limitation of antibiotic resistance. A broad range of commercialized products, based on this property of ROS have been introduced for sterilization of wounds. Some products contain super-oxidized solution or gel manufactured through the electrolysis of ultra-pure water and NaCl. An inorganic bactericidal substance, hypochlorous acid (HOCl) is a dynamic initiator of ROS. HOCl has proven to be efficacious against a wide spectrum of pathogens either as stabilized neutral or acidic HOCl-solutions (Wang et al., 2007).

11.7

Conclusion

Conventionally, bandages were used merely to cover an injury without any biological activity. The new generation of bandages, that is, SMART bandages aims to perform not only the conventional functions but also some biological functions,

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such as stimulus responsiveness, drug delivery, oxygen therapies, and moisture control for better healing. The emergence of SMART wound monitoring devices has significantly contributed to the field of optimal wound care treatment by improving clinical outcomes and accelerating the management of hard-to-heal wounds.

Acknowledgment The authors thank the Director, INMAS, for his continuous support. Images are created using Biorender.com

Authors’ contributions Kirtida Gambhir—Writing—original draft, Data curation, Visualization; Nishant Tyagi—Writing—review and editing, Investigation, Conceptualization; Yogesh Kumar Verma—Writing—review and editing, Conceptualization, Supervision.

Compliance with ethical standards Not applicable.

Permissions All the figures and tables have been created by the authors.

Conflict of interest The authors declare no conflict of interest.

Research involving human participants and animals Not applicable.

Informed consent Not applicable.

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Fiber and textile in drug delivery to combat multidrug resistance microbial infection

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Deepa Dehari1, Aiswarya Chaudhuri1, Dulla Naveen Kumar1, Gopal Nath2 and Ashish Kumar Agrawal1 1 Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (BHU), Varanasi, Uttar Pradesh, India, 2Department of Microbiology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India

12.1

Introduction

The worldwide market for medical fabrics has immense potential in the biomedical field; it’s worth was USD 24.70 billion in 2020 and is predicted to increase at a CAGR of 4.5% between 2021 and 2028 (Research, 2021). In 2014, the market worth was 13.94 billion (USD), accounting for 10 percent of the European technical textile market, and it was expected to grow around 12 percent shortly (Lawrence, 2014; Rostamitabar et al. 2021). Medical textile is an emerging area within the textile industry that has seen a considerable increase in research over the past decade, and it is quickly becoming a key portion of the textile industry. Because of technological breakthroughs, particularly but not primarily in nanotechnology, the technological healthcare textile sector is undergoing tremendous evolution and extension, especially in fields such as wound and tissue repair, personal protective clothing or equipment (PPE), sterile gauze, surgical hosiery, and implantable textiles (e.g., vascular grafts, surgical suture, reabsorbable polymers) (Morris and Murray, 2020). Due to their distinct physical and chemical characteristics, textile fibers are considered ideal transporters of drugs to the skin as well as other areas of the body. Textile materials have been extensively used in wound dressing/bandages, synthetic tissue and bone graft implants, scaffolds for tissue regeneration and repair, and several other topical treatments as drug delivery systems (Davies, 2018; Ratner et al. 2004). Textiles are favorable to microbial growth (bacterias and fungus) due to their wide surface area and moisture-retaining tendency. Evidence showed that microorganisms are considered omnipresent and can proliferate rapidly based on nutrition, humidity, and temperature conditions. Certain bacterial species may proliferate by double folds almost every approx 30 minutes, under optimal conditions (temperature 36 C 40 C, and pH 5 9), with an estimation that one bacterium cell unit can multiply to 1,048,576 cells in about 7 hours. Microbial colonization has several detrimental effects both on the textile and humans. These drawbacks include decreased Fiber and Textile Engineering in Drug Delivery Systems. DOI: https://doi.org/10.1016/B978-0-323-96117-2.00006-6 © 2023 Elsevier Ltd. All rights reserved.

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mechanical efficiency, objectionable odors, stains, discoloration, and an increased risk of infection. As a result of the growing community for awareness of pathogenic consequences, significant R&D, innovations, and techniques in recent years, various efforts have been performed to minimize or eliminate the growth of microorganisms residing over the textiles. Bacterial contamination is a major problem, especially for fabrics that are being used in hospitals as therapeutic products or for healthcare and sanitation care, as well as protective apparel, animal feed, food sector, and water cleaning systems. Microbial contamination in hospitals is most commonly caused by Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, Enterococci, and Pseudomonas aeruginosa (Khan et al. 2017). Bacterial resistance to antibacterial drugs has become a severe problem as it decreases their effectiveness, and textile durability as well as shover harmful impacts to the environment and human health. MDROs (multidrug-resistant organisms) is a public health emergency, as it makes the treatment of healthcareassociated infections difficult with currently available antibiotics. MDRO infections are becoming a major cause of mortality and morbidity worldwide. The discovery of novel antibiotics demands considerable time and a lot of financial and labor investment. High doses of antibiotics will be used to treat MDRO infections, resulting in severe toxic and adverse effects, necessitating the development of alternate treatments (Lee et al. 2019). This book chapter mainly describes the recently developed textile fabric for antimicrobial activity.

12.2

Common textile antimicrobial agent

Antimicrobial compounds have become increasingly popular in textiles in recent decades. Antimicrobial textiles are functionally active textiles that can show static or cidal activity towards microorganisms. A summary of commonly used fabric textile materials with antimicrobial activity has been presented in Fig. 12.1 (Table 12.1). Further, we have summarized antimicrobial agents, polymers and nanoparticles (NPs) reported that are being used to prepare textile materials with antimicrobial activity.

12.2.1 Quaternary ammonium compounds Quaternary ammonium-derived products with symmetric alkyl ammonium complexes constituted of a hydrophilic portion and a hydrophobic alkyl chain have mainly been utilized in natural fibers like wool, in which they constitute covalent linkage with the substrate, or with the synthesized fibers like nylon, in which they construct ionic interactions (Table 12.1). It was observed that the antimicrobial efficacy of the compound is affected by the size of the hydrocarbon chains, the availability of a perfluorinated group, and the number of cationic ammonium groups. Although the QACs are lethal to a variety of microorganisms, including Gram 1 ve and Gram 2 ve bacteria, parasites, viruses, and fungi, still, they are not considered

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Figure 12.1 Common textiles antimicrobial agents.

sporicidal (e.g., Clostridium sporogenes), or antitubercular (e.g., Rhinovirus) (Jiao et al. 2017).

12.2.2 Polybiguanides Polybiguanides, like polyhexamethylene biguanides, are polycationic amines made up of repeating subunits of cationic biguanides that are separated by aliphatic chains and are considered potential antimicrobial drugs for both natural and manufactured textiles. They primarily interfere with the membrane permeability by creating an electrostatic interaction with negatively charged microbial cells (Ahani et al. 2017).

12.2.3 Triclosan Triclosan [5-chloro-2-(2,4-dichloro phenoxy)-phenol] has been utilized to polish fabric materials as an antimicrobial agent by blocking lipid production such as

Table 12.1 Textiles antimicrobial agent. S. no.

Textile antimicrobial agent

1

Quaternary ammonium compounds

G

G

G

2

Polybiguanides

G

G

3

Triclosan

Method of deposition

The commercial product (Manufactured by)

References

Disruption of bacterial cell wall integrity Denaturation of proteins Inhibition of DNA synthesis

Surface grafting/ coating Sol-gel Technique

Gerba (2015), Jennings et al. (2015), Morais et al. (2016), Periolatto et al. (2017)

Perforate the bacterial phospholipid membrane Block the DNA replication

Surface grafting/ coating Padding and exhaustion Surface grafting/ coating Polymerization

Sanitized (SANITIZED, Switzerland) Saniguard KC (LN Chemical Industries, Switzerland) BIOGUARD (AEGIS Microbe Shield, New Zealand) Cosmocil CQ Biozac ZS

Antimicrobial mechanism

G

G

G

Bocking lipid and fatty acid biosynthesis Generate oxidative stress Disruption of the integrity of the membrane

Irgaguard 1000 (Ludwigshafen, Germany) Irgasam (Sigma Aldrich) Microban (Cannock, United Kingdom) BiofresH (Salem, MA, United States) Silfresh (Magenta, Italy)

Gao and Cranston (2008), Mulder et al. (2007), Rosin et al. (2001) Dann and Hontela (2011), Shrestha et al. (2020)

4

Chitosan and its derivatives

G

G

G

5

6

Natural herbal products(neem oil, Aloe vera flavonoids, peptides, terpenoids, etc.)

Metals and their oxides(Ag, Au, Cu, ZnO, Au, and Ti)

G

G

G

G

G

G

G

G

G

G

Electrostatic interaction between the polycationic structure and the predominantly anionic components of the microorganisms leads to cell wall disruption Inhibition of the mRNA and protein synthesis Block of nutrient flow Bound to protein, bound to adhesins Membrane disruption Inhibition of enzyme synthesis Coagulation of the cell content Destabilization of the proton motive force with leakage of ions Disruption of cell wall Generate reactive oxygen species (ROS) Interference of electron transport chain Proteine Denaturation Damage DNA and inhibit its replication

Surface coating Crosslinking

Utex (Nantec Textile Co. Ltd) Eosy (Unitika) Crabyon

Abd El-Hack et al. (2020), Goy et al. 2009, Kravanja et al. (2019), Rabea et al. (2003a, 2003b)

Surface coating Mixing

Cubicin Ultrafresh (Thomson Research Associates) Sanitized AG (Clariant)

Joshi et al. (2009), Sher, 2009, Uddin (2014), Vadhana et al. (2015), Vergis et al. (2015)

Surface grafting Encapsulation Electrospinning

SmartSilver (Nanohorizon Inc.) Silverion2400 (PURE Bioscience, Inc.) Saniguard NanoZN (L.N. Chemical Industries)

Gold et al. (2018); Lemire et al. (2013)

(Continued)

Table 12.1 (Continued) S. no.

Textile antimicrobial agent

7

N-halamines

Antimicrobial mechanism

G

G

8

9

Natural dyes (Alizarine, tannin, berberine, coumarins and pupurine)

Enzymes (Lysozyme, Protease glucose oxidase, etc)

G

G

G

G

G

G

Method of deposition

Bonding between nitrogen and Cl microorganisms Interfering with the cell enzymatic and metabolic processes Natural dyes have proteinbinding ability Intercalate into bacterial cell wall & DNA Membrane disruption

Surface grafting Polymerizationrruption

Proteolytic activity Degradate polysaccharides Produce superoxide primary ROS)

Enzymatic surface modification

Surface coating

The commercial product (Manufactured by)

Alizarin Turkey red extract (Sodhni biotechruption Pvt. Ltd.) Kattha michigan brown extract (Sodhni biotech Pvt. Ltd.) Proteases (SigmaAldrich Chemicals Private Limited) LYSOLAC (Bioseutica B.V.)

References

Hui and DebiemmeChouvy (2013), Vadhana et al. (2015), Wang et al. (2020) Gupta et al. (2004), Kamboj et al. (2021), Nayak and Padhye (2014)

Morais et al. (2016), Thallinger et al. (2013)

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phospholipids, lipoproteins, and lipopolysaccharides, impacting cell membrane stability and functioning as a barrier to microbes (Iyigundogdu et al. 2017).

12.2.4 Chitosan Chitosan is a well-known natural antimicrobial agent that surpasses other chemicals due to its excellent biocompatibility and biodegradability. Encapsulation, coating, and crosslinking or bonding with the substrate are all methods that have been used to apply this to textile materials. Its positive charges are due to the primary amine group interacting with negative charges on the microbe’s surface, allowing it to permeate the bacterial cell wall, combined with DNA, and inhibit mRNA synthesis, preventing the synthesis of proteins (Table 12.1). Chitosan has also undergone some modifications to improve its antibacterial properties. For example, Wang et al. created chitosan-metal complexes of bivalent metal ions like Zu(II), Cu(II), as well as Fe(II), shows superior antibacterial effects against Gram 1 ve and Gram 2 ve bacteria, as well as fungus, due to the development of a significantly greater positive charge after complexion. There are many reports of nanocapsules made from polypeptide-grafted chitosan that have excellent antibacterial properties most significant advantages of chitosan as an antimicrobial agent for textiles, whether as a component of synthetic fibers or a finishing agent. Regrettably, the dependence of chitosan’s activity on pH and temperature limits its utilization (Gokarneshan et al. 2012; Nayak and Padhye, 2014; Wang et al. 2005).

12.2.5 Natural herbal products In recent years, significant development have been observed in the identification of novel antibacterial substances from natural herbal sources. These compounds may have a useful antimicrobial action while being safe, easily accessible, nontoxic, and environmentally friendly. In addition, harmful bacteria have shown resistance to these natural compounds. In addition, harmful bacteria have demonstrated no resistance to such natural compound. Plants have recently drawn attention as a major source of natural antimicrobials. Materials with strong antimicrobial properties, such as flavonoids, tannin, quinonoid, alkaloids, terpenoids, phenolic, and saponins compounds, have been extracted from various plant parts, including leaves, flowers, bark, roots, and rhizome (Periolatto et al. 2017). For example, natural ingredients such as neem oil and its derivatives, garlic, eucalyptus oil, and black seed oil, are commonly used through encapsulated into nanocarrier and textile carrier based drug delivery system (Ghayempour and Montazer, 2017). Moreover, both alone as well as in combination with essential oils (e.g., tea tree oil, eucalyptus oil, cinnamon oil, thyme oil, citronella oil, etc.), they can likewise fight against a wide range of bacteria and their infections. The utilization of essential oils as antimicrobial agents on textiles has increased in current decade because of their high efficiency, even if the true mechanism against microbes is unclear.

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12.2.6 N-halamines N-halamines are heterocyclic chemical substances with one or two covalent linkages between nitrogen and a halogen (N-X), most commonly chlorine (Cl). Nitrogen can take the forms of amide, amine, or imide, which consist of the most potent bactericidal characteristics. N-halamines cause microbial death by linking Cl and bacteria, interfering with cellular enzymatic and metabolic activities (oxidation). Nano N-halamines with enhanced antibacterial capabilities have been recently developed due to their greater surface area (Shabbir and Mohammad, 2017). Over the past few years, N-halamines have made significant development in textile finishing: from formaldehyde emission to formaldehyde-free, from tensile strength damaging to tensile strength preservation, from instability to stability, from micromolecule to polymeric N-halamine, and so on. Those have contributed significantly to the improvement of our living standards. Improved stability of N-halamine siloxanes in the vicinity of UV light and normal washing has been the attention of several studies, which should be a future scientific issue that needs additional exploration. N-halamine compounds have long-lasting and experienced a more excellent antibacterial activity, allowing them to inactivate a broad range of microbes quickly and completely without causing resistance (Ren et al. 2016).

12.2.7 Natural dyes Natural dyes like purpurin, alizarin and also a few synthetic dyes like basic dyes can act as antimicrobial agents. The main antibacterial mechanisms in natural dyes are tannin’s protein-binding capacity and the cationic character of basic dyes, which interrupts the negative bacterial cell membrane (Devi et al. 2017). Pomegranate’s antibacterial effect has been linked to the presence of flavonoids and phenolic constituents. Many other sources of natural dye are rich in naphthoquinone, including lapachol (from alkannet), lawsone (from henna), and juglone (from walnut), which have been reported to have antibacterial properties (Singh. et al., 2005) were tested 4 natural dyes viz Rumex maritimus, Acacia catechu, Quercus infectoria, Rubia cordifolia, and Kerria lacca against common pathogens Bacillus subtilis, E. coli, Proteus vulgaris, K. pneumonia, and P. aeruginosa. The dye Q. infectoria was found to have largest inhibition zone and significantly effective againsts microbial infections (Calis et al. 2009; Singh et al. 2005).

12.2.8 Enzymes Antibacterial efficiencies have been reported for amylase, alkaline pectinase, and laccase immobilized into cotton fibers. The antibacterial activity is affected by the kind of immobilized enzyme and also the microorganism’s nature and structure. (Ibrahim et al. 2007). Enzyme treatments are extensively employed in the fabric industrial process to catalyze biochemical processes because they improve wettability, dyeability, and other finishing processes without destroying the fiber composited. The impacts of protease enzyme pretreatment on coloring and

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antibacterial efficacy were investigated, and it was observed that the application of the alkaline protease enzyme increased the release of natural dyes with retaining an enhanced antibacterial effect. This was due to complete or partial cuticle disruption in wool, which allowed natural dye molecules to pernitrate fibers more easily. (Tawiah et al. 2016). Furthermore, various auxiliaries and chemicals are used in textiles, which frequently destabilize enzymes and thus minimize their activity. NPs and smart polymers have been proposed as viable solutions to these textile issues. Enzymes attached to nanomaterials or smart polymers increased diffusion by decreasing weight (mass) transfer limitations (Madhu and Chakraborty, 2017).

12.2.9 Metal and metal oxides Antimicrobial NPs, such as Ag, Au, Cu, ZnO, Au, and Ti NPs, were incorporated into fibers and fabrics via nano-finishing or nanocoating, or nanocrosslinking, resulting in promising results, excellent bioactivity, and a reduction in AMR to antibiotics. Metal and metal oxides like Au, Ag, Cu, and Pt are among the most effective antibacterial agents. Metal NPs were found to inhibit several microbial species in vitro test. The main parameters affecting antimicrobial effectiveness are the precursors used in metal nanoparticle synthesis, nanoparticle size, shape, and preparation methods. Metal ion toxicity resulting from metal dissociation from nanoparticle surfaces and reactive oxygen species (ROS) formation on nanoparticle walls are two prevalent mechanisms for antimicrobial activities, although both are still under investigation. The metallic NPs have a positively charged surface that encourages adhesion to the bacteria due to the negatively charged surface of bacteria, perhaps increasing their antibacterial effect (Dizaj et al. 2014). There are many reports on the application of NPs in textiles for antibacterial activity, UV protection, flame retardant, and hydrophilic or hydrophobic finishes. These active nanoreinforced textile structures could be utilized in numerous sectors, including hospital fabrics, medical textiles, surgical gowns, bandages, and wound dressings, among many others.

12.3

Nanoparticles-based fabrics for the treatment of antimicrobial infection

Many groups of NPs based textiles have been utilized for the treatment of antimicrobial infections. The NPs are either embedded in various surfaces of fabrics or coated on the surfaces of fabrics. It was observed that coating fabrics with NPs are often performed by an ultrasound-assisted coating method, which is considered a convenient method. Further, a one-step process was developed where NPs can be synthesized and eventually coated on the surface of the desired substrate simultaneously. It was later observed that the textiles coated with NPs via the ultrasoundassisted coating method were more durable and were able to withstand rigorous

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Figure 12.2 Nanoparticles based fabrics for the treatment of antimicrobial infection.

washing cycles. Among various NPs, silver NPs (AgNPs) exhibit a better antimicrobial properties. Inorganic NPs like metal and metal oxide-based NPs in textiles have gained the attention of scientists due to their capacity to tolerate harsh processing settings. Titanium dioxide (TiO2) and zinc oxide (ZnO)-based NPs are of specific interest as they are pretty stable and safe for human use. AgNPs and ZnO-NPs are considered feasible solutions for inhibiting the spread of infectious diseases due to their antibacterial activities. With the expansion in the global population and transmission of disease, day by day, microbes with antibiotics resistance gene is growing along with the manifestation of infections from these microbes. As people’s knowledge of health issues has grown, numerous people have been interested in antibacterial fabrics that safeguard the user from microorganisms. In addition, the demand for antibacterial fabrics is increasing in tandem with the rise in microbial resistance strains (Gokarneshan et al. 2012). The most common NPs used in infectious diseases include gold NPs, zinc oxide NPs, silver NPs, mesoporous silica NPs, and chitosan NPs (Fig. 12.2).

12.3.1 Silver nanoparticles Most of the mortality cases are due to the occurrence of infectious diseases, primarily due to the prevalence of drug-resistant bacteria and abuse of antimicrobial drugs. Currently, the employment of metallic NPs is considered an alternative strategy to treat microbial diseases or infections(Chen et al. 2014; Gokarneshan et al. 2012). Silver ions (Ag 1 ) and silver compounds like AgNPs are extensively utilized in numerous biomedical applications like tissue scaffolds, wound dressing materials, antibacterial filters, and medical devices (Kaler et al. 2014; Patel et al. 2019a). It was noted that for exhibiting an antibacterial activity, Ag 1 and AgNPs must have

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seeped from the surface of the fabrics at a concentration higher than the minimum inhibitory concentration (MIC) to conserve the biostatic activity and also at a concentration at which the metal is fatal to microbes (Simonˇciˇc and Klemenˇciˇc, 2016). From various studies, it was observed that Ag 1 is attracted either to the negatively charged bacterial cells attached to their membrane or the sulfhydryl groups present in bacterial DNA, resulting in inhibition of proliferation of bacteria and blocking of biofilm formation. AgNPs are applied onto fabrics mostly made of cotton, wool, and silk(Gokarneshan et al. 2012). According to the literature, it was found that the properties of the textiles directly influence Ag 1 binding, its adhesive capacity, and the adsorption efficiency of the textile. In general, AgNPs are bound easily on the rough surface of natural fabrics compared to the smoother surface of synthetic fabrics. In another context, as the surface area of the fabrics increases, the amount of AgNPs deposition also increases (Simonˇciˇc and Klemenˇciˇc, 2016). Son et al., developed a feasible method for the preparation of AgNPs-b antimicrobial ultrafine fibers. In this method, AgNPs were prepared by electrospinning of cellulose acetate (CA) solution with little amounts of AgNO3 followed by photoreduction. The prepared AgNPs were then stabilized in ultrafine CA fibers by interacting with carbonyl oxygen atoms present in CA. It was observed that the AgNPsbased ultrafine CA fibers showed an enhanced antimicrobial activity (Simonˇciˇc and Klemenˇciˇc, 2016; Son et al. 2006). Further, Son et al. developed polymeric nanofibers composed of AgNPs, by electrospinning polymer nanofibers with AgNO3 in the presence of UV radiation at 245 nm. It was observed that upon UV irradiation, the Ag 1 and the clusters of Ag 1 were dispersed and aggregated over the surface of nanofibers, showing an average size of 21 nm, required for exhibiting an enhanced antimicrobial activity (Son et al. 2006). Vankar et al. prepared AgNPs using an aqueous extract of Citrus limon (from leaves of lemon), which were then coated over cotton and silk fabrics. FTIR analysis suggested the formation of the AgNPs on the fabrics, along with visualization with scanning electron microscopy (SEM), UV VIS spectroscopy, transmission electron microscopy (TEM), and atomic force microscopy (AFM). The treated fabrics were also analyzed for antifungal activity by the Agar diffusion method against Fusarium oxysporum and Alternaria brassicicola. The treated fabrics demonstrated significant synergistic antifungal activity due to Ag 1 and essential oils of lemon leaves (Vankar and Shukla, 2012). Velmurugan et al. prepared AgNPs of Erigeron annuus (L.) pers flower extract, which was then dipped on cotton textile and tanned leather, as verified by SEM. The prepared product was then confirmed by HR-TEM, energy-dispersive X-ray spectroscopy, FTIR, and X-ray diffraction studies (X-RD). It was observed that the required amount of AgNPs was produced at pH 7, 2.0 mM Ag 1 ions, and 4% flower extract concentration. Further, the AgNPs-based fabrics showed increased antibacterial activity towards Gram-positive microorganisms like Brevibacterium linens and Staphylococcus epidermidis. The AgNPs-based materials exhibited maximum zone of inhibition relative to marketed AgNPs, flower extract, Ag 1 ions, and flower extract-AgNPs blend (Velmurugan et al. 2014).

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Ibrahim et al. prepared AgNPs-based cotton fabrics by γ-radiation or thermal curing using butyl acrylate as a binder. The AgNPs were ready to protect against undesirable microbial effects. Alternatively, AgNPs were also prepared by a biological method where the biomass filtrate of fungus Alternaria alternata was used. The prepared NPs were analyzed by TEM, UV-Vis spectroscopy, X-RD, etc. In addition to these, the treated fabrics were subjected to thermal stability, color strength, and mechanical stability. It was found that the treated fabrics demonstrated an improved qualitative and quantitative antimicrobial effect. Also, the treated fabric showed approx. completely bacterial reduction efficiency for E. coli (99.1%) and S. aureus (98.7%) even after 20 washing cycles. They further exhibited significant resistance to biodegradation caused by soil microbes (Ibrahim and Hassan, 2016).

12.3.2 Gold nanoparticles Gold NPs are considered the most stable metallic NPs that are resisted oxidation and chemical instability. AuNPs can be altered to obtain desired characteristics, such as particle size, shape, morphology, surface chemistry, etc. (Silva et al. 2019b). AuNPs can bypass the barrier of the skin, thereby enabling improved absorption and permeation of active agents with high molecular weight. In this context, AuNPs are established as an encouraging candidate for transdermal drug delivery systems (Cao-Mila´n and Liz-Marza´n, 2014; Singh et al. 2018). The antimicrobial efficacy of AuNPs depends upon their well-established surface chemistry, physical stability, and nanosize. It was observed that a bio-physical interaction is established between AuNPs and bacteria via aggregation, biosorption, and cellular uptake destroying the bacterial cell membrane and cellular toxicity. Various studies found that monodispersed AuNPs demonstrated improved bacteriostatic and bacteriocidal activity against Gram 1 ve and Gram 2 ve bacteria by creating a multivalent contact surface with the microbes, thereby changing their metabolite mechanism and release pathways. In this context, Dong et al. showed that electrostatic interactions are formed between AuNPs (anionic) and natural cellulose fibrous constructs (cationic) (Dong and Hinestroza, 2009). In addition to this, Radic et al. determined that treating the polypropylene nonwoven fabrics with air plasma treatment increased AuNPs deposition over the fabrics, resulting in increased bactericidal activity toward E. coli and S. aureus (Radic et al. 2013). It was further established that due to the immobilized nature of AuNPs over the surfaces of the fabrics, their antimicrobial activity is related to the production of Au31, which increases the oxidative stress of bacterial cells. The formed Au31 forms an electrostatic bond with cellular organelles of the bacteria that are negatively charged, facilitating cellular uptake and microbial penetration and resulting in an enhanced antimicrobial activity (Silva et al. 2019a,b). Wang et al. prepared AuNPs capped by various N-heterocyclic molecules (NAuNPs) and used them as a broad-spectrum antimicrobial agent. These N-AuNPs get attached to the bacterial surface, destroying the cell wall and inducing cell death. Further, ultrasonication was used to coat the surface of fabrics with

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N-AuNPs which further enhanced the antibacterial activity against multidrugresistant (MDR) bacteria, inhibiting the production of bacterial biofilms (Cao-Mila´n and Liz-Marza´n, 2014; Wang et al. 2012). Anwar et al. fabricated biogenic AuNPs on cotton cloth (AuNPs-CC). It was observed that the hydroxyl functional groups ( OH) present in the cotton (cellulose macromolecules), gradually reduce the Au 1 to NPs. Further, concentrated citrus lemon juice was used to aid the kinetic process of AuNPs preparation. The treated fabrics were characterized by FESEM (field emission scanning electron microscopy), EDS (energy-dispersive spectroscopy), etc. The FESEM images revealed that the AuNPs developed showed a particle size of B22 nm that is attached to the fabrics. Further, the XPS and XRD confirmed the development of biogenic AuNP over the surface of cotton cloth. The antimicrobial assay for the various microbial strain was carried out for both pristine-CC and AuNPs-CC. It was observed that the AuNPs-CC showed an enhanced antimicrobial activity over pristine-CC. Moreover, the Citrus limonassisted AuNP-CC also showed an antimicrobial property for pathogenic microbes (Anwar et al. 2021). Textiles have been functionalized with AuNPs using a variety of ways. The research integrating AuNPs with textiles has opened up new avenues for developing antimicrobials for sanitation and safety products and infection prevention (Mehravani et al. 2021).

12.3.3 Zinc oxide nanoparticles Zinc oxide (ZnO) is considered biocompatible and is used widely in biomedical applications. Zn is an essential element for cells; however, if deviated beyond threshold concentration, it can inhibit the activity of enzymes (dehydrogenase, thiol peroxidase, glutathione reductase, etc.) required for developing microbial growth and infections. It was also observed that lowering of Zn concentration blocks the activity of NADH oxidase, inhibiting the respiratory chain of E. coli. Additionally, it has been observed that inhibition of Zn ions blocks the cytochrome c oxidase in Rhodobacter sphaeroides, which reduces membrane potential, thereby inducing cell death(Asokan et al. 2010). Presently, NPs-based fabrics are used, showing improved antimicrobial activity. Various methods are used for ZnO-NPs fabrications on textile materials like ultrasonication, layer-by-layer deposition, hydrothermal method, sol-gel process, etc. Subash et al. developed ZnO-NPs treated fabrics that exhibited improved antimicrobial activity against Gram-positive and Gram-negative bacteria (Subash et al. 2012; Tania and Ali, 2021). Tobola et al. developed ZnO-NPs-based polyamide 6 (PA), polyethylene terephthalate (PET), and polypropylene (PP) textiles by the chemical bath deposition (CBD) process. The treated fabrics were characterized by SEM and XRD which revealed the formation of wurtzite ZnO microrods on the surface of the textile material. Additionally, Differential Scanning Calorimetry (DSC), FTIR, and AFM indicated that the antibacterial activity is due to the availability of rough surfaces and increased wetting ability of a textile surface. Further, it was found that the ZnO-NPs treated fabrics showed an enhanced antimicrobial activity compared to new fabrics (Fiedot-Toboła et al. 2018a,b).

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12.3.4 Mesoporous silica nanoparticles Due to the improved chemical stability, biocompatibility, and distinctive mesoporous structure, mesoporous silica NPs (MSNs) have been utilized in biological and medical applications and textile industries (Kwon et al. 2013). It was first discovered in 1992 by the Mobile Oil Corporation and has gained significant consideration for its larger surface area, higher pore volume, tunable pore diameter, and narrow pore size distribution (Antonelli et al. 1996). Also, due to the presence of a strong Si O bond, MSNPs are more stable and resistant to degradation and mechanical stress (Bharti et al. 2015). Various studies found that MSNPs are also used as antimicrobials, usually for treating biofilm formation. MSNPs show antimicrobial activity by physically damaging the microbial cell membrane, producing ROS, and developing endo-lysosomal burden (Selvarajan et al. 2020). Hashemikia et al. developed tetracycline-containing MSNPs, which were later loaded on cotton fabric for providing antimicrobial activity on the infected human skin. In this study, the MSNPs were surface functionalized by amino groups (SBA-15-NH2) via postimpregnation. The functionalized tetracycline-loaded MSNPs were then attached to the surface of cotton fabrics by using polysiloxane reactive softener as a fixing agent. Analysis was carried out for obtaining antibacterial activity, mineral content, and washing durability. In addition to these, the functionalized MSNPs were subjected to SEM (Fig. 12.3), EDX patterns, X-ray spectra, and thermal characterization. It was obtained that the tetracycline was released gradually for 48 hour with an improved antibacterial activity (Hashemikia et al. 2016).

12.3.5 Chitosan nanoparticles Chitosan (CS) is a polycationic biopolymer that shows an improved antimicrobial activity. It also serves as an immunological enhancer. Ali et al. examined the employment of CSNPs and Ag-loaded CSNPs on polyester fabric for analyzing antimicrobial properties for biomedical applications. It was observed that developed NPs were having efficient antimicrobial activity. Also, Ag-loaded CSNPs exhibited improved antibacterial activity due to the synergistic effect of Ag and CSNPs against the growth of S. aureus (Ali et al. 2011; Anjum et al. 2021). From various studies, it was observed that chitosan follows different mechanisms for exerting antimicrobial activity. However, the exact mechanism is still unclear. The most established mechanism involves the interaction of chitosan (positively charged) with negatively charged cellular surfaces of microbes, causing extensive alterations and cell permeation ability (Patel et al. 2019b). Such alterations result in the leakage of cellular materials like enzymes, proteins, electrolytes, etc., ultimately leading to cell death. Another theory linked with the antimicrobial activity of chitosan states that chitosan binds with DNA, which eventually inhibits transcription and translation, leading to the death of microbes. In such a mechanistic approach, the chitosan is hydrolyzed to a moiety having a lower molecular weight that further gets penetrated the bacteria’s cellular membrane. However, this mechanism is still under examination (Lim and Hudson, 2003).

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Figure 12.3 Scanning electron microscopy images of control fabric, samples S2, S8, and S8 after five washing cycles and after the drug release process. Source: Adapted with permission from Hashemikia, S., Hemmatinejad, N., Ahmadi, E., Montazer, M., 2016. A novel cotton fabric with anti-bacterial and drug delivery properties using SBA-15-NH2/polysiloxane hybrid containing tetracycline. International Materials Science and Engineering: C 59, 429 437.

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Risti´c et al. fabricated chitosan, and its water-soluble N, N, N-trimethyl derivative, which was further linked to cellulose fibers. The attachment was then established by quantifying the amino groups of chitosan via X-ray photoelectron spectroscopy. Additionally, the desorption kinetics of the CSNPs from the surface of the fibers was also investigated via the spectrophotometric method. Further, the CSNPs-based cellulose fibers showed antimicrobial activity (Risti´c et al. 2017). It was observed from the literature that burn wounds favor microbial growth facilitating a lag in wound healing (Patel et al. 2020). El-feky et al. fabricated a textile material coated with silver sulfadiazine (SSD)-loaded CSNPs to treat the burn wound and prevent bacterial growth. SSD-loaded CSNPs were prepared using SSD with different concentrations of chitosan and CM-β-CD. The SSD-loaded CSNPs were then embedded on wound dressing via a padding process associated with a cross-linker. The SSD-loaded CSNPs dressing showed effective antimicrobial activity against Gram-positive bacteria, Gram-negative bacteria, and candida on an infected burn wound (El-Feky et al. 2017). Rozman et al. fabricated chitosan-gold blended NPs (CS-Au@MMT/gelatin), which were later coated with overdressing to inhibit microbial growth and cure the wound-prone infection. It was observed that the CS-Au@MMT/gelatin showed a promising growth reduction against methicillin-resistant S. aureus, which is connected with wound-prone infection. Additionally, sonochemistry was employed to analyze the antimicrobial activity of CSNPs-based dressing. It was revealed that the antimicrobial effect of chitosan is influenced by the pH of the surrounding environment and its molecular weight (Rozman et al. 2019).

12.4

Electrospun-based fabrics for the treatment of antimicrobial infection

Microbial infection and biofilm formation cause a delay in wound healing which is not overwhelming for patients as well as healthcare services. For instance, in 2012 13, the UK observed an upsurge in the cost of treating wounds, that is, around d4.5 to d5.1 billion. Henceforth, novel strategies are required for an effective wound healing treatment, including antimicrobial agents loaded with electrospunned nanofibrous dressings and fabrics that could be administered topically. The nanofibers are usually composed of cellulose due to their distinct properties like tunable porosity, high ratio of surface-to-volume, surface functionalization with ease, integrity, and high-quality bound fabricating procedure. The various techniques by which the antibacterial agents can be entrapped within the core of nanofibers includes single-axial, co-axial, and tri-axial methods that are usually applied for topical DDSs. In recent times, biodegradable polymers like cellulose and their derivatives, artificial polymers, natural polymers, and hybrid materials are employed for such purposes. It was found that cellulose acetate (CA) has been applied extensively for its uniqueness like biodegradability, biocompatibility, chemical, and thermal stability. This section of the chapter provides an overview of

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various electrospinning techniques and their applications in therapeutics, like the association of CA fibers with antibacterial agents, antibacterial-loaded NPs, antioxidants, and anti-inflammatory agents (Khoshnevisan et al. 2018). It was also found that fibers obtained via electrospinning mimic the morphology and physicochemical properties of extracellular matrix tissues which makes them an appropriate material to be used as scaffolds for tissue engineering. Currently, the researchers are applying various methods like surface functionalization and loading of drugs within the scaffolds to enhance the scaffolds’ functionality and properties (Goh et al. 2013). Preem et al. prepared nano- and microfibrous dressing loaded with antimicrobial drugs via electrospinning for wound healing topically. The authors electrospunned polycaprolactone (PCL) and PCL/poly (ethylene oxide) (PEO) fiber mats which were loaded with chloramphenicol (CAM). The fibrous was analyzed in terms of shape, size, physicochemical properties, drug loading and drug release, cell viability, and antimicrobial activity. The authors took the aid of computational modeling, which in combination with physicochemical characterization helped to establish all the existing interactions between chloramphenicol, PCL, and PEO, which further suggested that a strong interaction did exist between the drugs and the polymers that resulted in a controlled release of drug from the system. Also, the cytotoxicity results showed that the fiber mats are safe for murine NIH 3T3 cells. In addition to these, a disk diffusion assay was conducted that showed that the fiber mats had enhanced antibacterial activity. Also, the biofilm formation assay exhibited that the slow release of CAM from the fibers mats prevented microbial biofilm formation onto the dressing, hence overcoming treatment failure (Preem et al. 2017). Yu et al. examined the application of the coaxial electrospinning process for the preparation of drug-loaded CA nanofibers. In the study, CA was used as a filamentforming matrix and ketoprofen (KET) was used as an antimicrobial drug modified coaxially by using sheath fluids composed of mixed solvents. With a 0.2:1 sheathto-core flow rate ratio, the nanofibers exhibited smaller average particle sizes with uniform surface morphologies and narrower size distribution compared to fibers formed from single fluid electrospinning. Additionally, the nanofibers prepared coaxially showed an improved zero-order drug release profile. Such a modified electrospinning protocol offers the development of functional polymer nanofibers with enhanced attributes (Yu et al. 2012).

12.4.1 Drug releasing characteristic of antimicrobials-loaded electrospun nanofibers It was observed from various studies that the mechanism of drug release is regulated by diffusion, the difference in osmotic pressure, and the degradation of polymers. For instance, at the initial stage of drug release, the mechanism involves diffusion where the undissolved therapeutics within the nanofibrous matrix are transported from a high concentration region to a low concentration region by creating a concentration gradient. Further, the second stage the release mechanism is

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controlled by making a difference in osmotic pressure between the nanofibrous matrix and the surrounding release media. In the third stage, the release is mainly controlled via polymer degradation. Theoretically, it was observed that therapeutics with lower molecular weight show rapid drug release profiles compared to those with higher molecular weights. Chen et al. illustrated the release mechanism of therapeutics from electrospun nanofibers. From the in vitro release study, it was observed that there was a burst release of drug in the initial stage of their release. Various antimicrobials were employed in the study, including amoxicillin, metronidazole, and lidocaine, which are water-insoluble drugs with log P 0.87, 0.02, and 2.44, respectively. It was noted that compared to amoxicillin, and metronidazole, lidocaine is relatively more water-insoluble resulting in its rapid release during the initial stage of the in vitro drug release study. Metronidazole showed a more rapid release from the cumulative drug release curves than the rest two in the second stage. Further, by studying the curves, it was pointed out that all three drugs’ cumulative drug release profile was flat and smooth. However, surprisingly, the expected release behavior in the third stage by polymer degradation was not observed, suggesting that a more even degradation behavior was observed by the poly(lactidecoglycolide) membranes as compared to the disk-shaped biodegradable carrier, as discussed in the previous study (Chen and Liu, 2015; Chen et al. 2013).

12.5

Antibiotics-loaded fabrics for the treatment of antimicrobial infection

A review of the publications reveals that the medical and healthcare industries place a higher priority on the design of highly effective textile fibers for a variety of biomedical applications. Textile materials’ fibrous character encourages them to play a leading role in the development of acceptable biomedical matrix substances. On the other hand, textile fabrics offer humidity and temperature that favor the proliferation of germs on their surfaces due to their porosity and vast surface area. This does encourage the antimicrobial procedures that give fabrics their biocidal properties. The healthcare textile business has prioritized textile resistance to pathogens (to emphasize antibacterial, antimicrobial, and antifungal textile). AgNPs are an example of this, as they have wide antibacterial action against Gram-positive and Gramnegative pathogens and are employed as antibacterial agents in the fabric industry. Rehan et al. developed a novel strategy for fabricating cotton gauze for biomedical applications, which could be used as antimicrobials and drug delivery systems. The novel strategy includes three specific steps: First, cationization of cotton gauze, which involves a reaction with 3-chloro-2-hydroxypropyl trimethyl ammonium chloride [Quat-188], or unionization involving partial carboxymethylation. Second, modification of cotton gauze for the formation of AgNPs in situ involving reaction with trisodium citrate (TSC), and third, the loaded of modified cotton gauze with oxytetracycline hydrochloride, which was employed as an antimicrobial drug. In this novel strategy, TSC was used because of its properties, which include its usage

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as a reducing agent used for converting Ag1 to Ag0, as a stabilizing agent used to prevent the AgNPs aggregations, and as a linker used to fix AgNPs over the surface of the cotton gauze. The altered cotton gauze was analyzed through physicochemical characterization and drug loading and compared with the unmodified cotton gauze. The facilities were comprised of UV VIS spectroscopy, SEM, Attenuated Total Reflectance Infrared Spectroscopy, and X-ray spectroscopy. Also, the antimicrobial assay of the cotton gauze was performed, which revealed that the modified one showed enhanced antimicrobial activity compared to the unmodified one, suggesting that the modified cotton gauze could be used as antimicrobials in the drug delivery system and biomedical textiles. (Rehan et al. 2017). While antibacterial composites serve a crucial impact in preventing the transmission of infectious diseases, their low antibacterial durability hinders their therapeutic applications. In such instances, nanofibers might serve as a feasible solution. Qui et al. fabricated nanofibers embedded-textiles (NFs-embedded textiles) associated with a long-lasting antibacterial activity. It was prepared by electrospinning where the antimicrobial drug was deposited over electrospun nanofibers, which were then embedded into fiber-mesh of cotton fibers. The mesh was spun, forming functional textiles. The prepared NFs-embedded fabrics showed an enhanced antimicrobial property, which was evident from the inhibition assay. The inhibition rate of NFs-embedded textiles was found to be 99.99% for both S. aureus and E. coli. Furthermore, the cytotoxicity study showed that the NFs-embedded textiles had a poor cytotoxic response in vitro study. Based on these characteristics, the textile companies were fabricating antibacterials based on sportswear with excellent antibacterial durability Fig. 12.4 ( . 95%) against both S. aureus and E. coli after washing for 35 cycles. The NFs-embedded textiles thus proved to be a novel material with durable functional textiles and antibacterial properties (Qiu et al. 2020). Treatment of wounds exists a challenge due to their complex healing process. It was observed that the type of dressing materials depends on the type of wound type, wound location, injury enlargement or deepening, as well as the health of the patient in real-time. Macha et al. fabricated a woven cotton fabric composed of PLA (polylactic acid) composites for biomedical applications. Three cotton fabrics were made via hand weaving using natural cotton yarn of 36 Tex, with pore sizes 0.5, 1.0, and 1.5 mm respectively. The handweaving method produces fabrics with controlled porosity. In the study, the author utilized PLA of different concentrations, namely 0.01, 0.03, and 0.06 g/mL, to evaluate the effect of the PLA/fabric ratio on the mechanical characteristics. Moreover, amoxicillin was employed as an antibacterial drug. The drug release profile was assessed by UV-Vis spectrophotometer, while mechanical characterization was analyzed using Instron 5566 universal materials testing system. Based on the findings suggested that drug-loading efficiency increases as fabric porosity decreases. The cotton fabrics followed a twostage release pattern, which includes diffusion or possibly super case II kinetics followed by dissolution. It was observed that the amount of amoxicillin released surpassed its minimum inhibitory concentration against S. aureus Further, it was perceived that when the percentage of PLA in composites increases, the composites’ capacity to absorb water decreases. It was thus suggested that to design a

Figure 12.4 Demonstrate antibacterial activity nanoformulation incorporated fabric materials. (A) and (B) represent the kinetic study of the nanoformulation incorporated fabric materials with control samples (Escherichia coli and Staphylococcus aureus, respectively). (C) represent an inhibitory zone of inhibition of nanoformulation incorporated fabric materials (E. coli). (D) A superficial antibacterial investigation is depicted in this diagram. (E) The findings of an antibacterial surface analysis of nanoformulation incorporated fabrics with various TR contents against E. coli. (F) and (G) Fabric is simulated into a cuboid. Conventional surface antibacterial textiles and nanoformulation incorporated fabrics are depicted as antibacterial activity in the presented diagram. Elsevier©. Source: Adapted with permission from Qiu, Q., Chen, S., Li, Y., Yang, Y., Zhang, H., Quan, Z., et al. 2020. Functional nanofibers embedded into textiles for durable antibacterial properties. Chemical Engineering Journal 384, 123241.

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dressing fabric for wound healing, all the aforementioned properties are needed to be taken under consideration so that it could also support tissue regeneration while restricting microbial infections. Hence, it was suggested that the devices developed could also be employed as a water-resistant dressing for wound healing applications, resulting in the inhibition of bacterial contamination (Macha et al. 2018). Elsner et al., developed antibiotic-eluting composite fibers as wound dressing material. These composite fibers were comprised of a core and shell. The core was made up of polyglyconate, while the shell was composed of a porous poly (dl-lactic-co-glycolic acid). Composite fibers were further loaded with antimicrobials namely ceftazidime pentahydrate, mafenide acetate, and gentamicin sulfate. Inverted emulsions were freeze-dried for the preparation of the shell. The inverted emulsions were further characterized for size, shape, drug loading, and drug release profile. Additionally, the inverted emulsions were stabilized by surface functionalization using albumin, resulting in an improved release profile of hydrophilic antimicrobials like mafenide acetate. A higher phase ratio of emulsion or an increased polymeric content or molecular weight of polymers shows a reduction in the burst release. The study extrapolated the modified drug release profiles, demonstrating that the unique composite fiber exhibited high promise in wound healing treatments (Elsner and Zilberman, 2009).

12.6

Application of nanoparticles against MDROs: merits and demerits

In the fight against bacterial resistance, NPs can be considered next-generation antibiotics. NPs can cure microbial infections (Table 12.1), although there are still a few hurdles to overcome before they can be successfully translated to clinical application, including a deeper understanding the way of NPs interact with cells, organs, and tissues, toxicity after short and prolonged exposure, appropriate dosage and identification of acceptable delivery methods (Baptista et al. 2018; Khorsandi et al. 2021). Greater drug absorption, precise drug distribution, therapeutic targeting, and fewer adverse effects have all been made possible by nanotechnology. NPs can combat the MDR problem by specifically targeting multiple targets in the bacterium cell and increasing the potency of existing antibiotics synergistically. Furthermore, organic NPs may be appropriate agents for therapeutic uses due to their biocompatibility and biodegradability characteristics (Khorsandi et al. 2021). NPs (such as chitosan, metallic, carbon nanotubes, nanofibers, mesoporous silica nanospheres etc.) can bypass drug resistance pathways in bacterias, disrupt biofilm formation, and interfere with other critical pathways when used alone or in combination with the right antibiotics (Baptista et al. 2018). Metal oxide NPs (MONPs) are the most researched family of NPs, and they’ve been identified to inhibit the growth of a broad range of Gram-positive and Gram negativities bacterias, making them potential candidates for treating AMR. Also, MONPs can withstand rigorous processing settings during manufacture,

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demonstrating their toughness and stability (Raghunath and Perumal, 2017). NPs can damage cell membranes and interrupt essential biological pathways, which come up as new antimicrobial mechanisms. NPs have shown synergy when used in combination with the optimum antibiotics, and they may help to reduce the major crisis of bacterial resistance (Pelgrift and Friedman, 2013). One of the many advantages of these compounds is the availability of several types of inorganic NPs and a variety of production processes. In comparison to organic materials, inorganic NPs are hydrophilic, nontoxic, exceedingly robust, and biocompatible. Because of their high cellular absorption capacity, low toxicity, and nonimmunogenic reaction, inorganic NPs have gotten a lot of interest as therapeutic, gene delivery carriers, and organ targeting (Loh and Lee, 2012; Lohse and Murphy, 2012; Loh et al. 2016). Some of its primary disadvantages include limited chemical stability, suboptimal drug release rates for the distinctive therapy, and the negative effects of the organic solvents employed for particle formation. Antimicrobial agents can also be carried by organic NPs (Baranwal et al. 2018). For clinical translation, proper guidelines for the manufacturing, scaled-up industrial production of nanomaterials, evaluation of physiochemical characteristics and their impact on biocompatibility, standardization toxicological assays, and the methods to correlate data from in vitro and in vivo assays are required (Lee et al. 2019). The pharmacological efficiency in clinical trials, as well as the safety, and tolerability of the nanoparticle system, must be considered in future preclinical investigations. Finally, the cost-effectiveness of clinical translation of these Nanomaterials’ therapeutic efficacy should be evaluated. (Lee et al. 2019; Zazo et al. 2016).

12.7

Conclusion

Antibacterial agents have been introduced into textile fabrics, resulting in essential advancements in the sectors of apparel, medicine, and industry. However, in addition to the antibacterial properties of antibacterial textiles against microbes, special attention should be made to their nontoxicity to humans and the environment. Antimicrobial textiles have been developed using both synthetic and natural fibers. Chemicals, metal-based NPs, plant and animal-derived substances, dyes, and mordants can all be used to impart antimicrobial characteristics. Antibacterial effects against bacteria, fungus, and viruses may be limited or wide in coated fabrics. Control and targeted delivery via textile fibers will be key in combating antimicrobial, and antibiotic resistance. Most notably, metal NPs allow various independent and potentially synergistic boost antibacterial activity and conquer antibiotic resistance on the very same platform. Multifunctional features of NPs can be adjusted through careful design to produce optimal infective capability and, as a result, improved antibacterial control. In light of worldwide awareness and regulations, future research should focus on antibacterial drugs and medical textiles derived from natural and biocompatible sources and green synthesis approaches.

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Acknowledgement The authors acknowledge the Indian Institute of Technology (BHU), Varanasi, India and the Ministry of Education (MoE), Government of India, for providing Scholarships.

Authors’ contribution Deepa Dehari: conceptualization data curation, manuscript writing, designing of images and tables Naveen Dulla, Aiswarya Chaudhuri: data collection, validation and editing manuscript, language and grammatical correction Gopal Nath: reviewing, editing, and help to draft the manuscript, Ashish Kumar Agrawal: read, reviewing, editing, and approved the final draft. The final version of the manuscript was examined and approved by all contributors.

Compliance with ethical standards Not applicable

Conflict of interest We have no conflicts of interest.

Research involving human participants and animals Not applicable.

Informed consent Not applicable.

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Emulsion templated threedimensional porous scaffolds for drug delivery

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Anilkumar Yadav, Meenal Agrawal and Rajiv K. Srivastava Department of Textile and Fibre Engineering, Indian Institute of Technology Delhi, New Delhi, India

13.1

Introduction

Over the past few years, the efficient delivery of drugs to the targeted site has been a topic of discussion. Most of the drugs are delivered through oral and parenteral routes. The significant limitations of these conventional administration routes include interactions with physiochemical factors, varying drug concentrations between two dosages, reduced bioavailability, and fast elimination (Kovrlija et al., 2021; Shariatinia, 2021). Furthermore, between two drug dosage cycles, the drug level in the blood first increases and then declines, resulting in either toxicity or ineffectiveness (Liu et al., 2014; Zhang et al., 2017). Additionally, the orally administrated drugs follow a long route before reaching the desired organ. Therefore, the initial intake concentration of the drugs is mostly higher than required to provide a sufficient drug level at the final targeted site. Such higher drug concentrations are undesirable and lead to off-target toxicity (especially in cancer therapy). These severe limitations of the conventional administration routes have encouraged the surging importance of drug delivery systems (DDS) capable of controlled and selective drug delivery by encapsulating or immobilizing drugs in carriers (Kumbar et al., 2006; Sharifi et al., 2016). These carriers are also used to administer factors or nutrients in pharmaceutical, cosmetics, and nutraceutical products (Ullah et al., 2016). The considerable technological and industrial interest in advanced DDS is also visible from their market value, which was $231 billion in 2020 and is estimated to be $310 billion by 2025 (Trucillo, 2021). Therefore, developing efficient DDS with attributes like an immune invasion, preservation of drugs against photo and chemical oxidation during processing and delivery, and sustained drug release at the target to allow intended therapeutic effects are of high significance (George et al., 2019; Kumbar et al., 2006; Zhou et al., 2018).

13.1.1 Drug delivery systems The origin of controlled DDS dates back to 1951 when the drug dissolution rate was studied as a factor to control its rate of bioavailability (Dokoumetzidis and Fiber and Textile Engineering in Drug Delivery Systems. DOI: https://doi.org/10.1016/B978-0-323-96117-2.00007-8 © 2023 Elsevier Ltd. All rights reserved.

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Macheras, 2006). With the advancements in material science and technology, a wide range of materials (organic and inorganics) have been explored to prepare efficient DDS (Sung and Kim, 2020). The inorganic systems generally include nanoparticles of iron oxide, gold, silver, silica, octacalcium phosphate, etc., whereas organic DDS are primarily based on natural and synthetic polymers like chitosan, gum tragacanth, alginate, proteins, peptides, lipids, polylactide, polyglycolide, poly (ε-caprolactone), etc. (Calori et al., 2020; Shariatinia, 2021). Polymer attributes like feasibility of fabrication into different shapes and sizes through melt, solution, or colloidal processing, ease of physical and chemical modifications, and tailor-made degradation kinetics make them potential candidates for several routine and advanced technological applications (Wu et al., 2012). Furthermore, biopolymers with excellent biocompatibility, improved therapeutics, and reduced toxicity and side effects are ideal materials for developing immune-invasive DDS through appropriate modifications (Jacob et al., 2018; Mazloom-Jalali et al., 2020, p. 8). Though the polymers initially have desired mechanical strength, it deteriorates over time due to biodegradation. To overcome this, polymer blends and composites have also been used to fabricate DDS with long-term mechanical integrity (HernandezMontelongo et al., 2014; Sharma et al., 2021). Polymeric DDS in various shapes and sizes, including micro- and nano-spheres (Zheng et al., 2021), electrospun fibers (Luraghi et al., 2021), hydrogels (Sun et al., 2020), and three-dimensional (3D) scaffolds (Calori et al., 2020) have been prepared. Although the micro- and nano-DDS are injectable through subcutaneous routes, which is advantageous, their burst release kinetics is undesirable for providing long-term therapeutic effects (Allison, 2008; Ulery et al., 2011). Electrospun nanofibrous drug carriers have a controlled zero-order release profile compared to micro- and nano-particle carriers. However, poor mechanical strength and pore-size distribution are serious concerns associated with electrospun matrices (Allison, 2008; Fernandes et al., 2014; Garg et al., 2015). The biocompatible and biodegradable 3D hydrogels are superior in carrying large amounts of water-soluble drugs and compounds, such as therapeutically active proteins and peptides. The drugrelease profile of these carriers depends upon the microstructure of hydrogels, macromolecular structure of the polymer, drug solubility, and drug-polymer interactions (Manasco et al., 2014; Sepantafar et al., 2017). Recently, poly(ε-caprolactone) (PCL)-based 3D foam scaffolds prepared using freeze-drying and supercritical CO2 (scCO2) demonstrated sustained release of an anticancer drug, 5-fluorouracil, lasting for .6 days (Salerno et al., 2017). Furthermore, photocurable four-arm PCL has also been incorporated into tunable porous morphology supporting cell attachment and growth (Aldemir Dikici et al., 2019). As scaffolds are inevitable components of tissue engineering, generation of drug-eluting scaffolds with interconnected pores is highly beneficial to overcome adverse responses at the implant site and to improve the fate of cell and tissue growth (Limongi et al., 2020; Salerno and Netti, 2021). The drug-eluting scaffolds stabilizing the drug before its release, eradicate multiple drug administrations by maintaining drug concentrations at optimal therapeutic levels, and offer the feasibility of spatiotemporal release of multiple drugs as well (Ardeshirzadeh et al., 2015;

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Baumann et al., 2017). Furthermore, the injectable and implantable scaffolds are also capable of sustained release of proteins, cells, and genes, thus expanding the limits of novel treatments in regenerative medicines for reconstructing and repairing damaged tissues (Hu et al., 2018b; Papa et al., 2018). Over the years, several classical and advanced techniques with their unique features and limitations have emerged to design and develop 3D porous scaffolds for tissue engineering of different shapes and sizes, intricate pore-morphology, and porosity (Woodruff and Hutmacher, 2010). These techniques include solvent casting, porogen leaching, gas foaming, supercritical CO2 method, thermally induced phase separation, electrospinning, stereolithography, selective laser sintering, 3D printing (fused deposition molding, direct ink writing), and emulsion templating. Among these different classical and modern techniques, emulsion templating is highly promising. It produces polymeric scaffolds with interconnected micro-structure, which provides controlled drug delivery and cell growth using biopolymers (Rath et al., 2012; Zhang et al., 2019).

13.1.2 Emulsion templating Reportedly, emulsions, specifically high internal phase emulsion (HIPE), having dispersed phase volume fraction (Φd) $ 0.74, have gained surging research interest owing to the generation of macroporous scaffolds (polyHIPEs) from a variety of polymers and of different shapes as well (Aldemir Dikici and Claeyssens, 2020; Kramer et al., 2021). The limit of Φd 5 0.74 represents the maximum packing density of closely packed uniform spherical droplets in a unit volume, above which uniform droplets separated by a thin continuous phase are assembled into polygonal configuration (Lissant, 1966). Polymerization of the continuous phase of HIPE followed by extraction of dispersed phase droplets produces scaffolds of high porosity and open-cell or interconnected pore-morphology, as shown in Fig. 13.1. It is posited that during polymerization, change in the continuous phase density causes shrinkage of the continuous phase leading to the formation of windows (secondarypores) on pore-surface, thus open-cell morphology (Menner and Bismarck, 2006).

Figure 13.1 Schematic representation for fabrication of 3D porous scaffold using high internal phase emulsion templating.

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Factors such as co-monomer content (Xu et al., 2016), concentration of emulsifier and emulsifier type [surfactant (Yu et al., 2015), co-surfactant (Zhou and Foudazi, 2021), and Pickering particles (Zheng et al., 2013)], mode of initiation (continuous or dispersed phase), and Φd (Barbetta et al., 2005; Robinson et al., 2014) govern the diameter and number of windows on pore-surface, and tune the degree of openness or pore-interconnectivity. The open-cell macroporous morphology imparts high permeability to the scaffolds and offer suitability for flow-through applications, whereas closed-cell scaffolds, generally, produced within Pickering HIPEs are desirable for encapsulation (Weinstock et al., 2019), sound insulation (Kovalenko et al., 2018), and energy storage (Tu¨rko˘glu et al., 2022). According to the Bancroft rule, stabilization of HIPE using a surfactant (emulsifier) soluble in the continuous phase is the most common strategy. A low HLB emulsifier, span 80, is most preferably used to stabilize w/o HIPEs (Bancroft, 1913). However, high concentrations of costly surfactants (ranging from 5 to 30 wt.%, and in some instances up to 60 wt.% w.r.t continuous phase) have been used to emulsify large volumes of the dispersed phase in the minor continuous phase and to improve the HIPE stability (Chen et al., 2021; Yadav et al., 2019). Use of such large amounts of costly surfactants is undesirable, and their removal from scaffolds before its final application adds to overall expenses (Zhang et al., 2019). Moreover, deterioration in the mechanical strength of the scaffolds, non-biodegradability, and toxicity of surfactants are few other limitations. The use of amphiphilic nanomaterials (Pickering particles: organic, inorganic, and hybrid) as substitutes to surfactants for HIPE stabilization have been successfully demonstrated, and such HIPEs are designated as Pickering HIPEs (Huang et al., 2019; Zhang et al., 2022). Pickering HIPE stabilization using very low amount of solid nanoparticles and their improved stability against coalescence makes them highly attractive (Chevalier and Bolzinger, 2013). Further, the use of biocompatible and biodegradable nanoparticles for preparing Pickering HIPEs and scaffolds from such HIPEs are also advantageous for food and tissue engineering applications (Abdullah et al., 2020; Shi et al., 2020). Interestingly, settling of Pickering nanoparticles at the interface of HIPE forming immiscible liquids restricts the interconnectedness between pores formed by rupturing of thin continuous phase. This eventually leads to the development of nanocomposite scaffolds of closed-cell morphology (Agrawal et al., 2020). Pioneered with scaffold synthesis using free radical polymerization of styrene and divinylbenzene within water-in-oil (w/o) HIPE templates in 1960s, emulsion templating has been expanded to wide range of polymers (both, natural, and synthetic) and polymerization chemistry (Gao et al., 2021; Jiang and Bismarck, 2021; Luo et al., 2021). Polymerization chemistry including, click-chemistry (Aldemir Dikici et al., 2021), step-growth (Kapilov-Buchman et al., 2021), chain-growth insertion (Slova´kova´ et al., 2014), atom transfer radical (Cummins et al., 2007), reversible addition fragmentation chain transfer (Benaddi et al., 2021), ring opening metathesis (Schallert and Slugovc, 2021), and ring opening polymerization (Yadav et al., 2020a, 2022) have been used to synthesize HIPE templated scaffolds. Furthermore, oil-in-water (o/w) and non-aqueous (oil-in-oil, o/o) HIPE templates have also been used to prepare hydrophilic and hydrophobic scaffolds for wide

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range of applications (Erdal et al., 2020; Tao et al., 2022; Yadav et al., 2020b; Zhu et al., 2020). Emulsion templated scaffolds have been applied as superabsorbent, catalytic-support (Mravljak et al., 2021), separator for battery (Danninger et al., 2020), precursor for porous carbon (Kapilov-Buchman et al., 2017), stationary phase in chromatography column (Hughes et al., 2015), encapsulating agent (Weinstock et al., 2019), tissue regeneration (Aldemir Dikici et al., 2021), and DDS (Hobiger et al., 2021), to name a few. The customized pore-morphology (open or closed-cell), controlled porosity and pore-size distribution, and high resiliency (mechanical, thermal, and chemical) make emulsion templated scaffolds a potential candidate for tissue engineering and drug delivery. Further, functionalization of scaffolds with anti-inflammatory and anti-bacterial drugs to suppress the inflammation immune responses and possible risk of infections at the site of implant is also desired (Baradari et al., 2012; Yang et al., 2020, p.; Zhu et al., 2011). A schematic representation illustrating the application of therapeutic incorporated 3D scaffolds as implants is shown in Fig. 13.2. Therefore, this chapter addresses emulsion templated 3D porous scaffolds for tissue engineering functionalized with drugs. The effects of scaffold’s porosity, poremorphology, pore-interconnectivity, and hydrophilicity on drug release profile have also been discussed. Furthermore, drug incorporated scaffolds designed with hierarchical porosity by integration of HIPE templates and 3D printing have been illustrated. Additionally, studies describing primarily Pickering o/w HIPE templates prepared using biodegradable and biocompatible nanoparticles for drug preservation within Pickering HIPEs have also been elaborated.

Figure 13.2 Schematic representation of therapeutics incorporated scaffolds as implants.

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13.2

Fiber and Textile Engineering in Drug Delivery Systems

Emulsion templated scaffolds

13.2.1 Conventional emulsion-based scaffolds Conventional emulsions are based on the use of amphiphilic surfactants to stabilize the emulsions. PolyHIPEs fabricated using these conventional emulsions have interconnected porous morphology due to the reasons mentioned earlier. The interconnectedness in polymeric scaffolds is highly desirable for applications like tissue regeneration, which further affects the drug release kinetics. The effect of interconnectedness on drug release was demonstrated in a studied carried by Corti et al. for polyacrylate-based scaffolds. Emulsion templated scaffolds of functional acrylates were evaluated for wound dressings as carriers to co-deliver hydrophobic drugs and biological molecules (Corti et al., 2019). For this purpose, w/o HIPEs were initially prepared, where the continuous phase comprised of butyl acrylate (BA) and glycidyl methacrylate (GMA), a low HLB polymeric emulsifier, and trimethylpropane triacrylate or 1,6-hexandioldimethacrylate. Furthermore, introduction of poly(ethylene glycol)methacrylate (PEGMA) in aqueous dispersed phase (Φd 5 0.8) improved the hydrophilicity of polyacrylate scaffolds. Redox initiators were used to cure the continuous phase at room temperature for 24 hours via radical polymerization, followed by purification of scaffolds in Soxhlet extraction and drying in an oven at 45 C. Varying amounts of PEGMA, crosslinker, and crosslinker functionality (bis or tri) led to significant morphological differences in polyacrylate scaffolds, specifically, collapsing of droplets, and decline in number and diameter of interconnections. Mechanical properties of polyacrylate scaffolds assessed through tensile and compression tests also showed dependency on PEGMA concentration and crosslinker functionality, as higher number of crosslink points led to higher stiffness. The MTT assay values measured by direct and indirect methods were .70% in most of the scaffolds, thus indicated good cytocompatibility of polyacrylate scaffolds for human fibroblasts. Furthermore, polyacrylate scaffolds did not show any antiangiogenic effect during in vivo CAM assay, confirming their potential as wound dressing materials. The drug release profile of curcumin incorporated polyacrylate scaffolds was evaluated in phosphate buffer saline (PBS, pH 5 7.4, containing 3 wt.% polysorbate 80). Based on the drug release profile, polyacrylate scaffolds were classified into two groups, one showing complete drug release in 100 hours to 140 hours, and the other showing incomplete curcumin release within this period. The second group of polyacrylate scaffolds comprised of PEGMA in the aqueous dispersed phase, which altered the interfacial interactions leading to the formation of reduced pore throats, therefore leading to reduced drug release rates. The polyacrylate-based scaffolds are advantageous in wound healing due to their high absorption and retention capacities of body fluids. Wynne and coworkers developed hemostatic wound dressing scaffolds within o/w HIPEs comprising acrylate monomers with/out poly(N-isopropylacrylamide) in continuous phase (McGann et al., 2017). Purified scaffolds depicted typical interconnected macroporous morphology with average pore-size ranging between 28 and 44 μm. The PBS uptake of scaffolds was comparable to the alginate-based wound dressing materials and

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reached as high as 65.5 g/g depending upon the monomer composition. HeLa cells seeded on the scaffolds remained viable for .48 hours and PrestoBlue-assay values, .70% for the prepared scaffolds confirmed their non-toxicity. Cell adhesion on some scaffolds was comparable to the wound dressing materials based on chitosan and poly(ethylene glycol) (PEG). The inclusion of calcium diacrylate into macromolecular structure of HIPE templated scaffolds led to high blood clotting ability than the control sample, rayon gauze. Further, antimicrobial activity against Staphylococcus aureus was observed till 72 hours for scaffolds loaded with ciprofloxacin or tetracycline. The initial burst drug release was the consequence of high scaffold swelling, which provided wide space for unobstructed diffusion of small molecules. Wound dressing and drug delivery scaffolds doped with antibiotics are highly attractive, and it has been demonstrated that wound healing scaffolds functionalized with iodine provide excellent antimicrobial activity over a broad spectrum of bacteria (Chen et al., 2016; Landsman et al., 2017; Meghan, 2017). In this respect, iodine functionalized macroporous scaffolds were prepared from o/w HIPEs comprising of sodium acrylate, poly(ethylene glycol)diacrylate and PEGMA in continuous phase and mineral oil in the dispersed phase (Lundin et al., 2019). Redox-initiators employed for polymerization of continuous phase and the purified scaffolds with/ out hemostatic agent (kaolin, alumina silicate) were functionalized using alcoholic iodine solutions (0.1 and 1.0 wt.%). Iodine loadings varied from 6.9 to 20.7 wt.%. An obvious change in scaffold’s color from white to brown was observed on functionalization. Raman and IR spectra of functionalized scaffolds suggested that iodine was incorporated as tri-iodide ions and formed a complex with carboxylate and carbonyl ester groups of amorphous polymer matrix, while the interactions between kaolin and iodine were insignificant. The iodine release in PBS at 37 C characterized using UV-Vis spectroscopy revealed that iodine was released as triiodide ions irrespective of kaolin and iodine loadings. The release rate of iodine from the scaffolds was dependent upon initial iodine loading, as higher initial concentration of drug created larger concentration gradient leading to faster release. Further, release profile of the drug showed an initial burst release and then sustained release profile, governed by the dissociation of tri-iodide-polymer complex. Iodine release from scaffolds demonstrated a power-law relationship and the kinetic parameter (k) considerably ,0.5 indicated that the diffusion pathway for tri-iodide ions was analogous to the pathway followed in an assembly of polydispersed spheres. The zone of inhibition indicated that the antimicrobial activity of iodine functionalized scaffolds against various gram-positive and negative bacteria was comparable to commercially available iodine based antiseptics. Use of thiol-ene chemistry to synthesize crosslinked biodegradable scaffolds (hydrolysis of ester linkages) within inverse HIPE has been widely reported, however, fabricated scaffolds were hydrophobic (Caldwell et al., 2012; Lovelady et al., 2011; Suˇsec et al., 2015). Hydrophilic scaffolds are highly appreciated in biomedical applications as hydrophilicity leads to enhanced cell attachment, proliferation, and allows better transportation of nutrients and metabolic-wastes (Lee et al., 2009). Therefore, various physical and chemical modifications have been performed

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to impart hydrophilicity in hydrophobic polymeric scaffolds (Wang et al., 2016). In this direction, degradable hydrophilic scaffolds of PEG were synthesized within o/w HIPEs via photo-induced thiol-ene crosslinking of PEG with diacrylate or dimethacrylate (Hobiger et al., 2021). The purified scaffolds had porosity B90% and interconnected macroporous morphology. The brittleness of the scaffolds was remediated by incorporating ethoxylated trimethylolpropane tri(3-mercaptopropionate) and/or 2-hydroxyethyl methacrylate (HEMA) in HIPE recipes. Water uptake ascribing to porosity and surface area of the scaffolds reached over 1000%. Most of the water uptake was observed within 15 minutes and reached to saturation in 1 hours, suggesting the generation of highly hydrophilic scaffolds. Incorporation of thiol crosslinker and HEMA in macromolecular structure improved the biodegradability of the scaffolds in PBS (pH 5 7.4) and acetate buffer (pH 5 4.9) due to increased number of hydrolyzable ester linkages. The release profile for an antiacne model drug, salicylic acid, in PBS depicted an expected initial burst release up to 24 hours followed by prolonged release curve. The highest drug retention was 30% after the release period of 48 hours. Enantiopure chiral drugs are of great importance due to their favorable pharmacological, adiaphorous, or toxicological effects depending on their stereoisomerism (Kasprzyk-Hordern, 2010). However, racemization of some unstable chiral drugs during processing or storage necessitates the development of carriers showing selective administration of preferred stereoisomer of the drugs (Reist et al., 1995). This leads to increased therapeutical effects and economics as the complex synthesis processes of enantiomerically pure drugs is eliminated (Yu et al., 2016). Therefore, drug carriers can be designed to carry out selective incorporation and release of such drugs using polymers presenting chirality. US FDA-approved biocompatible and mechanically strong polylactide (PLA) shows chirality (helical structure, in solution or crystalline state) when exists in pure enantiomeric states, poly(L-lactide) (PLLA), and poly(D-lactide) (PDLA) (Ikada et al., 1987; Tyler et al., 2016). The chirality of PLA was integrated with HIPE to create porous scaffolds of PLLA, PDLA, and poly(D, L-lactide) (PDLLA) and used as drug carriers for enantioselective release of chiral drugs (Yong et al., 2019). The continuous phase comprising of vinyl terminated PLA, BA (co-monomer), trimethylolpropane triacrylate (crosslinker), dichloromethane (solvent), and span 80 (surfactant) was cured via free radical polymerization using initiator, AIBN. Similar morphological properties were observed for all PLA scaffolds. PLLA scaffolds had specific surface area, pore diameter, and compressive modulus of 24.07 m2/g, 2.91 μm, and 0.22 MPa, respectively. Formation of a spindle or triangular morphology of MC3T3-E1 cells during cell growth study for 7 days, and CCK-8 assay value ( . 80%) represented cell viability and biocompatibility of PLA scaffolds. Interestingly, MC3T3-E1 cells demonstrated a higher proliferation rate on PLLA and PDLLA scaffolds than on PDLA scaffolds, indicating the effect of materials chirality on cell growth, adhesion, and diversification. Enantioselective loading and release behavior of PLA scaffolds were assessed against chiral drugs: cinchona alkaloids, (1)-cinchonine and (2)-cinchonidine and naproxen ( 6 ) as they undergo hydrogen bonding with helical polymeric chains through their hydroxyl groups of chiral carbon (Liang and Deng, 2016).

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PLLA scaffolds showed higher loadings (46.0 mg/g) for (2)-cinchonidine than PDLA and PDLLA scaffolds (B30 mg/g) whereas loading amount of (1)-cinchonine was similar for all PLA scaffolds (B30 mg/g). PLLA scaffolds also demonstrated higher loading for naproxen (2, 94.7 mg/g) than naproxen (1, 67.5 mg/g), while other PLA scaffolds had lesser and equal loadings for both (B46 mg/g). The discrimination demonstrated in drug loadings by PLLA scaffolds confirmed their enantioselective behavior was due to varying molecular stereo-configuration of chiral drugs (Liang et al., 2016). The significant difference in release profile of chiral drugs by PLLA scaffolds also confirmed the enantioselective release behavior owing to binding between chiral drug and helical polymeric chains. Furthermore, cyclic drug loading and release experiments (up to 3 cycles) illustrated similar drug loading efficiency and accumulative release profile, and hence confirmed the potential of PLLA scaffolds for selective administration of drugs.

13.2.2 Pickering emulsion-based scaffolds As stated earlier, Pickering emulsions have been popularized among the scientific community as these emulsions are stabilized using amphiphilic nanoparticles instead of surfactants and hence, lead to the formation of nanocomposite scaffolds in a single step. Further, the scaffolds developed within Pickering emulsions require simple purification step (drying), whereas scaffolds derived from conventional emulsions require rigorous purification (Soxhlet extraction). The Pickering nanocomposite scaffolds can further be extended for medical grade scaffolds by the incorporation of bioactive ceramics, such as hydroxyapatite nanoparticles (HA), into biodegradable scaffolds leading to enhanced bioactivity, biocompatibility, and osteoconductivity (Fu et al., 2011; Salerno et al., 2011; Zhou et al., 2012). Using this approach, nanocomposite scaffolds of poly(lactide-co-glycolide) (PLGA) were prepared within Pickering HIPEs and in situ functionalized with an antiinflammatory drug, ibuprofen for bone tissue engineering (Hu et al., 2014). W/o Pickering HIPEs constituting dispersion of hydrophobically modified HA in 7.5 wt.% PLGA solution in dichloromethane as continuous phase produced porous PLGA nanocomposite scaffolds on solvent evaporation and drying. The porous morphology of PLGA scaffolds was attributed to HA loadings (2.5 to 10 wt.%) and Φd (0.75 to 0.9). At a particular HA loading, pore diameter and number of interconnections increased with increasing Φd, whereas Young’s modulus and compressive stress of scaffolds diminished. The reinforcement of polymer matrix by increasing HA loadings enhanced the stress bearing ability of the scaffolds, whereas increasing Φd deteriorated the mechanical properties of scaffolds due to increase in porosity. All the scaffolds demonstrated a prominent weight gain during 14 days of biomineralization study due to apatite mineral deposition. The Ca/P molar ratio of deposited apatite on scaffolds was 1.65, which was significantly close to the standard ratio for natural bone. Ca/P ratio clearly indicated the potential bioactivity of fabricated scaffolds and the competing rate of apatite deposition against degradation of the scaffolds. The drug loading efficiency in the scaffolds was .97%. Further, in vitro release profile was studied in PBS at 37 C. Scaffolds demonstrated an initial burst release lasting for

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.40 hours followed by sustained release up to 192 hours. The increased hydrophilicity of the scaffolds due to increased HA loadings facilitated faster drug dissolution whereas electrostatic interactions between carboxyl groups of drug and surface hydroxyl groups of HA accounted for the prolonged drug release. Formation of confluent layer of mouse bone mesenchymal stem cells (mBMSCs) on the nanocomposite scaffolds during 7 days of in vitro cell growth study confirmed the biocompatibility of scaffolds. The increased pore wall roughness, hydrophilicity, and bioactivity of scaffolds due to higher HA loadings enhanced the cell adhesion and proliferation. In a similar manner, nanocomposite scaffolds of PCL and PLLA-grafted-HA (PLLA-g-HA) were prepared through solvent evaporation within w/o Pickering HIPEs (Φd 5 0.75 to 0.9) and in situ functionalized with ibuprofen (Hu et al., 2015). PCL solutions (2.5 to 10 wt.%, in dichloromethane) were used as continuous phase, followed by dispersion of Pickering stabilizer, PLLA-g-HA (2.5 to 10 wt.%, average diameter of 580 nm, and grafting efficiency of 5.5 wt.%, determined by thermal gravimetric analysis). Amounts of PCL and PLLA-g-HA in continuous phase and Φd effectively tailored the average diameter of interconnected pores, porosity, and mechanical strength of nanocomposite scaffolds. Increasing the loadings of PLLA-g-HA in continuous phase increased the hydrophilicity and poreroughness of scaffolds resulting in improved apatite minerals deposition, cell adhesion, and proliferation during in vitro biomineralization (28 days) and cell growth study (mBMSCs, 7 days). Appearance of distinguish peaks in FTIR spectra confirmed the successful incorporation of ibuprofen in scaffolds. The ibuprofen loadings .97%, indicated the feasibility of in situ drug incorporation within Pickering HIPEs. In vitro release behavior of the drug from the nanocomposite scaffolds in PBS followed the regular biphasic trend, as stated in the previous study, that is, burst release in initial 48 hours followed by a sustained drug release till 240 hours. PCL nanocomposite scaffolds have also been fabricated within w/o Pickering emulsions using PLLA-COOH grafted halloysite nanotubes (mHNT) as Pickering stabilizer (Hu et al., 2018a). 5 to 12.5 wt.% mHNT (average length and diameter 466.2 nm and 96.8 nm, respectively and PLLA-COOH grafting, 3.45 wt.%) were used to prepare Pickering emulsions of PCL (10 wt.% solution in dichloromethane) with highest Φd of 0.75. PCL Pickering emulsions were stable at room temperature for more than a month and depicted micron-sized polydispersed droplets. Emulsion parameters, namely mHNT loadings and Φd, effectively tailored the size-distribution of aqueous dispersed droplets as expected, and eventually the microstructure and porosity of PCL nanocomposite scaffolds generated on solvent evaporation. Appearance of wider carboxyl and stronger hydroxyl group peaks in FTIR spectra confirmed the successful loading of an antibacterial drug, enrofloxacin into the scaffolds (prepared with Φd, 0.5), and drug loading efficiency .97% indicated minimal drug loss during processing. The drug release behavior of the scaffolds was studied in PBS at 37 C. A burst release in initial 12 hours following prolonged release in subsequent 150 hours was observed. The drug release behavior of the scaffolds was dependent on the initial drug concentration and mHNT loadings. Higher initial drug concentration generated a high concentration gradient between scaffold and PBS, thus enhanced drug release rate, as stated earlier. Increasing mHNT loadings on the other

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hand reduced the scaffolds pore size and hence relatively reduced drug release rate due to better entrapment of the drug. During antimicrobial study against Escherichia coli, scaffolds loaded with 5 wt.% enrofloxacin indicated no difference in zone of inhibition over a period of 192 hours, thus proving the ability to provide long-term antimicrobial activity. Biocompatibility of PCL-mHNT nanocomposite scaffolds was assessed by in vitro seeding of mBMSCs on scaffolds. The cells transformed from spherical to bipolar and CCK-8 assay also had a good correlation with cell adhesion and proliferation over the incubation period of 5 days. The enhanced bioactivity and osteoconductivity of scaffolds were attributed to increased pore roughness and silica content with increased mHNT loadings. Bovine serum albumin (BSA), the most abundant human plasma protein, has been studied for both in vitro experiments and transplantations. It acts as a bio-supplement promoting cell adhesion and growth (Horva´thy et al., 2017; Kasa´lkova´ et al., 2014). It has further been incorporated within other biopolymers and studied for drug delivery. For example, PCL-incorporated-biopolymers (BSA and calcium alginate) based scaffolds reinforced with HA were prepared within o/w Pickering HIPEs (Hu et al., 2017). BSA played the role of stabilizer during emulsification of PCL solution (in dichloromethane, 1.5 to 4.5 wt.%, accounting to Φd of 0.8) in aqueous continuous phase. Prepared HIPEs were in situ crosslinked at room temperature for 24 hours and then freeze-dried to produce PCL incorporated biopolymer nanocomposite scaffolds. Increasing PCL concentration in dispersed phase reduced the pore-interconnections and scaffold porosity by increasing pore wall thickness, as PCL layer anchored on inner pore surface appeared to be fibrous to filmy in morphology. Reducing porosities enhanced mechanical properties of the scaffolds (compressive strength and Young’s modulus) while decreasing swelling rate and equilibrium swelling ratio in water which was attributed to hydrophobicity of PCL and reductions in interconnections. Though PCL incorporated nanocomposite scaffolds were biocompatible; the hydrophobicity of PCL decreased the cell proliferation rate on scaffolds, which further reduced with increasing PCL concentration in the dispersed phase. In situ loading of ibuprofen using gelation (crosslinking) and freeze-drying was studied, and the drug loading efficiency, .98% indicated the efficacy of the approach. The drug release profile at 37 C in PBS at two different pH, 2 and 7.4, followed the general trend, and the accumulative release amount of drug after incubation period of 168 hours was lower at pH 5 2 (56.9%) than at pH 5 7.4 (78.5%). It was further anticipated that at pH 5 2 occurrence of strong hydrogen between carboxyl groups of calcium alginate delayed the diffusion of PBS and hence reduced drug release.

13.2.3 Emulsion templated 3D-printed scaffolds 3D printing uses the layer-by-layer approach to fabricate porous scaffolds of predefined geometry and pore-architecture; however, generation of scaffolds with micron-size pores is a limitation (Ngo et al., 2018; Zhou et al., 2020). Interestingly, association of 3D printing with HIPEs offers fabrication of scaffolds with multiscale porosity (micro- to macro-pores originating from HIPE template and 3D printing, respectively), as shown in Fig. 13.3.

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In this direction, fabrication of 3D-printed biocompatible and biodegradable PLLA/PCL blend scaffolds of hierarchical porosity was demonstrated employing w/o Pickering HIPEs as precursor in 3D printer (Yang et al., 2017). The continuous phase of w/o HIPEs comprised of PLLA/PCL blend solution (50/50 wt.%, in dichloromethane). PLLA/PCL blend solution having critical viscosity of ,92 mPa.s at polymer concentrations ,6 wt.% allowed the formation of stable HIPEs (Φd 5 0.75), and at least 2.5 wt.% hydrophobically modified silica nanoparticles (mSiNP) was required to obtain HIPEs processable in 3D printer. Based on the viscosity of HIPEs, print-pressure ranging from 0.1 to 0.2 MPa was applied during 3D printing. 3D-printed PLLA/PCL blend scaffolds with interconnected hierarchical pores and porosity ( . 98%) were generated on solvent evaporation. mBMSCs proliferated favorably up to 7 days on scaffolds during in vitro cell growth study and formation of confluent layer on scaffold’s surface indicated excellent biocompatibility of prepared scaffolds. The release profile of enrofloxacin in PBS at 37 C followed the Hixson-Crowell model and high correlation coefficient values (R2, 0.895 to 0.999) indicated the drug erosion mechanism during its release. Rapid and almost complete drug release was presented by all the scaffolds over a short period of 10 hours, where B80% of the drug released within initial 2.5 hours. Similar methodology was also reported to fabricate 3D printed hierarchical porous bioactive, biocompatible PCL nanocomposite scaffolds within w/o Pickering HIPEs (Hu et al., 2019). Synergistic combination of hydrophobically modified rodshaped HA (7.5 to 15 wt.%) and mSiNP (1.5 wt.%) produced 3D printable w/o Pickering HIPEs (Φd 5 0.75) constituting PCL solution (6 to 12 wt.%, in dichloromethane) in continuous phase. The concentrations of PCL and Pickering stabilizers tailored the droplet size distribution, viscosity of HIPEs and eventually the printing parameters. Grid shaped 3D-printed PCL nanocomposite scaffolds, with porosity .96%, demonstrated hierarchical interconnected pores. The mechanical properties of scaffolds governed by the two mechanisms, reinforcement, and increased porewall thickness. Further, in vitro studies demonstrated enhanced bioactivity (apatite formation) and excellent cytocompatibility of PCL scaffolds against mBMSCs as nanoparticles tuned the pore-wall roughness and hydrophilicity of scaffolds. In vitro release profile of ibuprofen in PBS (pH 5 7.4 at 37 C) followed the general biphasic trend, initial burst release for 8 hours and then sustained drug release up to 50 hours. The initial fast drug release rate was associated with scaffolds high

Figure 13.3 Formation of multi-scale porous scaffolds using high internal phase emulsion incorporated 3D printing.

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porosity, which benefited the penetration of PBS in scaffolds and dissolution of drug adhered to outer surface. While sustained drug release was ascribed to increasing amounts of hydrophobic PCL in porous matrix of scaffolds. Four different pharmacokinetic models were used to study the drug release profile of PCL scaffolds and observed that Ritger-Peppas model with linear regression (RR2) value .0.9 fitted well and followed Fickian diffusion as value of constant (n) was ,0.5. Recently, shape memory polymers have also been explored for drug delivery as these shapes can be compacted into a small temporary shape which are easy to implant with minimal invasive processes. Later, these shapes can regain their original form using external stimuli. In this regard, Yang et al. fabricated multifunctional scaffolds using o/w Pickering HIPEs (Φd 5 0.75) of a shape memory polymer, poly (DL-lactide-co-trimethylene carbonate) (PLMC, 3 to 12 wt.%, in dichloromethane) as an ink in 3D printer (Wang et al., 2021). Varying combinations of hydrophobically modified HA (2.5 to 10 wt.%) and mSiO2 (2 wt.%) were used to prepare Pickering HIPEs of printable viscosity. Polymer concentrations and nanoparticles loadings dictating the microstructure and rheological properties of HIPEs customized the 3D printing parameters. Macroporous scaffolds with rough pore-wall were generated on solvent evaporation via freeze drying and the shape fixity and recovery ratios, .90% confirmed the excellent shape memory attribute of PLMC scaffolds. Increasing scaffolds mass during in vitro biomineralization study (up to 28 days) was supported by HA loadings in scaffolds, which increased the number of nucleation sites for apatite deposition. mBMSCs were favorably adhered, proliferated, and formed a confluent cell layer on scaffolds after 9 days of incubation, which confirmed the suitability of PLMC scaffolds for bone tissue engineering. Release profile of enrofloxacin from 3D-printed scaffolds (loading efficiencies, .96%) in PBS demonstrated initial burst release up to 24 hours followed a sustained release of .350 hours. Increasing amount of hydrophobic polymer, PLMC in scaffolds matrix hindered the diffusion of release medium in scaffolds and hence reduced drug release rate. Sustained drug release behavior of PLMC scaffolds was also confirmed from the antibacterial activity of drug loaded scaffolds against S. aureus bacteria as zone of inhibition was observed up to 7 days.

13.3

High internal phase emulsion templates for drug encapsulation

To treat various bacterial infections, conventionally used antibiotics are becoming ineffective over time owing to the developing antimicrobial resistance in these bacteria. To overcome this, novel approaches such as use of phytochemicals are being explored to reduce the reliance on antibiotics. One such drug is curcumin, which is derived from rhizome of turmeric and is shown to be effective against wide range of pathogens along with anticancer, anti-inflammatory, and antioxidant properties (Lopresti et al., 2014; Moghadam et al., 2015; Srivastava et al., 2011). However, its clinical success is limited because of poor photothermal stability and low water

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solubility leading to lower bioavailability. Such sensitive drugs can be delivered by encapsulating them in a carrier, which acts as a protective layer (Maheshwari et al., 2006). Lignin, occupying 30% of world’s biomass is the second most abundant biopolymer, has excellent UV absorption and antioxidation properties because of its aromatic skeleton and phenolic hydroxyl groups and can be used as an encapsulating media for carrying these drugs (Chen et al., 2017; Kai et al., 2016; Pan et al., 2006; Qian et al., 2015). Therefore, UV protecting ability of enzymatic hydrolyzed lignin-based Pickering HIPEs were studied for encapsulating curcumin and its release profile in PBS was investigated (Chen et al., 2019a). O/w HIPEs were prepared by ultrasonication using enzymatic hydrolyzed lignin (EHL, 1 to 10 wt.%) and sodium dodecyl sulfate (SDS, 0.5 to 2 wt.%) as emulsifier to encapsulate curcumin dispersed in soyabean oil (Φd 5 0.75 to 0.85). Aqueous continuous phase pH 5 11.5 to 6.5, Φd, and dosages of EHL and SDS governing the droplet size distribution tuned the rheological properties of HIPEs. Van der Waals forces due to the presence of EHL increased the viscoelasticity of HIPEs and typical shear thinning behavior with increasing shear rate was observed. The 3D network of EHL surrounding the dispersed droplets presented an effective protective barrier against UV-degradation for encapsulated curcumin and the residual curcumin level was improved with increasing lignin loadings. At 5 wt.% hydrolyzed lignin loading, the residual curcumin level after 72 hours of UV exposure was 60.3%. Further, varying hydrolyzed lignin levels increased the curcumin release rate from 72% to 98.4% in initial 1.5 hours as lignin particles aggregated in PSB buffer solution and led to HIPE destabilization. In a similar study, soyabean oil was used as a carrier to preserve and deliver curcumin. Carboxymethylated EHL synthesized by nucleophilic substitution was used as macromolecular surfactant for soyabean o/w HIPEs to encapsulate curcumin (Chen et al., 2020). Carboxymethylation of EHL incorporated sodium chloroacetate groups tuned the amphiphilicity of modified lignin depending upon the degree of grafting of COOH groups. O/w Pickering HIPEs (Φd 5 0.87) prepared with a synergistic combination of modified lignin (5 wt.%) and alkyl polyglycoside (3 wt.%) did not demonstrate any difference in complex viscosity when measured in the temperature range between 25 C and 70 C, thus indicating high thermal stability of Pickering HIPEs. The curcumin retention in HIPEs after 72 hours of UV exposure was dependent upon particles loadings and it reached up to 65.4%. In comparison to gliadin/chitosan hybrid particles and sulfomethylated lignin systems, curcumin retention was two folds (Chen et al., 2019c; Zeng et al., 2017). Thermal (at 60 C, 7 days) and storage (at room temperature, 30 days) stabilities of encapsulated curcumin were indicated by high retention values of 73% and 92.5%, respectively, which attributed to high phenolic hydroxyl content of lignin. In this direction, corn o/w HIPEs (Φd 5 0.8) stabilized using hybrid Pickering particles, zein/pectin (protein/polysaccharide) were also assessed for protecting curcumin (Zhou et al., 2018). Zein/pectin ratios tailored the extent of hydrogen bonding, electrostatic, and hydrophobic interactions, which in turn governed the wettability, zeta potential of particles at a particular pH, and interfacial tension through self-assembly of particles at the interphase. The ordered close-packed 3D

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network of zein/pectin at oil-water interphase offered the protection against UV radiations to curcumin through two mechanisms: delayed energy transmission and absorption of UV-radiations through aromatic amino acid residues of zein. The residual levels of curcumin in oil phase of HIPEs stabilized with Tween 20 and zein/pectin were 0.06% and 15.11%, respectively after 61 hours of UV radiation (340 nm), suggesting the high protection efficacy of zein/pectin stabilized Pickering HIPEs for curcumin. Another such sensitive drug having high biological significance is β-carotene. It acts as a precursor for the formation of vitamin A and promotes osteogenic differentiation (Dabouian et al., 2018). Lignin and alkyl polyglucoside were used as stabilizers to prepare o/w Pickering HIPEs (Φd 5 0.8) encapsulating β-carotene (Chen et al., 2019b). The effects of stabilizer dosage (lignin, 1 to 5 wt.% and alkyl polyglucoside, 3.5 wt.%) on HIPEs micro-structure, protection ability for β-carotene against thermal and photo oxidative degradation, extent of fatty acids release (in vitro digestion), and bioaccessibility of β-carotene were evaluated. The residual β-carotene contents in the dispersed phase after 7 days of incubation were 94% and 56%, respectively, at 25 C in light and 55 C in dark. The residual β-carotene contents after photo and thermal oxidative degradation generally varied with type of oil used as the dispersed phase, and dosages and molecular weight of lignin. The release rate of free fatty acids (indicating lipid digestion efficacy) and bio-accessibility of β-carotene were higher for Pickering HIPEs with higher lignin content. Incremental dosages of lignin reduced the average droplet size, hence created droplets of higher surface which in turn accelerated the in vitro digestion and bio-accessibility of β-carotene through micellization process. Similarly, sunflower o/w HIPEs (Φd 5 0.8) stabilized using glutaraldehyde crosslinked gelatin spheres (0.5 to 1.5 wt.%) were used as encapsulating medium for β-carotene to protect from oxidation (Tan et al., 2017). Formation of CH 5 N bonds from Schiff base in conjunction with C 5 C bonds of glutaraldehyde was responsible for autofluorescence of crosslinked gelatin particles and ensured easy detection of particles at o/w interface or in continuous phase (Wei et al., 2007). At least 0.5 wt.% gelatin particles (235.9 6 2.2 nm) were required to formulate Pickering HIPEs with room temperature stability .3 months and efficient encapsulation of β-carotene. β-carotene retention of .90% in dispersed oil phase during room temperature storage of 27 days reflected the high protection efficacy of gelatinstabilized Pickering HIPEs. The efficacy of Pickering HIPEs for protecting β-carotene against oxidation was benefited from fact that the 3D network of gelatin particles surrounding dispersed droplets hindered the diffusion of degrading free radicals. Use of OSA-starch/chitosan complex was also beneficial as a Pickering stabilizer for encapsulating and preserving high levels of β-carotene in corn o/w HIPEs than only OSA-starch complex (Yan et al., 2021). The OSA-starch/chitosan complex supported the preparation of highly stable Pickering HIPEs with β-carotene loadings up to 2 wt.%, which was only 0.5 wt.% in low stability HIPEs stabilized with OSAstarch. Increasing pH of aqueous continuous phase from 3 to 7 offered the non-

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Newtonian flow behavior and ascribed to pH responsive emulsifying ability of OSA-starch/chitosan complex. The effectiveness of OSA-starch/chitosan complex for protecting the encapsulated β-carotene from photo (UV) and thermal degradation (60 C) was confirmed form the high retention values, .70%, after 10 days of storage. This enhanced stability was attributed to closely packed 3D network of OSA-starch/chitosan complex enveloping oil-droplets and presence of majorly crystalline β-carotene rather than soluble. Furthermore, in vitro digestion in gastric fluids and bio-accessibility of β-carotene were differed in pH range of 4 to 6, depending upon lipase-lipids interactions. Biocompatible whey protein isolate (WPI) nanoparticles produced by Ca21induced crosslinking at pH 5 6 were used to prepare corn o/w Pickering HIPEs (Φd 5 0.8) for stabilizing β-carotene over a storage period of 30 days at 50 C (Yi et al., 2020). The contact angle of Ca21 crosslinked WPI nanoparticles enveloping the dispersed droplets was B67 degrees. The droplet size, storage (G’), and loss (G’’) modulus of Pickering HIPEs were the functions of nanoparticle loading. The WPI nanoparticles effectively stabilized Pickering HIPEs at room temperature over a storage period of two months with a slight increase in size of dispersed droplets. β-carotene retention in HIPEs after 30 days of storage at 50 C were 59% and 70% at nanoparticles loadings 0.2 and 1 wt.%, respectively and attributed to closely packed dense layer of nanoparticles enveloping the dispersed droplets. Further, in vitro digestion study indicated that decreasing droplet size increased the lipolysis rate of β-carotene due to increased surface area because of enhanced lipase and lipid interactions. O/w Pickering HIPEs stabilized with spherical casein nanogels (average hydrodynamic diameter, 179 nm and zeta potential at neutrality, 216.4 mV) were used as carriers for controlled release of hydrophobic drug, indomethacin (Chen and Zhang, 2019). The aqueous continuous phase pH values of 4 and 2 (near to isoelectric point of casein) were most favoring for HIPE stability as increasing pH (neural to alkaline) caused high surface negativity of casein nanogels leading to HIPE instability. Casein nanogel dosages (0.25 to 1.5 wt.%) controlled the size of dispersed droplets due to progressive decrease in interfacial tension and offered gel-like properties to Pickering HIPEs. In vitro release profile of indomethacin in PBS (pH 7.4) was depended upon the packing density (concentration) of casein nanogels at oilwater interphase and the initial burst release varied between 5 hours and 2.7 hours. Pickering HIPEs stabilized using starch particles have shown potential suitability in food and pharmaceutical applications. However, to be a Pickering stabilizer, hydrophobic modification of starch is essential to impart appropriate amphiphilicity (Pei et al., 2016; Tan et al., 2012). In this respect, starch particles were modified with butyl glycidyl ether to produce amphiphilic thermo-responsive 2-hydroxy-3butoxypropyl starch particles (B120 nm) and used to encapsulate the β-carotene within o/w Pickering HIPEs (Wang et al., 2020). Increasing nanoparticle loadings from 0.5 to 4 wt.% decreased the droplet size distribution at Φd of 0.8 as large number of nanoparticles were present at oil-water interface. During the rheological characterization, Pickering HIPEs exhibited gel type behavior where the storage and loss modulus were tailored by nanoparticles loadings. The release rate of β-carotene from HIPEs was

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controlled by the thermo-responsive behavior of 2-hydroxy-3-butoxypropyl starch particles and it decreased with increasing temperature from 27.5 C to 37.5 C. It was proposed that increasing temperature led to an enhancement in particle size due to the coiling effect of extended threadlike chains, thus, tightening of particle packing and decreasing the β-carotene release rate.

13.4

Conclusion

High internal phase emulsion templates and HIPE templated scaffolds have immense potential in serving as controlled drug delivery vehicles due to their ease of fabrication using vast range of polymeric materials. The specific surface area, porosity, and pore architecture can be easily tuned to tailor the drug release profile of the scaffolds. Variations in pore size, interconnectedness, and porosity can easily be achieved by adjusting the material and process parameters involved in making of HIPE. Stabilizer concentrations and volume fractions of internal phase have shown to effectively tune the porosity and interconnectedness of scaffolds, which in turn controls the release profile of the drugs. Furthermore, co-monomer concentration and dispersed phase composition (e.g., addition of hydrophilic polymer) control the interfacial interactions, thus scaffolds’ morphology. Pore interconnectedness provide uniform drug loading within the scaffolds and characteristic release profile, which otherwise is difficult to achieve using conventional drug encapsulation methods. Initial burst release of drugs followed by its prolonged release is highly desirable for applications like tissue engineering where the site of implants is highly susceptible for infections in the initial few hours. Advanced methods such as 3D printing provide additional utility of HIPE templated scaffolds by inducing hierarchical porosity in the scaffolds, which can be used to alter the drug release profile from the same scaffold.

Acknowledgments Authors gratefully acknowledge the support provided by Indian Institute of Technology Delhi.

Individual authors’ contributions Anilkumar Yadav: Writing Meenal Agrawal: Writing Rajiv K. Srivastava: Conceptualization, writing, and editing.

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Compliance with ethical standards Not applicable.

Conflict of interest We have no conflicts of interest.

Research involving human participants and animals Not applicable.

Informed consent Not applicable.

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Nanotubes-based brain targeted drug delivery system: a step toward improving bioavailability and drug enhancement at the target site

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Parul Mittal1,2 and Puja Panwar Hazari1 1 Divison of Cyclotron and Radiopharmaceutical Sciences, Institute of Nuclear Medicine and Allied Sciences, Delhi, India, 2Department of Zoology, Delhi University, Delhi, India

14.1

Introduction

Brain pathologies includes brain cancer, Alzheimer’s disease (AD), traumatic brain injury (TBI), Parkinson’s disease (PD), stroke, and multiple sclerosis. These are some of the most prevalent brain disorders that have become a significant concern due to the increase in not only the elderly population but also the younger population (Teleanu et al., 2018). The brain is one of the most complex and vital organs. It performs several functions such as motor coordination, processing information, memory storage, perception, learning, etc. It requires protection against the contamination with the environmental substances and foreign moieties, which can bring a change in the inner and outer concentrations of the neuronal cells. Otherwise it can cause impairment in nerve conduction and dysfunction the body control processes. Inevitably the role of the blood-brain barrier (BBB), which acts as the brain’s first defense against circulating toxins and pathogenic agents through a selective permeable system (Alexander, 2018). The BBB is a physiological barrier that helps in the regulation of the passage of cells, ions, and molecules across the brain and blood. Neurodegenerative disorders are characterized by impairments in cognitive abilities, dementia, difficulty in understanding the language, lack of personality skills, difficulty in solving daily problems, emotional behavior, and perception. The disturbances in the neural pathways causing neurological imbalance lead to various neurological disorders, such as Alzheimer’s, Parkinson’s disorder, Huntington’s disease, and many other neurocognitive disorders. Alzheimer’s disease attributes for about 60% 70% of neurodegenerative disorders (Mittal et al., 2021). The neurological damage caused by these disorders can be associated with TBI. Any injury in the brain due to increase in intracranial pressure, reduction of cerebral blood flow, or swelling of the brain can cause TBI (Barlow, 2013). There are several underlying mechanisms associated with these neurological disorders, such as genetic, Fiber and Textile Engineering in Drug Delivery Systems. DOI: https://doi.org/10.1016/B978-0-323-96117-2.00009-1 © 2023 Elsevier Ltd. All rights reserved.

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environmental factors, mitochondrial dysfunction, changes in processes involving protein folding or functioning, accumulation of misfolded protein, abnormalities in the protein responsible for proper functioning and development of the brain, dysregulation in the immune system, and imbalance in neurological function leading to neuronal death (Satapathy et al., 2021). The prognosis and treatment of brain disorders are still challenging due to the complex structure of the central nervous system (CNS). The major obstacle for treatment of brain disorders is the blood-brain barrier, limiting the drug’s entry into it. The route of administration of drugs is also one of the significant essential factors for drug delivery to the brain. There are two routes for the delivery of therapeutic drugs to the CNS, it can be either invasive or noninvasive. The invasive pathway is based on administering the drug surgically directly into the brain. It does not cause systemic toxicity and provides a sufficient dose to the brain. In comparison, the noninvasive route is dependent on the anatomical structure of the brain capillaries, directional transfer of the fluids across the brain and extracellular environment (Agrawal et al., 2018). For efficient brain drug delivery, the size of the drug molecule should be small with high lipophilicity and partition coefficient. Smaller particles can cross BBB easily. In cancer, there is growth of abnormal cells that spread from one part of the organ or tissue to throughout the body in an uncontrolled manner. This invasive spread disturbs the physiological function of normal cells and affects human health severely (Tang et al., 2021). Malignant brain tumor accounts for approximately 1% of all cancers in the United States. Brain cancer has become the leading cause of cancer death in women aged less than 20 years and men less than 40 years old. In 2021, 83,570 people were diagnosed with brain cancer and, 18,600 people died due to this cancer. Malignant brain cancer is more common in men than women. Gliomas are a category of neuroepithelial tumors that can occur through the brain and CNS. Malignant glioma usually occurs in the supratentorial region of the brain, that is, cerebrum lobes. Gliomas have similar histologic properties to the normal glial cells of the brain (oligodendrocytes, astrocytes, and ependymal cells). Glioblastoma (GBM) is the aggressive form of brain tumor that accounts for 25% of all tumors (Miller et al., 2021). The most common symptoms of the primary brain tumor include changes in personality, cognitive changes, nausea, aphasia, hemineglect, headaches, visual field deficiency, and urinary incontinence hemiparesis. Of all the symptoms, the headache gets worse over time in people over 50 years. The main reason behind the death due to brain cancer is the reoccurrence of tumor at the same site where the primary tumor was present initially. The maximal survival of patients after brain tumors is nearly two years even after the therapy due to brain cancer metastasis throughout their body. It is very challenging to treat the metastases stage of cancer as the patient with brain cancer is already malnourished, fragile, and full of comorbidities, decreasing the chances of their survival and treatment. Treatment of brain cancer is quite challenging due to the complex structure of the brain, which hinders the delivery of anticancer drugs and drives the expansion and progression of brain cancer. Although there are so many treatment strategies

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available, such as gene therapy, radiotherapy, chemotherapy, phototherapy, and immunotherapy, due to the aggressive progression, high revival, and proliferation rate of brain tumor, it becomes very complicated to perform brain surgery. It is very challenging to perform brain surgery to remove the delicate tumor part without causing any damage to the healthy part of the brain or CNS. This is due to the histopathological variability of tumor tissue at the molecular and genetic levels. This hinders the treatment of tumor as it decrease the predictability of tumor response to any kind of treatment. Neuroimaging helps in the diagnosis of CNS-based disorders by using multimodal imaging like magnetic resonance imaging (MRI) and positron emission tomography (PET). Diagnosis of brain cancer and other CNS disorders can be made using radioimaging techniques that help locate and confirm the anatomical region of tumor (Zelenak et al., 2013). These techniques include computed tomography imaging (CT) and MRI. MRI provides the structural and functional information of the brain. Another molecular imaging technique which is used to investigate the metabolic processes involved in tumor or neurological diseases is known as PET. PET enables us to identify the site of metastasis in the brain by assessing the different metabolic processes of the human body, such as the detection of oxygen metabolism, blood flow consumption, DNA synthesis rate, receptor binding, and enzyme activity. PET imaging has better sensitivity in detection of the tumor, amyloid plaques, tau lesions, and neuroinflammation caused by the neuropathologies (Mittal et al., 2021). Systemic brain delivery is not successful in treating brain cancer due to the presence of BBB. Nanotechnology-based strategies include chemical alteration of chemotherapeutic drugs and prodrugs, local delivery of the drug into the brain by neurosurgery, temporary disruption of tight junctions across BBB, and nanoparticlemediated drug delivery system. Nanomedicine is the theranostic branch of nanotechnology that has enabled the diagnosis of brain tumors (Thorat et al., 2019). This enables the procedure of primary treatment and initiation of secondary treatments wherever necessary along with the monitoring of therapy response. This is referred to as “theranostic nanomedicine.” The advantage of nanotubes for brain cancer treatment is discussed in more detail in this chapter. Nanotechnology is very useful for targeting drug delivery across the brain. The development of nanoparticles with unique features can be helpful for the treatment of CNS-based disorders. Nanoparticles can be polymer, lipid, ceramic, metal, carbon, nanocomposites or magnetic. Carbon nanotubes (CNTs) are becoming exemplary for brain-targeted drug delivery due to their small size, large surface area, good bioavailability, low toxicity, and ability to get modified. These spatial features enable them to penetrate the BBB and efficiently deliver the drug inside the CNS. CNTs are also used as a therapeutic agent since they possess neuro-regenerative activity, this makes them very useful for the treatment of neurodisorders (Henna et al., 2020). Since carbon is hydrophobic in nature, it makes CNTs hydrophobic too, which enhances the drug delivery process as it increases drug permeability across the biological membrane. For brain targeting, crossing the BBB is the most crucial aspect.

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The physiochemical properties of carbon nanostructures can be modified, which decreases the toxicity of CNTs and increase biocompatibility. Modification of CNTs with carbon or amino groups can make them soluble in aqueous solvents and increase their biocompatibility. Apart from smaller size and biocompatibility, they are involved in neuroregeneration and neuron outgrowth. Neuroregeneration is the process of restoration and repairment of neurons destroyed in neurodegenerative disorders. Carbon nanostructures are promising tools for treating neurodegenerative disorders by repairing and regrowth of degenerated nerve cells and helps in the regeneration of new neurons (John et al., 2015). This chapter summarizes the application of CNTs in neurological disorders and brain cancer targeting the brain delivery of both in vitro and in vivo (Fig. 14.1).

14.2

Carbon nanotubes as a loaded vehicle for therapeutic delivery

Carbon nanotubes are allotropes of carbon identified in 1991 by Sumio Iijima. They are widely used for various applications such as components for

Figure 14.1 Schematic illustration of applications of carbon nanotubes in neurological diseases both in vitro and in vivo (Xiang et al., 2020). Source: Image reproduced with permission Xiang, C. et al., 2020. Biomimetic carbon nanotubes for neurological disease therapeutics as inherent medication. Acta Pharmaceutica Sinica B. Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences, 10 (2), 239 248.

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biosensors, materials for electrodes, materials reinforcement, and drug carriers in biomedicine (Simon et al., 2019). They are formed by rolled-up graphene sheets into a smooth cylinder with a nanometer diameter. CNTs have the capacity to load the exorbitant amount of drugs into their hollow tubular structure. This increases the efficiency of therapeutic molecules. The large surface area aspect allows them to show multiple degree of functionalization with biocompatible functional groups. They are also able to release the drug in a regulated manner at the specific site. These novel features of CNTs make them attractive tool for several applications in nanomedicine (Rahamathulla et al., 2021).The high penetration ability and drug loading capacity enable CNTs to deliver the drug into the neoplastic cells and do selective destruction. This prevents the distribution of drug to the neighbouring cells and further prevents in decreasing the lethality of the cells, mainly in case of cancerous cells. The main advantage of brain-targeted drug delivery is to use a small amount of drug with fewer side effects to reach the target at a specific site. Specific-site targeted drug delivery enhances drug effectiveness and decreases the chances of toxicity and nonspecific effects (Hilder and Hill, 2009). Advantages of CNTs CNTs have excellent thermal stability, large surface area, and small size. They are nonbiodegradable, biocompatible, and nonimmunogenic. They are rich in electronic properties and have high mechanical strength. They are light in weight and chemically stable. They exhibit minimum cytotoxicity. CNTs are open end on both sides, which makes their inner surface accessible and helps incorporation of species within nanotubes subsequently. 7. They have a higher inner volume relative to the diameter of nanotubes for better entrapment of the molecule. 8. They are capable of being modified for chemical and biochemical functionalization (Pandey and Dahiya, 2016). 1. 2. 3. 4. 5. 6.

There is a variety of structures in nanotubes; short, long, single-walled CNTs (SWCNTs), double-walled CNTs (DWCNTs), multi-walled CNTs (MWCNTs), open, closed, or even in spiral shape. The diameter of CNTs for SWCNTs can range from 0.4 to 2 nm, whereas it ranges from 2 to 100 nm for MWCNTs. Single-walled CNTs are made up of a single layer of graphite sheet rolled up in the shape of a cylinder held by vander wall force making them more flexible and twistable. Whereas multi walled CNTs are made by arranging single-walled CNTs in concentric cylinders, which gives them the shape of a tree trunk (Jain et al., 2021). SWCNTs are able to penetrate the cell membrane more efficiently with high cargo capacity and prolonged circulation of the drug. This makes them more suitable for chemotherapy and cancer diagnosis as they have become the suitable carrier for delivering the drug to the tumor cells. SWCNTs are difficult in synthesis as compared to multi-walled CNTs. SWCNTs are potential nanocarriers for the effective drug delivery and beneficial for bone cell growth, cancer therapy, neuropathologies, and imaging (Lacerda et al., 2006; Redondo-g et al., 2020).

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Neurological disorder and requisite for drug delivery across the blood-brain-barrier

Delivery of therapeutic drugs is restricted due to BBB. Due to this, the treatment of several neuropathologies and brain cancer becomes challenging. BBB separates the extracellular fluid of the brain from the bloodstream. Nanoparticle-based brain targeting approaches are used to transport molecules greater than 100 nm in size that are not able to cross BBB. To improve brain delivery, nanomaterials are conjugated with targeting moieties to support the receptor mediated transcytosis of drug across the BBB. Nanomaterials such as CNTs can be conjugated with biological moieties and can cross BBB via receptor-mediated pathway by diffusion.

14.3.1 Blood-brain-barrier It is a semipermeable membrane that allows nutrient uptake by the brain and keeps out toxic substances. The BBB membrane is composed of various cells, such as endothelial cells, astroglia, pericytes, and perivascular mast cells. It is responsible for rigorous control of molecules and ion exchange between two compartments and attains homeostasis in the brain (Lipsman et al., 2018). The prophylactic barrier also possesses carrier function through passive diffusion or transport-mediated crossing. The endothelial cell forms the capillary wall restricting the passage of substance from blood, astrocytes end-feet ensheathing the capillary and providing the biochemical support to cell, and pericytes embedding in the capillary basement membrane (Brasnjevic et al., 2009). BBB separates blood in the brain capillaries from the brain parenchyma. Tight junctions are created by the endothelial cells in the brain and due to the absence of fenestration cause trans-cellular transport through two membranes via passive diffusion or transporter-mediated passage. So the molecular weight and degree of ionization become imperative for crossing BBB. Due to the high trans-endothelial resistance in the brain endothelium, the passage of the small ions into the brain is very poor (Tajes et al., 2014). Pericytes are present around the astrocytes, and endothelial cells are around the brain microvessels. Pericytes provide structural support to the capillaries. They play an essential role in the formation, maturation, and regulation of BBB structure. The combined action of astroglial cells, endothelial, and pericyte cells helps in the regulation of vasculature property (Alexander, 2018). Shityakov et al. (2015) has shown in vitro penetration of functionalized MWCNTs with fluorescein isothiocyanate (FITC) into the microvascular cerebral endothelial cells by crossing BBB. MWCNT-FITC did not show any changes in tight junction proteins or endothelial electric resistance and no cytotoxicity during the treatment of the in vitro BBB model. This suggested the biocompatibility property of CNTs and, thus they can be used as nanocarriers for delivering drugs to the CNS (Cao and Luo, 2019). Fig. 14.2 depicts the ability of CNTs to cross the BBB and deliver the drug to the CNS.

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Figure 14.2 Functionalized carbon nanotubes can effectively cross the blood-brain barrier and enter the central nervous system for bioimaging and drug delivery. Source: Figure reproduced with permission Cao, Y., Luo, Y., 2019. Pharmacological and toxicological aspects of carbon nanotubes (CNTs) to vascular system: a review. Toxicology and Applied Pharmacology 385 (October), 114801.

14.3.2 Role of carbon nanotubes in neurological disorders The neuron is the basic unit of the brain system comprised of a cell body, axons, and dendrites. Transmission of signals occurs between neuron cells and effector cells through the bundle of axons made up from the collection of neurons and known as nerves. The frontal part of a neuron, the dendrite, is responsible for carrying the signal from the tip to the cell body of the same neuron, which is further transmitted by the axon toward the terminal end of the axon to effector cells. Any damage to these neurons results in an interruption in the transmission of signals between the effector cells and brain, affecting the functioning of the nervous system. Any alteration or abnormality in the nervous system function results in neurological disorders. The most common neurological disorders include AD and PD. Every year, over 90,000 people are affected by neuropathologies. The typical hallmark of these neuropathologies includes an aggregation of the protein. The aggregation of misfolded protein in the brain results into mitochondrial dysfunction, excitotoxicity, production of reactive oxygen species (ROS), and dyshomeostasis of metals, such as iron.

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With an increment in oxidative stress, there is a spike in the expression of inflammatory cytokines promoting neuroinflammation, which further leads to cell death (John et al., 2015). The therapeutic approaches using small molecules, peptides, and monoclonal antibodies have gained little success in these neuropathologies. There is a functional soluble protein/peptide conversion into a highly organized fibrillar state in these neuropathologies. Nanomaterials with multifunctional approaches has shown the ability to decrease the oxidative stress and overcome the barrier across BBB. Nanotubes can improvise the targeted delivery of drugs across the BBB and thus enhance the efficacy of delivered drugs in the brain. Nanotubes target nucleation kinetics and control the formation of amyloid or sync proteins. CNTs can accelerate the fibrillation process of β2 microglobulin by decreasing the lag phase for fibrillar nucleation. SWNTs and MWNTs have been shown to inhibit the aggregation of αS protein and amyloid protein formation strongly. This suggests that CNTs can be considered potential inhibitors for αS protein aggregation in PD models and amyloid protein in AD models (Agrawal et al., 2021).

14.3.3 Role of carbon nanotubes in Alzheimer’s disease Alzheimer’s disease is a chronic neurocognitive disorder characterized by accumulation of extracellular amyloid protein, intracellular neurofibrillary tangles, and neuroinflammation. In AD, there is loss of neurons and synapses in the cerebral cortex and subcortical areas, leading to degeneration of certain areas such as the temporal lobe, parts of the frontal cortex, parietal lobe, and cingulated gyrus. There is hyperphosphorylation of tau protein responsible for formation of microtubule protein and accumulation of misfolded amyloid protein, which forms amyloid plaques inside the brain. These plaques affect neuron growth and lead to neuron degeneration and affects the functions of brain (Lipsman et al., 2018). Alzheimer’s disease is the prevailing form of dementia occurring in the elderly people. The early symptoms of this disease include loss of memory, inability to focus or concentrate, anxiety, mood swings, behavioral issues, and withdrawal from society and family. Alzheimer’s disease is caused by an amalgamation of genetic, lifestyle, and environmental factors. In the early onset, AD stems from mutations in three different genes: APP, the presenilin1 (PSEN1) and presenilin 2 (PSEN2) genes. Diagnosis of AD is based on a cognitive test, which failed in detecting early onset of AD. Radioimaging modalities like PET scans or MRI can detect the structural changes of brain at the advanced stage of the disease. Several Aβ-targeting compounds such as stilbenes, thioflavin T derivative (Pittsburgh compound B, PiB), and benzothiazoles have been identified as PET imaging agents for the diagnosis of AD. These compounds have good penetration ability across BBB and high in vivo binding affinity toward Aβ. However, their clinical use is limited due to the short half-life of the radioisotope as a molecular probe for AD diagnosis. To improvise the brain delivery, the nonpermeable compounds are conjugated to the nanostructures which are capable of translocating the drugs across the BBB. For this purpose, functionalized CNTs (f-CNTs) are used to conjugate the molecules with them. PiB derivatives Gd3 1 complexes-Gd (L2) and

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Gd (L3) were noncovalently conjugated to MWCNTs and characterized by thermogravimetric analysis (TGA), inductively coupled plasma mass spectrometry (ICPMs), fluorimetry, and Kaiser test. In vivo biodistribution and brain uptake studies by SPECT showed that these conjugates could cross the BBB with a significant accumulation of the conjugates inside the brain. Thus, f-MWNTs act as potential carriers in theranostic applications for the delivery of PiB compounds in the brain and helps in the initial diagnosis of AD (Costa et al., 2018) (Fig. 14.3). An anti-Alzheimer’s drug berberine, an isoquinoline alkaloid, is conjugated on the surface of MWCNTs. It was further modified with polymer, polysorbate, and biological moiety, such as phospholipids, to increase the bioavailability of the drug. The toxicity of the conjugate molecule was assessed on SHSY-5Y (human neuroblastoma cell line). No significant toxicity was observed. The nanoformulation was further administered to rats, and memory recovery was observed after the 18th to 20th day of administration. This showed the successful drug delivery of loaded phospholipid/polysorbate with functionalized MWCNTs for the treatment of Alzheimer’s disease by reducing amyloid beta-protein aggregation at the target site (Agrawal et al., 2021).

Figure 14.3 Nanomaterials-mediated drug delivery in the treatment of a patient who has Alzheimer’s disease. Source: Image reproduced with permission Faiyaz, M. et al., 2021. Nanomaterials in Alzheimer’s disease treatment: a comprehensive review. Frontiers in Bioscience - Landmark, 26 (10), 851 865.

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In AD, the levels of acetylcholinesterase enzyme increase, which is responsible for the breakdown of neurotransmitter acetylcholine (ACh) into acetyl-CoA and choline. This depreciates the levels of acetylcholine in the brain, which deteriorates the cholinergic neurotransmission inside the brain and leads to impairment of neurons. To improvise the neurotransmission in the brain, acetylcholine can be directly delivered into the brain along with SWCNTs having diameters of 0.8 to 1.6 nm and variant lengths of 5 300 nm. Due to the poor lipophilicity of ACh, it cannot be delivered alone into the brain. So, it is conjugated with SWCNT as a nanocarrier to increase the effectiveness and biosafety of the ACh drug in the brain. This helps in the improvement of memory function and other cognitive functions of the brain (Al Garalleh, 2018; Faiyaz et al., 2021).

14.3.4 Role of carbon nanotubes in Parkinson’s disease Parkinson’s disease is the degenerative pathology of the brain and the second most widespread neurodegenerative disorder affecting the population. It affects one in every 100 adults above the age of 65. In Parkinson’s disease, there is an agglomeration of misfolded α-synuclein (α-syn) protein in inclusions called Lewy bodies (LB) in dopaminergic neurons, which results in the dysfunctioning motor coordination. Misfolded aggregation of α-syn localizes in the mitochondria and causes fragmentation of mitochondria and decreases the membrane potential of it (Li et al., 2021). PD occurs by the death of dopamine-generating cells in the midbrain, primarily in the substania nigra region of brain. This decreases the levels of dopamine in the brain, which is a catecholamine neurotransmitter and leads to severe difficulties, such as instability of posture, rigidity, slow body movements (bradykinesia), and tremor. There are several Anti-Parkinson’s drug available commercially, but out of all, (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoic acid (levodopa) has been proven to be the most effective drugs for the treatment of PD for symptomatic relief. Levodopa (LD) is the amino acid precursor of dopamine which is decreased in Parkinson’s disease, so when levodopa is administered orally into the system, it is able to cross the BBB. However, the problem is that minimal amount of the drug reaches the CNS, which is not sufficient for neurotransmission. Since levodopa’s elimination half-life is very small, that is, 50 minutes without carbidopa, therefore an inhibitor of dopamine decarboxylase, also known as carbidopa, is also given with LD to enhance the effectiveness of levodopa and to prevent the rapid metabolization of levodopa. Therefore, to achieve maximal drug efficiency, levodopa is conjugated with nanomaterial that can increase the bioavailability of LD into the brain (Tan et al., 2018).

14.3.5 Role of functionalized carbon nanotubes in drug delivery in Parkinson’s disease In Parkinson’s disease, to improve the bioavailability of the drug in the CNS, functionalized CNTs (f-CNT) have been chosen as a therapeutic carrier due to good

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penetration ability. Delivery of LD is achieved using a carboxylated single-walled carbon nanotube (SWCNT COOH) (Tan et al., 2018). A nanohybrid SWCNT COOH LD was made by π π stacking interaction between LD and SWCNT COOH. SWCNT COOH-LD formation was further characterized by various techniques like Raman spectroscopy, TEM, FTIR spectroscopy, elemental analysis, and field emission scanning electron microscopy (FESEM). The toxicity of nanohybrid was assayed by MTT in vitro on Parkinson’s cell line model PC12 cells, and the cells were found viable. This shows SWCNT COOH LD can act as a therapeutic drug for treating CNS disorders, PD. Further, to prevent the dispersity and cytotoxicity of this nanohybrid drug, it was incorporated into four different biopolymers. The biopolymers used were tween 80, tween 20, polyethylene glycol (PEG), and chitosan. The coating of biopolymers to SWCNTs increases the stability of their hydrophobic surfaces and improves drug delivery in an effective and controlled manner to the target site. The nonionic surfactants like tween 20 and tween 80 prevent the nonspecific surface adsorption of the drug and act as stabilizers to prevent the aggregation of the protein. To study the drug release pattern, pH plays a crucial role in nanoparticles. Different pH effects were observed in levodopa kinetics at pH 7.4 and pH 4.8 (Tan et al., 2015). The two different pHs were chosen based on the human body’s physiological environment, which is at pH 7.4, whereas pH 4.8 represents the pH of the human stomach. Burst release is a process in which there is an immediate release of large amount of drug in the media before maintaining any stable condition in the environment (Huang and Brazel, 2001). To prevent the burst release of LD, it is coated with an effective system such as a biocompatible polymer or tween 20 surfactants so as the drug does not release immediately and there will be a prolonged effect of the drug in the target site. There was observed slow and sustained release of the LD from the conjugates at pH 7.4, whereas a faster but lower amount of LD was released at pH 4.8. This can be due to the alteration of the COOH group (hydrophilic) to hydrophobic at the acidic environment, leading to aggregation of the complex and hindering the release of levodopa from SWCNT COOH LD. This also shows the release of the drug is pH-dependent. Thus, several factors are essential for an ideal nanocarrier to achieve an optimal therapeutic effect, such as absorption of the drug, administration, pH dependency, and route of administration (Tan et al., 2018).

14.4

Plausible drug delivery strategies by carbon nanotubes in brain cancer therapy

For brain cancer treatment, several therapies are available, such as chemotherapy, surgery, radiotherapy, immunotherapy, thermotherapy, etc., still these therapies are less effective as they are not able to cross blood-brain barrier efficiently. The treatment of brain cancer becomes difficult due to the complex structure of brain. There is expansion and progression of brain cancer due to the molecular changes in cancerous cells. The use of novel anticancer therapy drugs is scary due to the poor solubility of drug,

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lack of selectivity, poor distribution, and the incompetence of drugs to cross cellular barriers. These drugs are not able to overcome multi-drug resistance. For the past few years, CNTs-based drug delivery system has gained success in the treatment of brain cancer by the transportation of drugs inside the brain due to their ability to penetrate the BBB. Using a receptor targeting mechanism, the receptor such as low-density lipoprotein receptor-related protein, overexpressed in brain tumor are targeted (Meher et al., 2018). The anti-cancerous drugs are conjugated to the walls and tips of CNTs. Specific binding of the ligand with the CNTs on their surface recognizes cancerspecific receptors on the cell surface and helps deliver therapeutics selectively and effectively at the tumor site (Ji et al., 2010). In a report by Liu et al., an anticancer drug, doxorubicin (DOX) has been loaded on the surface of PEG conjugated with SWCNT. The drug release is pH-dependent at the tumor site, pH is acidic, and DOX is released in an acidic environment quickly, whereas DOX does not release from CNTs in neutral and alkaline pH and thus does not cause any toxicity to the healthy parts of the body. This is due to the permeability and retention effect of CNTs. Another drug, 5-fluorouracil has been conjugated to the ligand folic acid and delivered using PEG-SWCNTs in human breast cancer cells MCF-7. Conjugation of a drug with PEG increases its solubility, enhances the biocompatibility of the drug delivery system, and elongates the circulation time of the drug into the blood (Simon et al., 2019). The biocompatibility of MWCNTs was investigated on human neuroblastoma cells SH-SY5Y by Vittorio et al. There was no intracellular ROS production with prolonged incubation of MWCNTs in the culture the cells were viable. Functionalized SWCNTs having phospholipid-bearing PEG were conjugated with protein A and then they were further coupled with the monoclonal antibody, that is, fluorescein-labeled integrin αvβ3. This leads to the formation of SWCNT-integrin αvβ3 monoclonal antibody (SWCNTPEG-mAb). Integrin ανβ3 is a common form of integrin, which is upregulated on many cancerous cells and endows a lot to tumor progression. SWCNT PEG-mAb displayed high fluorescence signal on integrin αvβ3-positive U87MG cells, whereas no fluorescence signal was observed on integrin αvβ3-negative MCF-7 cell. This showed the specific binding of the drug with integrin αvβ3-positive U87MG cells due to specific recognition of the drug with the receptor present on the cellular membrane. Thus, CNTs exhibit high target efficiency in drug delivery systems along with low cellular toxicity (Ou et al., 2009). To study the in vitro drug delivery system of CNTs, functionalized PEGCNTs conjugated with an adjuvant CpG oligodeoxynucleotide were fluorescently labeled with Cyo5.5. They were injected into an intracranial GL261 glioma intratumorally to see the anti-glioma effect. PEG-CNTs enhanced the uptake of CpG in glioma cells and, the tumor growth was inhibited (Guo et al., 2017). Ren et al. developed PEGylated MWCNTs as a dual-targeting ligand. They loaded them with the drug DOX and a ligand angiopep2 (ANG) to target LDL receptor-related protein receptor, which is overexpressed on C6 cells, glioma male Balb/c mice, and BBB. The dual targeting system was assessed using in vivo fluorescence imaging and an intracellular tracking process. This dual targeting system is a good choice for the delivery of anti-cancer drugs at the specific site (Ren et al., 2012).

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Another approach involves integrated molecular targets, such as an antibody, which can be conjugated with CNTs for anti-tumor therapy. Wang et al. combined SWNTs with anti-CD133-conjugated chitosan to form anti-CD133-CS/SWNTs. This conjugate was used for the treatment of GBM. This nanosystem showed excellent targeting ability of CNTs-ab conjugate to GBM-CD133 1 cells, which is required to eliminate cancer cells upon NIR irradiation without causing any damage to the surrounding cells. Peptides can be conjugated with CNTs to boost the active targeting of drugs in the CNS. RGD peptide is conjugated with functionalized SWCNT and encapsulated with topoisomerase I inhibitor camptothecin (CPT) to form (CPT@f-CNT-RGD) for the treatment of malignant melanoma (Tang et al., 2021).

14.5

Repair and regeneration of neurons by carbon nanotubes

The human nervous system comprises the CNS and the peripheral nervous system (PNS). The two of them encompass neurons and neuroglia. Neurons are the nerve cells inside the brain which are responsible for transmitting information from the signals throughout the nervous system, whereas neuroglia aid the function of neurons. PNS consists of Schwann cells, brain nerves, spinal nerves, and ganglia. These different cells interact with other cells to transmit sensory messages to and from the spinal cord. Regeneration of neurons axon occurs by the proliferation of Schwann cells and macrophages, which remove the debris from the site of injury. Schwann cells guide the newly formed axon to stimulate. PNS is self capable of repair and regenerating on its own, whereas CNS lacks the ability to self-repair and regenerate (Seil and Webster, 2010). The treatment available for the damage of CNS does not promise full regain and restoration of the tissue and functioning of motor coordination. To repair the CNS, regrowth of injured axons, the regeneration of new nerve cells and the plastic remodeling of the neuronal circuit is required. The regrowth of an axon requires proper axonal spatial organization and reconstruction of functional synapses, which further requires an unfavorable and inhibitory environment. A successful stem cell transplantation needs survival of the cell and appropriate differentiation of a stem cell toward neuronal lineage.

14.5.1 Nanomaterials act as scaffolds for neuroreconstruction The key to functional impairment of neurons is “neurological implants,” which increase the chances of survival of necrotic neurons, growth of axons, and transmission of synaptic neurons. Biomaterials such as polyglycolic acid (PGA), polylactic acid (PLA), and polyhydroxybutyrate (PHB) have been used as synthetic polymers for the growth of nerve cell and axon organization. They are biodegradableabsorbable materials except for PHB, which is nonabsorbable, and act as artificial nerve conduits for the regeneration of nerve cells. Although these polymers are

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FDA-approved yet they lack mechanical strength and are not suitable for any chemical modification (Biazar et al., 2010). Another biomaterial based on collagen that FDA has approved is NeuraGen. The patient using this implant could tolerate splinting and exercise without any repercussions. Also, people with this implant have less postoperative pain as compared to those having direct suture repair (MacDonald et al., 2008). NeuraGen has been proved to be an effective nerve implant, but lacks mechanical stability. Therefore, these polymers have been conjugated with CNTs to improve their mechanical strength, which can improve their electrical conductivity and show better viability of neuronal cells (Oprych et al., 2016). Nowadays, neuroregeneration-supporting scaffolds have been developed, which help promote the cellular organization toward a functional neuronal lineage. Over the past decades, nanotechnology and neuroscience have gained impressive growth together for the strategies to regenerate neuronal cells and tissues using scaffolds based on nanomaterial. Neuroregeneration involves the regrowth/restoration or repairment of the degenerated neurons forming the new axons, glia, myelin sheath, synapses, and new neurons. So, for neuroregeneration, an ideal scaffold is required to meet several requirements, such as it should favor neuronal differentiation, exhibit electrical activity like neurons, biodegradable, and bioactive for growth factor delivery. It should be nonimmunogenic, biocompatible, support the plastic rearrangements of neuronal networks, and endogenous extracellular matrix deposition. The discovery of carbon-based nanomaterials such as graphene, fullerenes, and CNTs has significant applications in nerve cell regeneration. This is due to the ability of nanomaterial to interact with neuronal membranes and favor neuronal adhesion in the CNS. The nanomaterials are able to recreate the micro-environment like an extracellular matrix and control cell adhesion, which is a crucial step for the interaction between neuronal membrane and nanostructure (Fabbro et al., 2013b). CNTs exhibit morphological similarities to the neurons. The dimensions of small CNT bundles are similar to the dendrites dimensions, which are branched extensions of nerve cells. The morphology similarity of CNTs with the neurons increases the possibility of repairing and stimulating the neural network and helps gain insight into the mechanism of neuron functions. The electrical conductivity property of CNTs enables them to control the interaction with neurons by changing in ionic conductance and transmission of synapses (Cellot et al., 2009).

14.5.2 Improving neurocompatability of carbon nanotubes by surface functionalization One limitation for CNTs is their low solubility in both the aqueous and organic solvents, which leads to their aggregation in the medium. Poor dispersity and aggregation make them more cytotoxic for the body. Thus, surface functionalization is important to make them less toxic. To overcome these limitations, the surface of CNTs has been functionalized to modify the chemical structure of CNTs to make them soluble and disperse in the solvents. The modification can be achieved by

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covalent bonding or noncovalent. These modifications increase their solubility, structural alterations, drug loading capacity, and decrease the degradation capacity and cytotoxicity. The addition of functional groups, such as carboxyl or amino, to CNTs by chemical bond refers to covalent functionalization of CNTs. This can be achieved by oxidation under strong acidic conditions (conc. H2SO4 or conc. HNO3), which results in the production of the carboxylic acid group (COOH) or alcoholic group (OH) on the CNTs. Sometimes, the carboxylic group can make the CNTs toxic, in that case they are further modified by their conjugation to amine or alcohol group by esterification, amidation to obtain ester or amide linkage, respectively. This chemical bonding makes stable and robust chemical bonds into the sp2 hybridizes carbon framework of CNTs. Oxidation of CNTs opens the end caps of CNTs and produces exposed functional groups, enhancing their solubility and biocompatibility. Covalent bonding of CNTs with PEG enhances the size, hydrophilicity, and solubility in the aqueous phase, increasing the circulation period of CNTs into plasma and decreasing the rate of its clearance from kidney (Rastogi et al., 2014). The noncovalent modification includes physical adsorption of amphiphilic surfactant molecules on the surface of CNTs by π π stacking, electrostatic interaction, or Van der Waals interaction (Fig. 14.4). Noncovalent modification has an advantage over covalent modification as it preserves the intrinsic properties of CNTs and makes the functionalization procedure simpler. It also preserves the aromatic structure of carbon and thus electronic properties of CNTs compared to pristine CNTs. Specific biocompatible polymers, such as tween 20, tween 80, chitosan, PEG, pluronic F-127, and proteins (like bovine serum albumin) are used to maintain the stability of CNTs after noncovalent modification (Costa et al., 2016). In

Figure 14.4 Schematic diagram depicting different types of surface functionalization of carbon nanotubes.

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noncovalent modification, the use of poly-L-ornithine (PLO) and polyethyleneimine (PEI) polymers has shown remarkable neuron attachment and neuron outgrown subsequently (Hwang et al., 2013). The use of polycations (having a positive charge) with the CNTs also promotes neuron growth as they can enhance the electrostatic interaction between the plasma membrane of neuronal cells possessing negative charge and CNTs (Sucapane et al., 2009).

14.5.3 Applications of carbon nanotubes for neural cell function There are two ways by which biofunctionalized CNTs can control the function of neurons; first, by the addition of soluble CNTs directly into the cell culture media of neurons (Fig. 14.5). This allows the direct interaction of the carbon structure of CNT to interact with the neuron culture, and it allows them to expand/disperse within the cells. The alternate strategy involves the modification of CNTs for the attachment of substrate/scaffolds. This enhances the neurofunctionality of CNTs as a part of an implantable device, multi-composite scaffolds, and activity of the component attached, such as proteins (neurotrophic factors, ECM components), nucleic acids, and therapeutic drugs (small molecules). The affinity of the neurons connected with the CNTs can be changed by the charge, polarity, roughness or physiochemical properties of CNT scaffolds. The large surface area ratio of CNTs exhibits less interfacial impedance and shows stronger charge injection capacity due to electrochemical coupling via electron transfer between neurons and CNTs (Kam et al., 2009).

Figure 14.5 Figure depicting regeneration of neuron from the interaction of neuronal cells with the carbon nanotubes.

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CNTs as a scaffold is a storage house of several proteins and enhance the electrical activity of neuronal cells. The discontinuous and tight coupling of SWCNT/ MWCNT with the neuronal membrane favor the direct electrical coupling required for neuronal transmission. Fabbro et al. studied the culture of hippocampal neurons on MWCNTs and demonstrated the increased expression of a membrane protein “paxillin.” Paxillin is involved in intracellular signaling pathways and forms focal adhesions between the cells. This showed the translation of elctrophysiochemical properties of CNTs into the specific neuronal signals (Fabbro et al., 2013a,b). CNTs boost the synaptic activity of hippocampal neurons along with the formation of primary neurons network. A report showed the preparation of optically transparent MWCNTs growing on fused silica substrates. These CNTs have supported the growth of intact hippocampal organotypic cultures. The overall anatomical and functional neuronal connections were preserved. This showed another property of CNT-based material, which can initiate the sprouting of functionally active fibers crossing the damaged areas inside the brain (Pampaloni et al., 2020). In 3D printing technology, CNTs can be added to make the scaffolds supportive for the growth and differentiation of nerve cells (Fig. 14.6). One such example has been shown in which aminated MWCNTs have been integrated in a polyethylene glycol diacrylate matrix (PEGDA) scaffold. The different concentrations of aminated MWCNTs have been evaluated for good growth of nerve cells. The higher concentrations of positive charge in aminated MWCNTs-PEGDA scaffolds have shown better neuronal growth and development (Lee et al., 2018; Carneiro et al., 2019).

Figure 14.6 Application of carbon nanotubes in 3D printing technology for the growth and differentiation of nerve cells (Redondo-g et al., 2020). Source: Image reproduced with permission Redondo-g et al., 2020. Recent advances in carbon nanotubes for nervous. 2020.

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Neurotoxicity and biocompatibility of carbon nanotubes

The physicochemical properties of CNTs such as length, size, structure, number of walls, type of functional group attached, surface interaction groups, and purity determine the level of cellular toxicity. The toxicity can be assessed via measuring cell viability, production of ROS, and inflammation of the cells. The different pathways used for the entry of CNTs into the organism include inhalation, ingestion, and injection. The bloodstream transports the drugs for cancer or brain pathologies to the liver, lungs, heart, kidneys, brain, and other organs. The metabolism of most of the drugs occurs in the liver, so the toxicity of CNTs should not be underestimated in the liver. Accumulation of CNTs leads to macrophage damage, swelling of the cell, necrosis, blood coagulation, and causes nonspecific inflammation. Ji et al. have reported the hepatotoxicity of MWCNT in mice. There was an increase in liver weight, rupture and atrophy of hepatocyte cells, and nuclear cohesion on exposure to functional MWCNT in mice. This displayed the hepatotoxicity and oxidative stress caused by the functional MWCNTs (Ji et al., 2009). The factors responsible for the toxicity of CNTs include metal impurities and dimensions of CNTs. During the synthesis of CNTs, a catalyst such as cobalt (Co), nickel (Ni), molybdenum (Mo), and iron (Fe) is used, which gets trapped at the surface of amorphous carbon within the nanotubes. These trapped metal ions in the CNTs can cause ROS production resulting in oxidative stress (Pulskamp et al., 2007). It further reduces the viability of the cells. Several processes can remove these impurities like, annealing at high temperature, steam purification, and acidic treatment by reflux action (Huang et al., 2003). CNTs free of these metal impurities are safe to use and do not cause any inflammation to the human body. The length and diameter of the CNTs have shown an effect on their toxicity. CNTs with a length of 10 20 μm showed long-term bioretention and asbestos behavior (heat resistant) in the peritoneal mesothelium. Macrophages cannot engulf such long CNTs and form granuloma by frustrated phagocytosis. SWCNTs show less toxicity as compared to MWCNTs. MWCNTs with a thick diameter (B150 nm) or tangled diameter (B2 20 nm) are less immunogenic, toxic, and carcinogenic as compared to thin diameter of MWCNTs (B50 nm) (Yuan et al., 2019). To overcome this, short length and control of the diameter of CNTs can reduce the harmful effects on human health for drug delivery (Nagai et al., 2011). Incomplete bonding effects, sp3 hybridized carbon atom, topological effects, and doping with elements other than carbon can obstruct the surface of CNTs. These obstructions can cause pulmonary toxicity.

14.7

Cellular fate of carbon nanotubes

Carbon nanotubes penetrate into the cell by various mechanisms, such as endocytosis, pinocytosis, phagocytosis, and membrane adsorption (Fig. 14.7). The cellular

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fate of CNTs also depends on their physiochemical properties like functionalization, surface chemistry, metal impurities, and the processes, such as biodistribution and degradation kinetics. Clathrin or caveolae-dependent pathway clears the molecules less than 200 nm in size, whereas molecules of more than 500 nm are internalized by nonphagocytosis. CNTs in size 300 400 nm are passed through cytoplasmic translocation. An energy-dependent process of internalization of molecules from the environment is called endocytosis. Endocytosis is classified into pinocytosis, phagocytosis, and receptor-mediated endocytosis. In receptor-mediated endocytosis, CNTs enter cells by early endosomal vesicles and the ligands bind to the specific receptors present on the membrane. Once they are internalized, the ligands get separated from the receptor due to a change in pH and the receptors go for recycling and are reused again. In a nonreceptor-mediated pathway, nanotubes diffuse across

Figure 14.7 Different pathways of carbon nanotubes (CNTs) internalization into the cell. (A) Penetration of CNTs into the cell through nonreceptor-mediated endocytosis: (1) formation of endosomes having drug-containing CNTs, (2) CNTs with drug internalized, and (3) drug releases from the endosomes. (B) Entry of CNTs through receptor-mediated endocytosis: (4) CNTs bind with the ligand binds to the receptor and forms endosomes, (5) drug release from the receptor inside the endosomes (6, 7, 8) after drug release, the receptor get dissociated and moves for next cycle after regeneration. (C) Third pathway for entry is independent of endocytosis: (9) Drug-loaded CNTS penetrates directly into the membrane and (10) then there is a release of the drug directly from the CNTs (Rastogi et al., 2014). Source: Image reproduced with permission Rastogi, V. et al., 2014. Carbon nanotubes: an emerging drug carrier for targeting cancer cells. Journal of Drug Delivery 2014, 1 23.

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the cell membrane via nanopenetration in an energy-independent manner also known as passive diffusion. In another pathway, CNTs bind to the cell surface receptor and forms clathrin-coated pits on the membrane of the cell. Then they enter into the cell as a complex of “receptor and ligand.” CNTs bind to the specific cellular receptors in phagocytosis and form large endocytic vesicles known as phagosomes. The phagosomes fuse with lysosomes, leading to the formation of phagolysosomes and releasing the drug from CNT (Prajapati et al., 2020). In the human body, CNTs are identified as foreign entities and are not easily taken up by the body. They can be taken by the reticuloendothelial system (RES), which flushes them out of the body. If they are not recognized by RES, they are flushed through the renal, lymphatic, and billiary systems. When the CNTs are not recognized by RES, macrophages and neutrophils engulf them and degrade them by oxidative stress. For human use, the primary concern is the toxicity of CNTs. To avoid the toxicity and side effects of the nanomaterial, it should be biodegradable. According to the reports of Rongtao Hu, in the presence of certain enzymes such as horseradish peroxidase (HRP) and hydrogen peroxidase, carboxylated SWCNTs undergo enzymatic degradation and thus are biodegradable inside the body (Hu et al., 2019). Zhao et al.(Zhao et al., 2011) demonstrated the enzymatic degradation studies of MWCNTS by incubation of MWCNTs with HRP. The biodegradation was confirmed by dynamic light scattering (DLS) and the morphological changes during biodegradation were shown by TEM images. Nunes et al. evaluated the in vivo degradation of functionalized CNTs after the administration of CNTs into the cortex region of the brain. TEM and Raman spectroscopy showed the structural interaction of neurons with the CNTs (Meneghetti and Bianco, no date).

14.8

Conclusion

Carbon-based nanomaterials are promising nanocarriers for the delivery of anticancer drugs for cancer therapy and drugs for neuropathologies. The unique properties of CNTs make remarkable progress in improving the drug delivery system. The toxicity of CNTs is of less concern due to their biocompatible nature, which can be modified by controlling various parameters of CNTs. Conjugation of CNTs with functional groups can make them biocompatible, which can be used as an efficient biocompatible contrast agent for imaging or biosensors. This can increase the lifetime of the drug within the body and allow the drug enhancement at the target site. Several ex vivo models based on different cell lines were used to study the toxicity of carbon tubes at the targeted site. All of them showed no toxicity and validated the use of CNTs for therapeutic drug delivery systems. The compilation of this literature gives us useful information for the multiple applications of CNTs in biomedical use, which can be further explored in future.

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Acknowledgements The authors thank Director INMAS Dr. Anil Kumar Mishra for his continuous support.

Individual authors’ contributions PM performed an article search and then selected and drafted the manuscript. PPH conceptualized and reviewed the final version of the text.

Compliance with ethical standards Not applicable.

Conflict of interest The authors declare that they have no conflict of interest.

Research involving human participants and animals The manuscript does not involve any study on animals or humans.

Informed consent The manuscript has been reviewed by the authors and approved for submission by the authors.

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Huang, X., Brazel, C.S., 2001. On the importance and mechanisms of burst release in matrixcontrolled drug delivery systems. Journal of Controlled Release 73 (2 3), 121 136. Available from: https://doi.org/10.1016/S0168-3659(01)00248-6. Hwang, J.Y., et al., 2013. Biofunctionalized carbon nanotubes in neural regeneration: a minireview. Nanoscale 5 (2), 487 497. Available from: https://doi.org/10.1039/c2nr31581e. Jain, N., Gupta, E., Kanu, N.J., 2021. Plethora of carbon nanotubes applications in various fields a state-of-the-art-review. Smart Science 00 (00), 1 24. Available from: https:// doi.org/10.1080/23080477.2021.1940752. Taylor & Francis. Ji, S.rong, et al., 2010. Carbon nanotubes in cancer diagnosis and therapy. Biochimica et Biophysica Acta - Reviews on Cancer 1806 (1), 29 35. Available from: https://doi.org/ 10.1016/j.bbcan.2010.02.004. Elsevier B.V. Ji, Z., et al., 2009. The hepatotoxicity of multi-walled carbon nanotubes in mice. Nanotechnology 20 (44). Available from: https://doi.org/10.1088/0957-4484/20/44/445101. John, A.A., et al., 2015. Carbon nanotubes and graphene as emerging candidates in neuroregeneration and neurodrug delivery. International Journal of Nanomedicine 10, 4267 4277. Available from: https://doi.org/10.2147/IJN.S83777. Kam, N.W.S., Jan, E., Kotov, N.A., 2009. Electrical stimulation of neural stem cells mediated by humanized carbon nanotube composite made with extracellular matrix protein. Nano Letters 9 (1), 273 278. Available from: https://doi.org/10.1021/nl802859a. Lacerda, L., et al., 2006. Carbon nanotubes as nanomedicines: from toxicology to pharmacology. Advanced Drug Delivery Reviews 58 (14), 1460 1470. Available from: https:// doi.org/10.1016/j.addr.2006.09.015. Lee, S.J., et al., 2018. 3D printing nano conductive multi-walled carbon nanotube scaffolds for nerve regeneration. Journal of Neural Engineering . Available from: https://doi.org/ 10.1088/1741-2552/aa95a5. Li, A., et al., 2021. Emerging nanotechnology for treatment of Alzheimer’s and Parkinson’s disease. Frontiers in Bioengineering and Biotechnology 9, . Available from: https://doi. org/10.3389/fbioe.2021.672594May. Lipsman, N., et al., 2018. Blood brain barrier opening in Alzheimer’s disease using MRguided focused ultrasound. Nature Communications 9 (1), 1 8. Available from: https:// doi.org/10.1038/s41467-018-04529-6. MacDonald, R.A., et al., 2008. Carbon nanotubes increase the electrical conductivity of fibroblast-seeded collagen hydrogels. Acta Biomaterialia 4 (6), 1583 1592. Available from: https://doi.org/10.1016/j.actbio.2008.07.005. Meher, J.G., et al., 2018. Carbon nanotubes (CNTs). Nanotechnology-Based Targeted Drug Delivery Systems for Brain Tumors . Available from: https://doi.org/10.1016/B978-012-812218-1.00014-2 Elsevier Inc. Meneghetti, M. and Bianco, A., no date. Preliminary R C research in vivo degradation of functionalized carbon nanotubes after stereotactic administration in the brain cortex P reliminary C ommuniCation, pp. 1485 1494. Miller, K.D., et al., 2021. Brain and other central nervous system tumor statistics, 2021. CA: A Cancer Journal for Clinicians 71 (5), 381 406. Available from: https://doi.org/ 10.3322/caac.21693. Mittal, P., et al., 2021. Comprehensive review on design perspective of PET ligands based on β-amyloids, tau and neuroinflammation for diagnostic intervention of Alzheimer’s disease. Clinical and Translational Imaging. Springer International Publishing 9 (2), 153 175. Available from: https://doi.org/10.1007/s40336-021-00410-7. Nagai, H., et al., 2011. Diameter and rigidity of multiwalled carbon nanotubes are critical factors in mesothelial injury and carcinogenesis. Proceedings of the National Academy

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Functional designing of textile surfaces for biomedical devices

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Chetna Verma1, Ankita Sharma1, Pratibha Singh1, Manali Somani1, Surabhi Singh1, Shamayita Patra2, Samrat Mukhopadhyay1 and Bhuvanesh Gupta1 1 Bioengineering Laboratory, Department of Textile and Fibre Engineering, Indian Institute of Technology, New Delhi, India, 2Shri Vaishnav Vidyapeeth Vishwavidyalaya, Indore, Madhya Pradesh, India

15.1

Introduction

The domain of biomaterials is fascinating and has emerged as an integral part of the human healthcare systems. These materials offer an excellent support system to the human being by virtue of their bio receptivity and biocompatibility with the living system. These materials may be used as sterilization wrap, surgical gowns, drapes as PPE kits and other hygiene textiles (Greenhalgh et al., 2019). These days, it has also become more important to have these fabrics with antiviral features to protect people from COVID-19 infection (Ma et al., 2021; Raza et al., 2021). However, the textiles which have close contact with the body tissues may be termed as the biotextiles such as in wound care, surgical sutures, implants, tissue replacement, and tissue engineering. These materials have the inherent features of biocompatibility, nontoxicity, and precise matching of mechanical properties, such as modulus and tenacity in contact with the body tissues. This domain of biotextiles is very innovative and requires a very creative design of the textile material by careful selection of the approaches and the processing conditions (Gulati et al., 2021). Polyethylene terephthalate (PET) is a very interesting textile and has several remarkable features of chemical resistance, high tensile strength, ease of processing, and biocompatibility (Anjum et al., 2020). According to the Textile Exchange Market 2019, it is the most produced and consumed fiber (almost 51.5% of textile fibers) globally . This polymer has been utilized in several biomedical applications, such as surgical sutures, wound care systems, and antimicrobial implants (Arslan et al., 2014; Ma et al., 2005; Quartinello et al., 2019). PET chemical inertness and hydrophobic nature are the consequence of a lack of active functional groups on its surface. Thus, the material requires a series of surface modifications before preparing for the specific application without any significant change in the inherent properties (Jingrun et al., 2008; Singh et al., 2005; Sun et al., 2020). Considerable efforts have been made for the functional designing of PET surfaces for their application in the biomedical field. PET is an inert material, and it is Fiber and Textile Engineering in Drug Delivery Systems. DOI: https://doi.org/10.1016/B978-0-323-96117-2.00004-2 © 2023 Elsevier Ltd. All rights reserved.

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Figure 15.1 Schematic representation of polyester surfaces using plasma processing.

not easy to attach other functional groups to it. PET can be suitably modified by various approaches such as chemical modification, graft copolymerization, and plasma processing. All these methods have some positive and negative factors. While the chemical and graft copolymerization method may employ some hazardous chemicals it may also leave a product with some chemical contamination as the residue. In contrast to this, plasma processing is an extremely useful technique that offers an attractive and sustainable approach for surface modification for the immobilization of biomolecules. This method includes plasma exposure under argon, oxygen, carbon dioxide, or perfluoro hexane, which makes the surface hydrophilic and hydrophobic, respectively. Both types of surfaces were found with excellent biocompatibility during in vitro and in vivo evaluation (Pigłowski et al., 1994). Due to these surface modifications, PET finds its application in surgical sutures, wound care systems, and tissue engineering (Fig. 15.1) (Anjum et al., 2017). However, these applications may be accompanied by significant infection from microbes. These problems may be overcome by developing surfaces that may lead to bacterial resistance or may eventually kill them once the microbes approach the surgical site. This involves both, the surface functionalization and bioactive coating of the surface (Gupta et al., 2000; Siow et al., 2006). The designing of such surfaces is the most viable approach for the development of materials that have perspectives in healthcare. An overview of the functional designing of PET in the following section would offer precise information on this subject.

15.2

Functional designing of polyester

Pristine PET has low moisture regain (0.4%), which makes PET hydrophobic and results in poor adhesion, low wettability, and thus, not favorable to immobilize the biomolecule. Thus, such hydrophobicity and generation of static charge limit the

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application of the PET in healthcare sector. There are several ways to functionalize and develop polyester for specific requirements. This can be chemical modification or the plasma as well as graft copolymerization modification. All these methods have some positive and negative factors. While chemical and graft copolymerization method may employ some hazardous chemicals, it may also leave a product with some chemical contamination as the residue. Plasma on the other hand is far better and leaded to virtually a pure product which is a major requirement in a biomaterial fabrication for biomedical applications. Further, we have discussed various modification methods of PET in the subsequent sections.

15.2.1 Chemical functionalization Chemical surface functionalization is an attractive approach to improve hydrophilicity via changing atoms or molecules due to several chemical reactions. The chemical reactions involve breakage of polyesters at the specific sites, that is, ester bonds (Al-Balakocy et al., 2021; Raza et al., 2017). These reactions result in creation of active sites for the immobilization of certain biomolecules, which further enhanced biological functionality of the polyester surface (Nemani et al., 2018). Wet chemical functionalization is a chemical treatment that involves the treatment of matrix with several reagents, such as acids, basic, and other chemicals. The process, as a result, leads to the formation of the functional groups, such as hydroxyl, carboxyl, amino, and sulfonic acid on the PET surface. Moreover, most of the surface chemical treatment approaches involve wet methods where the PET is sprayed or dipped with a chemical solution to increase its surface properties as well as to remove surface debris and microbes to facilitate a sterile environment, which is crucial for biomedical applications (Ratner, 1995). The methods that have been carried out commonly for chemical modification of PET surface are hydrolysis, and aminolysis. Depending on the method, various functional groups such as OH, NH2, and COOH emerge onto the surface of PET (Lorusso et al., 2021; Padhye and Nadaf, 1979). Such approaches are pre-functionalization method in the fabrication of surfaces for biomedical applications, including engineering antibacterial and antifouling surfaces as illustrated in Fig. 15.2.

Figure 15.2 Schematic representation of chemical functionalization process of polyethylene terephthalate surface.

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Hydrolysis of PET generally cleaves ester bonds to yield COOH and OH groups on the modified surfaces. This can be done via two facile approaches, that is, acid, and alkaline hydrolysis. Acid hydrolysis occurs in the presence of various H2SO4, HCl, or HClO4, and various organic acids, such as acetic acid or lactic acid. Alkaline hydrolysis occurs in the presence of metal hydroxides such as NaOH or KOH (AlSabagh et al., 2016; Namboori and Haith, 1968). Harsh et al. fabricated a bilayered wound dressing based on cotton and PET that provides high exudate absorption capacity and excellent antimicrobial property for wound healing applications. The surface of PET layer is modified via alkaline hydrolysis to develop desired carboxyl groups on the polyester surface and subsequently, PEG-silver is immobilized onto the functionalized surface. Such hydrolyzed sample immobilized with silver ions showed excellent antimicrobial activity against E. coli and Staphylococcus aureus, suggesting that these materials may provide interesting candidates for the development of wound care systems. Aminolysis of PET is simple approach which occurs with the broad number of amines such as hydrazine, benzyl amine, ethylene diamine, hexamethylene diamine, and aniline that allows the amine to be covalently inserted into the polymer structure, generating active functional groups such as NH2, COOH, and OH2, which may further be explored to incorporate other bioactive molecules for acting as a scaffold in human healthcare sector (Bech et al., 2007; Gupta and Bhandari, 2019). Zhou et al., reported that the PET fabric shows excellent wettability after being treated with dilute ethylene diamine (EDA). The insertion of EDA into the PET polymeric network results in a cleavage of ester bonds and the formation of amide bonds with consequent exposure of active groups and hydroxyl surface groups (Zhou et al., 2017). McCarthy et al. functionalized PET surface via aminolysis with polyamines for the generation of amine functionality. These amines generated a positive charge on the surface, which could adsorb negatively charged polymer and hence could be an interesting candidate for tissue engineering (Fadeev and McCarthy, 1998). Recently, Yang et al. reported facile method for introducing amine functionalities onto PET surface via UV-light-induced aminolysis reaction. These generated amines are employed for electrostatic immobilization of proteins (Yang et al., 2005). While chemical surface treatment provides a broad range of chemical reagents to fastidiously treat polymeric scaffolds at large scale, they still require a conscientious way as the reaction rate is solely dependent on the reagent concentration, material composition, and treatment time. Additionally, post modification steps such as rinsing, washing, and drying are further required before processing of the polymer substate for future applications, which perpetually escalates the amount of toxic waste generated. Thus, surface modification through wet chemical approaches is enticing but it degrades the structural stability of the biomaterials by altering the bulk crystallinity phase which is a major concern in the end-application.

15.2.2 Plasma activation Surface functionalization of polymers using plasma techniques is a current technology of surface activation. Plasma technique stands out from chemical-based

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techniques as: (1) it decreases/eliminates the solvent usage, (2) mitigate the treatment time and energy, (3) reduces the health risks, and (4) decreases the wastewater ˇ ´ et al., 2019). The plasma technique modifies the physicochemical load (Spitalsky properties of the PET without altering the bulk property. It introduces various functional groups on the surface depending on the plasma discharge used (Wrobel and Kryszewski, 1978). The air plasma technique alters the surface morphology and surface chemistry, as it generates various functional group like hydroxyl, carbonyl, carboxyl, hydroperoxide. Air plasma is been used to enhance the wettability, dyeability, printability, and adhesion of PET fabric (Agnhage et al., 2016; Behary et al., 2012; Drobota et al., 2019; Khalifa and Ladhari, 2016; Zhang et al., 2017). Drobota et al. enhanced the surface wettability of PET using air plasma and reported that the water contact angle decreased from 79.7 degree to 40 degree because plasma process generated radical, carboxyl, and hydroxyl functionality (Drobota et al., 2019). In the research done by Shen et al., the air plasma produced the abundance of C O, C 5 O, and COOH groups on the PET and introduced the nitrogen on the surface which was further confirmed by XPS study. The plasma functionalization increased the roughness of surface which improved the immobilization of aminopropyltriethoxysilane (APTES) as compared to only APTESmodified PET surface as observed in surface topographic images by AFM. This modification further result in better adsorption of Ag nanoparticles to make it antimicrobial in nature (Fig. 15.3) (Shen et al., 2017). Plasma enhances the interfacial interaction and adhesion of the PET fabric by introducing the hydrophilic groups and increasing the surface roughness. The nitrogen plasma is an effective technique to modify the surface topography and incorporate the nitrogen species on the surface. The nitrogen plasma-modified PET have nitrogen-rich functional group like primary amine (2NH2), imine, or nitrile functional group, as well as oxygenated functional groups (Shekargoftar et al., 2018). In an innovative work carried out by Zhang and coworker the PET-knitted fabric was modified with the nitrogen plasma to generate hydrophilicity on the surface and reduce the antistatic property of PET fabric. The nitrogen plasma enhanced the hygroscopicity of the fabric as the decay time of plasma functionalized PET reduced to 27.31 seconds from 56.62 seconds. The plasma functionalization of PET fabric enhanced the immobilization of silk fibroin/chitosan microsphere, which was confirmed by using SEM and XPS analysis (Zhang et al., 2019). The nitrogen-rich surfaces enhance the cell adhesion, protein coupling, biocompatibility, and hemocompatibility. Gorenˇsek et al. functionalized the PET surface to enhance the Ag nanoparticle adhesion on the surface. The Ar/N2 (50:50) plasma roughened the PET surface and generated globular structure which enhanced the adhesion of the nanoparticles (Gorenˇsek et al., 2010). Kolar et al. enhanced the hemocompatibility of PET using N2 plasma and O2 plasma. Both the plasma functionalized showed better hemocompatibility as compared to pristine PET, but the antithrombogenic property of O2 treated PET was somehow better than that of N2 treated ones as the polarity of oxygen groups was even higher than nitrogen (Kolar and Primc, 2016).

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Figure 15.3 Schematic representation of AgNPs attachment to the modified polyethylene terephthalate surface. Source: Adapted with permission from Shen, T., Liu, Y., Zhu, Y., Yang, D.Q., Sacher, E., 2017. Improved adhesion of Ag NPs to the polyethylene terephthalate surface via atmospheric plasma treatment and surface functionalization. Applied Surface Science 411, 411 418.

The carbon dioxide plasma treatment introduces oxygenated functional groups on the surface, which increases the surface energy of the substrate and enhances the hydrophilicity, wettability, and adhesion of the polymers. The CO2 plasma introduces functional groups including carboxylic acid, ketone /aldehyde, and hydroxyl groups. The functionality generates during the plasma process is because of a homolytic splitting of the ester bonds, a release of volatile products (mainly CO and CO2), reactions of radicals with oxygen, and a subsequent formation of hydroxy group. Ledakowicz and coworker modified the PET fabric using CO2 plasma and discussed the effect of plasma modification on chemical structure. CO2 plasma modification was also being used to immobilize the bioactive component on the PET surface and the immobilized surface was used for the biomedical application (So´jka-Ledakowicz and Kudzin, 2014). Tkavc et al. functionalized the PET surface with the O2 and CO2 plasma to improve the adsorption of the chitosan on the PET surface. The chitosan immobilized surface showed good antimicrobial property (Tkavc et al., 2014). The biological response of PET is not adequate, so it is covered with a thin coating to increase its biocompatibility. Kolar M et al. treated PET with oxygen and nitrogen plasma to immobilize heparin on its surface. Further, they determined the hemostatic response by monitoring the density of adhered blood platelets and their morphological properties. The density of adheres blood platelets was smaller on Oatom treated samples, but polarity was higher than the N-atom treated sample.

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Thus, oxygen treated sample shows a better anti-thrombogenic character (Kolar and Primc, 2016). Stular D et al. studied the combination of oxygen and ammonia plasma to increase the adsorption of the temperature and pH-sensitive nanogel (PNCS) to impart smart thermoregulation. Ammonia plasma increased nitrogen functional groups while oxygen plasma increased oxygen functional groups. The combination of ammonia and oxygen plasma imposed significant adsorption of PNCS nanogel to the fiber surface, which was not attainable when used ammonia ˇ plasma alone (Stular et al., 2018). Sasmazel et al. investigated biofunctionalization of three-dimensional nonwoven polyester fabric disk by low-pressure water/O2 plasma for L929 cell cultivation. In situ oxalyl chloride vapors were used in RF plasma reactor to convert OH functionalities into COCl groups, further converted into COOH functionalities by hydrolysis using air moisture. The successful bio functionalization followed by immobilization of 146.09 and 4.81 nmol/cm2 of insulin (Sa¸ ¸ smazel et al., 2010). Gupta and group designed the antimicrobial infection-resistant PET suture for different application. The PET suture was hydrophobic in nature so the bioactive agent could not immobilize, so they functionalized the PET suture with CO2 plasma and generated the hydrophilic functional group on the surface. The effect of CO2 plasma exposure time on carboxyl content was studied and found that the carboxyl content increased with the increase in plasma exposure. The functionalized suture was immobilized with the different bioactive agent like Ag ions, Ag 1 Aloe vera gel, chlorhexidine digluconate, and Ag nanogels. The antimicrobial PET suture showed rapid healing as compared to the pristine PET suture without causing any infection on the site (Anjum et al., 2019).

15.2.3 Graft copolymerization The modification of polymers through graft polymerization offers an attractive approach for introducing desirable properties for the needed application. The process of graft polymerization is a procedure wherein the first step an active chemical site is created in the pre-existing polymer. This site could be a free radical or an active group, which may initiate the polymerization of a monomer leading to the formation of a copolymer structure. Graft copolymerization, in general, can be defined as the process in which monomers polymerize in the vicinity of the preexisting polymer where the monomer forms the side chain on the polymer backbone. Fig. 15.4 shows the graft copolymer structure. Several studies have been reported on the surface modification of PET fibers, membranes, and textile materials to make them suitable candidate for their use as implants and biomedical scaffolds (Gotoh and Yasukawa, 2011; Kabajev and Prosycevas, 2004; Kamel et al., 2011). Plasma-induced graft polymerization is one of the most alluring approach for introducing the specific properties to the surface of polymeric materials (Gupta et al., 2000; Kou et al., 2003; Yamaguchi et al., 1996). This approach is highly selective, where the modification is achieved to a few nanometers extent without changing in the bulk properties of material. Isabella et al. outlined the process of graft polymerization of acrylic acid onto plasma

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Figure 15.4 Schematic representation of graft copolymer structures.

treated PET surfaces for the immobilization of proteins, which promoted an excellent cell adhesion, growth, and proliferation on the surface for biomedical applications. In this study it was observed that plasma processing is an extremely helpful and simple method to fabricate functionalized PET membranes for the biomolecule immobilization for biomedical applications (Bisson et al., 2002). In another study, PET films were treated with argon RF plasma for the creation of active radicals and afterwards oxygen plasma was done to generate hydroperoxides as well as other functional groups on the surface of film. Subsequently, plasma activated graft polymerization of acrylic acid were carried out onto the PET surface of the films. Thus, such grafted surfaces provided functional sites for the binding of protein biomolecule (Gupta et al., 2002). At the same time, Bisson et al. reported the growth of human bladder smooth muscle cells on the modified PET (Bisson et al., 2002). In this study, PAA-grafted PET films, onto which serum protein of the culture medium adsorbed spontaneously, proved to be better matrices than films on which collagen has been immobilized.

15.3

Applications of functional polyesters

PET has exceptionally outstanding properties like physical, chemical, mechanical attributes like good stability against body fluids, and high radiation resistance for sterilization. Thus, it has eminence potential in various biomedical applications such as wound care systems, suture designing, and tissue engineering, etc. (Gupta et al., 2000; Morshed et al., 2019). PET is the most widely used polymer for the development of advanced human healthcare devices, such as skin-contacting materials, wound dressings, sutures, and surgical implants. Such devices often demand excellent tissue compatibility, biodegradability, and antimicrobial potential for their efficient performance at the site of application. Plasma treatment has been

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considered as a versatile, facile, and sustainable green approach which incorporates the functionality to the material surface without compromising the bulk properties. Change in the surface chemistry may be utilized for the immobilization of bioactive agents for different biomedical applications. Thus, a detailed discussion on various applications of plasma functionalized polyesters is summarized in subsequent sections.

15.3.1 Antimicrobial surfaces Microbial infections are the major contributors to mortality, which starts from the microbial adhesion and their subsequent proliferation at the site of injury. Infections related to chronic wounds exert almost $3 billion economic burden on the health management sector. Thus, the fabrication of antimicrobial biomaterials has invited scientific attention toward the paradigm shift in wound care systems (Kalantari et al., 2020). Plasma treatment is an attractive approach which may enable various functionalities to the PET surface that can be utilized for the immobilization of different bioactive agents. In this regard, one of the study has been undertaken to enhance the surface hydrophilicity of PET-woven fabric by applying dielectric barrier discharge (DBD) plasma followed by their immersion in the chitosan solution with different degree of deacetylation (DD%) (Sophonvachiraporn et al., 2011). It was evident from the antimicrobial studies that plasma-activated PET fabric immobilized with chitosan solution having 98% of DD showed larger zone of inhibition as compared to PET fabric immobilized with chitosan solution of 85% of DD against E. coli and S. aureus. Similarly, the colony count method indicated the almost complete ( . 99%) reduction of viable colonies in chitosanimmobilized plasma-treated PET fabric. Nano form of silver is well documented as the bioactive agent for microbial inhibition due to their broad-spectrum antimicrobial activity. Thus, silver nanoparticles (AgNPs) have been utilized for the surface functionalization of different textile materials (Verma et al., 2021). In this regard, Xiaolong Deng et al. reported the three-step preparation of antimicrobial PET fabric by surface functionalization of atmospheric pressure plasma (Deng et al., 2015a). First, plasma treatment has been carried out to deposit a layer of organosilicon followed by the dip coat in the suspension of silver nanoparticles (AgNPs). Then, another organosilicon layer with different thicknesses (without barrier layer, 10 nm barrier layer, 50 nm barrier layer) was deposited on the surface by plasma jet system to stabilize the AgNPs. Antimicrobial activity of functionalized fabric with varying thickness layers of organosilicon was tested against Pseudomonas aeruginosa, S. aureus, and Candida albicans, which revealed excellent antimicrobial activity of all the activated fabrics. However, the fabric with 50 nm barrier layer showed lesser activity than the fabric with 10 nm thickness of the barrier layer and the fabric without any barrier layer. This study was further extended by optimizing the conditions of plasma functionalization and barrier layer deposition with 10 nm thickness. Further, the different concentrations of AgNPs (1, 2, 5, and 10 mg/mL) were utilized for the antimicrobial finishing of plasma functionalized PET fabric (Deng et al., 2015b). The colony

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count method was utilized to evaluate the antimicrobial potential which indicated that the number of viable colonies was reduced with increase the concentration of AgNPs. Hence, complete reduction of microbial colonies was observed for the 10 mg/mL concentration of AgNPs in the plasma-functionalized PET fabrics. Herbal extracts are considered to be excellent antimicrobial agents, which are non-toxic and biocompatible in nature. Thus, one of the studies reported the preparation of antimicrobial PET wound dressings with aqueous extract of rhizome Atractylodes macrocephala (RAM) (Shu et al., 2017). Initially, PET nanowoven fabric was activated by argon plasma followed by the acrylic acid (AA) grafting. Further, pristine and AA grafted fabrics were immersed in aqueous extract of RAM and their antimicrobial activity was evaluated with the help of zone of inhibition analysis. A comparative study between non-plasma treated PET fabric with RAM extract (PET-RAM) as well as AA grafted PET with RAM (PET-AA-RAM) exhibited a mild microbial susceptibility whereas, plasma-treated PET with RAM extract (PET-PT-RAM) and AA grafted on plasma-activated PET with RAM extract (PETPT-AA-RAM) resulted in the larger zone diameter. Such findings indicated that plasma treatment helped in the enhanced antimicrobial activity of PET nonwoven dressings. Healthcare associated infections occur due to nosocomical pathogens that are transmitted through touch surfaces like (door handles, call buttons, toilet seats, etc.) and are the main cause of patient’s morbidity. Thus, one of the study reported the comparative investigation of alkyldimethylbenzylammonium chloride (ADBAC) adsorbed disinfectant wipes composed of different textile materials, such as polyester (PET), 55% cellulose/45%PET, and cotton (Song et al., 2020). The samples were prepared by employing DBD plasma followed by adsorption of ADBAC. Antimicrobial analysis indicated that non-plasma-treated PET samples showed almost similar log reduction values as pure ADBAC which enhanced after the plasma functionalization of PET surface due to the high deposition of ADBAC. Sutures are the integral part of surgeries and trauma management. The basic work of suture is to hold torn tissues together to facilitate and hasten healing following a deep injury or surgical procedure (Dennis). At the time of recovery, the sutures are more prone to infection due to unhygienic conditions and poor maintenance. S. aureus, a type of Gram-positive bacteria, is a major infection-causing bacteria and is responsible for 23% of infection. Recently many researches are focusing on designing of antimicrobial suture. Bioactive agents are immobilized over the suture surface to impart the antimicrobial activity. The antimicrobial suture inhibits the bacterial growth to avoid the onsite infection and helps in rapid healing with no scar formation. Gupta and group designed the antimicrobial infection resistant PET suture for different application. The PET suture was hydrophobic in nature so the bioactive agent could not immobilize, so they functionalized the PET suture with CO2 plasma and generated the hydrophilic functional group the surface. The effect of CO2 plasma exposure time on carboxyl content was studied and found that the carboxyl content increased with the increased in plasma exposure. The functionalized suture was immobilized with triclosan, 2,4,4-trichloro-2-hydroxydiphenylether. Triclosan-

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immobilized suture exhibited excellent antibacterial activity microbes and has bacteriostatic and bactericidal nature (Anjum and Gupta, 2018). Bhouri et al. designed antibacterial dyed PET suture, which is better visible at the surgical site and antibacterial in nature. The PET suture surface is plasma functionalized by oxygen gas and grafted with the acrylic acid (AA). Chitosan is immobilized over the AA grafted PET suture by dip-coat method. The chitosan imparts the antimicrobial property to the suture and also enhances the dyeability of PET suture with acidic dye. Another study reported the preparation of antimicrobial PET sutures by immobilizing nanosilver nanogel on the plasma functionalized PET surface (Anjum et al., 2017). Carbon dioxide plasma has been used to functionalize the surface with carboxyl functionality and antimicrobial potential of the nanosilver nanogel (nGelPET) as well as chlorhexidine (Clx-PET) immobilized sutures have been studied with the help of zone of inhibition and colony reduction studies (Fig. 15.5). Polyethylene glycol (PEG) was used for reducing the silver nitrate and TEM studies have been carried out to visualize the nanoparticles. TEM analysis showed that the size of the nanoparticles was found in the range of 10 15 nm. This analysis revealed that nanosilver nanogel and Clx-immobilized sutures showed significant antimicrobial activity with clear zone of inhibition in the proximity of sutures in comparison with control. Further, histological analysis implicated the smooth healing after the suture implantation without any inflammation. Same research group has modified the suture development by incorporating A. vera (AV) for the rapid healing effect (Anjum et al., 2019). PET monofilament sutures were prepared by the melt spinning of PET chips at ambient conditions followed by the carbon dioxide plasma. The functionalized surface was immobilized with ionic silver (PET-Ag) and AV (PET-Ag-AV). A comparative study has been carried out between PET, PET-Ag, and PET-Ag-AV sutures in terms of their antimicrobial as well as wound healing potential. Antimicrobial analysis indicated the

Figure 15.5 Schematic presentation for the fabrication of plasma functionalized nGel- and Clx-based polyethylene terephthalate sutures. Source: Adapted with permission from Anjum, S., Gupta, A., Sharma, D., Kumari, S., Sahariah, P., Bora, J., Bhan, S., Gupta, B., 2017. Antimicrobial nature and healing behavior of plasma functionalized polyester sutures. Journal of Bioactive and Compatible Polymers 32, 263 279.

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significant colony reduction in PET-Ag and PET-Ag-AV sutures in comparison to pristine PET suture (Fig. 15.6A). These observations were further confirmed by the bacterial adherence on the suture surface was analyzed with the help of FESEM analysis, which indicated that deposition of bacterial colonies on the pristine PET suture whereas there was no presence of bacteria on PET-Ag and PET-Ag-AV surfaces (Fig. 15.6B). Wound healing studies revealed a high degree of inflammation for the pristine PET suture while for the PET-Ag suture, noticeable inflammation was observed due to silver ion release. In comparison to these two, there was no inflammation

Figure 15.6 Antimicrobial studies of pristine polyethylene terephthalate (PET) and functionalized PET. (A) Colony count method. (B) Microbial adhesion analysis by FESEM studies where, (a) Pristine PET, (b) PET-Ag, (c) PET-Ag-AV. Source: Adapted with permission from Anjum, S., Gupta, A., Kumari, S., Gupta, B., 2019. Preparation and biological characterization of plasma functionalized poly(ethylene terephthalate) antimicrobial sutures. International Journal of Polymeric Materials and Polymeric Biomaterials 69, 1034 1042.

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around the site of application of PET-Ag-AV suture and excellent wound healing property due to the synergistic effect of AV. Thus, the fabrication of antimicrobial sutures with the healing effect of AV may be utilized as the candidate for surgical interventions in the near future.

15.3.2 Tissue engineering Tissue engineering is a multidisciplinary field, which involves the principle of both engineering and life sciences for the designing of 3D biological substitutes, to repair, regenerate, or restore the functioning of damaged or injured tissue. PET has been widely engaged for the fabrication of biomaterials for tissue engineering applications, however, its chemically inert nature, highly hydrophobic, and low surface free energy limits its application to restore tissue functions. Therefore, plasma-functionalized PET surface allows immobilization of certain biological moieties on the substrates, which ideally regulate the cell-tissue biological functions and enhance the scaffold’s integration in the body as well as endorsing cell proliferation and differentiation. Esmaeil et al., immobilized collagen on the surface of plasma-activated PET nanofibrous mats to enhance the scaffold biocompatibility for the development of keratoprosthesis skirt material for corneal tissue engineering (Biazar et al., 2017). In this study, plasma modification was carried out using low-pressure RF plasma sustained in CO2 for 1 minute to introduce carboxyl and hydroxyl functionality on the surface of PET nanofibers. Later, collagen was covalently bonded to the plasma functionalized PET surface using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide/N-hydroxysuccinimide (EDC/NHS) as a crosslinker. The authors examined the behavior of limbal epithelial progenitor cells (LEPCs) cultured on the untreated, plasma-modified, or collagencoated PET fibers and it was noticed that the collagen crosslinked surface showed significant cellular expansions of various markers, enhanced adhesion and viability as compared to untreated PET fibers as evidenced by DAPI staining. In similar study by Daniele et al., electrospun PET (ePET) mats were first exposed to radio frequency glow discharges (RFGD) plasma in the presence of ammonia gas (NH3), followed by immobilizing gelatin hydrogel to the plasma activated animated surface by in situ Michael-type addition-based crosslinking reaction (Pezzoli et al., 2017). Cytocompatibility analysis were performed with NIH 3T3 fibroblast cells on the pristine and gelatin coated ePET scaffolds to evaluate cell adhesion, viability and proliferation. It was perceived that the cell adherence and proliferation were much better on the gelatin immobilized ePET mats as compared to pristine. Gelatin-immobilized electrospun PET mats are thus suitable candidate for the development of biomimetic and biocompatible vascular grafts.

15.4

Conclusion

In this chapter, we have discussed a plasma processing technology that could play a crucial role in enhancement of biomedical performance of PET fabric via surface

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functionalization of the fabric without altering the bulk properties of the material. PET is a biocompatible, and nontoxic polyester, which is required to functionalize to achieve optimal hydrophilicity and cell-interactive property so that they can widely employ for several biomedical applications, such as for drug delivery vehicles, infection-resistant meshes, regenerative medicine, wound healing, and tissue engineering applications. Thus, the method of plasma processing is propelling to the forefront for the surface activation of such functionally inactive PET surfaces to utilize them in healthcare sector. Plasma technology is a promising sustainable and green approach that uses several gases such as oxygen, nitrogen, argon, hydrogen, and carbon dioxide, to create the desired surface functionality on the PET surface to a few nanometers range without altering the bulk properties of the material. Further, these active sites created on the surface are used for the immobilization of bioactive agents and hence, use such material for biomedical application. Although the process has led to the significant revolution in the fabrication of functionalized PET surfaces for healthcare sector but still the future may seem more development in the healthcare domain.

Acknowledgments The authors duly acknowledge the Department of Textile and Fibre Engineering, Indian Institute of Technology, New Delhi.

Individual authors’ contributions All authors have equal contribution.

Compliance of interest We have no conflicts of interest.

Research involving human participants and animals Not applicable.

Informed consent Not applicable.

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Isha Gupta1,2, Sonia Gandhi1 and Sameer Sapra2 1 Institute of Nuclear Medicine and Allied Sciences (INMAS), Defence Research and Development Organisation (DRDO), Delhi, India, 2Department of Chemistry, Indian Institute of Technology Delhi (IITD), Delhi, India

16.1

Introduction

A composite is a “multi-component material comprising multiple, different (nongaseous) phases in which at least one phase is a continuous phase.” This material’s properties are superior to any of its constituents. Here, the discontinuous phase (filler) is embedded in the continuous phase (matrix) (Work et al., 2004). Fig. 16.1 shows different classes of composites. Recently, awareness of sustainable development has led researchers to replace conventional composites with bio-based composites or biocomposites. Biocomposites have at least one component of bio-based polymer or biopolymer (Bahrami et al., 2020; Rajak et al., 2019). These composites are biocompatible, biodegradable, low cost, and have better mechanical properties. It has compelled researchers to expand their applications in several fields such as electronics, construction, packaging, biomedical, filtration, drug delivery, implants, and cosmetics (Bahrami et al., 2020). In the early 1990s, Toyota found that the montmorillonite nanoparticles (NPs) reinforced rubber had improved dimensional stability and barrier properties (Shchipunov, 2012). Therefore, a new class of composite called “nanocomposites” has emerged. Nanocomposites have at least one phase dimension in the nanometer range (Work et al., 2004). This chapter aims to discuss the application of NPs as fillers or reinforcement in the matrix, and these NPs are called nanofillers. Nanofillers are particles having at least one dimension in the range of 1 nm to 1 µm. So, NPsreinforced composites show improved properties, such as dimensional stability, permeability, bioavailability, strength, optical, thermal, catalytic, and electrochemical compared to conventional microcomposites (Bhatia, 2016; Kendre et al., 2021). Nanocomposites’ properties depend on components, synthesis process, morphologies, and interfacial interactions between the components (Jeevanandam et al., 2019). Nanocomposites having biopolymers as the continuous phase are commonly called nano-biocomposites, bio-nanocomposites, nanocomposites, bio-based Fiber and Textile Engineering in Drug Delivery Systems. DOI: https://doi.org/10.1016/B978-0-323-96117-2.00010-8 © 2023 Elsevier Ltd. All rights reserved.

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Figure 16.1 Classes of composites. Source: Created with GIMP (The GIMP Development Team, 2019. GIMP. Available from: https://www.gimp.org).

plastics, NPs reinforced biocomposites, bio-hybrids, or green composites (Abdulkhani et al., 2020). In this way, nano-biocomposites have superior properties compared to standalone biopolymers. Fig. 16.2 shows the applications of nanobiocomposites in medicine. This chapter aims to discuss different classes of nano-biocomposites based on the dimension of NPs, the types of biopolymers, and nanofillers employed for synthesizing nano-biocomposites. Additionally, the preparation methods such as blending, in situ polymerization, and in situ sol gel for nano-biocomposites are explained briefly. It also investigates different techniques used to understand and study the interaction of nanofillers in the biopolymer matrix. The last section covers recent developments of metal/metal oxide reinforced biocomposites in controlled drug delivery. This chapter elaborately studies the application of nanobiocomposites for drug delivery due to their increased drug targeting, solubility, oral bioavailability, rate of dissolution, surface area, rapid onset of therapeutic action, water uptake capacity, and bioadhesion. At the same time, they also show decreased toxicity, drug resistance, and dose requirement.

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Figure 16.2 Application of nano-biocomposite in medicine. Source: Created with GIMP. The GIMP Development Team, 2019. GIMP. Available from: https://www.gimp.org.

16.2

Nano-biocomposites

In nano-biocomposite, carbon-based, silicate-based, metal-based, ceramic-based, or organic-based NPs are dispersed in the biopolymer matrix (Jeevanandam et al., 2018). The large interfacial area between polymer and fillers improves the nanocomposite properties (Fu et al., 2019). The polymers bind fibers, distribute stress between fibers, impart durability, and protect fibers from extreme changes. At the same time, the fibers impart dimensional stability, strength, and stiffness (Christian, 2016). The filler can be sheets, fibers, or particles (Rastogi, and Pal, 2019). Therefore, nano-biocomposites can be classified into three types: nano-layered, nano-filamentary, and nano-particulate (Fig. 16.3).

16.2.1 Nano-layered reinforced biocomposites (2-D biocomposites) In this class of composites, two-dimensional nanofillers, graphene and layered silicates, are dispersed in the matrix of biopolymers. The nanofillers have a thickness of one to a few nanometers. Layered silicates, such as saponite, montmorillonite,

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Figure 16.3 Classes of nano-biocomposites. Created with GIMP. Source: The GIMP Development Team, 2019. GIMP. Available from: https://www.gimp.org.

and hectorite, are commonly employed for polymer nanocomposites (Aljibori et al., 2012; Fu et al., 2019; Jeevanandam et al., 2018). They show better properties such as tensile, heat distortion temperature, thermal stability, optical transparency, and conductivity due to greater interfacial interaction between the matrix and the layered silicate (Rastogi, and Pal, 2019).

16.2.2 Nano-filamentary reinforced biocomposites (1-D biocomposites) In this class of composites, one-dimensional nanofillers such as nanofibers and nanotubes (carbon nanotubes or nanofibres) are added to the biopolymer matrices. These nanofillers have two dimensions in the nanometer. Nanotubes can be synthesized by arc, chemical vapor deposition, and laser furnace (Fu et al., 2019; Kaurav et al., 2018; Paravastu et al., 2019; Sohani et al., 2015).

16.2.3 Nano-particulate reinforced biocomposites (0-D biocomposites) These composites have NPs embedded in matrices. These nanofillers have all three dimensions in the range of nanometers, such as nanoclusters and quantum dots.

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Much research has been done to synthesize spherical NPs. These syntheses influence the size and morphology of NPs, affecting their properties (Fu et al., 2019; Kaurav et al., 2018; Paravastu et al., 2019; Sohani et al., 2015).

16.3

Biopolymer

The matrix is an essential composite component, even if it is less rigid and more ductile. This chapter highlights biopolymers as the matrix (continuous phase). Biopolymers (or bio-based polymers) are synthesized or derived from living organisms. In recent years, they have been used for delivering drugs to the target organ because these polymers are non-toxic, biocompatible, biodegradable, ecofriendly, non-carcinogenic, nonimmunogenic, cheaper, and readily available. They are converted into carbon dioxide, water, and biomass on degradation. Hence, they can be recycled by nature. They have wide applications in biomedical and tissue engineering (Yadav et al., 2015). Fig. 16.4 demonstrates the different classes of biopolymers. Among all, natural and synthetic biopolymers are mainly employed for drug delivery applications (Hasnain et al., 2020). Natural polymers are obtained from living organisms or made from renewable resources by polymerization. They are further divided into polysaccharides, proteins, and lipids. These polymers have high water uptake capacity, biodegradability, and biocompatibility. A few studies have even reported that the blend of two biopolymers as a matrix shows synergistic properties, resulting in high water permeability and better mechanical properties (Wang et al., 2018). Commonly used polysaccharides such as cellulose, chitin, chitosan, and alginate have glycosidic linkages, whereas proteins such as silk, collagen, and keratin have long chains of amino acid residues (Xiong et al., 2018). The limitations of natural polymers are their uncontrolled hydration rate, batch-to-batch variation, and slow production rate. As per Food and Drug Administration (FDA), complex carbohydrates made from the fermentation of microbes, plants, and animals are generally recognized as safe (Jamro´z et al., 2019; Nalone et al., 2018). The limitations of neat proteins are mechanical properties and sensitivity to moisture (Jamro´z et al., 2019). Synthetic biopolymers are acknowledged for being easy to prepare, low cost, and lightweight. Their structural, mechanical, and chemical properties can be manipulated for drug delivery applications. These polymers can be natural (poly (ethylene glycol), poly (lactic acid), poly (glycolic acid)), and partially natural (polyethylene, polyamide). These polymers’ limitations include low biocompatibility, toxic byproducts on degradation, and poor wound healing capacity. The other biopolymers for drug delivery applications are lipid and natural rubber (Jamro´z et al., 2019; Wang et al., 2018). For drug delivery applications, the ideal biopolymer matrix should be biocompatible, safe, easy to apply, and able to be loaded with a high amount of drug. The other reasons for employing biopolymers are their ability to control the morphology and size of NPs; and to decrease production costs (Hasnain et al., 2020; Shariatinia, 2020).

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Figure 16.4 Different classes of biopolymers. Created with GIMP. Source: The GIMP Development Team, 2019. GIMP. Available from: https://www.gimp.org.

16.4

Nanofillers

For developing nano-biocomposites, nanofillers are used in place of conventional fillers. (Fu et al., 2019; Jamro´z et al., 2019; Jeevanandam et al., 2018; Wang et al., 2018). Due to their unique characteristics, these materials have gained immense attention from researchers in a broad range of disciplines (Khan et al., 2019). The NPs or nanofillers are divided depending on size, morphology, and chemical properties into carbon-based, metal or metal oxides, organic, and other NPs (silicate and ceramics) (Fig. 16.5) (Fu et al., 2019; Jamro´z et al., 2019; Wang et al., 2018). Silicate-based NPs are in the form of sheets or platelets with at least one nanoscale dimension (Jamro´z et al., 2019). The most common layered silicates are montmorillonite, hectorite, and saponite. The properties of layered silicates are challenging to determine independently; therefore, they are generally estimated in the composite form. The nanomaterials are impermeable to liquids and gases and have excellent barrier properties (Fu et al., 2019). Ceramics NPs are non-metallic, amorphous or polycrystalline, porous, dense, or hollow. These NPs have gained attention from researchers due to their application in different fields, such as

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Figure 16.5 Different classes of nanofiller. Source: Created with The GIMP Development Team, 2019. GIMP. Available from: https:// www.gimp.org.

catalysis, imaging, and photodegradation (Khan et al., 2019). Carbon-based NPs are entirely made up of carbon, including carbon nanotubes (CNT), carbon fibers, carbon black, graphene, and fullerene (Ealias and Saravanakumar, 2017). CNT is manufactured by arc discharge, laser furnace, and chemical vapor deposition (CVD) (Fu et al., 2019; Jeevanandam et al., 2018). Dendrimers, micelles, nanocelullose, chitosan, and liposomes come under organic NPs. These NPs are also known as nanocapsules because of the hollow core. These NPs are nano-toxic, biodegradable, and sensitive to stimuli such as light and heat. Due to these reasons, these particles are preferred for the entrapment of drugs that can be released under the influence of stimuli (Ealias and Saravanakumar, 2017; Jeevanandam et al., 2018). The metals, their oxides, and sulfides NPs come under the category of inorganic NPs. These particles exhibit versatile attributes like high reactivity, high surface area-to-volume ratio, crystalline or amorphous, pore size, surface charge, shapes and color, and sensitivity to environmental factors (Ealias and Saravanakumar, 2017). Broadly, the synthesis routes of NPs are divided into two categories: top-down (etching, chemical and thermal decomposition, laser ablation, and sputtering) and bottom-up (sol gel, chemical vapor deposition, and green synthesis) (Ealias and Saravanakumar, 2017). These NPs also exhibit antimicrobial, antioxidant, photocatalytic, ultraviolet shielding, antifouling, dielectric, flame retardancy, thermal conductivity, wrinkle resistance, and electromagnetic shielding properties (Jamro´z et al., 2019).

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Metal/metal oxide nanoparticles-reinforced biocomposites

In the previous sections, we have discussed the influence of fillers and matrix on the composite properties. The composite can be isotropic (random filler arrangement) or anisotropic (ordered filler arrangement) (Chavali et al., 2019). Due to the large surface area-to-volume ratio and quantum confinement, metal or metal oxide NPs impart unique properties than their bulk counterparts in the composite (Hong, 2019). The interparticle interaction serves as a molecular bridge in the matrix. The choice of polymer, nanofiller, and interaction of NPs influences the deployment of nanocomposite in a wide range of applications (Table 16.1) (Vodnik and Bogdanovi´c, 2019). However, the good dispersion of NPs in a biopolymer matrix is challenging and needs to be addressed cautiously. (Xiong et al., 2018). Metal NPs such as Silver (Ag), Gold (Au), Cadmium (Cd), Cobalt (Co), Copper (Cu), Zinc (Zn), Lead (Pb), Iron (Fe), Selenium (Se) have been investigated for biomedical applications (Yaqoob et al., 2020). They have distinct properties such as surface area and pore size, chromophore properties, surface charge density, amorphous and crystalline structures, color and shapes, and sensitivity to external factors (Ealias and Saravanakumar, 2017). Frequently used metal oxide NPs for biological applications are iron oxide (Fe2O3), magnetite (Fe3O4), zinc oxide (ZnO), cerium oxide (CeO2), silicon dioxide (SiO2), titanium dioxide (TiO2), bismuth oxide (Bi2O3), copper oxide (CuO), gold oxide (Au2O3), aluminum oxide (Al2O3), calcium oxide (CaO), and magnesium oxide (MgO) (Yaqoob et al., 2020). Metal oxides are classified into two categories: magnetic (mainly iron oxide) and non-magnetic (rest of metal oxides) (Jeevanandam et al., 2019). Metal oxide NPs have superior properties to metal NPs because of their higher reactivity, efficiency (Xiong et al., 2018), easy processability, and dispersibility within the matrices (Ealias and Saravanakumar, 2017).

16.5.1 Preparation methods for metal/metal oxide reinforced biocomposites The preparation methods for metal/metal oxide NPs-reinforced biocomposites are broadly categorized into direct mixing, in situ polymerization, and sol gel, as explained in Fig. 16.6 and Table 16.1.

16.5.1.1 Direct mixing or blending Direct mixing, blending, or ex situ is the most convenient and straightforward method for preparing low filler volume reinforced biocomposites. In this method, two components are directly mixed without setting any prior limitations for the components (Fu et al., 2019; Haldorai and Shim, 2014; Uthale et al., 2021; Wang et al., 2018). The two components can be mixed by melt blending or solution blending (Haldorai and Shim, 2014; Uthale et al., 2021). Polymer and nanofillers are mixed directly in melt blending

Table 16.1 Metal and their oxide nanoparticles reinforced biocomposites for drug delivery applications. Nanoparticles

Biopolymers

Preparation method

Therapeutic application

Reference

Silver (Ag) NPs

Chitosan Chitosan-alginate Chitosan-alginate

In situ sol gel In situ sol gel Solution blending Solution blending In situ sol gel Blending

Antibacterial Wound dressing Antimicrobial filtration, cancer treatment Antimicrobial

Shah et al. (2018) Shah et al. (2019) Venkatesan et al. (2017) Lin et al. (2015)

Biomedical application Antimicrobial, Wound healing property Chronic Wound

Hajji et al. (2017) Thanh et al. (2018)

Antibacterial wound dressing

Chen et al. (2020)

Wound healing

Gupta et al. (2022)

Controlled drug delivery

Marı´n et al. (2018)

Magnetic hyperthermia

Kloster et al. (2018)

Bone cancer therapy

Sundaram and Murugesan (2015)

Chitosan-cellulose Chitosan poly(vinyl alcohol) Polycaprolactone gelatin Bacterial cellulose Carboxymethylchitosan—sodium alginate—polyvinyl alcohol Chitosan-gelatin Magnetite (Fe3O4) NPs

Gelatin Chitosan Hydroxyapatite

Solution blending In situ sol gel Solution blending Solution blending Solution blending Ball milling

Gupta et al. (2020)

(Continued)

Table 16.1 (Continued) Nanoparticles

Biopolymers

Preparation method

Therapeutic application

Reference

Zinc oxide (ZnO) NPs

Chitosan

In situ sol gel

Qiu et al. (2019)

Poly(lactic acid)

Solution blending Solution blending Solution blending Solution blending Melt blending (Grafting) Solution blending In situ sol gel Laser ablation Solution blending Solution blending Solution blending Solution blending

Antibacterial packaging and dressing Food packaging and biomedical applications Antimicrobial Burn wound

Khalid et al. (2017a)

Wound healing

Bakil et al. (2020)

Wound care

Burn wound

Sakthiguru and Sithique (2020) Kalishwaralal et al. (2018) Mao et al. (2021) Menazea et al. (2020) Doostmohammadi et al. (2021) Arumugam et al. (2019) Khalid et al. (2017b)

Wound healing

Ismail et al. (2019)

Chitosan-polyvinyl alcohol Bacterial cellulose Sodium alginate Carboxymethyl chitosan Selenium (Se) NPs

Chitosan Bacterial cellulose—gelatin Polyvinyl alcohol—chitosan Polycaprolactone—gelatin

Titanium dioxide (TiO2) NPs

Polyvinylidene fluoride—poly(methyl methacrylate) Bacterial cellulose Gellan gum

Cardiac tissue engineering Wound dressing Antimicrobial Wound dressing Bone repair applications

Shankar et al. (2018) Abdeen et al. (2018)

Cerium oxide (CeO2) NPs

Chitosan—hydroxyethylcellulose Chitosan—cellulose acetate Gelatin Polycaprolactone—gelatin Polyvinyl alcohol—chitosan

Gold (Au) NPs

Gelatin Cellulose—keratin Bacterial cellulose

Solution blending Solution blending Solution blending Solution blending Solution blending Solution blending In situ sol gel Solution blending

Antibacterial Wound dressing Wound dressing Wound healing Wound dressing Cancer therapy Chronic ulcerous infected wounds Bacteria-infected wounds

Kızılkonca et al. (2021) Kalaycıo˘glu et al. (2020) Raja and Fathima (2018) Rather et al. (2018) Kalantari et al. (2020) Zhang et al. (2017) Tran et al. (2018) Li et al. (2017)

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Figure 16.6 Preparation methods for nano-biocomposites. Source: Created with GIMP. The GIMP Development Team, 2019. GIMP. Available from: https://www.gimp.org.

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without adding any solvent. On the other hand, the filler and polymers are first dissolved in the solution and then mixed in solution blending (Uthale et al., 2021). In this process, inorganic NPs are first synthesized and then mixed with polymers, leading to physical encapsulation or entrapment of the NPs in the polymer matrix (Wang et al., 2018).

16.5.1.2 In situ polymerization The in situ method overcomes the drawbacks of ex situ. The nanofillers are first well dispersed in monomer or monomer solution, followed by polymerization, resulting in nanocomposite formation (Fu et al., 2019; Haldorai and Shim, 2014; Uthale et al., 2021). This method can further be divided into solution, emulsion, graft, and atom transfer polymerization (Haldorai and Shim, 2014). This method is suitable for insoluble polymers (Grothe et al., 2012).

16.5.1.3 In situ sol gel In situ sol gel, sol gel, in situ deposition, or in situ particle processing is a bottom-up method. This method combines in situ deposition and in situ polymerization (Fu et al., 2019; Uthale et al., 2021). In this method, the inorganic precursor is first added to the monomer solution, and then it is reduced by any reducing agent, ultraviolet (UV), heat, or polymer with high reducing strength. Metal ions such as Au, Ag, and Cu, which have high reduction potential, act as oxidizers in the polymerization of the monomer (Folarin et al., 2011; Grothe et al., 2012). Then, the solution polymerizes, forming nano-biocomposites (Haldorai and Shim, 2014; Hanemann and Szabo´, 2010; Uthale et al., 2021). The other methods for preparing composites are melt intercalation and template synthesis. The preparation methods are selected based on particle distribution in the polymer matrix. The advantages and disadvantages of the three methods are discussed in Table 16.2.

16.5.2 Characterization of polymer nanocomposites Characterization is an integral part of research after developing the nanobiocomposite to investigate and evaluate the influence of nanofiller on the performance and to study the interaction between the two components of the composite before deploying the material for any application. This section covers different techniques used in characterization (Fig. 16.7) (Dey et al., 2020).

16.5.2.1 Physical and analytical characterization The physical characterization is used to analyze dimensional stability in nanofiberbased composites to ascertain shelf life and applicability. Porosity and water absorption are essential parameters for tissue engineering. Resin chemical shrinkage helps develop a good quality product by describing surface failure and helps produce good surface-quality products. The spectroscopic studies determine molecular structure, weight, grafting percentage, and filler-polymer interaction in composites

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Table 16.2 Advantages and disadvantages of preparation methods. Preparation method Direct mixing/blending 1. Melt blending

Advantages G

G

G

No solvent requirement Low cost Large scale production

Disadvantages G

G

2. Solution blending

G

G

G

In situ polymerization

G

G

In situ sol gel

G

G

G

De-aggregation No degradation of polymer or compatibilizer Preparation parameters can be adjusted easily Good dispersion Surface modification of the nanofillers for better compatabilization Simple Miscibility control Proper dispersion

G

G

G

G

G

Degradation of Polymer or compatibilizer at high temperature Aggregation Not suitable for conventional blending process

Stability of polymer and nanofiller might be compromised Material contraction Expensive and toxic precursor Greater shrinkage

(Dey et al., 2020; Folarin et al., 2011). Here, X-ray diffraction will provide the information on morphology and crystallinity of the nano-biocomposite. High peak intensity will imply an ordered arrangement (Folarin et al., 2011).

16.5.2.2 Mechanical characterization The nano-biocomposites have superior mechanical properties to micro-biocomposites. The two parameters, hardness and tensile strength, correlate and indicate the composite’s toughness, ductility, and wear resistance (Dey et al., 2020).

16.5.2.3 Other characterization Rheology analysis helps estimate the quality and service life of the material and can be determined by shear, torsion, tension, and compression (Dey et al., 2020). Transmission electron microscopy (TEM), scanning electron microscopy (SEM), and atomic force microscopy (AFM) help study composites’ morphology (structure, pore size, and surface) without affecting the integrity. The main challenges faced while preparing the sample for TEM or SEM are the soft, non-conductive, and moisture-sensitivity of biopolymer. While imaging the composite through SEM, the surfaces are coated with a thin layer of gold or platinum. For TEM, the conventional method does not provide the finer details, such as nanofiller distribution in the matrix of biopolymer. This issue can be resolved by first embedding the sample in the resin, then slicing it with an ultramicrotome, and finally, obtaining the micrographs. While, the cryotome can be used for soft samples with glass transition temperatures lower than room temperature. For cryotome, no embedding of composite

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Figure 16.7 Characterization of nano-biocomposites. Source: Created with GIMP Development Team, 2019. GIMP. Available from: https://www. gimp.org.

is needed prior to sectioning; however, it is a time-consuming method. Freezeetching is also an alternative for soft samples. AFM is a topography imaging technique used to determine the interactions, surface roughness, and surface chemistry (Mittal, 2012; Oksman and Moon, 2014). In vitro, in vivo, and ex vivo investigations are needed to analyze the biological efficiency for drug delivery applications. These investigations will pave way for basic science to be translated for the benefit of humanity.

16.5.3 Controlled drug delivery applications of nanobiocomposites Due to the need for sustainable development, research to use biocomposites in various applications has expanded over the past decade (Abdulkhani et al., 2020).

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Incorporating small-sized, uniformly distributed, and stabilized metal and their oxide NPs into the biopolymer matrix results in high-performance multifunctional nanocomposites (Zare and Shabani, 2016). They can be a good replacement for unsustainable and non-renewable conventional composites (glass and carbon fiber-based) (Abdulkhani et al., 2020). Recent studies have reported that these materials might be used for controlled, targeted, combinational, tissue engineering, stimuli-sensitive (pH, temperature), implant, and antimicrobial drug delivery in the future. Researchers are still investigating materials for safe administration through different routes, such as oral, ocular, intramuscular, intravenous, and intramuscular.

16.5.3.1 Antibacterial agents Researchers are keen on developing new antimicrobial materials due to increased microbial resistance. Many studies have already proved the antibacterial properties of NPs, such as Ag, Au, Cu, TiO2, and ZnO, leading to advanced applications of NPs in biomedical engineering, medical textiles, clothes, and sportswear (Vodnik and Bogdanovi´c, 2019). When synthesized under strict conditions, they are stable, biocompatible, and sustainable. Due to their small size and high surface area-tovolume ratio, particles penetrate the bacterial membranes and interact with cell walls by electrostatic attraction, Van der Waals forces, receptor-ligand, and hydrophobic interactions. The possible antibacterial action of NPs is illustrated in Fig. 16.8 (Yaqoob et al., 2020). Shah et al. evaluated the efficacy of chitosan/silver nanocomposite against P. aeruginosa, S. aureus, and two strains of methicillin-resistant S. aureus (Shah et al., 2018). Similarly, Shah et al. also loaded chitosan/silver nanocomposite with moxifloxacin (fourth-generation fluoroquinolone antibiotic) in their other study. This study also confirmed the augmented antibacterial activity due to the presence of Ag NP in the composite (Shah et al., 2019). Venkatesan et al. developed chitosan-alginate composites of biosynthesized Ag NPs, which formed an inhibition zone of 11 6 1 and 10 6 1 mm against E. coli and S. aureus, respectively (Venkatesan et al., 2017). Lin et al. observed a noticeable inhibition zone of 2.6 and 2.0 cm for Ag NPs reinforced chitosan cellulose matrix against E. coli and S. aureus, respectively (Lin et al., 2015). When chitosan/ZnO nanocomposite was developed by in situ sol gel, the film annihilated the E. coli and S. aureus within 2 hours of exposure (Qiu et al., 2019). Menazea et al. synthesized polyvinyl alcohol/chitosan blend doped with Se NPs by laser ablation route, and the composite easily penetrated the gram-negative bacteria (E. coli and P. aeruginosa) than the gram-positive bacteria (S. aureus and B. subtilis) (Menazea et al., 2020). Tran et al. synthesized Au-reinforced cellulose-keratin composite by one-pot method and evaluated the antibacterial activity against methicillin-resistant S. aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) (Tran et al., 2018). Nevertheless, NPs should be appropriately characterized before deploying as antibacterial agents.

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Figure 16.8 Antibacterial action of nano-biocomposites. Created with GIMP. Source: The GIMP Development Team, 2019. GIMP. Available from: https://www.gimp.org.

16.5.3.2 Oral cavity care NPs can be helpful in oral cavity care through restorative, implantology, endodontics, prosthetics, cancer, and periodontology (Nizami et al., 2021). Nanofiller reinforced biocomposites also deliver antimicrobial drugs to prevent dental infections. Therefore, researchers have attempted incorporating NPs into toothbrushes and prosthodontics. Endodontic treatment involves eliminating bacterial infections in the root canal system, which can delay the periapical healing (Chavali et al., 2019; Enan et al., 2021). Ghorbanzadeh et al. prepared Ag NPs reinforced baseplate through in situ sol gel and tested against cariogenic bacteria. During orthodontic therapy, the composite can reduce the formation of tooth plaque and cavities (Ghorbanzadeh et al., 2015). Resin composites incorporating ZnO NPs strongly restrict Streptococcus mutans strains, according to Hojati et al., without compromising the mechanical properties of the resins, except that the depth of cure of the resin was reduced at high NPs levels (Hojati et al., 2013).

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16.5.3.3 Tissue engineering Tissue engineering involves repairing, replacing, or regenerating tissue or organs. The attack of microbes hinders this process, leading to infection (Murali et al., 2019). Here, NPs are preferred for regenerating tissues because of their tunable properties, low toxicity, targeted delivery potential, and controlled behavior (Yaqoob et al., 2020). Khalishwaralal et al. confirmed that chitosan-SeNPs films promote cellular migration by transferring electrical signals, strengthening its application in cardiac tissue engineering (Kalishwaralal et al., 2018). Doostmaohammadi et al. loaded Vitamin E in the composite solution of Se NPs-containing polycaprolactone/gelatin and then prepared fiber via electrospinning. As Se and Vitamin E are antioxidants, accelerated the wound healing process (Doostmohammadi et al., 2021). Ismail et al. investigated the wound healing efficacy of TiO2 reinforced gellan gum films on an incision wound model, and the biocomposite healed the wound within 14 days compared to the treatment of neat biopolymer (Ismail et al., 2019). The rats treated with a composite of gelatin-CeO2 showed collagen deposition and leukocyte infiltration compared to rats treated with gelatin on the 12th day (Raja and Fathima, 2018).

16.5.3.4 Cancer therapy Recent studies have pointed out that the delivery and efficacy of NPs-based therapies have fewer adverse effects. The NPs can be promising carriers for immune, photo or thermal ablation therapies, and controlled or stimuli-sensitive drug delivery due to their size, shape, and shell thickness, and ability to absorb light (Fig. 16.9) (Vodnik and Bogdanovi´c, 2019; Yaqoob et al., 2020). Delivery of therapeutic agents directly to the tumor cells is a critically challenging process. Yet, NPs can be easily transported through the cell. The growth of cancer cells depends on various factors, such as pH, protein, cytoskeletal function, endoplasmic stress, and free radicals. Traditional treatments are limited due to drug toxicity, drug resistance, and lack of specificity. NPs can be tuned by changing the size, shape, surface modification, and synthesis routes (Yaqoob et al., 2020). The chitosan-alginate-AgNPs composite had an IC50 of 4.6 mg to eradicate MDA-MB 231 cells (Venkatesan et al., 2017). Hyperthermia has earned interest of researchers, as cancer cells can be killed directly in a short span of time, whereas normal cells remain unaffected. Marı´n et al. developed magnetite reinforced gelatin films, and nanocomposite was used to evaluate the controlled delivery of acetaminophen under the influence of a magnetic field (Marı´n et al., 2018). Fe3O4 hydroxyapatite formed a hysteresis loop than the pure hydroxyapatite NPs; therefore, magnetite nanocomposites can be used for bone cancer therapy (Sundaram and Murugesan, 2015). Among all shapes of NPs, nanorods, nanocages, and nanocubes have shown significant absorption and photothermal effect by absorbing photons, which transformed into phonons-lattice vibrations to generate a localized temperature jump. The NPs show strong surface plasmon resonance on absorbing light in near-infrared range, ultimately heating and destroying the cancer cells (Vodnik and Bogdanovi´c, 2019; Yaqoob et al., 2020). Zhang et al. reported controlled and easy diffusion of Au NPs from gelatin matrix

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Figure 16.9 Nano-biocomposite-based cancer therapy. Source: Created with GIMP. The GIMP Development Team, 2019. GIMP. Available from: https://www.gimp.org).

composite. The composite scaffolds with Au nanorods of 65 nm seemed to have the best photothermal efficiency and cell death efficiency (Zhang et al., 2017).

16.5.3.5 Other drug delivery application Although insulin therapy is used to treat diabetes (both Type I and Type II), recent findings have shown that high insulin concentrations during insulin therapy cause substantial side effects in diabetic individuals, including hypoglycemia and weight gain. NPs can be employed as controlled drug delivery agents for insulin to reduce these toxic side effects. Extensive research is already being conducted to find the composite that can detect and target diabetic cells, deliver insulin, and manage delivery to maintain a normal blood glucose level. Nanocomposite membranes can potentially be employed to purify blood in conditions of renal impairment (Jeevanandam et al., 2019).

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Conclusion Biopolymer matrix nanocomposites are promising carriers for delivering the drug due to their non-toxic, biocompatible, biodegradable, eco-friendly, cheaper, readily available, and easy to manipulate properties compared to synthetic polymer matrix nanocomposites. Incorporating nanofiller in the polymer matrix, lead to decreased toxicity, controlled drug release, low dose required, increased oral bioavailability, and increased drug targeting in drug delivery. On that account, nanocomposites can also be engaged in tissue engineering, antimicrobial filtration, and biosensors. The present chapter enlighted the field of biopolymer nanocomposites, metal and metal oxide nanofillers, and recent development related to their drug development applications. With research and development regarding employing biopolymer matrix nanocomposite, green therapeutics will find their way into the drug delivery, which can boast of high efficiency and low or no side effects. In this material, biopolymers influence the workability and tenacity while nanofillers influence rigidity, dimensional, and thermal stability. Hence, this chapter unlocks the innovative methods and applications of nanomaterials for drug delivery. Still, this field of drug delivery is in its infancy and requires thorough investigation before the commercial application of composites. Efforts are being made to develop these composites through suitable techniques and study their characteristics for drug delivery applications.

Acknowledgments The authors are grateful to the Director, Institute of Nuclear Medicine and Allied Sciences, Defence Research and Development Organisation, Delhi, India, and the Indian Institute of Technology, Delhi, India, for the funding. Isha Gupta is immensely thankful to the University Grants Commission in New Delhi, India, for her fellowship (No. 114562).

Authors’ contributions I. Gupta: Conceptualisation, Writing—Original draft preparation. S. Gandhi: Project administration, supervision, Writing—Review and Editing. S. Sapra: Supervision, Writing—Review and Editing. All authors have read and agreed to the published version of the manuscript.

Compliance with ethical standards Not applicable.

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Conflict of interest We have no conflicts of interest.

Research involving human participants and animals Not applicable.

Informed consent Not applicable.

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Index

Note: Page numbers followed by “f” and “t” refer to figures and tables, respectively. A AA. See Acrylic acid (AA) Acrylic acid (AA), 452 453 ADBAC. See Alkyldimethylbenzylammonium chloride (ADBAC) Adipose tissue-derived stem cells, 322 323 Alginate dressings, 340 Alkyldimethylbenzylammonium chloride (ADBAC), 452 ALS. See Amyotrophic lateral sclerosis (ALS) Alzheimer’s disease, role of carbon nanotubes in, 424 426 Aminopropyltriethoxysilane (APTES), 446 447 Amyotrophic lateral sclerosis (ALS), 185 Antibacterial/antiviral agents, delivery of, 146 147 Antibiotic agents, 111 Antibiotics-loaded fabrics, 376 379 Anticancer agents, delivery of, 145 146 Antigen-presenting cells (APCs), 147 Antimicrobial activity test of textile materials, 23 Antimicrobials-loaded electrospun nanofibers, 375 376 Antioxidant drugs, 109 110 APCs. See Antigen-presenting cells (APCs) Apligraf, 324 APTES. See Aminopropyltriethoxysilane (APTES) Arc discharge, 135 136 Atomic force microscopy, 134 135 AVflo, 56 B Bandages, next-generation biomarkers and their applications in, 344t

commercially available, 343t conventional dressings, limitations of, 341 342 conventional wound dressings, 337 341 bioactive wound dressings, 340 composite dressings, 341 medicated dressings, 340 341 modern wound dressing, 338 340 tissue-engineered skin substitutes, 340 traditional wound dressing, 338 drug delivery dressings, 346 347 oxygen therapies, 347 349 hyperbaric oxygen therapy, 347 348 topical oxygen therapy (TOT), 348 349 reactive oxygen species in infection control, 337 in inflammatory phase, 334 336 in proliferative phase, 336 in re-epithelialization, 336 337 self-healing wound dressings, 346 wound dressings with monitoring capacity, 342 346 moisture controlling dressings, 346 pH responsive, 343 345 reactive oxygen species-responsive, 345 thermo responsive, 345 uric acid-based biosensors, 345 346 wound oxygenation, 343 BBB. See Blood-brain-barrier (BBB) Bioactive wound dressings, 340 Biocompatibility, 2 3 Bioconjugation techniques, 14 16 Biomaterials, 73 81 background, 73 for bigger molecules, 103 biomaterials’ evolution for drug delivery, 103 104

488

Biomaterials (Continued) polymers as responsive biomaterials, 105 108 RNA delivery, 104 105 characteristics of ideal dressing and lacunae with present biomaterial dressings, 87 88 conductive biomaterials, 80 81 for drug delivery, 102 108 fibers, characterization of, 83 85 analytical techniques, 84 morphological techniques, 84 techniques for mechanical studies, 84 85 fibers, synthesis of, 81 83 electrospinning, 83 melt spinning, 82 wet spinning, 81 82 ideal characteristics of, 313t intracellular targeting, 98 methods for drug delivery system, 98 102 electrospinning, 101 102, 101f microfluidic fiber fabrication, 99 100 molding method, 100 self-assembly, 100 101 nanoparticle-based wound therapies, 88 natural polymers, 74 77 chitosan, 74 75 collagen, 75 76 gelatin, 76 hyaluronic acid, 75 silk fibroin (SK), 76 77 phytoactive molecule-loaded polymers, 80 silk in drug delivery system, 115 119 biological therapeutic delivery, 116 117 films/coatings, 117 118 gene delivery, 116 microcapsules, 118 nanofiber hydrogels, 118 119 nanoparticles, 118 skin, anatomy of, 85 for small molecules, 103 synthetic polymers, 77 80 poly(ε-caprolactone), 79 polyethylene glycol, 79 80 polyglycolic acid, 79 polylactic acid, 78 79

Index

polylactic-co-glycolic acid, 80 polyvinyl alcohol, 77 78 wound healing and repair, 85 87 hemostasis phase, 86 inflammation phase, 86 87 proliferation phase, 87 remodeling phase, 87 Biomaterials-based fibers in drug delivery systems, 109 119 electrospun cellulose acetate, 109 115 alternative to cellulose acetate, 111 115 Biopolymer, 465 Blending electrospinning, 49 50, 289 Blood-brain-barrier (BBB), 422 427 carbon nanotubes, role of in Alzheimer’s disease, 424 426 in drug delivery in Parkinson’s disease, 426 427 in neurological disorders, 423 424 in Parkinson’s disease, 426 Bone engineering, 152 Bony defect replacement therapy, 154 Bovine serum albumin (BSA), 399 Brain cancer therapy, carbon nanotubes in, 427 429 Brain-targeting drug delivery, 148 BSA. See Bovine serum albumin (BSA) C CA. See Cellulose acetate (CA) Cancer treatment, 293 294 Carbon nanotubes (CNTs) agricultural applications, 156 in Alzheimer’s disease, 424 426 -based nanohybrid application, 155 heavy metal toxicity remediation, 155 superior oil sorbents, 155 biocompatibility of, 139 biodegradability of, 140 biodistribution of, 139 in biosensing, 143 144 blood-brain-barrier (BBB), 422 427 cellular fate of, 434 436 characterization techniques, 133 135 atomic force microscopy, 134 135 Fourier transform infrared spectroscopy, 135 proton nuclear magnetic resonance, 134

Index

Raman spectroscopy, 133 scanning electron microscopy (SEM), 133 134 thermogravimetric analysis, 134 transmission electron microscopy, 133 in dentistry, 153 154 bony defect replacement therapy, 154 dental restorative materials, 154 in drug delivery, 145 149 antibacterial or antiviral agents, delivery of, 146 147 anticancer agents, delivery of, 145 146 brain-targeting drug delivery, 148 gene delivery, 148 lymphatic targeting, 148 ocular drug targeting, 148 149 in Parkinson’s disease, 426 427 proteins and peptides, delivery of, 147 transdermal delivery, 149 vaccine delivery, 147 future aspects, 156 in imaging, 149 151 fluorescence imaging, 150 magnetic resonance imaging, 150 151 optical and nonoptical imaging, 149 150 photoacoustic imaging, 151 photoluminescence imaging, 150 as a loaded vehicle for therapeutic delivery, 420 421 modification, 141 143 chitosan-layered carbon nanotube, 142 143 folate-anchored carbon nanotubes, 142 PEGylation, 141 142 peptide conjugation, 143 nanomaterials act as scaffolds for neuroreconstruction, 429 430 for neural cell function, 432 433 neurocompatability, 430 432 in neurological disorders, 423 424 neurotoxicity and biocompatibility of, 434 in Parkinson’s disease, 426 in plant growth, 156 plausible drug delivery strategies in brain cancer therapy, 427 429 properties of, 128 130 electrical properties, 128 129 mechanical properties, 129 130

489

optical properties, 130 physical properties, 128 thermal properties, 130 in regenerative medicines, 154 155 repair and regeneration of neurons by, 429 433 synthesis of, 135 138 arc discharge, 135 136 catalytic chemical vapor deposition (CCVD), 137 138 chemical vapor deposition (CVD), 137 laser ablation, 136 137 thermal therapy, 153 photodynamic, 153 photothermal, 153 in tissue engineering, 151 153 bone engineering, 152 neural engineering, 152 153 toxicity, 140 141 cytotoxicity, 141 neurotoxicity, 140 types of, 130 132 double-walled carbon nanotubes (DWCNTs), 131, 132f justified on the basis of chirality, 132 multi-walled carbon nanotubes (MWCNTs), 129t, 131, 132f single-walled carbon nanotubes (SWCNTs), 129t, 130 131, 132f Catalysis and energy storage, 267 268 Catalytic chemical vapor deposition (CCVD), 137 138 CBN. See Cubic boron nitride (CBN) CCVD. See Catalytic chemical vapor deposition (CCVD) Cell-based wound dressing, 324 Cellulose acetate (CA), 109, 111 115 Chemical vapor deposition (CVD), 137 Chitin, 74f Chitosan, 74 75, 74f, 365 Chitosan-layered carbon nanotube, 142 143 Chitosan nanoparticles, 372 374 CIA. See Collagen-induced arthritis (CIA) Circulatory system, hollow fibers associated with, 187 188 Cisplatin (CPT), 110, 231 CNTs. See Carbon nanotubes (CNTs) Coating methods, 11 12 Coaxial electrospinning, 50, 289 290

490

Coaxial electrospray, 291 Co-electrospinning, 13 14 Collagen, 75 76 Collagen-induced arthritis (CIA), 192 193 Colloidal particle, electrospinning of, 42 43 Composite, electrospinning of, 43 Composite dressings, 341 Concentration, 44 Conductive biomaterials, 80 81 Controlled drug delivery, mechanisms of, 6 11 distribution-controlled release, 9 pharmacokinetics of drug release, 9 11 temporally controlled mechanism of drug release, 7 9 diffusion-controlled release, 7 dissolution-controlled release, 7 osmotic-controlled release, 7 9 Conventional dressings, limitations of, 341 342 Conventional emulsion-based scaffolds, 394 397 Conventional wound dressings, 337 341 bioactive wound dressings, 340 composite dressings, 341 medicated dressings, 340 341 modern wound dressing, 338 340 alginate dressings, 340 hydrocolloid dressings, 339 hydrogel dressings, 339 semipermeable film dressings, 338 339 semipermeable foam dressings, 339 tissue-engineered skin substitutes, 340 traditional wound dressing, 338 Core shell, 51 Cosmetics and skin treatment, 273 274 CPT. See Cisplatin (CPT) Cubic boron nitride (CBN), 149 Curcumin, 111 CVD. See Chemical vapor deposition (CVD) Cytotoxicity, 141 D Damage-associated molecular patterns (DAMPs), 310 DAMPs. See Damage-associated molecular patterns (DAMPs)

Index

DBD plasma. See Dielectric barrier discharge (DBD) plasma Dentistry, carbon nanotubes in, 153 154 bony defect replacement therapy, 154 dental restorative materials, 154 Dermis, 85 Dielectric barrier discharge (DBD) plasma, 451 Diffusion-controlled release, 7 Digestive system, hollow fibers associated with, 188 189 Dissolution-controlled release, 7 Distribution-controlled release, 9 DNA nanostructures, 219 222 DNA aptamers in functionalizing, 222 223 driving forces of self-assembly of, 220 221 and drug delivery, 228 229 dynamic DNA nanotechnology, 227 228 DNA tweezers, 227 228 DNA walkers, 228 formulation of, 221 222 future perspective, 238 239 Holliday junction in designing, 222 -mediated drug delivery, 231 235 modes of drug delivery, 230 231 passive delivery, 230 self-delivery, 230 231 nano-bio interface, 217 218 nanoscience, evolution of, 215 217 pros and cons of, 235 238 DNA nanostructures/DNA origami structures, 236 237 DNA origami in immune system, 237 238 3D-DNA nanostructures, 224 227 DNA nanotubes, 226 227 DNA origami, 225 226 DNA polyhedral, 224 225 2D-DNA nanostructures, 224 DNA tiles and lattices, 224 DNA nanotechnology, 219 advantages of, 219 Double-walled carbon nanotubes (DWCNTs), 131, 132f DOX. See Doxorubicin (DOX) Doxorubicin (DOX), 232 233, 428 Drug delivery dressings, 346 347

Index

Drug encapsulation, 401 405 Drug-loaded nonwoven textiles, 4 5 Drug-loaded woven fabrics, 3 4 Drug-releasing textile materials, 19 23 antimicrobial activity test, 23 applications, 24 26 classes of, 3 6 nonwoven electrospun fabrics, 5 6 nonwoven fabrics, 4 5 phase separation, 6 self-assembly in fabrics, 6 woven fabrics, 3 4 controllability of drug release from textile materials, 21 22 controlled drug delivery, mechanisms of, 6 11 diffusion-controlled release, 7 dissolution-controlled release, 7 distribution-controlled release, 9 osmotic-controlled release, 7 9 pharmacokinetics of drug release, 9 11 estimation of drug-loading efficiency, 21 future prospective, 26 27 historical development, 3 interface reactions, 23 mechanical and physical properties, 20 morphological and chemical characterization, 20 Fourier transform infrared spectroscopy study, 20 scanning electron microscopy, 20 stability study, 22 Dry-jet wet spinning technique, 177 Dry spinning, 176 DWCNTs. See Double-walled carbon nanotubes (DWCNTs) Dynamic DNA nanotechnology, 227 228 DNA tweezers, 227 228 DNA walkers, 228 E ECM. See Extracellular matrix (ECM) EDA. See Ethylene diamine (EDA) Electrodes in fuel cells, 268 269 Electrospinning, 13 14, 41 47, 41f, 47t, 83, 101 102, 101f, 178 180, 259 266, 260t, 261f, 262f, 288 291 applications of, 291 300 barrier membranes, 299 300

491

cancer treatment, 293 294 controlled release, 295 296 enzyme immobilization, 294 filtration, 296 ocular delivery, 292 tissue regeneration, 296 299 transdermal delivery, 292 293 wound healing, 300 blending, 289 coaxial, 289 290 coaxial electrospray, 291 of colloidal particle, 42 43 of composite, 43 electrospray, 290 291 emulsion, 290 environmental parameters, 264 266 method for incorporation of drug using, 48 51 blending electrospinning, 49 50 coaxial electrospinning, 50 core shell, 51 electrospray, 50 51 emulsion electrospinning, 50 layer-by-layer self assembly, 51 of organic polymer, 42 polymer solution, 261 263 processing conditions, 263 264 of small molecules, 43 44 surface modification, 290 Electrospray, 50 51, 290 291 Electrospun-based fabrics, 374 376 antimicrobials-loaded electrospun nanofibers, 375 376 Electrospun cellulose acetate, 109 115 alternative to cellulose acetate, 111 115 Electrospun nanofibers, 51 55 advantages of, 286 288 ease of fiber functionalization, 288 high surface area-to-volume ratio, 286 288 nanofibers synthesis from variety of polymers and materials, 288 biochemical stimuli-responsive, 55 biomedical applications of, 57 61 cancer research, 60 61 regenerative medicine, 59 60 wound dressing and antimicrobial agent, 60 electric field responsive, 54

492

Electrospun nanofibers (Continued) light-responsive, 53 54 magnetic field responsive, 54 55 multi stimuli-responsive, 55 pH-responsive, 52 53 thermo-responsive, 53 Electrostatic interactions, 221 Emulsion electrospinning, 50, 290 Emulsion templated 3D-printed scaffolds, 399 401 Emulsion templated scaffolds, 394 401 conventional emulsion-based scaffolds, 394 397 emulsion templated 3D-printed scaffolds, 399 401 Pickering emulsion-based scaffolds, 397 399 Emulsion templates, high internal phase, 401 405 Emulsion templating, 391 393 Enantiopure chiral drugs, 396 397 Encapsulation methods, 12 13 Endocrine system, hollow fibers associated with, 190 191 Endothelial progenitor cells in wound healing, 321 Enzymes, 366 367 immobilization, 294 Ethylene diamine (EDA), 446 Extracellular matrix (ECM), 75, 260 261, 334 335 F Fabrication of drug delivery systems, 11 19 bioconjugation techniques, 14 16 coating methods, 11 12 encapsulation methods, 12 13 fiber spinning techniques, 13 14 hollow fibers methods, 14 ion complexes methods, 16 17 nanotechnology in fabrics, 18 19 plasma treatment methods, 17 Fabrication techniques, 254 266 drawing process, 256 257 electrospinning, 259 266, 260t, 261f, 262f environmental parameters, 264 266 polymer solution, 261 263 processing conditions, 263 264

Index

melt blowing, 258 259 phase separation, 255 256 self-assembly, 257 258 template synthesis, 254 255 FBS. See Fetal bovine serum (FBS) f-CNT. See Functionalized carbon nanotubes (f-CNT) Feeding/flowing rate, 46 Fetal bovine serum (FBS), 236 237 Fiber spinning techniques, 13 14 Fluorescence imaging, 150 Folate-anchored carbon nanotubes, 142 Fourier transform infrared spectroscopy (FTIR), 135 study on textile materials, 20 Functionalized carbon nanotubes (f-CNT), 426 427 Functional polyesters, applications of, 450 455 antimicrobial surfaces, 451 455 tissue engineering, 455 G GBM. See Glioblastoma (GBM) Gelatin, 76 Gene delivery, 148 Glioblastoma (GBM), 418 GM-CSF. See Granulocyte-macrophage colony-stimulating factor (GM-CSF) Gold nanoparticles, 370 371 Graft co-polymerization, 14 15 Graft copolymer structures, 450f Granulocyte-macrophage colony-stimulating factor (GM-CSF), 193 H HealSmart, 57 Hixson-Crowell model, 399 Holliday junction in designing DNA nanostructures, 222 Hollow fibers, 169, 171 172 associated with different organ systems, 185 198 circulatory system, 187 188 digestive system, 188 189 endocrine system, 190 191 immune system and lymphatic system, 192 193 integumentary system, 191 192

Index

nervous system, 185 187 renal system, 194 reproductive system, 194 196 respiratory system, 189 190 skeletal system, 196 197 for drug delivery, 173 174 drug delivery systems, 169 171 drug-loading in hollow fiber, 181 183 drug release kinetics, 184 185 fabrication techniques for, 175 181 electrospinning, 178 180 melt spinning, 177 178 microfluidic spinning, 180 181 solution-based technique, 175 177 ion exchange hollow fiber membranes, 174 175 mechanism of drug release via hollow fiber, 183 184 methods, 14 prospects, 199 types of hollow fibers, 172 Hyaluronic acid, 75 Hydrocolloid dressings, 339 Hydrogel dressings, 339 Hydrogels, 118 119, 309 Hydrogen bonding, 221 Hydrophobic effect, 221 Hydroxypropyl cellulose fibers, 102 Hyperbaric oxygen therapy, 347 348 Hypodermis, 85 I IEMs. See Ion exchange membranes (IEMs) Immune system and lymphatic system hollow fibers associated with, 192 193 Infection control, reactive oxygen species in, 337 Inflammatory phase, reactive oxygen species in, 334 336 Infrared spectroscopy (IR), 20 Integumentary system, hollow fibers associated with, 191 192 Intracellular targeting, 98 Ion complexes methods, 16 17 Ion exchange hollow fiber membranes, 174 175 Ion exchange membranes (IEMs), 174 175 IR. See Infrared spectroscopy (IR)

493

L Laser ablation, 136 137 Layer-by-layer self assembly, 51 LD. See Levodopa (LD) Levodopa (LD), 426 LIBs. See Lithium-ion batteries (LIBs) Lithium-ion batteries (LIBs), 269 270 Lymphatic targeting, 148 M Magnetic resonance imaging (MRI), 106, 150 151 MDROs. See Multidrug-resistant organisms (MDROs) MDROs (multidrug-resistant organisms), 379 380 Medicated dressings, 340 341 Melt spinning, 82, 177 178 Mesenchymal stem cells in wound healing, 322 Mesoporous silica nanoparticles, 372 Metal and metal oxides, 367 Metal/metal oxide nanoparticles-reinforced biocomposites, 468 479 nano-biocomposites, controlled drug delivery application of, 475 479 antibacterial agents, 476 cancer therapy, 478 479 oral cavity care, 477 tissue engineering, 478 polymer nanocomposites, characterization of, 473 475 mechanical characterization, 474 other characterization, 474 475 physical and analytical characterization, 473 474 preparation methods, 468 473 direct mixing or blending, 468 473 in situ polymerization, 473 in situ sol gel, 473 Metronidazole, 375 376 Microcapsules, 118 Microfluidic fiber fabrication, 99 100 Microfluidic spinning, 180 181 Modern wound dressing, 338 340 alginate dressings, 340 hydrocolloid dressings, 339 hydrogel dressings, 339 semipermeable film dressings, 338 339

494

Modern wound dressing (Continued) semipermeable foam dressings, 339 Moisture controlling dressings, 346 Molding method, 100 Molecular weight, 44 45 Mononuclear phagocyte system (MPS), 237 238 MPS. See Mononuclear phagocyte system (MPS) MRI. See Magnetic resonance imaging (MRI) Multi-walled carbon nanotubes (MWCNTs), 129t, 131, 132f MWCNTs. See Multi-walled carbon nanotubes (MWCNTs) N Nano-biocomposites, controlled drug delivery application of, 475 479 antibacterial agents, 476 cancer therapy, 478 479 oral cavity care, 477 tissue engineering, 478 Nano-bio interface, 217 218 Nanofiber-based drug delivery systems clinically used electrospun nanofiber, 56 57 AVflo, 56 HealSmart, 57 PK Papyrus, 57 ReBOSSIS, 56 57 RIVELIN patch, 56 SurgiCLOT, 57 electrospinning, 41 47, 41f of colloidal particle, 42 43 of composite, 43 of organic polymer, 42 of small molecules, 43 44 electrospinning, method for incorporation of drug using, 48 51 blending electrospinning, 49 50 coaxial electrospinning, 50 core shell, 51 electrospray, 50 51 emulsion electrospinning, 50 layer-by-layer self assembly, 51 electrospun nanofiber-based drug delivery systems, biomedical applications of, 57 61

Index

cancer research, 60 61 drug delivery, 58 59 regenerative medicine, 59 60 wound dressing and antimicrobial agent, 60 electrospun nanofibers, 51 55 biochemical stimuli-responsive, 55 electric field responsive, 54 light-responsive, 53 54 magnetic field responsive, 54 55 multi stimuli-responsive, 55 pH-responsive, 52 53 thermo-responsive, 53 future perspectives, 61 62 Nanofiber fabrication, multifaceted approach for application of nanofibers, 266 274, 267f catalysis and energy storage, 267 268 cosmetics and skin treatment, 273 274 drug delivery, 271 272 electrodes in fuel cells, 268 269 lithium-ion batteries (LIBs), 269 270 tissue engineering, 270 271 water treatment, 266 267 wound healing, 272 273 drawing process, 256 257 electrospinning, 259 266, 260t, 261f, 262f environmental parameters, 264 266 polymer solution, 261 263 processing conditions, 263 264 melt blowing, 258 259 phase separation, 255 256 self-assembly, 257 258 synthetic polymeric materials for nanofibers, 271t template synthesis, 254 255 Nanofiber hydrogels, 118 119 Nanofibers, 5 6, 13 14, 15f Nanofibers’ fabrication, governing parameters affecting, 44 47 ambient parameters, 47 applied voltage, 46 concentration, 44 feeding/flowing rate, 46 molecular weight, 44 45 polymer solvents, 46 surface charge density/conductivity, 45 46

Index

surface tension, 45 tip to collector distance, 46 47 viscosity, 45 Nano-filamentary reinforced biocomposites, 464 Nanofillers, 466 467, 467f Nano-layered reinforced biocomposites, 463 464 Nanoparticle-based wound therapies, 88 Nanoparticles, 118 Nanoparticles-based fabrics, 367 374 chitosan nanoparticles, 372 374 gold nanoparticles, 370 371 mesoporous silica nanoparticles, 372 silver nanoparticles, 368 370 zinc oxide nanoparticles, 371 Nano-particulate reinforced biocomposites, 464 465 Nanotechnology in fabrics, 18 19 National Institute of Biomedical Imaging and Bioengineering (NIBIB), 73 74 Natural biomaterials, 313, 314t Natural dyes, 366 Natural herbal products, 365 Natural hydrogels in market, 320 321 Natural polymers, 74 77 chitosan, 74 75 collagen, 75 76 gelatin, 76 hyaluronic acid, 75 silk fibroin (SK), 76 77 Nervous system, hollow fibers associated with, 185 187 Neural cell function, applications of carbon nanotubes for, 432 433 Neural engineering, 152 153 Neurocompatability, 430 432 Neurological disorders, role of carbon nanotubes in, 423 424 Neuroreconstruction, nanomaterials act as scaffolds for, 429 430 Neuroregeneration-supporting scaffolds, 430 Neurotoxicity, 140 N-halamines, 366 NIBIB. See National Institute of Biomedical Imaging and Bioengineering (NIBIB) n n staking, 221 Non-steroidal anti-inflammatory (NSAIDs), 109 110

495

Nonwoven electrospun fabrics, 5 6 phase separation, 6 self-assembly in fabrics, 6 Nonwoven fabrics, 4 5 NSAIDs. See Non-steroidal antiinflammatory (NSAIDs) O Ocular delivery, 292 Ocular drug targeting, 148 149 Optical and nonoptical imaging, 149 150 Organic polymer, electrospinning of, 42 Osmotic-controlled release, 7 9 Oxygen role in wound healing, 333 337 infection control, reactive oxygen species in, 337 inflammatory phase, reactive oxygen species in, 334 336 proliferative phase, reactive oxygen species in, 336 re-epithelialization, reactive oxygen species in, 336 337 Oxygen therapies, 347 349 hyperbaric oxygen therapy, 347 348 topical oxygen therapy (TOT), 348 349 P PAMPs. See Pathogen-associated molecular patterns (PAMPs) Parkinson’s disease carbon nanotubes in, 426 functionalized carbon nanotubes (f-CNT) in drug delivery in, 426 427 Pathogen-associated molecular patterns (PAMPs), 310 PEG. See Polyethylene glycol (PEG) PEGDA scaffold. See Polyethylene glycol diacrylate matrix (PEGDA) scaffold PEGylation, 141 142 PEI. See Polyethyleneimine (PEI) PEO. See Polyethylene oxide (PEO) Peptide conjugation, 143 PET. See Polyethylene terephthalate (PET) PEVA. See Polyethylene-vinyl acetate (PEVA) Pharmacokinetics of drug release, 9 11 Photoacoustic imaging, 151 Photodynamic therapy, 153 Photoluminescence imaging, 150

496

Photothermal therapy, 153 Phytoactive molecule-loaded polymers, 80 Pickering emulsion-based scaffolds, 397 399 PK Papyrus, 57 Plasma treatment methods, 17 Polybiguanides, 361 Poly(ε-caprolactone), 79 Polyester, functional designing of, 444 450 chemical functionalization, 445 446 graft copolymerization, 449 450 plasma activation, 446 449 Polyethylene glycol (PEG), 79 80, 103, 453 Polyethylene glycol diacrylate matrix (PEGDA) scaffold, 433 Polyethyleneimine (PEI), 105 Polyethylene oxide (PEO), 100 101 Polyethylene terephthalate (PET), 443 Polyethylene-vinyl acetate (PEVA), 24 26 Polyglycolic acid, 79 Polylactic acid, 78 79 Polylactic-co-glycolic acid, 80 Polymer nanocomposites, characterization of, 473 475 mechanical characterization, 474 other characterization, 474 475 physical and analytical characterization, 473 474 Polymers as responsive biomaterials, 105 108 Polymer solvents, 46 Polyvinyl alcohol, 77 78 Proliferative burst, 334f, 336 337 Proliferative phase, reactive oxygen species in, 336 Proteins and peptides, delivery of, 147 Proton nuclear magnetic resonance, 134 Pseudomonas aeruginosa, 4 Q Quaternary ammonium compounds, 360 361 R RA. See Rheumatoid arthritis (RA) Raman spectroscopy, 133 RBDSs. See Reservoir-based delivery systems (RBDSs)

Index

Reactive oxygen species in infection control, 337 in inflammatory phase, 334 336 in proliferative phase, 336 in re-epithelialization, 336 337 ReBOSSIS, 56 57 Re-epithelialization, reactive oxygen species in, 336 337 Regenerative medicines, carbon nanotubes in, 154 155 Renal system, hollow fibers associated with, 194 Reproductive system, hollow fibers associated with, 194 196 Reservoir-based delivery systems (RBDSs), 40 Respiratory system, hollow fibers associated with, 189 190 Rheumatoid arthritis (RA), 192 193 RIVELIN patch, 56 RoA. See Rosmarinic acid (RoA) Rosmarinic acid (RoA), 110 S Scanning electron microscopy (SEM), 133 134 of textile materials, 20 Scanning probe microscope (SPM), 217 SCs. See Stem cells (SCs) SELEX. See Systematic evolution of ligands by exponential enrichment (SELEX) Self-assembly, 100 101 Self-healing wound dressings, 346 SEM. See Scanning electron microscopy (SEM) Semipermeable film dressings, 338 339 Semipermeable foam dressings, 339 SF. See Silk fibroin (SF) Silicate-based NPs, 466 467 Silicon rubber, 103 Silk fibroin (SF), 76 77, 115 116 Silk in drug delivery system, 115 119 biological therapeutic delivery, 116 117 films/coatings, 117 118 gene delivery, 116 microcapsules, 118 nanofiber hydrogels, 118 119 nanoparticles, 118 Silk microcapsules, 118

Index

Silver nanoparticles, 111, 368 370 Single-walled carbon nanotubes (SWCNTs), 129t, 130 131, 132f Skeletal system, hollow fibers associated with, 196 197 Skin, anatomy of, 85 Small molecules, electrospinning of, 43 44 Solution-based technique, 175 177 dry-jet wet spinning technique, 177 dry spinning, 176 wet spinning, 175 176 SPM. See Scanning probe microscope (SPM) Stem cells (SCs), 309, 322 323 Stimuli-responsive drug delivery using smart electrospun nanofibers, 51 55 biochemical stimuli-responsive electrospun nanofibers, 55 electric field responsive electrospun nanofibers, 54 light-responsive electrospun nanofibers, 53 54 magnetic field responsive electrospun nanofibers, 54 55 multi stimuli-responsive electrospun nanofibers, 55 pH-responsive electrospun nanofibers, 52 53 thermo-responsive electrospun nanofibers, 53 Surface charge density/conductivity, 45 46 Surface modification electrospinning, 290 Surface tension, 45 SurgiCLOT, 57 SWCNTs. See Single-walled carbon nanotubes (SWCNTs) Synthetic biomaterials, 313 314, 315t Synthetic hydrogels in market, 321 Synthetic polymers, 77 80 poly(ε-caprolactone), 79 polyethylene glycol, 79 80 polyglycolic acid, 79 polylactic acid, 78 79 polylactic-co-glycolic acid, 80 polyvinyl alcohol, 77 78 Systematic evolution of ligands by exponential enrichment (SELEX), 223

497

T Temporally controlled mechanism of drug release, 7 9 diffusion-controlled release, 7 dissolution-controlled release, 7 osmotic-controlled release, 7 9 Textile antimicrobial agent, 360 367 chitosan, 365 enzymes, 366 367 metal and metal oxides, 367 natural dyes, 366 natural herbal products, 365 N-halamines, 366 polybiguanides, 361 quaternary ammonium compounds, 360 361 triclosan, 361 365 Textile materials antimicrobial activity test of, 23 controllability of drug release from, 21 22 estimation of drug-loading efficiency of, 21 Fourier transform infrared spectroscopy study on, 20 interface reactions of, 23 mechanical and physical properties of, 20 scanning electron microscopy of, 20 stability study of, 22 Textiles antimicrobial agent, 362t Textile surfaces, functional designing of functional polyesters, applications of, 450 455 antimicrobial surfaces, 451 455 tissue engineering, 455 polyester, functional designing of, 444 450 chemical functionalization, 445 446 graft copolymerization, 449 450 plasma activation, 446 449 TGA. See Thermogravimetric analysis (TGA) Theranostic nanomedicine, 419 Thermogravimetric analysis (TGA), 84 85, 134 3D-DNA nanostructures, 224 227 DNA nanotubes, 226 227 DNA origami, 225 226 DNA polyhedral, 224 225 Tissue-engineered skin substitutes, 340

498

Tissue engineering, 270 271 carbon nanotubes in, 151 153 bone engineering, 152 neural engineering, 152 153 Tissue regeneration, 296 299 Topical oxygen therapy (TOT), 348 349 TOT. See Topical oxygen therapy (TOT) Traditional wound dressing, 338 Transdermal delivery, 149, 292 293 Transmission electron microscopy, 133 Triclosan, 361 365 Tubes by fiber templates (TUFT), 13 14 TUFT. See Tubes by fiber templates (TUFT) 2D-DNA nanostructures, 224 DNA tiles and lattices, 224 U Uric acid-based biosensors, 345 346 V Vaccine delivery, 147 Viscosity, 45 Vitamin B9, 142 Voltage, applied, 46 W WASTE. See Wetting-assisted templating (WASTE) Water treatment, 266 267 Wet spinning, 81 82, 175 176 Wetting-assisted templating (WASTE), 13 14 Wound, classification of, 308t Wound dressings with monitoring capacity, 342 346 moisture controlling dressings, 346 pH responsive, 343 345 reactive oxygen species-responsive, 345 thermo responsive, 345

Index

uric acid-based biosensors, 345 346 wound oxygenation, 343 Wound healing, 272 273, 300 application of hydrogel in, 318 321 natural hydrogels in market, 320 321 synthetic hydrogels in market, 321 approaches, 312, 312t biomaterial used in, 312 314 natural biomaterials, 313, 314t synthetic biomaterials, 313 314, 315t inflammatory molecules in, 311t limitation of biomaterials dressing in wound healing, 324 phases of, 310f physiology of, 309 312 hemostasis, 310 inflammation, 310 proliferation, 311 remodeling, 311 312 and repair, 85 87 hemostasis phase, 86 inflammation phase, 86 87 proliferation phase, 87 remodeling phase, 87 stem cells in, 321 323 adipose tissue-derived stem cells, 322 323 application of stem cells loaded biomaterials, 323 endothelial progenitor cells, 321 mesenchymal stem cells, 322 Wound healing dressings, 315 318 cell-based, 324 Wound shock, 73 Wound therapies, nanoparticle-based, 88 Woven fabrics, 3 4 Z Zinc oxide nanoparticles, 371