Handbook of Nanofibers 9783319536545, 9783319536552

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Ahmed Barhoum Mikhael Bechelany Abdel Salam Hamdy Makhlouf Editors

Handbook of Nanofibers

Handbook of Nanofibers

Ahmed Barhoum • Mikhael Bechelany Abdel Salam Hamdy Makhlouf Editors

Handbook of Nanofibers With 508 Figures and 62 Tables

Editors Ahmed Barhoum Institut Européen des Membranes (IEMM, ENSCM UM CNRS UMR5635) Montpellier, France

Mikhael Bechelany Institut Européen des Membranes IEM – UMR 5635, ENSCM, CNRS Univ Montpellier Montpellier, France

Abdel Salam Hamdy Makhlouf University of Texas Rio Grande Valley Edinburg, TX, USA

ISBN 978-3-319-53654-5 ISBN 978-3-319-53655-2 (eBook) ISBN 978-3-319-53656-9 (print and electronic bundle) https://doi.org/10.1007/978-3-319-53655-2 © Springer Nature Switzerland AG 2019 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

Preface

Part I: Fundamental Aspects, Experimental Setup, Synthesis, Properties and Characterization Fibers with diameters in the nanometer range are usually called as “nanofibers.” Nanofibers can be generated from different polymers and hence have different properties and applications. Nanofibers are the most promising nanomaterials that can be produced on a large scale. The development of nanofibers-based systems has enhanced the scope for utilizing these nanomaterials in a wide range of applications, from the fields of health and energy to automotive and aerospace. Therefore, the intensive current research in this area is driven toward the fabrication, characterization, and application of nanofibrous systems for industrial and medical purposes. This volume (Vol. 1) covers the fundamental aspects, experimental setup, synthesis, properties, and characterization of different nanofibers-based systems. In particular, this volume highlights in detail the following topics: • The history of nanofibers technology, types and classifications, fabrication techniques, critical processing parameters, fiber alignment, physical and chemical properties, bulk and surface functionalization, and other treatments to allow practical applications • All recent aspects of nanofibers technologies, from experimental setup to industrial applications • New physical and chemical techniques for nanofibers fabrication, in-depth treatment of their surface functionalization, and characterization • The unique properties of nanofibers that can be obtained by modifying their diameter, alignment, morphology, and composition and by manipulating the arrangement of atoms and molecules • The properties and morphology of several kinds of nanostructured fibers, such as metal oxides, natural polymers, synthetic polymers, and hybrid inorganicpolymers and carbon-based materials • The different techniques for designing nanofibers, self-assembly in nanofibers, critical parameters of synthesis, fiber alignment, modeling and simulation, and characterization methods.

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• A critical discussion and comparison between nanofibers-based systems and micro-sized fibers • The challenges in nanofibers-based systems and the interdisciplinary perspectives of science, biology, engineering, and technology, incorporating both fundamentals and applications This is a valuable reference for materials scientists; biologists; physicians; chemical, biomedical, manufacturing, and mechanical engineers working in R&D industry; and academia, who want to learn more about how nanofibers-based systems are commercially applied.

Part II: Technologies, Emerging Applications, and Future Markets This is the second volume of the Handbook of Nanofibers. This volume explores the technological challenges of nanofibers, the emerging applications, and the global markets of nanofibers-based systems. Nanofibers are the most promising nanomaterials that can be produced on a large scale. A huge amount of ongoing research and development and technology implementation in academia and industry are aiming to utilize nanofibers-based systems in a wide range of industrial and medical applications, e.g., drug delivery, tissue engineering, medical implants, medical diagnostics and therapy, biosensors, catalysis, energy harvesting, energy storage, water/waste treatment, papermaking, textiles, construction, automotive, aerospace, and many more. This volume provides an in-depth discussion about the challenges of nanofibers technology and their future markets. In particular, it highlights in detail the following topics: • The major applications of nanofibers, and the architecture of nanostructured materials and their emerging developments • Recent progress in the direct/indirect synthesis of nanofibers and their potential applications • An outlook on the opportunities and challenges for the fabrication and manufacturing of nanofibers in industry • An in-depth look at the nature of nanofibers and architecture nanostructured fibers in terms of their applicability for industrial uses • Polymeric, carbon, metallic, and metal oxide, and ceramic nanofibers that are prepared by direct and/or indirect synthetic routes • In-depth insight and review on the most recent advances, and industrial applications of the different types of nanofibers-based systems with unique structures and compositions • The challenges and interdisciplinary perspective of nanofibers-based systems in science, biology, engineering, medicine, and technology, incorporating both fundamentals and applications

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This volume demonstrates how cutting-edge developments in nanofibers translate into real-world innovations in a range of industry sectors. This is a valuable reference for materials scientists; biologists; physicians; chemical, biomedical, manufacturing; and mechanical engineers working in R&D industry; and academia, who want to learn more about the future global markets, emerging applications, and the technology challenges of nanofibers-based systems. Montpellier, France Montpellier, France Edinburg, TX, USA April 2019

Ahmed Barhoum Mikhael Bechelany Abdel Salam Hamdy Makhlouf Editors-in-Chief

Contents

Volume 1 Part I Fundamental Aspects, Experimental Setup, Synthesis, Properties, and Characterization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Nanofiber Technologies: History and Development . . . . . . . . . . . . Ahmed Barhoum, Rahimeh Rasouli, Maryam Yousefzadeh, Hubert Rahier, and Mikhael Bechelany

2

Fabrication of Nanofibers: Electrospinning and Non-electrospinning Techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . Dalapathi Gugulothu, Ahmed Barhoum, Raghunandan Nerella, Ramkishan Ajmer, and Mikhael Bechelany

1 3

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Different Methods for Nanofiber Design and Fabrication . . . . . . . Ibrahim Alghoraibi and Sandy Alomari

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Advances in Melt Electrospinning Technique . . . . . . . . . . . . . . . . . Mahmoud Mohammed Bubakir, Haoyi Li, Ahmed Barhoum, and Weimin Yang

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Design of Porous, Core-Shell, and Hollow Nanofibers . . . . . . . . . . Maryam Yousefzadeh and Farzaneh Ghasemkhah

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6

Polymer-Based Nanofibers: Preparation, Fabrication, and Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Masoumeh Zahmatkeshan, Moein Adel, Sajad Bahrami, Fariba Esmaeili, Seyed Mahdi Rezayat, Yousef Saeedi, Bita Mehravi, Seyed Behnamedin Jameie, and Khadijeh Ashtari

7

Carbohydrate-Based Nanofibers: Applications and Potentials . . . Sajad Bahrami, Moein Adel, Fariba Esmaeili, Seyed Mahdi Rezayat, Bita Mehravi, and Masoumeh Zahmatkeshan

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Contents

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Native Crystalline Polysaccharide Nanofibers: Processing and Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pieter Samyn and Anayancy Osorio-Madrazo

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Mixed Metal and Metal Oxide Nanofibers: Preparation, Fabrication, and Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Vasanthakumar Arumugam and Kandasamy G. Moodley

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Various Techniques to Functionalize Nanofibers . . . . . . . . . . . . . . Sakthivel Nagarajan, Sebastien Balme, S. Narayana Kalkura, Philippe Miele, Celine Pochat Bohatier, and Mikhael Bechelany

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Dyeing of Electrospun Nanofibers . . . . . . . . . . . . . . . . . . . . . . . . . . Muzamil Khatri, Umair Ahmed Qureshi, Farooq Ahmed, Zeeshan Khatri, and Ick Soo Kim

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Nanofibers and Biofilm in Materials Science . . . . . . . . . . . . . . . . . Hideyuki Kanematsu, Dana M. Barry, Hajime Ikegai, Michiko Yoshitake, and Yoshimitsu Mizunoe

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Cellulose Nanofibers: Fabrication and Surface Functionalization Techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Kai Zhang, Ahmed Barhoum, Chen Xiaoqing, Haoyi Li, and Pieter Samyn

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A Broad Family of Carbon Nanomaterials: Classification, Properties, Synthesis, and Emerging Applications . . . . . . . . . . . . . Ahmed Barhoum, Ahmed Esmail Shalan, Soliman I. El-Hout, Gomaa A. M. Ali, Sabah M. Abdelbasir, Esraa Samy Abu Serea, Ahmed H. Ibrahim, and Kaushik Pal

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Characterization and Evaluation of Nanofiber Materials . . . . . . . Taha Roodbar Shojaei, Abdollah Hajalilou, Meisam Tabatabaei, Hossein Mobli, and Mortaza Aghbashlo

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Optical Spectroscopy for Characterization of Metal Oxide Nanofibers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Roman Viter and Igor Iatsunskyi

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Electrical Properties of Nanowires and Nanofibers . . . . . . . . . . . . Cristina Buzea and Ivan Pacheco

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Volume 2 Part II Technologies, Emerging Applications, and Future Markets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

Electrospun Nanofibrous Scaffolds: A Versatile Therapeutic Tool for Cancer Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Preethi Gopalakrishnan Usha, Maya Sreeranganathan, Unnikrishnan Babukuttan Sheela, and Sreelekha Therakathinal Thankappan Nair

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Application of Nanofibers in Ophthalmic Tissue Engineering . . . . Davood Kharaghani, Muhammad Qamar Khan, and Ick Soo Kim

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Nanofibrous Scaffolds for Tissue Engineering Application . . . . . . Sakthivel Nagarajan, S. Narayana Kalkura, Sebastien Balme, Celine Pochat Bohatier, Philippe Miele, and Mikhael Bechelany

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Structural Multifunctional Nanofibers and Their Emerging Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Dalapathi Gugulothu, Ahmed Barhoum, Syed Muzammil Afzal, Banoth Venkateshwarlu, and Hassan Uludag

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Advances in Nanofibers for Antimicrobial Drug Delivery . . . . . . . Rahimeh Rasouli and Ahmed Barhoum

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Functional Nanofiber for Drug Delivery Applications . . . . . . . . . . Rana Imani, Maryam Yousefzadeh, and Shirin Nour

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Nanofibers for Medical Diagnosis and Therapy . . . . . . . . . . . . . . . Priyanka Prabhu

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Nanofiber Electrodes for Biosensors . . . . . . . . . . . . . . . . . . . . . . . . Subhash Singh

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Nanofibers for Medical Textiles . . . . . . . . . . . . . . . . . . . . . . . . . . . Muhammad Qamar Khan, Davood Kharaghani, Zeeshan Khatri, and Ick Soo Kim

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Recent Trends in Nanofiber-Based Anticorrosion Coatings . . . . . . Akihiro Yabuki and Indra W. Fathona

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Nanofibers for Membrane Applications . . . . . . . . . . . . . . . . . . . . . Anbharasi Vanangamudi, Xing Yang, Mikel C. Duke, and Ludovic F. Dumée

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Electrospun Membranes for Airborne Contaminants Capture . . . Riyadh Al-Attabi, Y. S. Morsi, Jürg A. Schütz, and Ludovic F. Dumée

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Contents

Design of Heterogeneities and Interfaces with Nanofibers in Fuel Cell Membranes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Marta Zatoń, Sara Cavaliere, Deborah J. Jones, and Jacques Rozière

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Nanofibers as Promising Materials for New Generations of Solar Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1017 Ahmed Esmail Shalan, Ahmed Barhoum, Ahmed Mourtada Elseman, Mohamed Mohamed Rashad, and Mónica Lira-Cantú

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Nanofibers for Water Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . 1049 Elise des Ligneris, Lingxue Kong, and Ludovic F. Dumée

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Engineering Nanofibers as Electrode and Membrane Materials for Batteries, Supercapacitors, and Fuel Cells . . . . . . . . . . . . . . . . 1105 Liu Haichao, Haoyi Li, Mahmoud Mohammed Bubakir, Weimin Yang, and Ahmed Barhoum

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Emerging Applications of Cellulose Nanofibers . . . . . . . . . . . . . . . 1131 Ahmed Barhoum, Haoyi Li, Mingjun Chen, Lisheng Cheng, Weimin Yang, and Alain Dufresne

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1157

About the Editors

Dr. Ahmed Barhoum Ph.D. Institut Européen des Membranes (IEMM, ENSCM UM CNRS UMR5635) Montpellier France Dr. Ahmed Barhoum is currently a postdoc researcher at Institut Européen des Membranes, Université de Montpellier and Lecturer (tenured) of Nanotechnology at the Chemistry Department, Helwan University. He obtained his Ph.D. and postdoc-fellow in Chemical Engineering from Vrije Universiteit Brussel and he was also previously a researcher at Grenoble Institute of Technology (France, 2012), Leibniz Universität Hannover (Germany, 2015), and Institut du Europeen Membrane (France, 2016), Université de Montpellier (France, 2018). His current research program as scientist is related to the synthesis of nanoparticles, nanofibers, and thin films for applications in the fields of energy production, wastewater treatment, electrochemical biosensors, and drug delivery. His research program includes: (i) establishment of new methods for designing nanomaterials (electrospinning, atomic layer deposition, sol-gel hot injection, wet carbonation, photoreduction, UV-irradiation synthesis, microwave synthesis, ultrasonic irradiation synthesis), and (ii) use of specific morphologies (0D, 1D, and/or 2D) to give the final material new features and high performance. Dr. Barhoum has won several scientific grants and prizes for his academic excellence: Institut français d’Égypte postdoc (2018), Research Foundation Flanders (FWO) postdoc (2016), Research Foundation Flanders (FWO)-PhD (2015), Medastar Erasmus Mundus (2012), Welcome xiii

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About the Editors

Erasmus Mundus (2012), Institut français d’Égypte and Campus France (2012), Gold Medal from the Egyptian Syndicate of Scientific Professions (2007), Gold Medal from Helwan University (2007), and many more. He is an expert evaluator for several funding organizations, e.g., National Science Center (Poland), Czech Science Foundation (Russia), Swiss National Science Foundation (SNSF, Switzerland), and a reviewer for 20+ peerreviewed journals, including American Chemical Society, Elsevier, Wiley, Springer Nature, Bentham Science, MDPI, and Scientific Research. He is an editorial board member for several peer-reviewed journals, including Research & Reviews Journal of Chemistry, Chemistry of Advanced Materials, and International Journal of Materials Science and Applications. Dr. Barhoum is also co-organizer of four conferences, editor of four handbooks published by Elsevier and Springer Nature, author and co-author of more than 70 publications, and effectively supervised 10 Ph.D. and master’s students. Dr. Mikhael Bechelany Ph.D. Institut Européen des Membranes, IEM – UMR 5635 ENSCM, CNRS, Univ Montpellier Montpellier, France Dr. Mikhael Bechelany (born in March 1979) obtained his Ph.D. in Materials Chemistry from the University of Lyon (France) in 2006. His Ph.D. work was devoted to the synthesis and characterization of silicon and boronbased 1D nanostructures (nanotubes, nanowires, and nanocables). Then, he worked as a postdoc at EMPA (Switzerland). His research included the fabrication of nanomaterials (nanoparticles and nanowires), their organization, and their nanomanipulation for applications in different fields, such as photovoltaic, robotic, chemical, and biosensing. In 2010, he became a scientist at CNRS. His current research interest in the European Institute of Membranes (UMR CNRS 5635) in Montpellier (France) focuses on novel synthesis methods for metals and ceramics nanomaterials, such as atomic layer deposition (ALD), electrospinning and/or on nanostructuring using natural lithography (nanospheres and/or membranes). His research efforts include the design of nanostructured membranes for energy (gas separation, photovoltaic, biofuel cells, and osmotic energy

About the Editors

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harvesting), environmental (water treatment, (bio)sensors and packaging), and health (DNA sensing, tissue engineering, drug delivery). Dr. Bechelany is the coordinator of several international, European, national, and industrial projects (more than 30 projects). He supervised more than 20 Ph.D. students and 6 postdocs. Dr. Bechelany is the editor of several book chapters and special issues. He is also an editorial board member for several peer-reviewed journals. At the end of 2018, he is the author and co-author of more than 175 publications, 13 book chapters, 6 patents, 25 conference papers, and 30 invited talks. He is the co-organizer of 13 conferences and the co-founder of 3 start-ups.

Dr. Abdel Salam Hamdy Makhlouf Ph.D. University of Texas Rio Grande Valley Edinburg, TX, USA Professor Makhlouf experts 26 years with a blend of industrial and academic leadership experience as a full professor of materials science and technology, full professor of advanced “nano-bio” manufacturing engineering, and materials/metallurgical engineering consultant. He is responsible for providing research leadership, maintaining a high standard of quality in STEM graduate and undergraduate teaching, and connecting consultancy/research activities to industry applications. He has strong contributions to the fields of materials science, chemistry, and engineering with more than 220 publications, including 17 books for Springer and Elsevier, covering a broad and cross-disciplinary research competence in advanced materials, nanotechnology, smart coatings, corrosion, biomaterials, waste/water treatment, and materials for energy applications. Prof. Makhlouf won numerous national and international prestigious prizes and awards, such as the Humboldt Research Award for Experienced Scientists from the Max Planck Institute, Germany; Fulbright, NSF, and Dept. of Energy fellowships, USA; Shoman Award in Engineering Science; State Prize of Egypt in Advanced Science and Technology; and many more. He has a strong record of external research funding through competitive grants, industry grants, and consultancies. He has coordinated several international projects with USA, France,

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About the Editors

Germany, Peru, KSA, and Italy. He has been PI, co-PI, or team leader on several international grants – NSFand DOE-funded grants. He laid the groundwork for the proposed research and successfully administered the projects, collaborated with other researchers, and produced several publications from each project. Prof. Makhlouf has proven effective leadership and management at the department, college, and university levels. He has been organizer, head speaker, and chair at numerous highly prestigious international conferences. He is senior editor and board member of many international journals, panellist and reviewer for the USA NSF, and for the German Academic Exchange Service (DAAD). He is member of the European Science Foundation, expert evaluator and rapporteur for the EU’s FP7, expert in the German Aerospace Center, reviewer for the US Fulbright Commission, and many more. Prof. Makhlouf is a consultant/reviewer for several universities: reviewer for the Faculty Promotion and Tenure/Post Tenure Committees (e.g., Ghent University, University of Texas, Tezpur University, and Jazan University). He is a consultant for King Saud University, reviewer for the master’s program for Al-Imam University, and reviewer for the American University in Sharjah. He created and delivered four courses for mechanical and manufacturing engineering master students and received a very high teaching evaluation. He effectively supervised and graduated ten Ph.D. and master’s students, and three postdoctoral scientists.

Contributors

Sabah M. Abdelbasir Central Metallurgical Research and Development Institute (CMRDI), Helwan, Cairo, Egypt Esraa Samy Abu Serea Chemistry and Biochemistry Department, Faculty of Science, Cairo University, Giza, Egypt Moein Adel Department of Medical Nanotechnology, School of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran Deputy of Research and Technology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran Department of Medical Nanotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran Syed Muzammil Afzal Sri Shivani College of Pharmacy, Warangal, Telangana, India Mortaza Aghbashlo Department of Mechanical Engineering of Agricultural Machinery, Faculty of Agricultural Engineering and Technology, College of Agriculture and Natural Resources, University of Tehran, Karaj, Iran Farooq Ahmed Center of Excellence in Nanotechnology and Materials, Mehran University of Engineering and Technology, Jamshoro, Pakistan Ramkishan Ajmer West Zone Central Drugs Standards Control Organization, Mumbai, India Riyadh Al-Attabi Faculty of Science, Engineering and Technology, Swinburne University of Technology, Hawthorn, VIC, Australia Institute for Frontier Materials, Deakin University, Geelong, Waurn Ponds, VIC, Australia Ibrahim Alghoraibi Physics Department, Damascus University, Damascus, Syria Faculty of Pharmacy Department, of Basic and Supporting Sciences, Arab International University, Damascus, Syria Gomaa A. M. Ali Chemistry Department, Faculty of Science, Al-Azhar University, Assiut, Egypt xvii

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Contributors

Sandy Alomari Physics Department, Damascus University, Damascus, Syria Vasanthakumar Arumugam Department of Chemistry, Faculty of Applied Sciences, Durban University of Technology, Durban, South Africa Khadijeh Ashtari Department of Medical Nanotechnology, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran Unnikrishnan Babukuttan Sheela Laboratory of Biopharmaceuticals and Nanomedicine, Division of Cancer Research, Regional Cancer Centre, Thiruvananthapuram, Kerala, India Sajad Bahrami Department of Medical Nanotechnology, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran Student Research Committee, Iran University of Medical Sciences, Tehran, Iran Sebastien Balme Institute of European Membranes (IEM), University of Montpellier, Montpellier, France Ahmed Barhoum Institut Européen des Membranes (IEMM, ENSCM UM CNRS UMR5635), Montpellier, France Dana M. Barry Clarkson University, Potsdam, NY, USA Mikhael Bechelany Institut Européen des Membranes, IEM – UMR 5635, ENSCM, CNRS, Univ Montpellier, Montpellier, France Celine Pochat Bohatier Institute of European Membranes, IEM UMR-5635, University of Montpellier, ENSCM, CNRS, Montpellier, France Mahmoud Mohammed Bubakir Department of Mechanical and Electrical Industrial Engineering, Gharyan Engineering College, Gharyan, Libya State Key Laboratory of Organic-Inorganic Composites, Beijing University of Chemical Technology, Beijing, China Cristina Buzea IIPB Medicine Corporation, Owen Sound, Canada Sara Cavaliere Institut Charles Gerhardt Montpellier, UMR CNRS 5253, Agrégats Interfaces et Matériaux pour l’Energie, Université de Montpellier, Montpellier Cedex 5, France Mingjun Chen College of Mechanical and Electrical Engineering, Beijing University of Chemical Technology, Beijing, China Lisheng Cheng College of Mechanical and Electrical Engineering, Beijing University of Chemical Technology, Beijing, China Elise des Ligneris Deakin University, Geelong, Institute for Frontier Materials, Waurn Ponds, VIC, Australia Alain Dufresne CNRS, Grenoble INP, LGP2, University of Grenoble Alpes, Grenoble, France

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Mikel C. Duke Institute for Sustainability and Innovation (ISI), College of Engineering and Science, Victoria University, Melbourne, VIC, Australia Ludovic F. Dumée Institute for Frontier Materials, Deakin University, Geelong, Waurn Ponds, VIC, Australia Soliman I. El-Hout Central Metallurgical Research & Development Institute (CMRDI), Helwan, Cairo, Egypt Ahmed Mourtada Elseman Electronic and Magnetic Laboratory, Advanced Materials Division, Central Metallurgical Research & Development Institute (CMRDI), Cairo, Egypt Fariba Esmaeili Department of Medical Nanotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran Indra W. Fathona Engineering Physics, School of Electrical Engineering, Telkom University, Dayeuhkolot, Bandung, Indonesia Farzaneh Ghasemkhah Department of Textile Engineering, Amirkabir University of Technology (AUT), Tehran, Iran Preethi Gopalakrishnan Usha Laboratory of Biopharmaceuticals and Nanomedicine, Division of Cancer Research, Regional Cancer Centre, Thiruvananthapuram, Kerala, India Dalapathi Gugulothu Balaji Institute of Pharmaceutical Sciences, Narsampet, Warangal, India Liu Haichao College of Mechanical and Electrical Engineering, Beijing University of Chemical Technology, Beijing, China State Key Laboratory of Organic-Inorganic Composites, Beijing University of Chemical Technology, Beijing, China Abdollah Hajalilou Faculty of Mechanical Engineering, Department of Materials, University of Tabriz, Tabriz, Iran Igor Iatsunskyi NanoBioMedical Centre, Adam Mickiewicz University, Poznan, Poland Ahmed H. Ibrahim Center for Materials Science, Zewail City of Science and Technology, Giza, Egypt Hajime Ikegai National Institute of Technology, Suzuka College, Suzuka, Japan Rana Imani Department of Biomedical Engineering, Amirkabir University of Technology (AUT), Tehran, Tehran, Iran Seyed Behnamedin Jameie Neuroscience Research Center (NRC), Iran University of Medical Sciences, Tehran, Iran

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Contributors

Deborah J. Jones Institut Charles Gerhardt Montpellier, UMR CNRS 5253, Agrégats Interfaces et Matériaux pour l’Energie, Université de Montpellier, Montpellier Cedex 5, France Hideyuki Kanematsu National Institute of Technology, Suzuka College, Suzuka, Japan Davood Kharaghani Nano Fusion Technology Research Group, Division of Frontier Fibers, Institute for Fiber Engineering (IFES), Interdisciplinary Cluster for Cutting Edge Research (ICCER), Shinshu University, Ueda, Nagano, Japan Davood Kharaghani Nanofusion Technology Research Lab, Division of Frontier Fiber, Institute if Fiber Engineering, Interdisciplinary Cluster for Cutting Edge Research (ICCER), Faculty of Textile Sciences, Shinshu University, Ueda/Nagano, Japan Muzamil Khatri Nano Fusion Technology Research Group, Division of Frontier Fibers, Institute for Fiber Engineering (IFES), Interdisciplinary Cluster for Cutting Edge Research (ICCER), Shinshu University, Tokida, Japan Zeeshan Khatri Nano Fusion Technology Research Group, Division of Frontier Fibers, Institute for Fiber Engineering (IFES), Interdisciplinary Cluster for Cutting Edge Research (ICCER), Shinshu University, Tokida, Japan Center of Excellence in Nanotechnology and Materials, Mehran University of Engineering and Technology, Jamshoro, Pakistan Ick Soo Kim Nano Fusion Technology Research Group, Division of Frontier Fibers, Institute for Fiber Engineering (IFES), Interdisciplinary Cluster for Cutting Edge Research (ICCER), Shinshu University, Tokida, Japan Lingxue Kong Deakin University, Geelong, Institute for Frontier Materials, Waurn Ponds, VIC, Australia Haoyi Li College of Mechanical and Electrical Engineering, Beijing University of Chemical Technology, Beijing, China State Key Laboratory of Organic-Inorganic Composites, Beijing University of Chemical Technology, Beijing, China Mónica Lira-Cantú Nanostructured Materials for Photovoltaic Energy Group, Catalan Institute of Nanoscience and Nanotechnology (ICN2), CSIC, and the Barcelona Institute of Science and Technology (BIST), Barcelona, Spain Bita Mehravi Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran Department of Medical Nanotechnology, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran Philippe Miele Institute of European Membranes, IEM UMR-5635, University of Montpellier, ENSCM, CNRS, Montpellier, France

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Institut Universitaire de France (IUF), University of MESRI, Paris, France Yoshimitsu Mizunoe The Jikei University, School of Medicine, Tokyo, Japan Hossein Mobli Department of Mechanical Engineering of Agricultural Machinery, Faculty of Agricultural Engineering and Technology, College of Agriculture and Natural Resources, University of Tehran, Karaj, Iran Kandasamy G. Moodley Department of Chemistry, Faculty of Applied Sciences, Durban University of Technology, Durban, South Africa Y. S. Morsi Faculty of Science, Engineering and Technology, Swinburne University of Technology, Hawthorn, VIC, Australia Sakthivel Nagarajan Institute of European Membranes, IEM UMR-5635, University of Montpellier, ENSCM, CNRS, Montpellier, France Crystal Growth Centre, Anna University, Chennai, India S. Narayana Kalkura Crystal Growth Centre, Anna University, Chennai, India Raghunandan Nerella Balaji Institute of Pharmaceutical Sciences, Narsampet, Warangal, India Shirin Nour Department of Biomedical Engineering, Amirkabir University of Technology (AUT), Tehran, Tehran, Iran Anayancy Osorio-Madrazo Institute of Microsystems Engineering IMTEK Laboratory for Sensors, and Freiburg Materials Research Center FMF, University of Freiburg, Freiburg, Germany Ivan Pacheco Department of Pathology, Grey Bruce Health Services, Owen Sound, Canada Department of Pathology and Laboratory Medicine, Schülich School of Medicine and Dentistry, Western University, London, ON, Canada Kaushik Pal Department of Nanotechnology, Bharath University, Chennai, India Priyanka Prabhu Shobhaben Pratapbhai Patel School of Pharmacy and Technology Management, SVKM’s NMIMS, Mumbai, India Muhammad Qamar Khan Nano Fusion Technology Research Group, Division of Frontier Fibers, Institute for Fiber Engineering (IFES), Interdisciplinary Cluster for Cutting Edge Research (ICCER), Shinshu University, Ueda, Nagano, Japan Umair Ahmed Qureshi Center of Excellence in Nanotechnology and Materials, Mehran University of Engineering and Technology, Jamshoro, Pakistan Hubert Rahier Department of Materials and Chemistry, Faculty of Engineering, Vrije Universiteit Brussel, Brussels, Belgium

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Contributors

Mohamed Mohamed Rashad Electronic and Magnetic Materials Department, Advanced Materials Division, Central Metallurgical Research & Development Institute (CMRDI), Cairo, Egypt Rahimeh Rasouli Department of Medical Nanotechnology, International Campus, Tehran University of Medical Sciences, Tehran, Iran Seyed Mahdi Rezayat Department of Medical Nanotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran Taha Roodbar Shojaei Department of Mechanical Engineering of Agricultural Machinery, Faculty of Agricultural Engineering and Technology, College of Agriculture and Natural Resources, University of Tehran, Karaj, Iran Jacques Rozière Institut Charles Gerhardt Montpellier, UMR CNRS 5253, Agrégats Interfaces et Matériaux pour l’Energie, Université de Montpellier, Montpellier Cedex 5, France Maya Sreeranganathan Laboratory of Biopharmaceuticals and Nanomedicine, Division of Cancer Research, Regional Cancer Centre, Thiruvananthapuram, Kerala, India Yousef Saeedi Department of Pharmacology, Faculty of Science, University of Utrecht, Utrecht, Netherlands Pieter Samyn Applied and Analytical Chemistry, Institute for Materials Research (IMO-IMOMEC), Hasselt University, Diepenbeek, Belgium Jürg A. Schütz CSIRO Manufacturing, Waurn Ponds, VIC, Australia Ahmed Esmail Shalan Electronic and Magnetic Materials Department, Advanced Materials Division, Central Metallurgical Research & Development Institute (CMRDI), Cairo, Egypt Subhash Singh Division of Research and Development, Mechanical Engineering Department, Lovely Professional University, Phagwara, Panjab, India Sreelekha Therakathinal Thankappan Nair Laboratory of Biopharmaceuticals and Nanomedicine, Division of Cancer Research, Regional Cancer Centre, Thiruvananthapuram, Kerala, India Meisam Tabatabaei Microbial Biotechnology Department, Agricultural Biotechnology Research Institute of Iran (ABRII), Agricultural Research, Education, and Extension Organization (AREEO), Karaj, Iran Hassan Uludag Department of Chemical and Materials Engineering, University of Alberta, Edmonton, AB, Canada

Contributors

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Anbharasi Vanangamudi Institute for Sustainability and Innovation (ISI), College of Engineering and Science, Victoria University, Melbourne, VIC, Australia Institute of Frontier Materials (IFM), Deakin University, Waurn Ponds, VIC, Australia Banoth Venkateshwarlu Cental Drugs Standards Control Organization, Mumbai, India Roman Viter Institute of Atomic Physics and Spectroscopy, University of Latvia, Riga, Latvia Chen Xiaoqing College of Mechanical and Electrical Engineering, Beijing University of Chemical Technology, Beijing, China Akihiro Yabuki Graduate School of Engineering, Hiroshima University, Higashihiroshima, Japan Weimin Yang College of Mechanical and Electrical Engineering, Beijing University of Chemical Technology, Beijing, China State Key Laboratory of Organic-Inorganic Composites, Beijing University of Chemical Technology, Beijing, China Xing Yang Institute for Sustainability and Innovation (ISI), College of Engineering and Science, Victoria University, Melbourne, VIC, Australia Michiko Yoshitake National Institute for Materials Science, Tsukuba, Japan Maryam Yousefzadeh Department of Textile Engineering, Amirkabir University of Technology (AUT), Tehran, Iran Masoumeh Zahmatkeshan Neuroscience Research Center (NRC), Iran University of Medical Sciences, Tehran, Iran Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran Department of Medical Nanotechnology, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran Marta Zatoń Institut Charles Gerhardt Montpellier, UMR CNRS 5253, Agrégats Interfaces et Matériaux pour l’Energie, Université de Montpellier, Montpellier Cedex 5, France Kai Zhang College of Mechanical and Electrical Engineering, Beijing University of Chemical Technology, Beijing, China

Part I Fundamental Aspects, Experimental Setup, Synthesis, Properties, and Characterization

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Nanofiber Technologies: History and Development Ahmed Barhoum, Rahimeh Rasouli, Maryam Yousefzadeh, Hubert Rahier, and Mikhael Bechelany

Contents Introduction to Nanotechnology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . History and Development of Nanofiber Technologies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Types of Nanofibers and Nanofibrous Materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Classification of Nanofibers Based on Their Chemical Composition . . . . . . . . . . . . . . . . . . . . . . . Unique Properties of Nanofibers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Emerging Applications of Nanofibers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Energy Production and Energy Storage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Environmental Protection and Improvement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biomedical Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion and Future Outlooks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4 6 11 11 20 22 22 25 29 33 33

A. Barhoum (*) Institut Européen des Membranes (IEMM, ENSCM UM CNRS UMR5635), Montpellier, France e-mail: [email protected]; [email protected]; [email protected] R. Rasouli Department of Medical Nanotechnology, International Campus, Tehran University of Medical Sciences, Tehran, Iran e-mail: [email protected] M. Yousefzadeh Department of Textile Engineering, Amirkabir University of Technology (AUT), Tehran, Iran e-mail: [email protected] H. Rahier Department of Materials and Chemistry, Faculty of Engineering, Vrije Universiteit Brussel, Brussels, Belgium e-mail: [email protected] M. Bechelany Institut Européen des Membranes, IEM – UMR 5635, ENSCM, CNRS, Univ Montpellier, Montpellier, France e-mail: [email protected] © Springer Nature Switzerland AG 2019 A. Barhoum et al. (eds.), Handbook of Nanofibers, https://doi.org/10.1007/978-3-319-53655-2_54

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Abstract

Nanofibers are defined as fibers with diameters on the order of 100 nm. Nanofibers have been considered one of the top interesting studied materials for academicians and one of the greatest intriguing materials for modern industry. Nanofibers provide great opportunities for creating products with new properties via various physical and chemical modifications during or following the production process. Nanofibers bring promising solutions for fundamental problems in our life in various fields such as energy, environmental, and medical treatments. Researchers have turned to the development of a number of nanofiber fabrication techniques such as electrospinning, template-assisted synthesis, melt-blowing, bicomponent spinning, forcespinning and flash-spinning, chemical vapor deposition, and physical vapor deposition. However, the electrospinning is the widely used technique to produce continuous nonwoven nanofiber mats. In this chapter, a brief introduction to nanoscience and nanotechnology was discussed, and then the history and development of nanofiber technologies and production techniques are presented. In the following, types and classifications of nanofibers based on their origin and morphologies and their unique properties are explained, and finally, some current applications and their future perspectives are discussed. Keywords

Nanofibers · History · Types · Morphologies · Technologies · Emerging applications · Markets

Introduction to Nanotechnology Nanoscience and nanoengineering are emerging interdisciplinary fields of research. Nanoscience and nanoengineering can be included in the material, physical, chemical, biological, and environmental sciences. Nanotechnology is the nanoscience and nanoengineering technology conducted at the nanoscale (1–100 nm) [1]. Nanotechnology is one of the most important contents of the revolution in science and technology industry in the twenty-first century that can be compared with the industrial revolution. Nanotechnology will change the human-made equipment and lifestyle in the near future, and it is likely to have a profound impact on the worldwide economy [2–7]. It is widely felt that nanotechnology will be the next industrial revolution. Nanomaterials research takes a materials science to nanotechnology, leveraging advances in materials metrology and synthesis which have been developed in support of microfabrication research. Herein, there are some examples to imagine just how small that is the nanoscale: the thickness of a sheet of paper ~100,000 nm [8], the wideness of a human hair ~80,000 nm [9], and the diameter of human doublestrand DNA ~2 nm [10].

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The scientific story of the preparation of nanomaterials begins late. Since the 1990s, nanotechnology has developed rapidly, and new terms and new concepts have been emerging, such as nanoelectronics, nanomaterials, nanobiology, etc. Prof. Richard Feynman delivered the lecture in the title of “There’s Plenty of Room at the Bottom” on December 29, 1959, at California Institute of Technology at the American Physical Society meeting. He introduced new world on an atomic scale. Nanomaterials due to the possibility to manipulate on an atomic scale and emerge unique and novel physical and chemical properties have attracted much attention. The materials falling under the nanotechnology regime are likely to have one or more dimensions (length/width/height) in the nanometer scale, which exhibit novel or unique properties that cannot be extrapolated from the measurement of the same material properties at the larger scale. Within the nanotechnology field, there are a wide variety of terminologies used to describe its various facets. Nomenclature is a formal system that is used to consistently assign recognizable names based on a framework of rules. For the research community, a unique name for a specific nanomaterial would allow for the development of meaningful relationships between nanomaterial and their properties and effects. The prefix “nano” is derived from the Greek word, meaning “dwarf,” and was officially confirmed as standard in 1960 [11]. According to ASTM 2012, the nanotechnology refers to a wide range of technologies that measure, manipulate, or incorporate materials and/or features with at least one dimension between approximately in the range of 1–100 nm. Most regulatory authorities have used 1–100 nm to define the nanoscale, which is consistent with the ISO/ASTM standards. Some other organizations are recommending increasing the upper limit of nanoscale materials to 1000 nm, rather than the ISO and ASTM International determinations that scientific usage is 100 nm. Recent investigations suggested 20 nm as the size below which unique, size-dependent properties are to be observed, especially those associated with quantum confinement [12]. Some more terms used in nanotechnology are explained in Table 1 according to the international standards as brief. Several projects under the initiative have surveyed sources of nanomaterials and where they could be released. Sources of nanoparticles can be natural or anthropogenic or engineered (intentionally produced with specific properties). Scientists are beginning to recognize that all sources of nanomaterials are important in evaluating the possible impact of nanoscale materials on human health and the environment. Natural sources of nanomaterials include combustion products volcanic ash, forest fires, and ocean spray. Natural nanomaterials can also be formed through weathering processes of metal- or anion-containing rocks, as well as at acid mine drainage sites. Biological systems often feature natural functional nanomaterials. Nanomaterials may be also incidentally produced as a by-product of mechanical or industrial processes. Manufactured nanomaterials are materials engineered or manufactured by humans on the nanoscale with specific physicochemical composition and structure to exploit properties and functions associated with its dimensions. The risks or properties of nanomaterials are not determined by the intention of the manufacturer. The material source and manufacturing process may not change their final properties. The

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Table 1 Terminology for nanotechnology Term Nano Nanoscale Nanoparticle Nanofiber Nanocomposite Nanomaterials

Nanoscience

Nanotechnology

Definition The prefix is derived from the Greek word “Nannos,” meaning “very short man” Size range from approximately 1 nm to 100 nm Nano-object with all three external dimensions in the nanometric scale (1–100 nm) Nano-object with two similar external dimensions in the nanoscale and the third significantly larger Multiphase structure in which at least one of the phases has at least one dimension in the nanometric scale “A natural, incidental or manufactured material containing particles, in an unbound state or as an aggregate or as an agglomerate, where for 50% or more of the particles in the number size distribution, one or more external dimensions is in the size range of 1–100 nm” “Study, discovery, and understanding of matter in the nanoscale, where size- and structure-dependent properties and phenomena, as distinct from those associated with individual atoms or molecules or with bulk materials, can emerge” Nanotechnology is an emerging engineering discipline that applies methods from nanoscience to create usable, marketable, and economically viable products. In 1974, Japanese scientist Norio Taniguchi is the first person to use the term “nanotechnology,” which refers to the improvement of mechanical processing and precision of materials

Ref [13] BSI, 2011 ISO, 2008 CEN ISO, 2008 BSI, 2011 EU, 2011

BSI, 2011

[14]

naturally occurring nanofibers may exhibit similar properties to those that are manufactured. The fundamental issues of nanomaterials technology are as follows: (1) the ability to control the nanomaterial size at nanoscale; (2) the ability to tune the composition and the crystal structure such as defects, concentration gradients, etc.; (3) the ability to control the modulation bulk and surface structure; (4) the development of synthesis and/or fabrication methods for nanostructured materials; and (5) the better understanding of the influence of the fiber diameter, morphology, and interfaces help to get ideal physical, chemical, and mechanical properties of materials [15]. In this chapter, the nanofiber history, development, classification, and fabrication techniques are presented. In the following, the unique properties and some current applications and their future perspectives are discussed.

History and Development of Nanofiber Technologies The history of nanofiber technology is difficult to tease out from the general progress of nanoscience and nanotechnology [16–62]. The development of nanofiber production techniques has a notable history of nearly four centuries of discoveries and

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products. This section outlines the story of the inventions in nanofiber technologies that mainly relate to the development of electrostatic production and drawing of fibers. In the late 1600s, William Gilbert work was considered as an early example of what would grow to the modern scientific electrospinning technology [16]. Gilbert observed that when a piece of charged amber was brought near a spherical drop of water on a dry surface, the amber “pulls the nearest parts out of their position and draws it up into a cone.” This observation is the first record of what is now referred to as a Taylor cone [16]. In the following, electrically charged liquid droplets were researched more by other scientists. Another closely related work to electrospinning was done in 1749 when Nollet demonstrated how a water jet disintegrated when it was charged. Physicist Lord Rayleigh investigated the unstable states of electrically charged liquid droplets. The first description of a process recognizable as electrospinning was in 1902 when J. F. Cooley filed a US patent entitled “Apparatus for electrically dispersing fibers” [17]. The modern term “electrospinning” was popularized by Doshi, Reneker (1995), and many other researchers in the latter end of the twentieth century [18]. Since 1995, the number of publications about electrospinning has been increasing exponentially every year. In Table 2 a brief summary of work done in this period time is illustrated. Since 1995 there have been further theoretical developments of the driving mechanisms of the electrospinning process and then processing different types of materials for various applications. In 2005, the first book in the title of An Introduction to Electrospinning and Nanofibers was published by Prof. Seeram Ramakrishna and his co-authors. Nowadays the electrospun nanofibers have attracted enormous interest by scientist, and we can see the commercial-based nanofibrous materials in the market in ultrafiltration, medical, sensors, and so on. To date, there exist many different methods for nanofiber production like CO2 laser supersonic drawing [63], solution blow spinning [64], centrifugal jet spinning [65, 66], electrohydrodynamic direct writing, drawing [67], template synthesis [68], self-assembly [69], phase separation [70], freeze-drying synthesis [71], interfacial polymerization [72], solution blowing [64], electrospinning [73], etc. [74]. Electrospinning is the most commonly used technique to produce nanofibers because of the straightforward setup, the ability to mass-produce nonwoven nanofiber mats. Nowadays, it becomes one of the most commercial methods for fabrication of nanofiber materials. The science behind electrospinning has a history that stretches back to the earliest days of the scientific investigation. This enabling technology is simple and robust and can be readily modified to try new experimental techniques. These factors have led to a boom in academic publications across the world [38]. Electrospinning is widely used because of the simple setup, low-cost setup, ability to mass production of continuous nanofibers, high simplicity, and flexibility in controlling the diameters, compositions, and orientations of the nanofibers, depending on intended application purposes [75]. The electrospun nanofiber formation from different materials and their potential applications are extensively studied. Electrostatic spinning technology has the advantages of simple equipment, convenient operation, and high production efficiency. Electrospinning is applying a high

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Table 2 Timeline of electrospinning, history, and development of nanofiber technology till 2008 Description Physicist William Gilbert performed an experiment in which a spherical waterdrop on a dry surface deflects into a cone shape by coming close to electrically charged amber Georg Mathias Bose published a paper entitled “Electricity – its discovery and development, with poetic sketches” The unstable states of electrically charged liquid droplets were investigated by Physicist Lord Rayleigh. He noted when equilibrium was established between the surface tension and electrostatic force, the liquid was ejected in tiny jets. He published several valuable papers on the instability of jets, the influence of electricity on colliding waterdrops, and the equilibrium of liquid conducting masses charged with electricity Schwabe invented a number of methods for spinning silk and creating artificial fibers In 1988, Charles Vernon Boys described the process in a paper on nanofiber manufacture The observation of electrostatic atomization of conductive fluid under an applied voltage American inventor John Francis Cooley patented the first work about electrospinning. In the same year, Morton patented a simpler low-throughput machine Zeleny published paper entitled “Discharge of Electricity from Pointed Conductors Differing in Size” Burton and Wiegand worked on the effect of electricity on streams of waterdrops By publishing the work by Zeleny published on the behavior of fluid droplets at the end of metal capillaries, the efforts to mathematically model the behavior of fluids under electrostatic forces began from that time Macky did some investigations on the deformation and breaking of waterdrops in strong electric fields Formhals published the first patent describing the experimental production of nanofibers Onsager investigated the electric moments of molecules in liquids N.D. Rozenblum and I.V. Petryanov-Sokolov generated electrospun fibers, which they developed into filter materials Commercial application of electrospun air filter materials known as “Petryanov filters” in the Union of Soviet Socialist Republics (USSR) English investigated the corona from a waterdrop Studied the phenomena occurring in the electrospray process Creation of hollow graphitic carbon fibers

Inventor Gilbert, 1628 [16]

Bose, 1744 [19] Rayleigh, 1978, 1879, 1882 [20–23]

Louis Schwabe, 1845 [24] Boys, 1887 [26] Lord Raleigh, 1897 [27] Cooley, Morton, 1902 [22, 33]

Zeleny, 1907 [29] Burton, 1912 [30] Zeleny, 1914a, 1914b, 1917, 1920 [31–34]

Macky, 1931 [35] Formhals, 1934 [36] Onsager, 1936 [37] N.D. Rozenblum and I.V. Petryanov-Sokolov, 1938 [38] Soviets, ~1940 [38]

English, 1948 [39] John Zeleny, 1914 [40] Radushkevich and Lukyanovich, 1952 [41] (continued)

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Table 2 (continued) Description Richard P. Feynman gave talk under-titled “There’s Plenty of Room at the Bottom – An Invitation to Enter a New Field of Physics” at the annual meeting of the American Physical Society at the California Institute of Technology (Caltech). This was the first published work about nanotechnology Between 1964 and 1969, Geoffrey Ingram Taylor produced the theoretical foundation of electrospinning. He studied the cone shape (Taylor cone) formed by the fluid droplet under the effect of an electric field. He further worked with J.R. Melcher in conducting fluids to develop the leaky dielectric model Professor Harold L. Simons published a patent for an instrument producing ultrathin and ultralight nanofiber fabrics with various patterns Development of a chemical vapor deposition (CVD) process for creating nanoscale carbon fibers Martin and Cockshott proposed the use of electrospun fibers as a wound dressing Annis et al. recorded study of electrospun fibers as implantable (vascular) graft Introduced manufacturing of electrospun polymeric nanofibers at industrial level Larrondo and John Manley electrospun continuous filaments of rapidly crystallizing polymers from their melts Assigned the first US patent for hollow carbon fibers Discovered multiwalled carbon nanotubes Discovered single-walled carbon nanotubes Reneker and Doshi published a paper that describes the electrospinning process and the processing conditions for producing electrospun fibers from different polymers with a variety of cross-sectional morphology and size range from 50 to 5000 nm Wang used electrospinning to fabricate inorganic fibers “Core-shell electrospinning process has been developed” “A review on polymer nanofibers by electrospinning and their applications in nanocomposites” was published by Prof. Seeram Ramakrishna and co-authors First scientific journal publication of electrospun continuous yarn The first book with the following title An Introduction to Electrospinning and Nanofibers published by Prof. Seeram Ramakrishna In 2005, Elmarco Company launched the Nanospider™, the first technology in the world to enable nanofiber production on an industrial scale In 2008, Receipt of CE Mark for Electrospun implantable graft (AVflo™ Vascular Access Graft by Nicast)

Inventor Feynman, 1959 [42]

Taylor, 1964, 1965, 1969, Melcher, 1969 [43–46]

Simons, 1966 [47]

Oberlin, Endo and Koyama, 1976 [48] Martin, 1977 [49] Annis, 1978 [50] Donaldson Co., the 1980s Larrondo, 1981 [51–53]

Hyperion Catalysis, 1987 [54] Sumio Iijima, 1991 [55] IBM Almaden Research Center and NEC, 1993 [56] Doshi, 1995 [57]

Wang, 2001 [58] Sun, 2003 [59] Haung, 2003 [60]

Smit, 2005 [61] Ramakrishna, 2005 [62]

http://www.elmarco.com

www.nicast.com

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voltage in the front end of the nozzle with the polymer solution or melt. At the tip of the nozzle, the droplets drop out of the nozzle and become a cone called a Taylor cone when the charge is concentrated and repelled. The repulsion of charges increases gradually, and the liquid ejects straight from the tip of the cone when the repulsion exceeds the surface tension. The surface charge density becomes larger because of the ejected solution getting thin. Then the repulsion of charge increases and stretches solution to flow by further. At this time, nanofibers are formed on the electrode due to the rapid increase in surface area of the solution flow [75]. Over the past two decades, many electrospinning models have been developed and patented including needleless electrospinning [73], multiple jets in electrospinning [76], bubble electrospinning [77], cylindrical porous hollow tube electrospinning [78], electroblowing [79], melt electrospinning [80], coaxial electrospinning [81], self-bundling electrospinning [82], nanospider electrospinning [83], 3D printing with electrospinning, etc. In addition, there are different types of collectors that have been developed for electrospinning setups such as a flat piece of metal, a screen, or even a rotating drum, a frame collector, which have been employed (see Fig. 1). It is expected that nanofiber electrospinning method will be widely promoted and applied in the industrial scale.

a

b

c

d

Wire

Solid cylinder

e

Disc

Wire drum

Solid cylinder

f

g with Nozzle e blad

HVDC (+) HVDC (+)

C HVD

HVD C (–)

Pin HVD C (–)

(–)

HVDC (+)

s

geblade

Knife ed

e

dgeblad

Knife e

Fig. 1 Different electrospinning setup and rotating collector: (a) solid cylindrical, (b) wire winded on an insulated cylinder, (c) wired drum, (d) disk collector, (e) sharp pin inside the rotating collector, (f) knife-edged electrodes, and (g) knife-edged electrode and needle system [84]. (Copyright 2011, Hindawi)

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Today, electrospinning equipment and nanofibrous materials are rapidly moving to commercialization. Nanofibers, with their unique properties, have been well applied in traditional industries and high-tech fields and have potential development prospects [85–91]. Among different types of nanofibers, electrospun nanofibers have attracted remarkable interest due to their incredible properties such as the easy control of production processes, large surface area to volume, flexibility in surface functionalities, low and tunable pore size, high and interconnected porosity, intrinsic 3D topography, and superior mechanical properties (i.e., stiffness and tensile strength) [60] for a range of applications in diverse areas such as regenerative medicine and tissue engineering [92, 93], drug delivery [94, 95], sensors [96–98], energy production and energy storage [99–101], filtration [102–104], catalysis [105, 106], textile [107, 108], and defense and security [109–111].

Types of Nanofibers and Nanofibrous Materials Over the past two decades, the developments of nanoscience and nanotechnology have created a wide range of nanomaterials including nanoparticles, nanofibers, nanorods, nanowires, and nanosheets. The first classification idea of nanomaterials was given by Gleiter in 1995 [112]. He classified the nanomaterials based on their crystalline forms and chemical composition [113]. However, the Gleiter scheme was not fully complete because the dimensionality of the nanomaterials was not considered. Various kinds of nanostructured materials are assayed and classified using dimensionality of the nanostructure itself and their components. In 2007, Pokropivny and Skorokhod reported a new classification scheme for nanomaterials, i.e., 0D, 1D, 2D, and 3D nanomaterials [114]. According to this classification, nanofibers can be considered as 1D nanomaterials with a diameter less than 100 nm. Up-to-date, many types of nanofiber materials have been reported, and, in the future, it is expected that varieties of other nanofibers and nanofibrous materials would appear. Nanofibers and nanofibril materials are generally classified based on their composition (e.g., polymers, metals, metal oxides, ceramics, carbon, and hybrid), size (e.g., diameter, length, pore size), and morphology (e.g., nonporous, mesoporous, hollow, core-shell, biocomponent, multicomponent) [115]. Nanofibers and nanofibrous materials were roughly classified into four main categories as follows.

Classification of Nanofibers Based on Their Chemical Composition A variety of fibrous materials such as natural polymers, synthetic polymers, ceramics, metal oxides, and even metals have been electrospun into uniform fibers with well-controlled sizes, compositions, and morphologies. Based on chemical composition, nanofiber materials are organized into four main types: carbon-based nanofibers, inorganic-based nanofibers, organic-based nanofibers, and compositebased nanofibers.

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Carbon-Based Nanofibers Carbon is considered as a unique chemical element. Special electronic structure of carbon provides the ability to form covalent bonds in the ring or long-chain form with other elements such as hydrogen and itself. Carbon nanofibers (CNFs) are 1D nanomaterials that are mainly composed of carbon. CNFs have a complex structure compared to the structure of carbon nanotubes (CNTs). CNFs have been recently innovated due to their unique properties, which have generated an interest in applications, including hydrogen storage, selective adsorption, polymer reinforcement, and as electrochemical catalysis. The orientation of carbon layers in CNFs affects their mechanical properties. CNFs have been classified as linear, sp2-based (one double bond, with two single bonds) discontinuous filaments, where the aspect ratio is greater than 100 [116]. Recent investigations revealed that the layers of graphitic planes of most carbon nanofibers are generally not aligned along the axis of the fiber. Carbon nanofibers have been classified into three different types as illustrated in Fig. 2, depending on the angle of the graphene layers that compose the filament [116]: (i) stacked or platelet carbon nanofibers in which the graphene layers stacked perpendicular to the fiber growth axis (Fig. 2a), (ii) ribbon or tubular carbon nanofibers in which the graphene layers are parallel to the growth axis (Fig. 2b), and (iii) herringbone or fishbone carbon nanofibers, in which the graphene layers accumulate at an angle between fiber growth and perpendicular axis (Fig. 2c). The different graphene layer arrangements depend on the geometric facets of the catalyst (metallic nanoparticle) and the gaseous carbon feedstock (hydrocarbon or CO gas) that is introduced during the synthesis processing. It was reported that the different graphene layer arrangements (basal and edge planes) play different roles in the chemical and physical behaviors of CNFs. For instance, the basal planes were suggested to have the capability of enhancing the adsorption of ethylbenzene, while a

b Basal plane

c Edge plane

Edge plane Edge plane Basal plane Basal plane

Fig. 2 Schematic illustrations of the three types of CNFs with different basal-to-edge surface area ratios: (a) platelet-type CNF, (b) tubular-type CNF, and (c) fishbone-type CNF [117]. (Copyright 2012, Elsevier)

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the edge planes modified with the oxygen-containing fragments are the active sites for the oxidative dehydrogenation reactions. Carbon nanofibers with graphene layers wrapped into perfect cylinders are called carbon nanotubes. Electrospun carbon nanofibers (CNFs) and vapor-grown carbon nanofibers (VGCNFs) are cylindrical nanostructures with graphene layers arranged as stacked cones, cups, or plates. The patent of Hughes and Chambers in 1889 is one of the first technical records concerning synthesis carbon nanofibers [118]. Catalytic chemical vapor deposition (CVD) coupled with thermal and plasma-assisted vapor deposition is the dominant commercial technique for the fabrication of VGCFNs. The chemical vapor deposition growth of CNFs is usually conducted with metal catalysts and gaseous hydrocarbon precursors under high temperature. Shown in Fig. 3 is the mechanism of nucleation and growth of carbon nanotubes and nanofibers. The mechanism of carbon nanotubes and carbon nanofibers typically involves (i) bulk diffusion of carbon atoms through the catalyst and (ii) carbon formation from hydrocarbons on single or dual metal catalyst: Ni, Co, Fe and some other transition

a CNT: bottom growth S1 S2 (Nucleation)

b CNT: top growth (Nucleation)

S2 S1

S1

c CNF: conic spiral growth S1 TEM

S2

SEM

S2

(Nucleation)

d

S2

e

S1 S2

S1

Top view

Fig. 3 Schematic illustration of several modes for the nucleation and growth of carbon nanotubes and nanofibers: (a, b) pentagon formation is the key to bend the initial graphene layer to a CNT. Euler’s rule evidences the need to have six pentagons formed for a 90
bend, turning the flat graphene into a perpendicular tube; (c, d) observed TEM dynamics of CNF growth evidence the spiral conic structure of these fibers which grow turning around; (e) growth by successive graphene layers, each pushing up previously formed ones [120]. (Copyright 2017, Elsevier)

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metal catalysts (e.g., Pt, Pd, and Cu) and many other transition metals are active. However, the differences in the growth mechanism are that the growth of CNTs involves the formation of perfectly cylindrical carbon structure with one or several graphene walls (Fig. 3a, b), while the growth of carbon nanofibers involves the formation of graphene structure arranged apparently as stacked cones (Fig. 3c). Alternatively, carbon nanofibers could be fabricated by the right combination of electrospinning of organic polymers and thermal treatment in an inert atmosphere. The electrospinning process typically involves (i) fabrication of electrospun polymer nanofibers through a facile electrospinning method and (ii) carbonization treatments of the as-obtained nanofiber which were then performed in an inert atmosphere (nitrogen or argon) [119]. Carbon nanofibers not only have the inherent properties of conventional carbon fibers but also have the characteristics of small size effect, large surface area effect, and quantum size effect. Multifunctional CNFs are required to change their surface properties prior to use. The surface texture, porosity, and specific surface area of the CNFs can be tuned by removing the most reactive carbon atoms from the nanofiber surface/bulk. The porous texture of the activated carbons depends strongly on the reaction conditions of the synthesis process and the nature of the carbon nanofiber precursor. To produce carbon nanostructures and to modify the dimensionality of carbon nanofibers, three main techniques are generally used: arc discharge, laser ablation, and chemical vapor deposition [121]. A high surface area is the most important factor in achieving the improved electrical, thermal, catalytic, and sensing properties. Thus, to control the surface area, nanopores should be introduced on the nanofiber surface. The template strategy is typically used with various inorganic materials such as metals or metal oxides (Sn, SiO2, ZnO2, CaCO3, Al2O3, etc.) to produce porous CNFs. These CNFs have a high surface area and high-volume percentage of mesopores. Activated mesoporous carbon nanofibers (AMCNFs) are synthesized by a sequential process of electrospinning, water etching-assisted templating, and acid treatment. Figure 4 shows a schematic illustration of the

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synthesis process of well-dispersed Fe nanoparticles supported into nitrogen-doped mesoporous carbon nanofibers by hydrogen activation for oxygen reduction reaction. The Fe/carbon nanofibers can be prepared via bicomponent electrospinning of PAN and FeC32H16N8 followed by carbonization of the obtained nanofiber in an inert atmosphere. Carbon nanofibers have been also widely used in catalysis, sensors, electronic devices, biomedicine due to the good electrical conductivity, high specific surface area, low density, and stable physical and chemical properties. CNFs are inherently inert and hydrophobic. Another important feature of the CNFs is the high thermal conductivity. Carbon nanofibers can be used as thermal interface materials to enhance contact thermal conductance for electronic packaging applications. The surface coating the CNFs with Pt NPs (of about 9–13 wt%) can increase the thermal conductivity of the CNFs by about three times, compared with uncoated carbon nanofibers [123]. Electrical conductivity is also a priority feature of CNFs when the CNFs are used in the manufacture of electronic devices, electrodes for batteries or supercapacitors, sensors, and electromagnetic shielding [116]. Hybrid CNFs are typically used as a barrier material for solid supercapacitor electrode material, nano-electrolyte storage site, and conductive polymer template material [124]. PAN nanofibers loaded with cobalt acetate were prepared through a facile electrospinning. Pre-oxidation and carbonization treatments of the as-obtained PAN/Co(acetate)2 membrane were then performed. CNFs and CNTs have been mixed in soy wax and paraffin wax with dosages of 1, 2, 5, and 10 wt% to prepare the phase change composites [125]. The results showed an increase in the thermal conductivity from 0.324 to 0.469 W/mK of the phase change materials with increasing the CNF content from 0 to 10 wt% [116].

Inorganic Nanofibers Inorganic nanofibers typically include metal nanofibers (such as Cu nanofibers, Ni nanofibers, and Ag nanofibers), oxide and sulfide nanofibers (such as CuO nanofibers, ZnO nanofibers, SnO2 nanofibers, BaTiO3 nanofibers, ZnS nanofibers), and composite nanofibers (such as LiCl/TiO2 nanofibers, Ag/ZnO nanofibers, TiO2/Bi2WO6 nanofibers). A large number of inorganic nanofibers have been prepared by the electrospinning following by a calcination step. Inorganic nanofibers are commonly used in various forms in our life. Nanofibrous products (e.g., membrane, electrodes, filters) made of metal, ceramic, and metal oxide nanofibers show better performance than those made of conventional bulk materials [126]. Inorganic nanofibers exhibit interesting optical and electronic properties as their size approaches the nanoscale. The main applications for inorganic nanofiber usage are electrodes for sensors [127] and batteries [128] and fillers for nanocomposites with high mechanical [129], electric, and magnetic features [130]. The inorganic nanofibers of some metal oxide (TiO2, ZnO, Fe2O3, SnO2, CeO2, and WO3) have been successfully applied in the field of photocatalysis. Based on the latest research, nanofibers are the desired solution to the toxicity and risks of using nanoparticles in healthcare products, mainly those producing sunblocks.

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The unique property of nanofibers completely eliminates the possible negative influence on consumer health while retaining the whitening effects of nanoparticles. Titania (TiO2) nanofibers have the same whitening effect as the nanoparticles that were used formerly. While nanoparticles may infiltrate into inner body membranes, nanofibers remain on the surface of the skin. Due to their high surface area, interconnected porous network structures, low basis weight, high heat resistance, relative strong mechanical properties, and relative solvent stability, inorganic nanofiber membranes have demonstrated desirable separation performances compared with polymer-based nanofiber membranes. Especially, constructing such membranes through filtration process will be promising to scale the laboratory process to industrial scale (Table 3). Electrospinning has been used in the production of inorganic nanofibers by using its precursor solutions. Mostly coaxial, colloid, melt, and solution electrospinning are typically used to produce metal oxide nanofibers [136, 137]. Inorganic nanofibers are then obtained from the sintering of their electrospun precursors. Certainly, sintering parameters such as temperature and heating rate will influence the fiber form and material phase. Typically, the fibers undergo three phases during the sintering process. Phase one involves the removal of residual solvents and water vapors from the fibers [138]. The second phase is where actual fiber shrinkage takes place as the organic materials are removed, polymerization, condensation, and structural relaxation proceed. Depending on the materials and temperature, phase three is where the inorganic material enters the glass transition stage. For the production of inorganic fibers, most sintering ends at phase two [139]. The formation of crystals with specific facet orientation is influenced by parameters such as the used chemical and the pH of the precursors. Beyond crystal phase and orientation, the interaction of the precursor solution with the environment during electrospinning and subsequent calcination also lead to physical changes in the resultant fiber [136].

Table 3 Some examples of inorganic nanofibers and their uses Nanofibers Titanium dioxide TiO2 Silicon dioxide SiO2 Zinc oxide ZnO Tin dioxide SnO2 Aluminum oxide Al2O3

Potential usage Dye-sensitive solar cells; photocatalysis; wastewater treatment; and cosmetics

Ref [131]

Biosensors; sorbents; and thermal insulators

[132]

Fuel cells; supercapacitors; and optoelectronic devices

[133]

Sensors; photocatalysis; batteries; and supercapacitors

[134]

High-temperature filtration; catalyst support; and polymer nanocomposites

[135]

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It has recently been recognized that ceramic nanocrystalline nanofibers are highly flexible due to their high surface area-to-volume ratio and nanograins [140, 141]. Ceramic nanocrystalline nanofibers have been suggested as an ideal candidate for building blocks for 3D elastic assemblies [142, 143]. However, electrospinning technique due to intrinsic limitations cannot easily assemble nanofiber into largescale 3D networks. Electrospinning typically forms a thin film network of the random or oriented nanofiber [144]. Wang et al. reported the manufacturing of large-scale 3D sponges based on a variety of ceramic (e.g., TiO2, ZrO2, and BaTiO3) nanofibers through an economic and efficient blow-spinning technique. The ceramic nanofiber sponges also reveal efficient energy absorption during cyclic loading, superior mechanical/chemical stability, ultralow density, and multi-functionalities, such as photocatalytic activity, thermal insulation, and elasticity-dependent electrical resistance [144].

Polymer Nanofibers Polymer-based fibers are ubiquitous in many spheres of human life such as cosmetics, clothing fishing nets, air-conditioning filters, cigarette filters, surgical masks, heart valves, and vascular grafts. Fibers used in these applications are typically microsized and made from a variety of polymers. To date, more than 50 different polymers have been successfully electrospun into ultrafine fibers with spinning voltage > spinning distance > melt temperature. Lyons [11] studied melt electrospinning technology, pointing out that with increased electric field, fiber diameter markedly decreased and as the melt feeding rate decreased, both sizes of Taylor cone and fiber diameter decreased. In PLA melt electrospinning experiments conducted by Zhou [47], he found that with higher melt temperature, fiber diameter reduced and fiber diameter distribution became narrower, and with increased electric field strength, fiber diameter decreased but has no big effect as temperature. Ratthapol [39] confirmed this in vacuum melt electrospinning experiments. The conclusion can be drawn that, in melt electrospinning, the system viscosity of the melt is at least an order of magnitude higher than the solution system, so melt viscosity is a vital factor in assessing the spinnability and fiber diameter of a material. With the same distance, increasing voltage and reducing the feeding rate of melt can effectively reduce fiber diameter but require a balance of efficiency and spinning of fiber diameter.

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Fig. 7 Representative SEM of each scaffold at different humidity levels. (a–c) Low humidity, (d–f) standard humidity, and (g–i) elevated humidity. No noticeable difference is seen within the imaging parameters of scaffold ordering, fiber diameter, or fiber surface morphology across all groups [63]

Air Auxiliary Parameters and Fiber Refinement Gas-assisted melt electrospinning has two advantages. First, jets accelerating with air tensile force rub on them resulting in jet thinning. Second, hot airflow controls temperature through the jet path, delaying solidification of fiber, which extends the thinning distance. Zhmayev [46], from Cornell University in the United States, studied the effect of gas assisting on PLA melt electrospinning fiber refining with gas-assisted melt electrospinning device (Fig. 8), finding that air-assisted fibers were 10% thinner than those without a gas stream, and by thermal-assisted electrospinning, it’s 20 times thinner. As with the increase in velocity and temperature of the gas, fiber diameter decreases, but a specific trend was not mentioned in the article. In the US Patent US7887311B2 [65], this feature has also been described, but only the specific embodiments of the solution, melt thinning effect, failed to make the embodiment.

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Fig. 8 Gas-assisted melt electrospinning device. (a) Schematic of the polymer melt electrospinning setup and (b) a thermal image of polylactic acid melt electrospinning without spinning region heating [46]

Material Characteristics and Fibrous Degree of Fineness Material modification of melt has a great influence on fiber refinement. Ogata [66] developed the carbon dioxide laser-heated melt electrospinning system to electrospun poly(L-lactide) (PLLA), adding poly (ethylene-co-vinyl alcohol) (EVOH) as a coating on PLLA, has a significant effect on decreasing the fiber diameter, that diameter dropped sharply from3 μm down to around 1 μm. Dalton [22] prepared blends of poly(ethylene glycol)-block-poly(ε-caprolactone) (PEG47-b-PCL95) and poly(ε-caprolactone) using the self-made electronic textile machine, finding that the ratio of the components has an impact on fiber diameter. Malakhow [67] used stearic acid and oleic acid as a plasticizer to reduce the viscosity of polyamide 6; by adding 10% of plasticizer, the average diameter of the fibers obtained was reduced by 40 times due to a decrease in the viscosity of the melt by 60 times. Wang [68] added diisooctyl phthalate (DIOP) to poly(methyl methacrylate) (PMMA), and fiber diameter dropped from 34.0 to 19.7 μm. Zhao Fengwen et al. [69] added 8% of stearic acid to polylactic acid (PLA), and the fiber diameter dropped from 5.37 μm down to 1.65 μm. Xia Lingtao et al. [70] added 8% hyperbranched polyester (HBPE) into polypropylene (PP), and fiber diameter dropped from 5–6 μm down to 1–2 μm. Molecular weight is an important factor in melt viscosity of a material. Lyons [71] used polypropylene (PP) with different molecular weight directly to spin polypropylene with an average molecular weight of 580,000, 190,000, 106,000 and 12,000 spun fiber with diameters of 466.15, 10.58, 6.92, and 3.55 μm, respectively. Lyons also found that stereoisomer of polymer structure has a significant effect on the diameter of the fiber. Under the same conditions of spinning, isotactic polypropylene with approximate molecular weight spun the fiber with an average diameter of 3.55 μm, while atactic polypropylene had an average diameter of up to 21.30 μm. Molecular weight can be controlled by adding a different amount of chain-cutting agents. A recent investigation found that by adding 5% (mass fraction) of Irgatec viscosity reducer, the diameter of the fiber will drop from 35.6  1.7 μm to 840  190 nm [38].

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The conductivity of polymer melt is a crucial factor in fiber refinement. It has a significant effect on fiber fineness. The solution system has a higher conductivity due to the easier migration of charge to the surface, while most of the melt has less surface charge, which means good dielectric. So the transfer of charge will hardly result in a weak electric field. Thereby, improvement of polymer melt conductivity in order of refining fiber became the focus of the field. Nayak [38] added sodium oleate and NaCl to the low viscosity polypropylene to increase conductivity; as a result, electrical conductivity increased from 10–9 to 10 6 S/cm, and fiber diameter dropped from 4 μm down to 0.3 μm, eliminating the effect of viscosity.

Laser Assistance and Fiber Refining In melt electrospinning process, in order to avoid interference between heating electrical control systems and high-voltage electrostatic, the researchers used a variety of heating methods. Laser heating due to advantages, such as concentrated energy, instantaneous melting, and noninterference, is widely used by researchers. Equipment and related researches are classified as laser melt electrospinning [71]. Laser power and the speed of bat material supplied are main parameters for controlling laser melt electrospinning. Voltage diversity has different impacts on diameter from other processes. Takasaki [72] has shown that fiber diameter decreases as the laser output power increases. Ogata et al. [37] showed fiber diameter decreased exponentially as the output power increased, and to a certain extent, fiber diameter remained constant. What needs to be aware of is that if the laser output power is too high, the polymers may decompose, resulting in droplets or beads. In the literature, researchers on voltage effect on fiber diameter obtained different results. The literature [71] showed that the fiber diameter decreases when the voltage decreases. The literature [36, 37] showed that as the voltage increases, fiber diameter decreases exponentially, finally reaching the fixed value. The authors of those articles think it is the disadvantages of laser heating that cause the different results. Due to instant heating of laser, it is unable to monitor the transient state of the melt. Also, fiber diameter is the result of interaction between the electrostatic field and surface tension forces; the uncertainty of the state of melt means the unstable surface tension. Some researchers conducted preliminary electrospinning experiments using composite melt material. Detta [40] melt electrospun PCL and poly(ethylene glycol)-block-poly(ε-caprolactone) (PEG-b-PCL) composite. PEG-block-PCL has low molecular weight, which is unable to form a continuous fiber. By adding PCL to improve its spinnability, fiber with a diameter of 6–33 μm can be obtained by adjusting the PCL ratio. Li [73] used custom-made platform for a study on PET/SiO2 blending material and prepared microfiber with a diameter of 500 nm–7 μm. Cong [74] melt electrospun PEG/PVDF composite with core-shell structure, discovering that 42.5% 4000 Da PEG composite material has the latent heat of fusion up to 68 J/g.

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Research Progress of Melt Electrospinning Devices There has been a substantial amount of research carried out on the fundamental aspects of electrospinning technique as a whole. The major issue that is yet to be resolved is the scaling up of the process for commercialization. Solution electrospinning apparatus is simple in its construction. Research groups have constructed the basic electrospinning setups to suit their experimental needs and conditions. Yet studies on melt electrospinning apparatus are still in the early stages, but it is improving. Due to the varying methods of material plasticity, several melt electrospinning devices have been developed, including laser heating [36, 37], electric heating [50], hot air [15] indirect heating, infrared irradiation [39] indirect heating, thermal bath heating [40], and so on. Most researchers use the indirect heating system. Because of the influence of solution electrospinning devices, they tend to put high-voltage electrode on the nozzle or needle. The use of electric heating or another direct heating method can easily lead to the heating of electric circuits or metal components, the breaking down of the high-voltage electrode, and, finally as a result, the termination of the whole spinning process. Aiming to solve the shortage of traditional needle nozzle equipment, Yang’s team at Beijing University of Chemical Technology developed a melt differential electrospinning method for preparing ultrafine fiber, smaller than 1 μm in diameter, with a yield of 10–20 g/h. Principle and equipment of melt differential electrospinning will be introduced in this chapter. Several examples of device innovation and inspiration will be described in this section.

Laser Melt Electrospinning Devices In 2006, Ogata [36, 37, 51], from the University of Fukui in Japan, developed laser-heated melt electrospinning apparatus (Fig. 9). It used to electrospun poly (ethylene-co-vinyl alcohol) (EVAL), poly(lactide) (PLLA), and polyamide 6/12, systematically testing the impact laser power and voltage had on fiber fineness and crystallinity. Polymer (billets or sheets) is rapidly molten and instantly reaches a very low viscosity, and then melt is slenderized by electrostatic force. Through this method, fiber can reach 1 μm in diameter or less. In 2009, Shimada [51] used a linear laser heating device to spin EVOH sheet melt for better spinning efficiency, with a distance of 5 mm between Taylor cones (Fig. 10). In 2011, Li Congju’s research group [71] spun different materials using laser melt electrospinning devices. Utilizing its advantages such as instant heating, low-energy consumption, and no interference with high-voltage electrostatic loading system, the laser may serve as a good experimental device, but temperature and viscosity of the polymer cannot be effectively controlled, as well as its high cost and security issue, which is needed to be carefully researched. So this technique is limited on the way to industrialization.

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Moving direction

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Fig. 9 Schematic diagram of laser melt electrospinning [36]

Fig. 10 Multi-Taylor cones of melt electrospun EVOH using linear laser heating device [51]

Screw-Feeding and Narrowly Stitches Melt Electrospinning Devices Precise control of the temperature and flow of polymer melt is an important key to melt electrospinning devices. Most researchers use microthrusters or air pressure to control the melt feeding velocity precisely. Lyons [11, 13] and Deng [45] adopted the single-screw extruder to the plasticized polymer and control flow. Due to the too large size of the screw, accuracy was not ideal. In order to achieve low flow velocity, they even decreased the screw speed to 0–1 r/min. Some researchers precisely controlled the flow using micro-screw [50]. Erisken [75] tried a twin-screw extruder (Fig. 11), realizing composite online blending and melt electrospinning. Twin-screw extruders were isolated from needles, so electrical interference does not occur. The device adopting the needle, which has a flow rate of only 0.9 mL/h, makes the screw’s function not fully used. It is a traditional way of forming plastic melt through

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Fig. 11 Micro twin-screw extruder for melt electrospinning and a three-needle die fixed on it (the right photo) [75]

Fig. 12 Sketch and processing picture of the “cleft”-type melt electrospinning [19]

screw realizing control of flow and temperature; choosing the right model combining with the efficient nozzle is an important way to realize industrialization in the future. Michal Komarek [19], from Technical University of Liberec, Czech Republic, proposed a “cleft”-type melt electrospinning device (Fig. 12), in order to increase the spinning efficiency and avoid needle jams. It was observed that the space of polypropylene jet is 6.3 mm. Materials with lower viscosity had uniform distribution, while materials with higher viscosity had large space between jets and uneven distribution of jets. This method is a desirable choice of needleless melt electrospinning, but tunnels need to be designed in an elaborate way to make flow uniformly distributed.

Disc Melt Electrospinning Devices Fang J. [18] from Australia, inspired by the electrode inversion method and needleless electrospinning “Nano Spider” invented by the Czechs, proposed a disc

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Fig. 13 Photos of the disc melt electrospinning setup [18]

as melt electrospinning device (Fig. 13). The finest fibers produced had an average diameter of 400  290 nm. But the device was able to work only when the melt viscosity was extremely low. Key issues like controllable steady mass production have not been studied yet.

Melt Electrospinning Direct Writing Technique Farrugia [76] using a 2D motion platform as the collector, through fitting the speed spinning and motion platform, obtained controllable linear-oriented fibers with a 3D structure. As Fig. 14 shows, the polycaprolactone (PCL) was used to electrospun in one embodiment, under the condition of 70  C, 12 kV spinning voltage, 30 mm spinning distance, and the receiving platform moving speed of 1 m/s. Fibers formed had multi-oriented alignment and diameter varying between 12.5 and 20 μm. It was expected to play an important role in tissue engineering. As early as 2006, Mitchell [77] invented the controllable melt electrospinning devices, in which he also designed indirect collecting platform with structures based on controllable movements in x-y-z directions to realize controllable collecting, but no direct writing feature was proposed. The spinning distance used was 170 mm, which was much longer than the direct writing demand and poor controllability of orientation.

Melt Differential Electrospinning Technique Melt differential electrospinning (MD-ESP) is a process in which melt flow is selforganized and divided into tens of minor Taylor cones under the stretching force of electric field, and that’s why it is named melt differential electrospinning. Figure 15a, b shows the section view of a typical melt differential electrospinning device. It consisted of five major components: melt inlet, melt distributor,

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Fig. 14 SEM images of three-dimensional fiber structure produced by melt electrospinning direct writing method [76]

umbellate nozzle, high-voltage power supply, and receiver plate. The processes of this method are shown below. First, melt the polymer, and extrude it forward, and transform it into the uniform ringlike flow. Then, distribute the ringlike flow to the umbellate nozzle with the help of a hot wind. At last, when the voltage surpassed a critical value, multiple jets around the rim of the nozzle were produced and collected to the receiver plate (Fig. 15). It was found that interjet distance of the multiple jets depends on the electric field strength, material properties, and melt viscosity. This process abandons the traditional capillary tube or needle, and realized tens of jets from one small head, and enabled the scaling-up preparation of nanofiber in solventless way. Since now, several thermoplastics including poly (lactic acid) (PLA) and polypropylene (PE) have been processed into nanofiber (Fig. 16).

Emerging Applications of Melt Electrospun Fibers Micro-/nanofibers produced by melt electrospinning technique have enhanced physicomechanical properties, the fibers have high specific surface area due to their small diameters, highly pores, no surface defects, smooth, and most importantly

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solvent-free. These unique characteristics plus the functionalities of the polymers themselves impart melt electrospun fibers with many desirable properties for advanced applications, such as biomedical, environmental, and energy applications. Highly new applications have been always explored for these fibers continuously.

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Fig. 16 Photo of (a) the pilot prototype of the polymer melt differential electrospinning device. (b) Pilot prototype in running

Fabrication of Nonwoven Fabrics Solution electrospinning nonwoven fabric layer (nonwoven) has been used to make protective clothing or clothing layer. Due to microlevel diameter, holes between fibers range from several microns to dozens of microns; melt electrospun fibers permit gas passing through freely. Through material modifications or transformation of fiber film as surface features, even superhydrophobicity and superoleophilicity can be achieved. These features can meet the requirements of protective clothing in medical or military fields, as well as be used for developing thin absorbent sportswear. Facing the contradiction between the high barrier and the high air permeability of traditional protective clothing, Lee [78] experimented basic properties of melt electrospun polypropylene webs and showed that melt electrospun polypropylene webs provided excellent barrier performance against the high surface tension challenge liquid and performance of 90–100% for challenge liquids with varying surface tension, while penetration rate for air reduced by almost 20% which is still higher than most of the materials currently in use for protective clothing. Polyethylene terephthalate (PET) and its recycled plastic are one of the main choices to produce thin and absorbent fabrics in the textile industry. Rajabinejad [79] used particles of recycled PET bottle to melt electrospun; fibers prepared were less than 100nm, which means it could be of a potential use in fields like protective clothing and

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Polymer inlet

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Fig. 17 Multi-nozzle melt electrospinning device [23]

others. Fibers in few micron or submicron level are able to get through the contradiction between the high barrier and the high air permeability of traditional protective clothing; therefore, it is necessary to carry out a series of studies and research work on scaling up melt electrospinning mass production as it is relevant and applicable to the textile manufacturers. Germany RWTH Aachen University research group reported an expanding research outputting through multi-nozzle melt electrospinning device that delivers a polymer melt to a 64-needle array [12] and can make filtration mesh at a rate of 18 m2/h (Fig. 17) and diameter of 552  260 nm.

Water Treatment and Membrane Filtration Physical filtration has many advantages like being compact, simple, and environmentally friendly and has been rapidly developed in recent years, especially membrane filtration. Microfiber membrane has stereoscopic micropore structure; therefore, it has a lot of potential applications in water treatment, air filtration, and oil-water separation. Li Shen [80] studied air filtration using PET membranes from melt electrospinning. PET microfiber layer from melt electrospinning with an average diameter of 2.54 μm was attached to the surfaces of the nonwoven substrate with an average fiber diameter of 12.25 μm. Twelve minutes later, the membrane of compound single jet filtrated over 90% of the particles whose size is over 2 μm. Li [81] studied the properties of melt electrospun polypropylene-oriented fibers used in

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water filtration, suggesting that combinations of the different orientated fiber membrane had smaller aperture than the random-orientated fiber and had higher efficiency in rejecting the 0.5 μm particles with a diameter of 2.49  0.418 μm and still maintained nearly the same permeate flux as that of the native membrane. The electrospun-oriented fiber membranes also showed good overall mechanical performance. Contamination of the marine environments by oil has become a specific and serious problem. And the most widely studied organic synthesis oil sorbent material is mainly on high oil-absorbing resin and oil-absorbing cotton microfiber, which are oleophilic and hydrophobic and have super high oil absorption rate and can be repeatedly used [82]. Polypropylene nonwoven fabrics are being widely used currently as oil-absorbing material because of their oleophilic-hydrophobic properties, good oil/water selectivity, high buoyancy, and scalable fabrication. But polypropylene ultrafine fiber cannot be solution electrospun at room temperature, while melt electrospinning technique overcomes this problem. Research and exploration of melt electrospinning in this area have just begun. Li [83] prepared a series of polypropylene ultrafine fibers fabricated by self-designed apparatus and made melt differential electrospinning device; the resulting polypropylene (PP) fibers showed the maximum oil sorption capacity of 129 g/g and 80 g/g in regard to motor oil and peanut oil, respectively. The oil sorption capacities for these fibers were approximately seven times that of commercial PP nonwoven fabricated by the melt-blown method. In addition, even after seven sorption/desorption cycles, the oil sorption capacity of the PP fibers made by melt differential electrospinning device was still maintained around 80 g/g, and above 97% of oil could be recovered which indicated excellent reusability and recoverability. Results also showed that porosity played a vital role in determining the oil sorption capacities. Melt electrospun nanofibers of biodegradable PLA also showed similar properties [84] (Fig. 18).

Biomedical Applications Since melt electrospinning is a solvent-free technique, various biomedical researchers have been interested in it. It is an excellent choice for cell cultivation and medical dilution, by eliminating complex solvent mixtures and removal process and simply by ensuring that the environment is safe or performing sterilization reprocessing after simple disinfection. Most melt electrospun fibers are a few microns in diameter, and the pores between fibers range from several microns to dozens. Fibers can be randomly formed or designed to make 3D structures by bonding or mutual support, which is a benefit to cell adhesion, movement, growth, and maturity. Based on the two reasons above, the application researches on melt electrospinning focus on the biomedical field mostly, especially tissue scaffold and wound dressing. In basic aspects of organic cultivation and the tissue scaffold, unlike the solution electrospinning, high-speed jet does not exist in melt electrospinning, which is uncontrollable, but the problem like swing because of low viscosity which

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Fig. 18 Oil sorption/ desorption cycles of melt electrospun PLA fibers (H201, H202, and H203 are three types of hyperbranched polymers) [84]

Fig. 19 Process of direct in vitro melt electrospinning [85]

may also result in uncontrollable deposition. Thus, most researchers used direct writing method or direct spinning method, which greatly shortens the spinning distance, only using linear part, generally less than 1–2 cm. There were many recent investigations in this field [85–89]. In 2006, Dalton firstly proposed to melt electrospun directly into cell Petri dish (Fig. 19) or what is known as “direct in vitro electrospinning”; the materials used were a blend of poly(ethylene oxide)-blockpoly(ε-caprolactone) (PEO-block-PCL) with PCL, and fibers were prepared with a diameter of 1–2 μm [85]. The cell proliferated, spread, and finally formed a multilayer and separated from the basic. In the year 2008, Dalton [86] published that controllable graphics of melt electrospinning could be used in tissue engineering, and by the x-y controlling speed of the work platform, linear electrospun fibers can

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Fig. 20 Porous tube fabricated by combining melt electrospinning with direct writing: (a) schematic presentation of the techniques. (b) Porous tube of PCL fabricated by melt electrospinning with direct writing; (c) SEM image of the obtained fibers, oriented at 60 to the central axis of the tube [87]

be obtained. The main influence to prepare complex graph structures was explored; one of the embodiments showed that the fiber prepared had a diameter of 0.96  0.19 μm and spinning distance could range from 200 to 400 μm. The researchers showed that graphics mainly were controlled by melt flow, voltage, the relative velocity of the jet, and the collector. In 2012, in order to avoid the uncontrollable sediments in solution electrospinning, Toby [87] tried melt electrospinning method using poly(ε-caprolactone) (PCL) to construct three-dimensional controllable-orientated tube scaffolds (Fig. 20) through coordinating speed of rotation and circumference; experimental statistic showed fiber diameter is in the range of 19.9–27.7 μm. Growing experiments of three types of cells showed that cells can penetrate freely between fiber layers and grow well, which lays the foundation of external vessel cultivation. Farrugia [76] also combined melt electrospinning technique with x-y receiving table and prepared poly(e-caprolactone) (PCL) scaffold using melt electrospinning in a direct writing mode, with fiber diameter of 7.5  1.6 μm, interfiber separation distances ranging from 8 to 133 μm, and an average of 46  22 μm, and the resulting scaffolds had a highly porous nature of 87%. Cells grow well by implanting on the top. Those studies have shown good controllability of melt electrospinning technique in scaffold printing for the combination of its linear jet parts and 3D work platform and collector; fiber diameter and porosity meet exactly the requirements for cell growth. Therefore, further researches in this field are needed. There are little researches on melt electrospinning used for wound dressings, but it is more easily and quickly to be commercialized. Lee [90] prepared poly(lactic acid) (PLA) micro-/ nanofibers using melt electrospinning with a diameter of 1.5  0.8 μm. Comparing melt electrospinning and solution electrospinning (spinning solution/chloroformacetone (3/1, v/v)), pre-osteoblast cells (MC3T3-E1) were cultured on both solution electrospun fibers and melt electrospun fibers in osteogenic media, and it was found that the BMP-2 and OCN expressions from cells on the melt electrospun fibers were

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6-fold and 1.8-fold greater than those on the solution electrospun fibers, respectively. In addition, melt electrospun fibers provided a significantly high cell viability approximately twofold greater than solution electrospun fibers. Hacker [91] did a research on thermoplastic polyurethane (TPU) used in wound dressings, particularly as a porous structured electrospun membrane. TPU was processed into a porous, fibrous network of beadless fibers in the micrometer range (4.89  0.94 μm), and the surface of the fibers was modified with poly(ethylene glycol) (PEG) and silver nanoparticles (nAgs) to improve their wettability and antimicrobial properties; fiber membrane showed favorable antibacterial properties, expected to be new antibacterial and moisture controllable wound dressings.

Conclusion and Future Outlook Despite the slow progress made in melt electrospinning process, device improvement and control, considerable challenges, but with a deep understanding of researchers and industry to it, the technology is gaining more and more attention. Despite those challenges, melt electrospinning remains an eco-friendly manufacturing method since no solvent is involved, and it has the potential to produce micro-/ nanofibers with a smooth and continuous surface, with the need of a new technology very different from solution electrospinning. The authors of this chapter think there are several points worthy of being focused on in the future: 1. The development of basic materials with low molecular weight and low viscosity should be strengthened in order to enhance research and develop industrialization facility. More attention should be given to eco-friendly polymers since most of the electrospun fibers obtained have been synthetic with the aim of achieving fibers with better biocompatibility and performance. 2. Further research on needleless melt electrospinning is needed, on the basis of recognizing characteristics of melt electrospinning; auxiliary air and auxiliary vibration method needs to be added to prepare ultrafine fiber with sub-micrometer and high efficiency. Melt direct writing technology is able to establish the ideal 3D structure through precise control, which attaches great importance to catalysts, sensors, or carrier of the tissue cells. This is the focus of interdisciplinary research. 3. Reasonable design of composite fiber membrane combining several technologies should be researched for applications to achieve high-efficiency filtration with high passing rate and low pressure, making full use of the melt electrospinning fiber layer in composite fibers and membranes. 4. The baggiest challenge is to completely understand the melt electrospinning mechanism. It is necessary to understand quantitatively and carry out melt electrospinning process efficiently, repeatedly, and safely, in the aim to control the properties, orientation, and mass production of the nanofibers. 5. Biomedical applications of melt electrospinning will be increasing and remain in the research literature, due to the nature and speed of commercializing

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regenerative medicine and tissue engineering concepts. The potential of scaling up this technology for commercialization, which government agencies, academia, and industry should pay attention to, is an important issue for further growth and development of the field. In the future, melt electrospun nanofibers will prove to be a promising candidate for a wider range of advanced applications.

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Design of Porous, Core-Shell, and Hollow Nanofibers Maryam Yousefzadeh and Farzaneh Ghasemkhah

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Porous Nanofibers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Porous Formation During Electrospinning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Porous Formation After Electrospinning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Characterization of Porous Nanofibers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Core-Shell and Hollow Nanofibers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Coaxial Electrospinning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Emulsion Electrospinning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Other Electrospinning-Based Methods for Core-Shell Nanofibers Formation . . . . . . . . . . . . . Characterization of Core-Shell or Hollow Nanofibers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion and Future Trend . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abstract

Electrospinning can be used to prepare various organic or inorganic nanofibrous structures. These structures could be related to the nanofibers arrangement relative to each other, as random, aligned, 3D, and yarn, or they could be related to the single nanofiber structure and morphology, or both. In the electrospinning process, nanofibers could be produced to have surface or internal porous structure. Considering the type of material which is used, different methods are introduced to get the desired porosity in nanofibers such as chemical etching, blend solution, effect of humidity, and different post-treatment methods. Also, by using different methods, it is possible to produce core-shell nanofibers or hollow ones. For fabrication of the core-shell nanofibers, one method is to use the special coaxial nozzle. However, there are other techniques to get core-shell nanofibers like M. Yousefzadeh (*) · F. Ghasemkhah Department of Textile Engineering, Amirkabir University of Technology (AUT), Tehran, Iran e-mail: [email protected]; [email protected] # Springer Nature Switzerland AG 2019 A. Barhoum et al. (eds.), Handbook of Nanofibers, https://doi.org/10.1007/978-3-319-53655-2_9

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emulsion precursor solution, different methods of surface coating, and so on. Based on the diversity of techniques, in this chapter an attempt is made to cover the most usable methods to get the porous, core-shell, and hollow nanofibers and present some applications for each. Keywords

Electrospinning · Porous nanofibers · Core-shell nanofibers · Hollow nanofibers · Micro tubes

Introduction Electrospun nanofibers usually exhibit a solid thin smooth structure. However, nanofibers with other morphologies and architectures could also be electrospun. The small diameter of electrospun nanofibers gave the resultant structure a high surface area to mass which makes it an excellent candidate to incorporate surface functionality or applications where high surface area is desirable. The broad range of nanofiber architectures could be produced via electrospinning including thin smooth nanofibers, porous nanofibers, ribbonlike nanofibers, core-shell nanofibers, branched nanofibers and nanofibers with fractal surface structures, with spindletype structure, or odd-shaped fibers such as barbed nanowires. With the design of how nanofibers arrange in the collector and production of random, aligned, different ordered nanofibers, and 3D structures, as described in detail by Yousefzadeh and Ramakrishna [1], the inter-fiber and inter-mat structure of nanofibers could enhance its performance in the desired application. The high surface area porous structures have found applications in many different areas. Large surface to volume ratio of nanofibers makes these materials having high potential for use in various applications where high porosity is desirable. The ability to form porous, core-shell, or hollow nanofibers or some combined structures like hollow porous nanofibers through electrospinning means that the surface area of the fiber mesh can be increased tremendously. With such versatility, electrospun nanofibers are being explored for use in many different applications. Nevertheless, the versatility of electrospun nanofibers can be seen in different research areas like healthcare, biotechnology and environmental engineering, defense and security, and energy storage and generation [2].

Porous Nanofibers Pores could be introduced to the surface of the nanofibers as a way for further increment of the surface area. Porous nanofibers contain lots of ellipse-like or sphere-like holes on the nanofibers surface or inside it and make a large surface area and light weight which could be useful for applications such as filtration, gas separation, fuel cells, catalyst support, supercapacitors, sensors, energy storage

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devices, and tissue engineering. For some applications, the total surface area and activity of the final devices can be significantly increased by introducing porous structure to the nanofibers. In tissue engineering, pores can function as anchorage for cells. The pores can increase the surface area in catalysis applications or filter. They can modify wetting properties of nanofibers which affect the matrix coupling in the case of nanofiber reinforcement, they can modify the release kinetics of drugs, and for biodegradable nanofibers, they can influence the kinetics of biodegradation [3]. Porous carbon nanofiber presents the opportunity to design energy storage materials which can be used in rechargeable lithium-ion batteries (LIBs) with fast charging capability, high capacity, and long life cycle. LIBs are considered as the most promising technology, among the various electrochemical energy conversion and storage devices for high electrochemical power sources and high energy [4]. Compared with the conventional graphite anode, porous carbon nanofibers show clear advantages in electrochemical behaviors in terms of high reversible capacity and relatively stable cycle performance [5]. High porosity make carbon fiber materials highly relevant for use in membrane applications for filtration and separation, as well as in vapor sensing, enzyme immobilization, and for use in tissue engineering. Furthermore, carbon materials are inert to a variety of chemicals, solvents, electrolytes, and biological entities. High porosity and large specific surface areas together with high electrical conductivity allow the application of carbon fibers as electrodes in energy storage devices. Charged electrolyte ions can be screened more efficiently upon adsorption to a porous carbon. Fiber electrodes lead to increased charge carrier density at the electrode and hence improved capacities. Precise control over the surface area and pore size would allow further improvement of the carbon fiber performance as electrodes as well as for filtration and separation applications [6]. The porous carbon nanofibers exhibit remarkable electromagnetic wave absorption properties when compared with conventional one-dimensional carbon materials [7]. The design and construction of reliable oxygen reduction reaction of electrocatalysts with high activity and durability are crucial issues in proton exchange membrane fuel cells, in which Wang et al. [8] demonstrated the high efficiency of hollow porous carbon nanofibers for this application. There are some reports for producing nanoporous spheres by electrospinning as a direct fabrication of biological materials. The pores could be a good template for the growth of second-generation nanostructures on the nanofiber surface. The porous nanofibers have a higher surface area. As a result, the loading capacity can be improved. Therefore, porous nanofibers with different porosity can be prepared for ultrathin layer chromatographic (UTLC) applications. Currently, there are mostly two methods that are used to achieve porous structures. One is controlling the electrospinning environment and solution interaction and the other is using sacrificial material as the pore generator. More studies have provided quantitative data on the extent of surface area increment on porous nanofibers compared to smooth fibers.

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Two main factors that play an important role in forming pores on the electrospun fibers during electrospinning are “breath figure” (BF) [9, 10] and “phase separation” [11, 12]. BF is a commonly observed phenomenon in daily life. One example is the fog that appears on a window when we breathe on it. This is also the origin of the name “breath figure.” The BF process is controlled by the complex heat and mass transfer, and these transfer processes are further dependent upon various experimental parameters, including temperature, humidity, air flow velocity, the physical properties of the solvents and the solution, and the physical and chemical properties of the polymers. Slight variation in any of these parameters can significantly change the pores’ sizes and shapes. In 1893 and 1911, the BF process was suggested as a water droplet condensation procedure on a solid surface by Aitken [13] and Rayleigh [14, 15], respectively. Then, Widawski [16] in 1994 reported the honeycomb film fabricated by the BF method using star polystyrene (PS) polymer or PS/polyparaphenylene (PPP) block copolymer as building units. In that process, the polymer solvent was an organic carbon disulfide (CS2). For honeycomb film formation, three significant factors were proposed: (1) material structure, (2) solvent, and (3) humid atmosphere. The basics of the BF mechanism are construction of a cold solution surface under a humid atmosphere, under which the moisture can condense on the cold surface. The wellaccepted mechanism of the entire BF process contains the following steps as shown in Fig. 1: (1) cooling of the solution and moisture nucleation, producing disordered small water droplets on the solution surface; (2) growth and self-assembly of the water droplets, forming a closely packed array of water droplet on the surface of the solution; and (3) evaporation of the solvent and water droplets, leaving a pore on the dry fiber [10]. Thus, it could be concluded that during the electrospinning, this phenomena occurs as a result of evaporative cooling due to rapid solvent evaporation and therefore significantly cooling the surface of the jet as it travels in electrospinning distance. The moisture in the air condenses and grows in the form of droplets by cooling the surface. The convection currents on the surface of the jet make the droplets remain as individual entities acting as hard spheres. As the jet dries, the water droplets make an imprint on the surface of the fibers in the form of pores in dried nanofibers [17, 18]. However, the introduction of water into the spinning jet may also result in phase separation, and this may also give rise to porous fibers as they are generally Solvent vapor

Water vapor Solvent vapor

Solvent vapor Water vapor

Cooling of solvent and nucleation of moisture

Growth and selfassembly of water droplets

evaporation of solvent and water droplets

(1)

(2)

(3)

Small and disordered water droplets As-cast polymer solution

Ordered water droplets array BFA film

Fig. 1 Formation mechanisms for BF on the film (Reprinted with permission from Ref. [10]. Copyright # 2015 American Chemical Society)

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non-water soluble. Phase separation is a complex phenomenon that depends on molecular parameters (miscibility of two polymers, concentration, and solvent), thermodynamic parameters (composition, temperature, and pressure), and processing parameters [12]. Phase separations may take place, leading to two types of phase structures as it is known from thermodynamics of mixtures and the corresponding phase diagram. They are the binodal and spinodal phase structures. They represent the regime of thermodynamic instability (inside the spinodal lines), the regime of metastability (inside the binodal lines yet outside the spinodal lines), and finally the regime of stability of homogeneous mixtures (outside the binodal lines including the critical point). The concentrations of two phases have been represented in the Binodal line that form in the case of phase separation with the chemical potential of the two components being equal, which is plotted in a temperature-concentration diagram. The spinodal is defined as the location for which the first and second derivatives of the free enthalpy of mixing with respect to the concentration become zero for a given temperature [3]. The schematic of the phase separation characteristic of a binary polymer blend is illustrated in Fig. 2a. The blend changes from one mixed phase to two individual phases during solvent evaporation. From a thermodynamic point of view, phase separation behaviors are related on the free energy G of the system. The borderline of phase separation is divided into spinodal (@G2/@c2 = 0) and binodal (@G/@c = 0) lines.

Fig. 2 (a) The binary polymer blend’s phase separation characteristics, (b) spinodal and binodal lines of a binary polymer blend as a function of composition and temperature, (c) a triplex phase diagram for the system with polymer A, B, and the solvent [12]. Creative Commons Attribution License

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As it is shown in Fig. 2b, the spinodal and binodal lines of a binary polymer blend as a function of composition and temperature. In high temperature the entropy is a governing factor, so one mixed phase is favored. When the temperature decreases, two individual phases are preferred by enthalpic interaction. Moreover, composition c has a remarkable impact on determining the borderlines of the phase separation. A triplex system consisting of polymer A, polymer B, and the solvent is considered, since a solvent is typically used to make a blended solution (Fig. 2c). By evaporating the solvent, two different phase separation modes as spinodal decomposition and nucleation and growth exist. The mode that the blend solution goes through affects the lateral or vertical phase separation. Phase separation characteristics may be affected by polymer, solvent, and electrospinning conditions. Miscibility is an important polymer property, which is commonly defined by considering the Flory-Huggins interaction parameter (χ). A low χ value means a weak driving force for phase separation. Also, molecular weight, concentration of the polymer, and composition are important properties. Choosing the solvent with a different boiling point affects the solvent evaporation rate. If a solvent with a low boiling point is used, the phase separation is fast. Surface tension and viscosity of the solution are also related to the solvent. The solubility is an important parameter that determines the structure of vertical phase separation. If the solubility of two polymers is different, the polymer with the lowest solubility solidifies first. Processing conditions strongly affect the phase separation kinetics. In electrospinning, the phase separation between solvents and polymer in the case of a single solvent or solvent mixtures, between polymers in spinning solutions composed of more than one polymer, and between a polymer and low molar mass additives and also condensation effects of water vapor on the surface of the jet can be exploited in a controlled way to specific surface topologies like pore formation inside and/or on the surface of electrospun nanofibers. If the phase diagrams are known for the solutions, the quantitative prediction for the electrospinning process is still difficult. The mechanical elongation and the time scale in which separation takes place will have major effects on the structure formation of nanofibers and pores formations.

Porous Formation During Electrospinning The porous nanofibers could be produced during the nanofiber formation by combining electrospinning with phase separation and/or breath figure (BF) mechanisms at the nanofibers surface. The driving force for the phase separation to take place may be by temperature, relative humidity, presence of nonsolvent, and relative volatility of solvent systems or doing some setup modification.

Temperature Phase separation occurs by lowering the temperature of the solution in thermally induced phase separation (TIPS). It is generally associated with a hydrophobic polymer dissolved in a water miscible and highly volatile solvent. The solution

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passes through the binodal curve to enter the metastable region in the phase diagram. Amorphous polymers produce microporous structures by liquid/liquid phase separation followed by the gelation of the polymer. In semicrystalline polymers, microporous structure formation has been observed because of combined crystallization and liquid/liquid phase separation. The evaporative cooling occurs on the electrospun jet in the distance between the syringe and the collector, although the temperature is kept constant during the electrospinning process. This can cause TIPS during jet solidification and fiber formation. The occurrence of pores only on the surface is a result of the evaporative cooling effect on the fiber surface temperature [19]. Pores formed through TIPS are typically circular since the pores are molded by water droplets.

Relative Humidity The surface morphology of electrospun nanofibers is affected by the polymer used, the high voltage applied, and the solvent, as well as the environmental conditions (e.g. humidity). Electrospinning in a very humid environment is one route to prepare the porous nanofibers where evaporative cooling at the surface of the nanofibers could lead to the condensation of moisture and the formation of BF and consequently tiny droplets of water precipitate onto the jet and generate phase separation. It can organize a regular pattern if the conditions are chosen appropriately. The size, shape, and distribution of the droplets on the surface are controlled among other parameters by the velocity of the electrospun jet and the humidity. As it was described earlier, it also causes vapor-induced phase separation (VIPS) and during that the polymer solution undergoes phase separation by penetration of nonsolvent from the vapor phase. During solvent evaporation the solution becomes thermodynamically unstable. The phase separation occurs into a polymer rich and a polymer poor phase. After phase separation, the concentrated phase solidifies soon and forms the matrix, while the polymer poor phase forms the pores. All these general aspects may be transferable to the formation of porous micro- and nanofibers. In high volatile solvents, if the vapor phase is saturated with solvent, skin formation can be hindered. In this situation, the pore formation is determined by the polymer concentration and the vapor pressure of the nonsolvent [19]. Typically, a hydrophobic polymer (non-water soluble), high volatility solvent to lock-in the feature, and a water-miscible solvent are necessary to facilitate VIPS. If the solvent evaporation is too slow, the formed feature would redissolve into the solution and a smooth fiber would form instead [11]. First, water vapor is absorbed into the jet due to the water-miscible solvent. Phase separation occurs as the hydrophobic polymer precipitates out of the solution when water is introduced, creating polymer-rich and polymer-poor regions within the jet. Finally, rapid evaporation of the highly volatile solvent locks in the phase-separated geometry, resulting in fibers with surface pores. Pores created by VIPS are typically irregularly shaped [11]. A summary of the theories describing the formation of pores on hydrophobic polymer fibers is illustrated in Fig. 3. These droplets then form pores in the solidified nanofibers after solvent evaporation. The extent of pore formation and the pore size can be tuned by varying the

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High Volatility solvent Non water miscible solvent

High Volatility solvent water miscible solvent

Low Volatility solvent water miscible solvent

Smooth fibers Thermally induced phase separation (breath figures)

Vapor induced phase separation

Circular pores

Irregular pores

Porous core

Fig. 3 Different fiber morphologies observed for hydrophobic polymer electrospun at high percent RH with different solvents [11] (Copyright # 2013, Mary Ann Liebert, Inc.)

humidity. Casper et al. [20] have reported the effects of relative humidity and polymer molecular weight on the formation of pores on the surface of PS electrospun fibers. It has been indicated that the amount of moisture in the air affects the surface morphology of electrospun PS fibers with tetrahydrofuran (THF) solvent. The smooth electrospun fibers without any surface features have been produced in an atmosphere of less than 25% humidity. By increasing the humidity above 30%, pores on the surface of the fiber begin to form. Increasing the amount of humidity causes an increase in the number of pores on the surface, the pore size, and its distribution. It was also declared that increasing the molecular weight of the PS results in larger, less uniform shaped pores. However, this result was observed only when the solution used a highly volatile organic solvent, such as chloroform, THF, and acetone [21]. The evaporation rate of solvent in the jet is affected by high humidity. When a fiber reaches to the collector, some solvent remains inside. This subsequently evaporates and leaves the porous. Jeun et al. [22] reported that the number of pores on the poly(L-lactide-co-D, L-lactide) (PLDLA) fiber surface, the pore diameter, and the pore size distribution increase with increasing humidity. Huang et al. [23] fabricated poly(acrylonitrile) (PAN) and polysulfone (PSU) nanofibers with surface features by simply varying the humidity in the process environment of each individually. The electrospun PSU fibers which were fabricated at high humidity have surface pores and higher specific surface area, while PAN fibers exhibit an increased surface roughness and no visible pores. The complex interaction between the nonsolvent (water), the hygroscopic solvent (DMF), and the polymer affects the fiber morphologies. Demir et al. [24] have investigated the formations of three different types of pores and different length scales on the electrospun PS fibers by varying the weight fraction of the polymer at a constant relative humidity of 35%. These types are interstitial pore spaces between the fibers, which is on the order of micrometer, surface and internal pores of fibers, the size of which is in a nanometer scale. The development of porosity of the two last types is induced by phase separation resulting from the rapid evaporation of water molecules from the PS/DMF system.

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Fig. 4 Scanning electron microscopy (SEM) images of polycaprolactone (PCL) electrospun fibers at relative humidity ranging from 5% to 75% [11] (Copyright # 2013, Mary Ann Liebert, Inc.)

Increasing relative humidity or decreasing polymer concentration would increase the pore formation. This is illustrated in Fig. 4. For polycaprolactone (PCL) as an intermediate hydrophobic nanofiber, its morphologies change by increasing the relative humidity from 5% to 75%. The broken electrospun fibers were obtained below 50% RH but formed thicker fibers with surface pores above 50% RH. DMF was used as a solvent for PCL, which allows for water absorption and the hydrophobic PCL precipitates out upon the absorption of water, and the highly volatile chloroform evaporates rapidly to lock in the pore geometry. The number and density of surface pores increased as the relative humidity was increased. Broken fibers at low humidity attributed to the increased electrostatic charge on the electrospinning jet due to reduction of water vapor in the air. During electrospinning, a portion of charge from the electrospinning jet is discharged to the water vapor molecules in the atmosphere. This is facilitated by the high dielectric constant of water, indicating that it has a high energy storage capacity by means of polarization. Therefore, a decrease in water vapor (low humidity environment) results in a decreased amount of electrostatic discharge since fewer water molecules are available for charge transfer. As a result, the charge density on the jet is higher at low humidity causing fiber breakage [11].

High Volatile Solvent The increased surface area of polymeric nanofibers due to pore formation was correlated with high volatility solvents used in the electrospinning process. The rapid evaporation of a high vapor pressure solvent cools the surface of the solidifying solute. Water vapor from the atmosphere condenses on these cold surfaces to form BF. The condensed water vapor initiates polymer phase separation between the solvent and the water droplet as formerly described.

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Bognitzki et al. [25] utilized the rapid evaporation of a highly volatile solvent dichloromethane (boiling point 40  C, vapor pressure 475 mbar at 20  C) to induce rapid phase separation of the polymer/solvent mixture (PLLA, polycarbonate, and polyvinylcarbazole) from condensed water vapor on the fiber surface. It was explained that this pore structure was generated from rapid evaporation of dichloromethane in solvent-rich regions, since the pore formation was reduced after using chloroform as the solvent. Also, the pores were stretched due to the uniaxial extension of the jet in the electric field (Fig. 5). Megelski et al. [19] observed a variety of structures on the fiber surfaces from the densely packed irregular shaped pore (PS/THF) to extremely rough surfaces with loosely packed elongated pores (PMMA/acetone). In this work, a variety of crystalline and amorphous polymers, including polycarbonate (PC), poly(ethylene oxide) (PEO), and poly(methyl methacrylate) (PMMA), were electrospun from different solvent systems as described in Tables 1 and 2 to compare their surface morphology and the influence of solvent vapor pressure. It was declared that when the exceptionally small diameters (10–1000 nm) of the smallest nanofibers are combined with a nonporous morphology, it can give rise to an extremely large surface area (100–1000 m2/g). It was stated that the solvent vapor pressure has a critical influence on the process of pore formation. However, solvent diffusion in polymers has an important affect in the evaporation process. The solubility parameters of the polymers and the solvents, the diffusion coefficients of the solvents, and the interaction parameters between polymer and solvent are parameters of influence. Figure 6a–d shows the effect of the decreasing vapor pressure of the solvent mixture on the observed microtexture for PS electrospun fibers from THF, THF/DMF (75:25), THF/DMF (50:50), and 100% DMF. The PS electrospun fibers from THF only have small pore size on the surface of the fibers. At a ratio of THF/DMF (75:25), the pores become larger, less uniform, and shallower than those on the fibers electrospun from 100% THF. Surface roughness and/or microtexture are observed at THF/DMF (50:50), but these features disappear when the fibers are spun from 100% DMF because of decreasing solvent volatility. PMMA is an amorphous polymer with high optical clarity making it important for applications where light transmission is necessary. The surface morphology of

Fig. 5 SEM images of porous nanofibers: (a) PLLA, (b) PC, (c) polyvinylcarbazole [25] (Copyright # 2001 WILEY-VCH Verlag GmbH, Weinheim, Fed. Rep. of Germany)

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Table 1 Electrospinning condition for four polymers to investigate the pore formation (Reprinted with permission from Ref. [19]. Copyright # 2002 American Chemical Society) Fiber o.d./ Flow rate Needle pore c (wt %) U (kV) d (cm) (mL/min) o.d. (mm) o.d. (μm/nm) 30 20 12 0.10 0.35 4–25/ 800 nm)

According to the pores dimension, various general techniques available for characterization of porous materials are illustrated in Fig. 14, in which some of the techniques are appropriate for polymeric nanofibers. Andrady et al. [55] discussed the various techniques in detail, and here, a brief summary is given.

Scanning Electron Microscopy (SEM) Microscopic imaging is routinely used in the initial characterization of nanofiber. SEM is capable of producing high-resolution images of a nanofiber surface and can determine whether it is smooth, rough, or has a porous structure. It is possible to measure the width and length of pores on the surface of the nanofibers, which give a directly perceived sense to understanding its construction features. Image analysis could be employed as an efficient tool to quantify the pore sizes. In SEM, FESEM, and other optical methods, only the surface of a pore can be observed in an image and yield two-dimensional representations of nanofibers and pores; so yield porosity information can be different from that obtained using other techniques.

Fig. 14 Techniques for characterization of porosity [55, 56] (Copyright # 2008 John Wiley & Sons, Inc.)

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Transmission Electron Microscopy (TEM) The pore structure of porous nanofibers can be clearly seen in TEM images. However, the presence of micropores needs to be studied using other techniques such as the Brunauer-Emmett-Teller (BET) nitrogen adsorption isotherms method. As already mentioned, the TEM also yields two-dimensional representations of nanofibers and pores. Atomic Force Microscope (AFM) The AFM is a very high-resolution scanning probe microscope. Similar to SEM and TEM, AFM can be used to characterize geometric properties of nanofibers such as fiber diameter, diameter distribution, fiber orientation, porosity, and surface roughness. However, an accurate measurement of the nanofiber porosity with AFM requires a rather precise procedure. Mercury Intrusion Porosimetry The porosity of a material is measured using intrusion porosimetry. In this method, a nonwetting liquid (usually mercury) that does not swell or dissolve the nanofibers is forced into the mat of nanofibers to assess the pore volume. It is widely accepted as a standard measure of total pore volume and pore size distribution in the macropore and mesopore ranges. However, this technique measures only the fraction of porosity accessible by mercury. Therefore, it excludes closed pores, small mesopores that are inaccessible by mercury, as well as very large pores readily flooded by mercury even before the application of pressure to initiate the measurement. Mercury intrusion measurements typically use high applied pressures (of up to thousands of psi) and may distort the inherent pore volume distribution of soft polymer nanofiber mats, and may also collapse the softer nanofibers into different cross sections. This technique could be used for measuring the porosity of nanofiber mats and is not suitable for porous nanofiber’s porosity measurement. Liquid Extrusion Porosimetry Flow-through liquid extrusion porosimetry avoids the use of very high applied pressures encountered in mercury intrusion measurements and is therefore well suited for characterizing relatively soft polymers, and no swelling of the fibers occurs. In this technique, a nanofiber mat is supported on a porous membrane and a layer of a wetting liquid is placed on its top surface. Gas pressure is applied over the liquid column and is gradually increased on the face of the mat until the gas is able to push the liquid through the largest of the pores in the mat, overcoming capillary forces. This allows a volume of liquid to be forced through the mat. The porous membrane supporting the mat is also saturated with the same liquid and its pore size is smaller than the smallest pore in the mat. Therefore, the liquid displaced from pores in the mat in turn displaces the same volume of liquid from the liquidfilled pores of the membrane it is in contact with. This displaced volume of liquid and the applied pressure are accurately recorded. As the gas pressure is increased, progressively smaller pores are cleared of the liquid held in them. The differential

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pressure is related to the pore diameter and the volume of liquid extruded is indicative of the pore volume. The dependence of the displaced volume on the pressure yields an estimate of the surface area. Any blind pores (e.g., surface porous features on individual nanofibers) that do not allow flow-through of liquid cannot be assessed by the technique. The fraction of blind pores can therefore be indirectly estimated by comparing liquid extrusion data to the intrusion porosimetric data (which quantifies both open and blind pores).

Capillary Flow Porometry The technique is similar to the liquid extrusion technique in that the nanofiber mat is saturated with a wetting liquid and gas pressure is applied to one surface of the mat. The surface free energy of the liquid with the fiber mat needs to be less than that of the mat with the gas. As with liquid extrusion, the liquid column occupying throughchannels will be displaced by the gas. In flow porometry, the gas displaces the liquid and the flow rate of gas as a function of the differential pressure is recorded. At lower pressures, the larger pores are cleared, allowing some gas flow. The lowest pressure at which this occurs is the bubble point. The bubble point, a classical measurement in textile and paper technologies, is the point at which pressure is just sufficient to initiate flow. The needed pressure depends on the surface tension of the liquid used, the surface energy of the nanofibers, as well as pore characteristics. As the gas pressure is gradually increased, the flow rate also correspondingly increases, with the smaller pores in the mat being cleared of the liquid as well. The distribution of interstitial pore sizes obtained by this technique, however, refers exclusively to that of the throat of the pores. This technique is mostly used for characterizing liquid filter media or studying the amenability of scaffolding to cell movements within it and is not suitable for nanofiber surface porosity measurement. Brunauer-Emmett-Teller (BET) BET analysis provides accurate specific surface area evaluation of materials by nitrogen multilayer adsorption measured as a function of relative pressure using a fully automated analyzer that relies on gas adsorption involving several key assumptions: 1. Gas interaction with the polymer occurs with a constant heat of adsorption and exclusively due to Van der Waals interactions between the gas and nanofiber surface (i.e., there is no significant sorption of the gas by the nanofibers). 2. Adsorbed molecules on the surface do not interact with each other. 3. Additional layers of gas molecules can be deposited on the surface of a complete or incomplete monolayer with the heat of adsorption being equal to heat of liquefaction of the gas. Experimentally, a sample of the nanofiber mat sealed in a chamber is maintained at a constant temperature well below its glass transition temperature and the chamber is evacuated. An adsorbate gas (usually N2 or a N2/He mixture, although other gases can be used) is admitted into the chamber in several increments until the entire

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surface of the porous mat is covered by a monolayer of gas. To allow sufficient gas molecules to be adsorbed by the weak Van der Waals interactions, however, the sample has to be cooled, normally to the boiling point of the gas (for N2 gas to 77.35 K). The BET could be used for measurement of surface area, pore volume, and porosity.

Other Approaches There are some other methods, which may not be routinely used for characterizing the prose nanofibers, but it is possible to obtain the porosity data. Nuclear magnetic resonance (NMR) is used to study the porous materials. The method relies on the fact that the different relaxation times of protons in water (or other fluids) in porous materials will decrease with the average pore diameter. Table 3 summarizes the general approaches to characterize the porosity of materials together with the information each is likely to provide according to ASTM F245004. Those that do not apply to electrospun nanofibers are also included for completion.

Core-Shell and Hollow Nanofibers As an innovative extension of electrospinning, this process could be used to fabricate polymer nanofibers with unique core-shell, hollow, or multi-channel structures. Electrospun core-shell fibers, as a kind of one-dimensional nanostructure material, have attracted special attention because these unique core-shell structures could further impart functional properties with desired multifunctions. In recent years, many modifications and extensions have emerged in the conventional electrospinning process in order to achieve the unique features and improve the quality and the functionality of the electrospun fibers. Fabricating the ultrafine core-shell or hollow nanofibers has gained much attention. Table 3 Summary of common techniques used to study the porosity of materials (ASTM F2450-04) Generic technique Microscopy Micro X-ray computer tomography Magnetic resonance imaging Measurement of density Porosimetry Porometry Diffusion of markers NMR

Information available Pore shape, size and size distribution, porosity Pore shape, size and size distribution, porosity (for larger pore size) [55] Pore size and size distribution, pore shape, porosity (for larger pore size) Porosity, pore volume Porosity, total pore surface area, pore diameter, pore size distribution Median pore diameter (assuming cylindrical geometry), throughpore size distribution, permeability Permeability Pore size and distribution

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The core-shell structure provides producing fibers from non-electrospinnable materials, hollow fibers, and fibers containing encapsulated particles or compounds for providing novel functional behaviors. These novel nanofibrous structures with high control on fiber properties, improving the mechanical properties with the hollow fiber morphology, control the delivery approaches of multiple drugs, and altering the biological properties offer high potential application for a wide range of novel approaches including energy storage, pharmaceuticals, and healthcare (drug delivery, gene delivery, and tissue engineering), filtration, catalysis, sensors, and food processing. Compared with single structure fibers, the coreshell fibers possess more attractive merits including controllable mechanical strength and better thermal and electrical conductivities. For example, the considerable enhancement in mechanical properties of core-shell fibers from silk fibroinsilk sericin was reported with a breaking strength of 1.93 MPa and a breaking energy of 7.21 J/kg, which exhibits 82% and 92.8% higher than those of single fiber, respectively [57]. Fabricating numerous geometrical architectures in the form of core-shell, hollow, and porous structures offers dimensional, directional, and compositional flexibility, the excellent physiochemical properties, which are beneficial in energy storage, lithium-ion batteries, supercapacitors, dye sensitized solar cells and luminescence, and photocatalytic environmental remediation [58]. Li et al. [59] obtained hollow Y2O3:Eu3+ nanofibers from calcination of coaxial electrospun PVP – PVP/[Y(NO3)3+Eu(NO3)3] core-shell nanofibers with considerably increased luminescent intensity. Many studies have increasingly reported the use of coaxially electrospun phase change materials (PCMs) in energy storage and conservation. The unique advantage of coaxial electrospinning is the ability to modulate the release kinetics by altering the fiber thickness and localization including the following release profiles: sustained release, involving the drug, biomolecules, or gene release at a predetermined rate for a specific period of time, and multiphase release, involving the release of a drug at two rates, or in two phases [60, 61]. For instance, applying strategies for modulating gene delivery is very important to achieve high gene transfection efficiency into target sites in human clinical uses. Incorporating multiple pDNA into polymeric scaffolds with core-shell structures is a powerful strategy to accomplish this purpose that can provide localized and sustained delivery of genes into the target site and promote the generation of blood vessels [62]. The triaxial electrospun nanofiber loaded with two different types of functional molecules has been reported to offer a versatile method creating functional nanofibers by providing both short-term and long-term treatment [63, 64]. For example, for wound dressing’s approaches, triaxial fibers which have a core with antibiotic drug and an outer shell layer loaded with an anesthetic drug can minimize pain at the early stage of the wound and prevent infection over the healing period. Figure 15 illustrates some variant fiber structures to load the drug, which could be produced by doing some modification in electrospinning setup or polymer solution. The core-shell fiber structure provides the feasibility of electrospinning the materials which could not be used alone due to their limited solubility, low

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Fig. 15 The schematic of single, coaxial, hollow, and triaxial fiber as a drug carrier [65] (Copyright # 2016 Elsevier B.V. All rights reserved)

molecular weight, or lack of required viscoelastic properties. Some natural polymers, conductive polymers, or metals that cannot form fibers by themselves could be formed into the fibers by using the concept of core-shell formation. These materials could be electrospun with shell polymer that is effectively electrospinnable. Hollow fibers with continued tubular shape have been produced via electrospinning and have high potential applications in different fields of science and engineering like biocatalyst, bioseparation, controlled release, and adsorbent materials. PMMA hollow nanofibers were coaxially electrospun from two immiscible liquids, followed by selective removal of the cores (mineral oil) as shown in Fig. 16a, which declared to have potential applications as microfluidic channels, storage devices, and even as fillers, which may increase the electrical and heat insulation of the composite material [66]. Using a similar setup, TiO2/polymer composites and ceramic hollow nanofibers were coaxially electrospun from two immiscible liquids, followed by selective removal of the cores. Yousefzadeh et al. [53] have fabricated polymer-free, inorganic TiO2 ultrafine nanofibers as shown in Fig. 16b by coaxial electrospinning of TTIP/PVP sol-gel, an immiscible liquid such as oil (glycerin), followed by selective removal of the inner oil.

Coaxial Electrospinning Coaxial electrospinning is a modification of the conventional electrospinning that was used for fabrication of hollow and core-shell micro-/nanofibers. In this process, at least two materials are independently delivered through a coaxial nozzle and drawn to form fibers with core-shell structures. The coaxial electrospinning has provided many novel designs of functional nanomaterial for variant applications. The greatest advantage of coaxial electrospinning is its versatility in the type of materials, which are used and also controlling the fiber diameter ranging from several tens of nanometers to micrometers. In the following sections, the general setup of coaxial electrospinning, modification in coaxial electrospinning, and the parameters, which have the effect on achieving uniform core-shell fibers, are described.

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Fig. 16 (a) SEM images of PMMA hollow fibers [66] (Copyright # 2008 Wiley Periodicals, Inc.). (b) FESEM images of hollow TiO2 nanofibers [53]

General Setup and Process of Coaxial Electrospinning A general setup for coaxial electrospinning is made by a modification in the conventional electrospinning nozzle which is composed of two coaxial capillaries instead of a single nozzle. Figure 17a schematically illustrates a basic setup of coaxial electrospinning. This arrangement of the coaxial electrospinning setup could be horizontal or vertical, and there have been several studies on the effect of experimental configuration on the quality of electrospun fiber [67]. In coaxial electrospinning, two polymer solutions are independently fed through inner/outer capillaries, the inner and outer of which are connected to the individual syringe pumps containing core and shell solution, respectively. Although the feeding rates of solutions are usually controlled by a syringe pump [68, 69], using air [70] or gas [71] pressures is also reported to control the solutions feed rates. In some studies, shell solution is exposed to the atmospheric pressure to flow by gravity [72]. The process of coaxial electrospinning is conceptually similar to typical electrospinning. Under applied high voltage, the polymer solutions are drawn out from the nozzle and form a compound droplet with a core-shell structure at the end of the nozzle. As a high electric field is applied, the charge accumulation occurs on the surface of the shell solution and then the charge-charge repulsion causes the elongation and stretch of shell solution to form a compound Taylor cone. Once the electrostatic force acting on the ejected polymeric solution overcomes the surface tension of the shell solution, a fine jet is formed from the cone. Via viscous dragging and contact friction, the stresses acting on the shell solution lead to core solution shearing. The core solution deforms into the compound cone and a compound coaxial jet extends at the tip of the cone as it is shown in Fig. 18. The stable condition of the compound cone is required for uniform incorporation of core material into the shell solution and subsequently the formation of uniform coreshell fibers. In order to keep a compound Taylor cone in dynamic stabilization, it is necessary to control and balance the flow rates of core and shell solutions. The coaxial jet accelerates toward the collector, whipping, and bending wildly. As the solution jet moves away from the coaxial nozzle, the jet is rapidly thinned and dried

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Fig. 17 (a) Schematic of the basic setup for coaxial electrospinning process [73] (Copyright # 2016, Royal Society of Chemistry), and the compound Taylor cone [74] (Copyright # 2003 Elsevier Science Ltd. All rights reserved). (b) The TEM image of core-shell nanofibers by F. Ghasemkhah

Fig. 18 The compound Taylor cones and electrified jets take shape with the gradual balance or increase in voltage from (a) to (c) during the coaxial electrospinning of PVP (outer) and a mineral oil (inner) solutions [76] (Copyright # 2008 IOP Publishing Ltd)

as the two solvents evaporate. Finally, the core-shell nanofibers are formed and deposited on the surface of the grounded collector [75, 76]. The novel nozzle with concentric metallic needles was originally used by Loscertales et al. [77] to electrospray core-shell nanoparticles from immiscible liquids. In a later study, they obtained inorganic and hybrid fibers, hollow fibers, and vesicles by using the sol-gel in the coaxial electrospinning process [78, 79]. In 2003, Sun et al. reported the fabrication of core-shell nanofibers through coaxial electrospinning [70]. Alternatively, a great deal of progress has been achieved, mostly by modifying and dressing up the original idea for better feasibility and

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applicability of core-shell and hollow nanofibers [72, 80]. Some of these studies reported coaxial electrospinning setup with a slightly different arrangement. Wang et al. [81] reported a simple setup which requires two independent syringes instead of using a specially coaxial nozzle. It can be setup easily by inserting the smaller needle from outside into the Taylor cone formed at the exit of the large needle. In another study, Chakraborty et al. [82] have used a different arrangement with a syringe located inside another syringe (syringe-in-a-syringe setup) to reduce the dead space of connecting tubes and nozzle in order to minimize the loss of solutions. Wang et al. [83] constructed a three-tube nozzle where the solvent vapor of shell solution was introduced by N2 carrier gas to encapsulate the Taylor cone and reduce the evaporation rate which results in the clogging of the Taylor cone.

Modifications and Advances in Coaxial Electrospinning There are some different studies and reports that indicate several modifications in electrospinning setup for fabrication of core-shell nanofibers. Multiaxial Electrospinning It is possible to engineer more than two layers of coaxial micro-/nanofibers, and with the elimination of some layers, the hollow and multilevel structures can be produced. Triaxial electrospinning setup is one of the advanced modifications for producing functional nanofibers, in which three polymer solutions are delivered into a compound Taylor cone through a triaxial nozzle as it is shown in Fig. 19a. Triaxial fibers

a

Outer sheath solution

Core solution

b

Hygroscopic sheath layer Burst release Sustained release

Intermediate solution

Hydrophobic intermediate sheath layer

High voltage supply

c

Instability

Conductive substrate

Fig. 19 (a) Schematic of triaxial electrospinning setup, (b) cross-section schematic of triaxial fibers loaded with dual drugs (Reprinted with permission from [63]. Copyright # 2013 American Chemical Society). (c) TEM image of a trilayer nanofiber (Reprinted with permission from Ref. [64]. Copyright # 2015 American Chemical Society)

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could be used for different drugs delivery with a dual delivery system which acts as an isolation layer between the shell and core layers in the intermediate layer (Fig. 19b) [63], or polymer solutions could also be loaded with nanoparticles containing drugs for controlling drug release and/or enhancing cell proliferation and migration. This approach can also introduce an extra middle fluid between the core and shell fluids of conventional coaxial electrospinning to work as an effective spacer between the other fluids even mutually miscible fluids, by decreasing their interaction [84]. In order to better understand the solvent interactions in triaxial jets, Khalf et al. [85] investigated the effect of solvent mixture properties such as boiling point and solvent incompatibility/miscibility. Also, the outer shell can selectively eliminate and expose the desired inner shell to obtain fibers of polymers that cannot be electrospun on their own [65]. Triaxial electrospinning was used as a versatile method for the facile preparation of trilayer nanofibers loaded with two different types of functional molecules to develop an advanced drug delivery system [63, 64]. Chen et al. [84] fabricated core-shell fibers with a special nanowire-in-microtube structure from two totally miscible fluids using triaxial electrospinning, in which the chemically inert middle fluid was introduced between the outer and the inner fluids as spacer. Thereby, from a three-layered core-shell structure that is shown in Fig. 20, selectively removing the middle layer of the as-spun fibers results in the formation of ultrathin fibers with an interesting nanowire-in-microtube structure with a hollow cavity between the shell and the core materials. The prepared core-shell fibers and the special hollow cavity structure with this method can introduce some extra properties into the conventional core-shell structure, which may possess potential applications such as optical applications and microelectronics. Lee et al. [86] fabricated tetra-layered SAN/PAN/SAN/PAN coaxial nanofibers using coaxial electrospinning with a concentric quadruple cylindrical nozzle system.

Fig. 20 (a) TEM image of a single fiber showing a continuous nanowire in the microtube, (b) cross-sectional SEM images of TiO2 fibers, which show the interesting wire-in-tube structure (Reprinted with permission from Ref. [84]. Copyright # 2010 American Chemical Society)

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Fig. 21 SEM images of multichannel nanofibers with variable diameter and channel number (a–d) corresponding to tube with channel number from two to five, (e) schematic illustration of the threechannel nozzle (Reprinted with permission from Ref. [87]. Copyright # 2007 American Chemical Society)

Subsequently, with the erosion of the first and third layers and converting the second and fourth layers into the carbonized structure through the heat treatment, doubletubular carbon nanofibers (CNFs) with a tube-in-tube structure were obtained. Finally, nanoparticles were incorporated between the two tubes in the double-tubular CNFs, to provide an inexpensive method for developing nanochannels and new multifunctional 1D nanomaterials. Multichannel Coaxial Electrospinning Mutichannel electrospun nanofibers could be fabricated in combination with dissolution/incineration of selected channels that have primarily been used to create multichannel nanofibers. Multichannel nanofibers can be prepared using a multichannel nozzle. In Fig. 21, the example of the multichannel TiO2 nanofibers and the schematic of the corresponding nozzle are shown. Paraffin oil was used as an inner fluid and titanium isopropoxide/PVP solution as the outer fluid during electrospinning. Therefore, applying post-heat treatment could remove the PVP and paraffin oil contents and convert isopropoxide into TiO2, so the final multichannel TiO2 nanofibers were remained [87]. Melt-Coaxial Electrospinning By the development of responsive material and nanotechnology, combining various functional material and nanostructures has recently received much attention for great prospects in smart materials. In addition, coaxial electrospinning provides fabrication of the core-shell or hollow fibers, which give small capsules to encapsulate the responsive or functional materials. The combination of melt electrospinning with the

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coaxial nozzle provides a facile method to encapsulate solids in a composite or polymer matrix to generate nanofiber-based smart materials and create new morphologies and architectures. Xia et al. [88] first invented melt coaxial electrospinning to encapsulate the phase change materials to the fabricated core-shell nanofibers. The heating tape with a temperature controller device was added on the inner fluid syringe of the conventional coaxial electrospinning setup to provide a thermal atmosphere for inner fluid and keep the molten and in fluid station as shown in Fig. 22a. The high voltage electric field draws a viscous droplet into an elongated jet and pulls out liquids from the coaxial nozzle to form thinner and thinner fibers. During the electrospinning process, by cooling the jet due to solvent evaporation, the inner fluid (melt hydrocarbon phase change materials) froze rapidly, leading to encapsulation in the outer fluid polymer solution (TiO2-PVP). In 2009, another group made an improvement for the melt coaxial electrospinning [89]. A whole thermal atmosphere heating system was appended on coaxial electrospinning as it is shown in Fig. 22b. The whole thermal atmosphere of the loaded system was more beneficial to prevent the inner dope freezing by jamming of the needle, and this ensured encapsulating phase change materials into poly(methyl methacrylate) nanofibers as reported. Other Modifications in Coaxial Electrospinning Some other innovations and modifications have been reported to achieve quality output. Lee et al. [90] developed a core-cut nozzle system with the elimination of the inner nozzle, such that the core fluid enabled formation of an envelope inside the shell solution. This configuration resulted in better balance between the surface tension and charge accumulation, thereby improving the coaxial electrospinning behavior of two fluids and significantly reducing the jet instability. There are several studies which utilized coaxial [91–93] or triaxial [92] electrospinning to encapsulate block copolymers (such as PS) as core inside thermally stable material (such as silica). The silica gel acts as a protection and provides thermal stability to fibers on annealing of the materials at temperatures higher than the core polymer glass transition to obtain equilibrium self-assembly without destroying the fiber morphology. Finally, after the interactions between the shell materials with encapsulated materials (copolymer), the fibers with lamellar and cylindrical morphology were obtained as shown in Fig. 23, which possess the potential for the applications in photonics, optical waveguides, wearable power, sensors, and sustained drug delivery. Lee et al. [94] reported a novel jetting procedure with electrohydrodynamic co-jetting. This approach could result in Janus-core and shell fibers, where the Janus core was defined by the parallel center jets. In this method, microfibers and microcylinders were prepared using coaxial co-jetting with two dissimilar core materials and PLGA solution was used as the shell stream. Coaxial configuration allowed preparation of well-aligned fibers from nonspinnable solutions, and PLGA acted as a sacrificial channel which stabilized the overall jet. Fibers were collected in the form of aligned fiber bundles and then after the cross-linking of each core

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a

Syringe pump

Polymer-coated silica capillary

PVP/Ti(OiPr )4

C16 - C20 Hydrocarbon Glass syringe

Epoxy seals

Plastic syringe

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Metallic needle Thermocouple High-voltage power supply

Heating tape

V

Temperature controller Al foil collector

b

Syringe pump Glass thermal tube Heating tape Inner dopes

Outer dopes

gh-voltage wer supply

V 45°C

Temperature controller HV

Fig. 22 (continued)

V

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polymer, the aligned bundles were converted to well-aligned microcylinders by microsectioning. Eventually, the PLGA shell could be removed to reveal the actual Janus fibers, and uniquely shaped building blocks fabricated by photo-patterning of one hemisphere of the microcylinders. Figure 24 schematically shows the preparation method of anisotropic microfiber bundles, following UV light through treatment onto a photo-mask. The coaxial co-jetting technique producing microfibers and microcylinders with distinct materials offers potential for applications such as sensors, microactuators, or type of patterned particles.

The Effect of Various Parameters on Coaxial Electrospinning As the coaxial electrospinning process is conceptually similar to conventional electrospinning, all variables that have an effect on the electrospinning process and fibers morphology also effect the formation and morphology of core-shell fibers in coaxial electrospinning. An increasing number of attempts are being made to determine the parameters that control the morphology and dimensions of the coaxial fibers. A brief review of effective parameters on the formation of core-shell fibers via coaxial electrospinning is given here. Systematic and Solution Parameters Many studies discuss the effect of the parameters that control the physical electrospinning mechanisms of a compound solution set, such as the interaction between the core and shell solutions (solution miscibility), the solution viscosity, interfacial tension, solution conductivity, and solvent vapor pressure. Kurban et al. [95] report a systematic method for selecting solvents which enable efficient identification of compatible core-shell solutions with parameters optimized for successful coaxial electrospinning. Miscibility of Core-Shell Solutions and Incompatibility The miscibility of core-shell solutions remarkably influences the process of coaxial electrospinning. Therefore, interaction between polymers and solvents of core-shell solutions is an important parameter that should be considered first. Also, it should be considered that at the tip of the nozzle where two solutions meet each other, the solvent in either of the solutions should not precipitate the other solution [96]. Furthermore, the interfacial tension between two solutions should be as low as possible to form a stable compound Taylor cone [97]. Different reports have been published about the issues of the miscibility of core and shell solutions. Many studies have reported that two immiscible solutions are the most convenient and desirable for the formation of core-shell fibers via coaxial as they ensure phase separation during the spinning process. Xia et al. [98] showed that ä Fig. 22 (a) Schematic of the melt-coaxial electrospinning setup used for fabricating TiO2-PVP nanofibers loaded with hydrocarbon PCMs (Reprinted with permission from [88]. Copyright (2006) American Chemical Society). (b) Schematic of the melt coaxial electrospinning setup with a whole thermal atmosphere [89] (Copyright # 2008 Wiley Periodicals, Inc.)

Fig. 23 TEM images of coaxially spun polystyrene-block-polyisoprene (as core) fibers with SiO2 shell (a) transition to alternating concentric-cylinder morphology after annealing at 175  C for 24 h, (b) parallel morphology on annealing at 175  C for 50 h [91] (Copyright # 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim). (c) Dislocation and long-range order in concentric lamellar structure of poly(styrene-b-dimethylsiloxane) (PS-PDMS) block copolymer as the core component and a PMAA as the shell (Reprinted with permission from Ref. [93]. Copyright # 2009 American Chemical Society). (d) TEM images of microtomed cross sections of annealed block copolymer (poly(styrene-b-isoprene) (PS-b-PI)(as a core) nanofibers with silica shell at 180  C for 2 days [92] (Copyright # 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim)

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Fig. 24 Preparation of poly(vinylcinnamate)(PVCi)/epoxy resin/PLGA Janus microcylinders by electrospinning with a dual–core-Shell nozzle configuration (Reprinted with permission from Ref. [94]. Copyright # 2013 American Chemical Society)

core-shell fibers could be produced from immiscible liquids via coaxial electrospinning from immiscible solutions and if immiscible polymers with miscible solvents were used as core/shell solutions, highly porous structures could be obtained through selective dissolution or calcination of fibers. On the other hand, some polymer solutions were coaxially electrospun with the same solvent to obtain a lower interfacial tension between the inner and the outer solvents. Polycarbonate (PC)/PMMA core-shell fibers were obtained by coaxially electrospinning the innerouter solutions with the same solvent (formic acid) [99]. Zhang et al. [72] obtained gelatin/PCL core-shell fibers using the same solvent as 2,2,2-trifluoroethanol (TFE). Therefore, it was believed that core-shell fibers could produce the inner-outer polymer solution with miscible solvents in coaxial electrospinning. Yu et al. [96] mentioned that due to the rapid electrospinning process, sufficient time could not be provided for fluids to diffuse each other. Therefore, interaction between core shell fluids during coaxial electrospinning was probably negligible. This declares that using miscible fluids in the same solvent could reduce interfacial tension and obtain thinner fibers. Diaz et al. [97] used coaxial electrospinning to encapsulate a hydrophobic fluid (industrial oil) inside hydrophilic PVP solution in DMF (as solvent). It was shown that the low surface tension between two liquids and the high viscosity of shell solution could prevent the varicose breakup of the inner fluid in the coaxial jet until the end of coaxial electrospinning. Even with immiscible fluids, heavy mineral oil was encapsulated inside the PVP solution in ethanol via coaxial electrospinning where mineral oil held a lower interfacial tension with the shell [98]. On the contrary,

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the lower viscosity of shell solution and the higher surface tension in the hydrophilic/ hydrophobic inner-outer solution systems lead to breakup of the hydrophilic inner fluid. Polymeric buckled nanofibers were produced by Chen et al. [100] using coaxial electrospinning from the rigid and flexible polymers in miscible or immiscible solvents through the exchange of core-shell fluids with each other. Sun et al. [70] also concluded that fibers with core-shell structures could be obtained using coaxial electrospinning from two solutions which were miscible or immiscible or even the core was nonspinnable itself. It was shown that the characteristic time of diffusion spreading of a sharp boundary between two miscible solutions due to their mutual diffusion was larger than the characteristic time of the bending instability of the order, and thus, no mixing took place. Diffusion Rate The diffusion rate of core-shell solutions is another parameter that affects the quality of the resultant core-shell structure. Formation of the core-shell fiber structure depends on both thermodynamic and kinetic factors [101]. In miscible inner-outer fluids, a rapid diffusion may cause a mix of two solutions [98, 102]. Arinstein et al. [103] demonstrated that the dominant parameter determining the core-shell fibers was the diffusion rate of the core solvent through the shell solution. In hydrophilic/ hydrophobic inner-outer systems, the appropriate diffusion rate also plays a significant role in addition to interfacial tension. Zhang et al. [101] stated that the mixture of different solvents could be properly controlled by the solvent diffusion rate and they obtained the fine compound Taylor and core-shell fibers. Therefore, it can be concluded that the additionally relatively low interfacial, tuning the diffusion rate is the prerequisite for the compound Taylor during the coaxial electrospinning process. Solution Viscosities The shell solution in coaxial electrospinning surrounds core material and acts as guidance for them. A sufficiently high viscosity of shell solution is required to overcome the interfacial tension between two polymer solutions and then develops a compound cone in steady state [97]. Therefore, the viscosity of shell solution is critical and should be electrospinnable to form a core-shell structure [75, 104]. According to the studies, it appears that the spinnability of the core fluid by itself is not as critical. However, it was observed in several studies that if the viscosity of the core fluid was too low, the jet breakup occurred [88]. Hereupon, core fluid must have minimum viscosity to prevent the jet breakup [75]. During the electrospinning process, the concentration increases by the solvent evaporating, this leads to more chain entanglements, subsequently resulting in an increase in the viscosity. By increasing the viscosity, the mobility of polymer chains decreases and restricts the ability of the polymer chains to phase separate. In order to form phase-separated core-shell structures, the molecules should have enough mobility to complete the coalescence process of phase separation prior to solidification [104].

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Solution Concentration Changes in solution concentration influence the viscosity and surface tension of the solution and also affect the fabricated fibers. In conventional electrospinning, an increase in solution concentration leads to an increase in fiber diameter. In the case of coaxial electrospinning, solution concentration also has a similar effect on fiber diameter. Studies have shown that an increase in core solution concentration by keeping the shell concentration constant leads to an increase in the core and overall fiber diameter which otherwise decreased the shell thickness as it had to stretch more to the circle around a relatively bigger core [105]. In other studies, an increase in overall fiber diameter was observed when the shell solution with higher concentration was used by maintaining core solution concentration at a constant concentration [106]. With increased core concentration, there was an associate gradual decrease in bead density and fabricate ultrafine fibers with a smooth surface [107, 108]. In low concentration of shell solution, fibers stuck together and an increment of the shell solution leads to obtaining uniform fibers with less entanglement [108]. While in hollow nanofibers, prepared with oil as the core, and PVP/TTIP as the precursor for the shell, an increase in the PVP content resulted in the increment of the fiber diameter from nano- to microscale [109].

Solvent Vapor Pressure The type of solvent used in coaxial electrospinning, in particular the solvent of core solution, can significantly affect the morphology of the resultant core-shell nanofibers [75]. As the vapor pressure of the solvent determines the rate of evaporation of the solvent of polymer jets, low or rapid evaporation can also have an effect on the resultant fiber morphology, determining the shape of the core, shell, and the overall fiber [60]. Li et al. [102] reported that using high vapor pressure of the solvent in the core solution created a thin layer at the interface of the core and shell due to rapid evaporation. This layer that acted as barrier tended to trap the interior solvent and diffused out more slowly. As the trapped solvent was left in the solidified structure, a hollow structure formed and then this caused the core structure to collapse ribbonlike configuration under atmospheric pressure [102]. Also, using high vapor pressure solvents in shell solution may produce unstable Taylor cones and lead to multiple jets [110]. As mentioned previously, the stabled compound Taylor cone is the requirement for the coaxial electrospinning and unstable Taylor cone can cause the formation of core-shell fibers with irregular structure and lead to separate fibers from the two solutions. Liu et al. [111] improved the core-shell efficiency of the fibers by adjusting the evaporation rate of the core solvent. They used three solvents with different boiling points to investigate the influence of solvent evaporation rates on the formation of the core-shell fibers structure. It was concluded the slightly higher evaporation rate of the core solvent compared to that of the shell caused the reduction of the time of individual stretching in the core solution, and thus, more core-shell fibers could be obtained.

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Solution Conductivity Solution conductivity is mainly determined by the polymer type, solvent used, and theavailability of ionizable salts. The conductivity of the solution can have an effect on the quality of the resultant electrospun fibers. Solutions with high conductivity, which have high surface charge density, cause an increase in the elongation force on the jet, resulting in fabrication of smaller diameter fibers due to an enhancement of the whipping action. The difference between the conductivity of the core and shell solutions can also affect the core-shell fiber formation. Based on Yu et al.’s [96] study, the higher conductivity in the core solution caused discontinuity in the coreshell structure due to pulling at a high rate by the applied electric field. On the other hand, studies have shown that by increasing the conductivity of the shell solution, finer and smoother fibers can be obtained because higher conductivity of the shell solution resulted in higher shear stress on the core fluid and subsequently higher elongation to form a thinner core. Yu et al. [112] manipulated the diameter of the resulting LiCl/PAN coaxial nanofibers by adjusting the LiCl concentrations in N,N, dimethylacetamide using an electrolyte solution (LiCl) as the shell. Other studies have shown that nonconductive or less conductive liquids can be successfully incorporated as the core into a higher conducting shell [98]. Similarly, increasing the solvent dielectric constant decreased bead formation and reduced the diameter of polyaniline/PMMA coaxial fibers [113]. Process Parameters Process parameters such as applied voltage strength, flow rate ratio of core-shell solutions, and capillary size have a significant effect on controlling the core-shell fibers in coaxial electrospinning [70, 72, 74, 99, 110]. A mathematical model was proposed by Huang et al. [114] to consider the effect of surface tension, electric fields, and shear thinning fluid properties on the two-phase flow. Chen et al. [66] obtained hollow fibers via coaxial electrospinning and evaluated the effect of parameters including the concentration of shell solution, the flow rates, the applied voltage, and the capillary size on the fibers morphology. They showed that the successful encapsulation of core material inside the shell polymer solution significantly affects the preparation of core-shell nanofibers by applying suitable processing parameters. Hereupon, the formation of core-shell fibers via coaxial electrospinning depends on the systemic and processing parameters which influence the structure and morphology of core-shell fibers, its diameter, and shell thickness [101]. Electric Field Strength In most studies, only one value of applied voltage has been reported to obtain the stabilized compound Taylor cone. In Moghe and Gupta [75], studies have shown that for given solution flow rates, a stable compound Taylor cone was formed in a small range of applied voltage. The voltage below the critical range led to dripping of the solutions and also mixing of two solutions for miscible solutions due to an increased size of the cone. In voltages above the critical range, the electric field strength exceeds the required value and the Taylor cone tended to recede and the jets tended

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to emanate from inside the capillaries. This created multiple jets from the solutions and no core-shell fibers were formed [75]. In several studies [98, 115, 116], it was concluded that in coaxial electrospinning, an increase in applied voltage resulted in the reduction of both core and shell fiber diameters due to the increased ejection of polymer fluid in a jet. However, Repanas et al. [106] reported that an increase in applied voltage initially led to an increase in average fiber diameter and further for higher voltages the fiber diameter did not increase and the differences in the average values were statistically insignificant. They claimed it could be possible that changes in the spinning distance would result in a different electrical field and influence the properties of fibers. At higher voltages in which the Taylor cone tends to be unstable, the electric field draws liquid at the tip of the nozzle at a relatively faster rate. This may result in the meniscus subsiding and breaking down within the inner walls of the nozzle, giving rise to a number of smaller menisci residing at the inner walls of the spinneret [66]. Chen et al. [117] observed a similar instability in the Taylor compound that was described as multijet mode when the voltage was raised considerably.

Solution Flow Rate In order to get a nice core-shell structure compound Taylor cone, one has to have utmost control of the inner and outer fluid injection speed to have a dynamic stabilization Taylor cone. A very high or very low speed of the inner fluid is not suitable. An appropriate injecting speed and rate of inner-outer fluid should be adjusted. Flow rates of inner and outer solutions can directly control the dimensions of core and shell layers in coaxial electrospinning [83]. However, in coaxial electrospinning, special attention must be paid to the difference in the flow rates of the two solutions. According to most studies, by keeping the shell flow rate, a range of core flow rates exits within which the stabilized compound Taylor cone and regular core-shell fibers are obtained. By delivering an insufficient amount of core solution in very low core flow rates, incorporation of the core into the shell does not continuously occur. Higher core flow rates cause the size of the core liquid Taylor cone to increase until the viscous drag applied by the shell solution is insufficient to surround the core solution and subsequently results in mixing of core and shell solutions. This results in the shell solution to not uniformly encapsulate core material [97]. In fact, the shell cannot uniformly encapsulate the fast moving core and the overall process becomes unstable [96]. Therefore, it can be concluded that the core flow rate should be lower than the shell as an optimum flow rates ratio has to be set [118]. Chakraborty et al. [82] demonstrated that at very low flow rate ratios, as there was insufficient shell solution to encapsulate the core solution, the inner-outer solutions formed pendant drops at the nozzle. With increasing flow rate ratios, the occasional encapsulation of the core solution into core-shell electrospun fibers occurred and then proper higher ratios allowed the formation of the stable compound cone and consistent core-shell fibers. At very high flow rate ratios, the ability of core-shell fiber formation did not change, but the encapsulation efficiency of the core solution was reduced.

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Fig. 25 The effect of core flow rate on the morphologies of (a) the Taylor cone and (b) jet [83] (Copyright # 2010, American Chemical Society)

Furthermore, some studies have reported the effect of inner-outer flow rates on the morphology and diameter of resultant fibers [83, 106]. An increase in core flow rate not only increases both the core and overall fiber diameter, but also reduces the fiber wall thickness [83, 106, 118]. Wang et al. [83] showed the effects of core flow rate on the morphologies of the Taylor cone, the whipping electrified jet, and the electrospun fibers. As shown in Fig. 25, by increasing the core flow rate, the Taylor cone became bigger, but the straight jet length was reduced. Therefore, it can be concluded that an optimum flow rate ratio has to be set, which has an effect on the thickness of the respective fiber components [119]. It is considerable that this effect on the thickness can depend on the polymer viscoelasticity. Nguyen et al. [120] reported a strong correlation between the core-shell feed rates, and the porosity and stability of the core-shell structure. They demonstrated that the better stability of the core-shell structures and higher fiber porosity was obtained at lower feed rates, while the high viscous stress at low feed rate resulted in breaking down the core into individual segments.

Emulsion Electrospinning Emulsion electrospinning is similar to typical solution electrospinning which has been used in conventional and modified forms to fabricate core-shell fibers from emulsion (water in oil (W/O) [121, 122] or oil in water (O/W)) [123]. During the electrospinning of a W/O emulsion, the aqueous drops were stretched into elliptical shapes along the axial direction of fibers resulting in the continuous core. The fast

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evaporation of the organic solvent relative to water phase and the more rapid increase of the organic matrix viscosity than that of the droplets aid the more rapid solidification of the outer layer than that of the inner core. The inward movement of drops due to the viscosity difference between the drop and the matrix and following their mergence eventually results in the dispersed drop in the emulsion and turns into the core, and the matrix becomes the shell of the core-shell fibers via emulsion electrospinning [122, 124]. On the other hand, during the electrospinning process of emulsion (O/W), emulsion drops are broken up into smaller droplets instead of the continuous core forming [121, 122]. With the rapid evaporation of the organic solvent and sharper increase of the drop phase viscosity than that of the matrix, drops do not deform more and readily break up. After that, the liquid drops or solid particles are encapsulated in the electrospun fibers. W/O emulsion electrospinning is particularly used in cases where hydrophilic drugs and bioactive molecules could be encapsulated within hydrophobic polymer nanofibers to avoid burst release and prolong the release time [101]. Even with the use of a proper emulsifying agent as necessary surfactants for reduction of the surface tension, the hydrophilic drugs always tend to distribute themselves on the fiber surfaces. Figure 26a illustrates the core-shell fiber formation mechanism in emulsion electrospinning. Viray et al. [125] utilized a novel way combining coaxial electrospinning and an emulsion in the core to facilitate microstructuring of core-shell fibers and the formation of drug reservoirs for enhancing drug release over a sustained period. With a controlled diffusion rate of the drug, the model drug Levetiracetam emulsified in a drug-free polymer solution (PLGA) was coaxially electrospun with another polymer solution free of drugs intended for implantation in the brain for epilepsy treatment.

a Stretching

Stretching

Moving inward & merged

Original emulsion

b

Stretching & evaporation

Partially de-emulsified Stretching & evaporation

Final fiber

Fig. 26 (a) Schematic mechanism for the formation of core-shell composite fibers during emulsion electrospinning. (b) CLSM images of core-shell structured nanofibers obtained from the W/O emulsions [122] (Copyright # 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)

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In other words, Bazilevsky et al. [126] achieved core-shell micro-/nanofibers via emulsion electrospinning in which solutions of PMMA and PAN in DMF were blended and left for 1 day during which it precipitated into PMMA droplets dispersed within a PAN matrix. The resulting emulsion was electrospun using an ordinary electrospinning setup and the PMMA droplets/precipitate percolated in the tip of a single-liquid Taylor cone from where it was ejected and wrapped within the PAN solution to give a core-shell fiber. Emulsion electrospinning with a newly developed stirring apparatus was used to incorporate nonviral gene vectors, plasmid DNA (pDNA), and pDNA complexed with linear poly-ethylenimine (pDNA-LPEI), within LTU scaffolds [127] .

Other Electrospinning-Based Methods for Core-Shell Nanofibers Formation Low productivity of the conventional needle-based coaxial process is a barrier for commercialization. A number of alternative high-productivity configurations in which electro-hydrodynamic (EHD) jets are emitted directly from a free liquid surface have been reported for single fluids. Free surface electrospinning is capable of producing fibers at rates that are two to three orders of magnitude higher than spinneret-based methods. Forward et al. [128] reported free surface electrospinning from a wire electrode to produce nanofibers with core-shell morphology. In this method, wire electrodes are mounted parallel on spindle and drawn through a bath comprising two immiscible liquids, layered one on top of the other. When the wire sweep through bath, a bilayer film on the wires formed wherein a liquid coated the wire and another liquid covered the bottom liquid. The coaxial jets directly developed from compound droplets of immiscible liquids entrained on wires, and controlled mass transfer processes to produce uniform, core-shell fibers. In another study, a modified free surface coaxial electrospinning was developed for massive production of core-shell nanofibers by utilizing a one stepped pyramid-shaped nozzle consisting of multiple coaxial nozzles that were each connected to the core and shell polymers as shown in Fig. 27. It was demonstrated that a large number of coaxial jets could be generated simultaneously on the edges of the stepped pyramidshaped spinneret, and it was estimated to have a fiber output 100-fold the normal coaxial electrospinning process, offering a launch pad for industrial production of coaxial nanofibers [129]. VYSLOUŽILOVÁ et al. [130] also designed two special equipments (based on needle and needleless technology) for production of core-shell nanofibers having a higher productivity rate. The principle of needleless method was coaxial electrospinning from a free liquid surface of a thin two-layer polymer. The two-layer polymers overflowed freely and a cascade was made by a spinning electrode. By this method, many polymer jets formed from a free liquid surface of a polymeric two-layer and thereby a great number of core-shell fibers fabricated on the collector. Several methods have been reported to fabricate core-shell nanofiber via conventional electrospinning which electrospun fibers used as template, following post

Electrospun

Collector

Reservoir

Core

Shell

b

c

1 µm

d

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558 nm

Fig. 27 (a) The scheme of the free coaxial electrospinning apparatus using a stepped pyramid nozzle, (b) a picture of coaxial jets in the electrospinning process. (c, d) SEM and TEM of core-shell structured fibers from free surface coaxial electrospinning [129] (Copyright # 2014 Elsevier B.V. All rights reserved)

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treating such as chemical vapor deposition. However, producing core-shell fibers by these template approaches have low efficiency. Some novel approaches have been reported to prepare the core-shell nanofibers with a single channel spinneret by developing the multiphase jet during the electrospinning process via phase separation. The kinetic factors play a much more important role in the development of these core-shell nanofibers. Thereby several methods have been reported to enhance the phase separation kinetic factors via electric field–induced phase separation, water vapor–induced phase separation [131], and thermal-induced phase separation [132]. For example, the solvent solubility parameter of the electrospinning solutions was altered by water vapor, which subsequently induced the phase separation before the solvent rapidly volatilized, to form core-shell structured nanofibers [131]. Recently, a novel method has reported in which the PVP/thiol-ene polymer core-shell nanofibers were prepared directly by electrospinning combined with in situ UV photo-polymerization. As thiol-ene monomer and the initiator migrated to the surface with the solvent evaporation during the electrospinning process, the phase separation occurred due to low surface energy and self-migration of small molecules. Then the photo-induced polymerization and cross-linking reaction took place simultaneously during the electrospinning process and thereby formed shell of fibers as shown in Fig. 28 [133]. In another work, the core-shell fibers were fabricated through a new procedure in which by blend electrospinning a PCL core and UV-induced graft polymerization to make up the outer PEG shell was used. The PEG shell thickness could be controlled by UV irradiation time, and core-shell structure PCL/PEG fibers could be achieved with smooth flexible morphology [134]. One-step-electrospinning based method has been reported to prepare hollow fibers made of organic polymer composites under pressurized carbon dioxide (CO2). In this method, PVP solution dissolved in dichloromethane was directly electrospun in sub and supercritical CO2. As CO2 was very poor solvent for polymer

Top view Phase separation

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Fig. 28 A modified electrospinning setup combined fibers with in situ UV photo-polymerization to fabricate core-shell nanofibers used by [133] (Copyright # 2016 American Chemical Society)

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Fig. 29 The TEM images of BSA/PCL core-shell fibers by Ghasemkhah

(PVP) and solubilized most organic solvents, the removal of DCM as a polymer solvent under pressurized CO2 occurred before the solution achieved the collector. In other word, the electrospun PVP fibers at room temperature seemed almost wet but dry fibers were obtained when electrospinning was conducted under pressurized CO2. At subcritical conditions (refer to temperatures and pressures at which the pure antisolvent was supercritical), when the CO2 pressure was 5 MPa, the hollow fibers were obtained. CO2 was miscible with the solvent, but was an antisolvent for the polymer. First the outer fiber skin occurred and then the diffusion of the solvent was subsequently suppressed, and the CO2 penetration into the jet induced the solution trapped inside the fiber to phase separate allowing CO2-rich bubbles. Subsequently growth and coalescence of CO2 bubbles resulted in formation hollow fibers [135].

Characterization of Core-Shell or Hollow Nanofibers As core-shell and hollow nanofibers are becoming increasingly popular in various applications, various techniques are required to confirm the fibers formation with core-shell configuration. Various typical techniques have been accomplished for characterization of core-shell and hollow nanofibers and here as an introduction, a brief summary is given.

SEM SEM is an important tool capable of producing high-resolution images of the fibers surface. This technique is useful in understanding and quantifying the core-shell fibers morphology. SEM images from only the fibers surface are not capable of verifying the formation of core-shell configuration and superlatively determine the diameter of the core and shell. However, characterization of core-shell nanofibers has also been accomplished by SEM. This characterization was performed after removal of the core of fibers by microsectioning in liquid nitrogen using a cryogenic microtome. Hollow fiber structures could also be characterized by taking SEM

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(or FESM) images from their cross section. As only the surface of fibers can be observed in an SEM image, to investigate the core-shell structures, other techniques should be used.

TEM The core and shell nanofiber structures can be clearly seen in TEM images. This method was based on utilizing different densities of these materials, which lead to each material transmitting different amounts of electrons. Figure 23d shows the cross section of the core-shell fiber and in Fig. 29, the TEM images from coaxially electrospun nanofibers with core-shell configuration, which were fabricated with bovine serum albumin (BSA) as core and PCL as shell. Confocal Laser Scanning Microscopy (CLSM) or Fluorescent Microscopy In order to visualize the presence and distribution of core material inside the coaxial fibers, fluorescent microscopy is applied by adding fluorescent material inside the core. The successful loading of BSA inside the nanofibers was indicated by means of fluorescent microscopy. Figure 30 demonstrates a uniform distribution of protein (indicated by red and green stain) in the fibers. Confocal microscopes are known for clear image quality, 3D mapping capabilities, and elimination of the need for sample processing prior to imaging. Moreover, confocal microscopy allows different cross-sectional planes of the fibers to be imaged, thus providing information about the three-dimensional distribution of the embedded luminescent molecules. Figure 31a shows a fluorescence image of a fiber mat, featuring bright light emission from the embedded chromophore. Merging transmission (Fig. 31b) and fluorescence (Fig. 31c) images, making the core clearly distinguishable from the weakly emissive shell (Fig. 31d, e) and allowing the welldefined core-shell interface and an almost uniform distribution of the chromophores loaded in the core to be appreciated. Similarly, the formation of core-shell structures was demonstrated by confocal analysis (Fig. 31f, g), showing core material localized in the inner region of fibers.

Fig. 30 The fluorescent microscopy images of BSA/PCL core-shell fibers with (a) Rhodamine B isothiocyanate-conjucated BSA as core, (b) fluorescein isothiocyanate-conjucated BSA as core by Ghasemkhah

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Fig. 31 Confocal microscopy of core-shell fibers encapsulating fluorescent materials. (a) Fluorescence micrograph of fibers, (b) confocal map of a core-shell fiber obtained grayscale signal, (c) corresponding fluorescence map, (d) merged signals, (e) Zoom highlighting spatially resolved fluorescence in the core and in the shell of the fiber, (f, g) confocal micrographs of core-shell fibers [69] (Copyrights # 2016 American Chemical Society)

Confocal Raman Microscopy Sfakis et al. [136] employed confocal Raman microscopy to confirm the core-shell structure of the PGS/PLGA nanofibers via direct observation of Raman signatures. In fact, confocal Raman microscopy, which combines confocal imaging with Raman spectroscopy, allows the analysis of chemical composition of each pixel of a sample in the XY (lateral) and Z (depth) directions with resolution under 1 μm.

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AFM For characterizing core-shell nanofibers AFM has been used, too. Chen et al. [137] suggested the differences in surface topography in core shell nanofibers in which the collagen as the shell, and thermoplastic polyurethane as the core. Using a height mode on the AFM, they were able to resolve the difference in surface roughness of the core-shell fibers, compared to a blend nanofiber.

Conclusion and Future Trend Today, electrospinning becomes an important process for generating versatile nanofiber morphologies and structures. The highly porous nanofibers made from different materials, found possible uses in different fields ranging from filters, textiles, tissue engineering, drug delivery, catalysis, sensors, and so on. Coaxial electrospinning is also an effective technique for fabrication of core-shell and hollow nanofibers. Although this technique has multiple advantages over traditional microencapsulation processes, further advancement is challenged by the complex physics of the process. The following extraction process or thermal treatment can remove the core phase, maintaining the complete sheath structure. The thermal treatment is much quicker and can stabilize and carbonize the polymer matrix at the same time. Most of the polymer solutions and their polymer composite matrices could be fabricated into porous, core-shell, and hollow nanofibers through the electrospinning. By appropriate post-treatments of the nanofibers, various inorganic nanofibers or nanotubes have been developed with much wider applications. These nanofibers possess extremely high specific surface area and combined properties, which have shown excellent efficiency over the traditional electrospun fibers. However, there are also some challenges, such as the dimension of nanofibers, the improved performance in their applications, and the expanded applications of these nanofibers. Therefore, more amazing and meaningful applications of the materials are envisioned to be achieved in the future when deployed in other fields. It is still expected that research into electrospinning and nanofibers will become more interdisciplinary in the near future.

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Polymer-Based Nanofibers: Preparation, Fabrication, and Applications Masoumeh Zahmatkeshan, Moein Adel, Sajad Bahrami, Fariba Esmaeili, Seyed Mahdi Rezayat, Yousef Saeedi, Bita Mehravi, Seyed Behnamedin Jameie, and Khadijeh Ashtari

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Processing Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Electrospinning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Melt Electrospinning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Solution Blowing or Air Jet Spinning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Forcespinning or Centrifugal Spinning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Drawing or Spinneret-Based Tunable Engineered Parameters (STEP) Method . . . . . . . . . . . Template Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Phase Separation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Self-Assembly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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M. Zahmatkeshan Neuroscience Research Center (NRC), Iran University of Medical Sciences, Tehran, Iran Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran Department of Medical Nanotechnology, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran e-mail: [email protected] M. Adel (*) Department of Medical Nanotechnology, School of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran Deputy of Research and Technology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran Department of Medical Nanotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran e-mail: [email protected] S. Bahrami Department of Medical Nanotechnology, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran Student Research Committee, Iran University of Medical Sciences, Tehran, Iran e-mail: [email protected] # Springer Nature Switzerland AG 2019 A. Barhoum et al. (eds.), Handbook of Nanofibers, https://doi.org/10.1007/978-3-319-53655-2_29

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Characterization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Physical Characterization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mechanical Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Chemical Characterization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion and Future Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abstract

Polymer-based nanofibers as an important group of materials have attracted considerable attention of research and industrial areas. Polymer nanofibers with diameters in submicrometer (24 months)

3D cell substrate, drug delivery system (DDS)

Biodegradable (6–12 months)

Nonwoven tissue engineering (TE) scaffolds Biomedical applications, wound healing, DDS General TE, DDS

Poly(glycolic acid) (PGA)

Poly(lactic-coglycolic acid) (PLGA)

Mixture of tetrahydrofuran and dimethylformamide

Polycaprolactone (PCL)

Mixture of chloroform and methanol, toluene and methanol, dichloromethane and methanol DMF + methylene chloride HFP, acetone

Poly(lactide-cocaprolactone) (PLCL) Polyurethane (PU)

Natural polymers Collagen

Dimethyl formamide, water

HFP

Gelatin

2,2,2-trifluoroethanol (TFE)/HFP

Chitin/chitosan

HFP/PBS HFP, TFA, acetic acid

Biodegradable (1–12 months), controllable copolymer ratio Biodegradable (>24 months), highly elastic

Biodegradable (12–16 moths), highly elastic, controllable copolymer ratio Good barrier properties, oxygen permeability

Vascular TE

Most abundant protein in the body, good biodegradability and biocompatibility in physiological environments Most abundant protein in the body, good biodegradability and biocompatibility in physiological environments Antibacterial activity, physicochemical properties

General TE

Nonwoven tissue template wound healing

General TE Scaffold for wound healing

Skin TE, wound dressings (continued)

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Table 4 (continued) Polymer Silk fibroin

Solvent Formic acid

Hyaluronic acid

DMF/water

Polymer blends Poly(glycolic acid) and chitin Collagen and poly (ethylene oxide) Poly(D,L-lactide-coglycolide), collagen, and elastin Poly(L-lactide-co-ecaprolactone) and collagen Poly (e-caprolactone) and collagen Poly(L-lactic acid) and hydroxylapatite (a) Poly (e-caprolactone) and poly(ethylene glycol) (shell) (b) dextran (core) Poly(D,L-lactic-coglycolic acid), PEG-b-PLA, and PLA Poly(L-lactide-coglycolide) and PEG-PLLA

Properties Obtained from silkworms and spiders, good biocompatibility, minimal inflammatory reaction Main component of ECM of connective tissue

Applications Nanofibrous scaffolds for wound healing Medical implant

HFP

–

General TE

10 mM HCl (pH 2.0)

–

General TE

HFP

–

Vascular TE

HFP

–

Vascular TE

HFP

–

Neural TE

DCM and 1,4-dioxane

–

Bone TE

(a) Chloroform and DMF (b) water

–

DDS: Drug delivery systems; (BSA)

DMF

–

Chloroform

–

DDS (Mefoxin, cefoxitin sodium) DDS (BCNU)

(lactic-co-glycolide) (PLGA), and copolymer of poly (L-lactide-co-E-caprolactone) [PLLA-CL)] have been applied for bone tissue engineering, heart grafts, wound dressing, and engineering to replace heart vessels [7]. Composite Polymers/Copolymers By mixing the natural and synthetic polymers in electrospinning process, it is possible to take the benefits of both natural polymers (cellular affinity) and synthetic polymers (mechanical properties). For example, PCL coated with gelatin (Fig. 6), PCL-PLLA coated with collagen, silk/PEO blend, collagen/PCL-PLLA blend, starch/PCL blend, hyaluronan and PCL, chitosan-PEO, PHBV with PDLLA blend,

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Fig. 6 Interaction of bone marrow stromal cells with [12] gelatin/PCL composite scaffolds after 7 days of cell culture: (a) cell ingrowth, and (b) layered cells (Reprinted by permission from Stojanovska et al. [9]. Royal Society of Chemistry. Copyright 2018)

PLLA or PLGA, or a mixture of natural polymers such as collagen and chondroitin sulphate, collagen and elastin, collagen and chitosan, collagen and PHBV, and gelatin with PHBV have been reported [18]. Furthermore, the cellular affinity, mechanical properties, morphology, structure, size and distribution of pores, biodegradability, and other physical characteristics can be adjusted using copolymers in electrospinning. For example, elastic poly (ethylene-co-vinyl alcohol) (PEVA) nanofibrous mat became stronger after the addition of poly (glycolide) (PGA) to the spinning blend. A three-block copolymer containing PLA, p-dioxanone, and PEG (PLA-b-DX-b-PEG) indicated a good balance between decomposition speed and hydrophilicity. Moreover, using methacrylic acid (MAA) in the copolymerization of methyl methacrylate (MMA) led to its thermal stability because the glass transition temperature of poly (methacrylic acid) (PMAA) is higher than PMMA and it also showed higher degradation temperature due to anhydride formation in high temperature. A new block copolymer including poly (p-dioxanone-co-L-lactide) -block-poly (ethylene glycol) (PPDO/PLLA-b-PEG) was e-spun for tissue engineering and drug release by Bhattarai et al. and it was demonstrated that the random deposition of PPDO and PLLA components and integration of PEG have significantly improved the biodegradability and hydrophilicity of scaffolds. Therefore, using copolymers is an important strategy to increase the properties of polymers for various applications [7].

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Blending of poly (ethylene oxide) and PCL polymers was allowed the development of nanofibrous scaffolds with appropriate porosity for growth and infiltration of cells on the scaffold. Since PEO is a polymer with high degradation rate while PCL slowly degrades, it has an important role in the creation of larger pores [18]. Combination of natural polymers such as chitosan, collagen, and gelatin with synthetic polymers was widely used for the scaffolds production. Composite nanofibers from natural and synthetic polymers have also been studied in vivo. For example, electrospun composite collagen/PCL nanofibers have been investigated for vascular tissue engineering [22]. Polymer Composite with Bioactive Inorganic Nanoparticles Electrospun blends of synthetic polymers and various bioactive inorganic materials such as hydroxyapatite (HA) and calcium phosphate have mainly been utilized as nanofibrous scaffolds for bone tissue engineering. Since bone possess a unique texture composed of organic fibrous matrix and inorganic apatite crystals, different studies have indicated that using polymer composites leads to increased attachment, proliferation, and differentiation of bone cells in vitro and bone tissue regeneration in vivo. Investigating the electrospun poly (L-lactic acid) (PLLA)/HA composite nanofibers demonstrated that incorporating of HA not only changed the general morphology of fibers but also indicated smooth interconnected nanofibers with high porosity. PLLA/HA composite nanofibers could present appropriate structure for osteoblasts seeding in targeted bone tissue regeneration due to the combination of mechanical strength advantages of HA with nanofibrous structure. Furthermore, it was found that HA/PLGA composite adjusts behavior of human mesenchymal stem cells (hMSC). The results showed that HA disperse homogeneously and the enhanced roughness depends on the amount of HA. HA integration leads to increased alkaline phosphatase activity, expression of osteocalcin, bone sialoprotein, and calcium mineralization in hMSC. A composite of synthetic polymers and demineralized bone powder (DBP) including PLA/DBP has also been reported to be effective for bone tissue regeneration. The osteoconductive effects of these electrospun composite nanofibers have been demonstrated in both in vitro and in vivo studies [22]. Electrospun Conductive Polymers Electrical stimulation has a crucial role in regulating cell behaviors such as attachment, proliferation, and differentiation. The effects of electrical stimulation in bone, cartilage, skin, and nervous tissue regeneration have been reported by several studies [25]. Conductive polymer nanofibrous scaffolds composed of polypyrrole (PPy), polythiophene, or polyaniline (PANi) not only act as a template for cell growth and tissue regeneration, but also can locally conduct physiological electrical signals to the site of damaged tissue. The experience of using conductive polymers in nerve tissue engineering demonstrated that electrical stimulation of PC12 cells through PPy conductive film led to significant neurite outgrowth.

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In addition, attachment and proliferation of heart myoblasts and neurite outgrowth in vitro were also indicated by using PANi. Despite the mentioned advantages, it is noteworthy that electrically conducting polymers are not biodegradable, so their remnants can result in the immunogenicity and chronic inflammation in the body which required secondary surgery. To overcome this limitation, a mixture of minimum amount of conductive polymers with synthetic polymers (PANi and PLCL) has been used to maintain electrical conductivity while minimizing the toxicity. These composite nanofibers display the significant increase in the number and length of myotubes, the expression of myogenic genes including myogenin, troponin T, and myosin heavy chain. Thus, the composite PLCL/PANi nanofibers can be used in muscle tissue engineering and investigating the electrical stimulation role in muscle cell differentiation. Growth and differentiation of PC12 cells on electrically conducting nanofibers have also been observed by the deposition of PPy on PLGA electrospun nanofibers indicating the potential of electrically conducting nanofibers in nerve tissue engineering [22].

Applications Tissue Engineering and Scaffolds An important field of electrospun polymer nanofiber applications is scaffolds for tissue engineering of various tissues including nerve, blood vessels, skin, muscle, bone, and cartilage, which in recent years has been much discussed (Figs. 7 and 8). The main goal of tissue engineering is to repair damaged tissues. Nanofibrous structures of biodegradable polymers due to the similar fibrous structure with the native ECM act as a support for the adhesion, proliferation, and differentiation of various cells, so they will have a huge potential in the scaffolds for tissue regeneration [8]. Keratin, elastin, and collagen fibers derived from the extracellular matrix (ECM) are the most widely used materials since they naturally have a fibrous nature and can be easily made into fibrous scaffolds. Proteins, polysaccharides, and other biological materials have also been investigated for scaffolds fabrication because of their unique features such as water solubility, water absorption, biodegradability, hydrophilicity/hydrophobicity, and biocompatibility. Furthermore, cellulose, dextran, amylose, chitin, hyaluronic acid, chondroitin sulfate, heparin, and glycosaminoglycan have been extensively applied as compounds for scaffolds. On the other hand, synthetic materials including poly lactic acid (PLA), poly glycolic acid (PGA), poly lactic co glycolic acid (PLGA), polyhydroxyalkanoates (PHA), polyvinyl alcohol (PVA), poly caprolactone (PCL), and bioactive ceramics also play a promising role in scaffolds production [27]. Although preliminary work with electrospun fibers has shown promise in the reconstruction of the certain types of tissues, more modifications of chemical, biological, and mechanical characteristics will allow them to further progress [24]. Therefore, the design of

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Fig. 7 Laser scanning confocal microscope images of immunostained α-actin filaments (A-1, A-2) and myosin filaments (M-1, M-2) in smooth muscle cells on aligned nanofibrous scaffold (A-1, M-1) and tissue culture polystyrene (A-2, M-2) after 1 day of cell culture. Potential aligned poly(Llactid-co-e-caprolactone) [P(LLA-CL)] (75:25) copolymer nanofibrous scaffold for blood vessel engineering [26] (Reprinted with permission from Behrens et al. [44]. Copyright (2014) American Chemical Society)

an ideal scaffold that mimics the structure and biofunctions of native ECM remains as a great challenge, and it should be considered as a critical remark in the design of TE scaffolds [3].

Wound Healing Dressing For wound healing, the high porosity of electrospun nanofibers can provide more structural space to accommodate the transplanted cells, facilitate the cell proliferation and migration, and improve the oxygen exchange, nutrients delivery, and waste outflow. On the other hand, the small pore size of nanofibrous scaffolds is able to limit the wound infection and dehydration during the wound healing. Moreover, the adjustable mechanical characteristics of electrospun nanofibers can retain the

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Fig. 8 (a) and (b) High-magnification confocal microscopy images of neurite morphology on (a) random and (b) aligned surface modified PLLA nanofibers with bFGF. Neurites oriented in the direction of aligned nanofibers while more neurite branching on random nanofibers was seen [10] (Reprinted with permission from Taghavi and Larson [45]. Copyright (2018) by the American Physical Society)

mechanical consistency between the TE grafts and the host tissue and also prevent the shrinkage and wrinkling of the wound during the implantation. Several natural and synthetic polymers have been electrospun into nanofibrous scaffolds for skin TE. Natural polymers, such as collagen, gelatin, silk, chitosan, and fibrinogen have been fabricated to the nanofibers for wound healing. Among them, collagen type 1 with two α1 chains and an α2 chain is an excellent specific candidate for the skin TE scaffolds. Since collagen is the main component of human skin ECM, it forms a fibrillar 3D network structure (diameter of fiber 50–500 nm) to regulate the attachment, proliferation, and differentiation in the skin texture. Electrospun cellulose acetate/gelatin nanofibers have been developed to mimic the ECM composition of the skin (a complex combination of proteins and polysaccharides). It was demonstrated that 25/75 cellulose acetate/gelatin nanofibers showed the specific adhesion properties and the increased fibroblast proliferation of human skin. However, both the low resistance to enzymatic degradation and the poor mechanical properties are considered as main problems of tissue engineering by natural polymers. On the other hand, a number of biodegradable synthetic polymers consisting PGA, PLA, PCL, and other copolymers are usually utilized for skin TE and others due to its favorable mechanical and biodegradable properties. For example, by PLGA electrospining with (85:15, 75:25) lactide/glycolide molar ratios can be achieved the desirable biodegradable scaffolds to replace the damaged skin. However, the hydrophobic surface and the lack of cell-detection signals limit the use of synthetic polymers. Lately, the composite nanofibrous scaffolds with both physical characteristics of synthetic polymers and the bioactivity of natural polymers have attracted much attention. In this regard, it is found that PLCL/collagen electrospun nanofibers

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in comparison with the net PLCL nanofibers not only increase the proliferation rate of MSCs, but also increase the differentiation of epidermal stem cells. Similarly, some biodegradable composite nanofibers such as PLGA/dextran, PCL/gelatin, PLCL/gelatin, and PLCL/fibrinogen have also been developed to skin tissue engineering, which obtained the promising results. Since prevention of infection during wound healing is essential for skin regeneration, a wide range of antibacterial nanofibers included with antibacterial factors (metal, organic, and inorganic) have increasingly emerged, which are effective treatments for both Gram-positive and Gram-negative bacteria during wound healing. Silver is the most commonly used metal antibacterial agent that illustrates a wide variety of biocidal activity with reduced bacterial resistance. In wound healing, silver demonstrates the capability to decrease surface inflammation, to enhance surface calcium, and to stimulate the production of epithelium. It has been indicated that the antibacterial activity of PLCL electrospun nanofibers against Staphylococcus aureus and Salmonella enterica can be enhanced by increasing the incorporated silver nanoparticles concentration. Moreover, PLA, PLGA, PVA, polysulfone, betacyclodextrin, and polyurethane (PU) were also electrospun into nanofibers and mixed or covered with silver nanoparticles to stimulate the antibacterial properties. Insertion of other inorganic materials such as titanium into the electrospun polymer nanofibers has also been demonstrated to show antimicrobial properties against the growth of several bacteria. PU/TiO2 nanofibers showed antibacterial efficacy against Pseudomonas aeruginosa and S. aureus. In addition, the electrospun silk fibroin/ TiO2 nanofibers showed not only good blood and cell compatibility, but also demonstrated good antibacterial activity against Escherichia coli under UV irradiation. It has been indicated that carbon nanotubes are very toxic to bacteria and kill germs on contact. Accordingly, Schiffman found that even at low concentrations (0.1–1 wt%) of single-walled carbon nanotubes embedded into electrospun polysulfone nanofibers, destroying of bacteria (E. coli) was observed. Inspired by nature, some natural antibacterial agents such as shikonin, alkannin, fusidic acid, chitosan, lysostaphin, and cinnamaldehyde have also been developed and merged into the electrospun nanofibers to provide the biocidal activity for wound healing [3]. Drug Delivery Different delivery systems including liposomes, polymer micelles, and nanofibers have been investigated to improve the therapeutic efficacy and reduce the toxicity of conventional dosage forms [28–31]. Electrospinning, due to the significant characteristics such as flexibility in the choice of materials and medicines, increasing loading capacity and encapsulation efficiency, simultaneous delivery of therapeutic agents, and the cost-effectiveness, provides an attractive candidate in drug delivery applications especially for wound covering materials and the topical chemotherapy after surgery [32]. Moreover, a localized and controlled release drug delivery system can be achieved by electrospun nanofibers because of their well-interconnected open porous structure and large surface area. Therefore, many attempts have been made to chemically or physically integrate bioactive molecules into the scaffolds after

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electrospinning. Entrapment of biomolecules into electrospun nanofibers is performed by dip-coating method as the simplest procedure. So, biomolecules in the form of pure solutions or emulsions are physically absorbed into nanofibers through electrostatic forces. Alternatively, in a blend electrospinning, bioactive molecules are mixed with polymer solutions to produce composite nanofibers. Because blend electrospinning encapsulates biomolecules into nanofibers better than simple dipping, more controlled release profile was observed [24]. Methods like blending, surface modification, and co-axial electrospinning have been applied for drug loading into nanofibers. However, some critical characteristics such as biocompatibility and biodegradability, effective control of drug release, and the sufficient mechanical performance should be considered for drug-eluting scaffolds. Biodegradability, drug release kinetics, and mechanical characteristics can be adjusted through accurate choice of polymers and electrospining parameters while biocompatibility property can be achieved via surface modifications. Biodegradability of drug-eluting nanofibers ensures effective drug release and avoidance of surgical removal after the drug delivery. Using nanofibers in drug delivery systems allows improved therapeutic index, the possibility of localized delivery, and reduced toxicity of drugs. Drug release from electrospun nanofibrous mats can occur through different routes, mainly diffusion, desorption, and destruction of scaffold. Release may be adjusted through precise control of fiber characteristics (diameter, pore size, porosity, etc.); moreover, blending of different modes of scaffold construction such as emulsion and co-axial electrospinning is also used to optimize the kinetics of release. Such systems have been used for rhodamine B 237 loaded PCL electrospun nanofibers including chitosan nanoparticles and for controlled release of other multiple hydrophobic and hydrophilic drugs. The drug loaded electrospun nanofibrous mats can be directly implanted into the tumor, which leads to higher drug bioavailability. In addition, the drug eluting nanofibers give special benefits such as the increased drug solubility, stability, and targeting. On the other hand, the drug eluting electrospun nanofibers constructed by mixing hydrophilic/hydrophobic polymers can be used to overcome the explosion effect [2]. While the classic drug delivery systems lead to delivery of drugs such as anticancer and antibiotics, electrospun nanofibers enable the integration of genes (DNA), RNA, cells, and different growth factors. Mainly, the carrier polymers were achieved by PLA, PLGA, and PCL while adjusting the biodegradability and the hydrophilic nature of fibers, and then setting behavior of release were obtained by adding other synthetic or natural polymers. The local chemotherapy field for the electrospun nanofiber mats is known only recently. Actually, the advantages of this treatment in comparison with the other dosage forms include the reduced system toxicity and the enhanced local drug concentration. Local cancer chemotherapy is a good choice for the treatment of unresectable tumor or prevention of recurrence after surgery [32]. Sensors and Biosensors In response to the urgent needs for the cheaper, faster, simpler, and more reliable detections, significant progress has been made in the development of highly

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sensitive chemical and biological sensors. In this regard, the process of electrospinning to produce polymer nanofibers has been used for sensing applications. For example, it was recently shown that certain optical sensors based on electrospun fluorescent polymer nanofibers indicated sensitivity up to three times magnitude more than it was obtained from film sensors to detect nitro compounds, ferric, and mercury ions. Moreover, the high surface area to volume ratio and the excellent electrical properties make electrospun conductive polymer nanofibers such as polyaniline (PANI) electrospun nanowires interesting candidate particularly for sensing applications [33]. Nanofibrous systems with very thin diameter of less than 20 nm show several amazing features including a large surface area, high porosity, and superior mechanical performance, which makes them optimized candidates for applications in ultrasensitive sensors and ultra-thin filters [34]. Moreover, nylon polymer due to the chemical resistance, desirable mechanical performance, durability, and biocompatibility has a wide variety of applications in biosensors, which should be modified physically or chemically before using. A miracle of nanofibers in sensing applications is where nylon nanofibers despite its polymer films, without any treatment show unique capacities including increased loading, sensitivity, stability, long life time, effective immobilization, and high reproducibility. Recently synthesized glucose biosensors from electrodes modified with composite nanofibers of CP PBIBA (conductive polymer) showed excellent properties of stabilizing matrix through increasing covalent bonding between GOx and the surface of composite nanofibers. It can also be applied for the development of various electrochemical biosensors [35]. Nowadays, the importance of environmental pollution leads to the development of gas sensor technology, which is influenced by gas sensing structures to detect target gases based on various sensing methods. So far, different electrospun nanofibrous materials including polymers as the sensing interfaces have been used to detect a wide variety of gases with a better limit of detection. H2 sensing test results achieved by the electrode modified with poly (vinylpyrrolidone) (PVP) /LiTaO3 electrospun composite nanofibers showed higher sensitivity and faster response to target gas compared to a flat filmbased sensor [34, 36]. It has been shown that the dynamic response of opto-chemical sensors was considerably intensified by detecting the actual sensing layers in the form of highly porous 3D membrane including the electrospun polymer nanofibers instead of a compacted layer while performance parameters such as accuracy, optical characteristics, and long-term stability of optical conventional sensors was simultaneously maintained [37]. PEDOT nanofiber-based biosensor shows significant improvement on sensitivity, detection limit, and longevity compared to PEDOT film counterpart in the heparin diagnosis. The technique can be used for various applications in food science, homeland security, and biomedical fields [38].

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Air filtration Solving the problem of air pollution, especially fine particles in the air, has become a necessity for our daily life and industrial applications. Moreover, microorganisms and volatile organic gases (VOCs) in the air can also cause great damage to human life [39]. Electrospun nanofibers to capture the volatile organic compounds (VOC) in the air were presented by various authors. So that more rapid adsorption and desorption of VOC through electrospun nanofibrous membranes (ENMs) was reported compared to usual activated carbon. In traditional HEPA filters, based on filtration theory, the nonslip flow mechanism is dominant; as the nanofibrous layer is coated on a conventional filter (Figs. 9 and 10), the sliding mechanism is overcome resulting from capability of smaller size of fiber to disturb the airflow [41].

Fig. 9 Nanofibers on a cellulose filter media substrate [40]

Fig. 10 ISO Fine dust loading on (a) cellulose and (b) cellulose/nanofiber composite [40] (Reprinted with permission from Cheng et al. [47]. Copyright (2008) American Chemical Society)

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Structural parameters of electrospun fibrous membranes such as fiber diameter and diameter distribution, surface area and pore size distribution, basis weight fiber, and density play important role in the filtration process which has significant effects on the performance of filter membranes. B. Maze et al. noted that fibers with smaller diameter will increase the available surface area, resulting in lower pressure drop. As a result, a suitable electrospun nanofibers diameter is critical to optimize the filtration performance. Moreover, Hung et al. reported that more basis weights resulted in improved filtration efficiency but not QF (Quality factor) of filters due to the pressure drop enhancement during the filtering process. It was demonstrated that stacking several layers of electrospun fiber membranes with a lower basis weight is more effective than a single layer of electrospun fibrous membrane with high basis weight. In a study by Kim et al., it was shown that a proper electrospun nanofibrous film thickness contributes to the air filtration media efficiency, but very thick films will decrease the air filtration performance resulting from the increased pressure drop through the filtration media. Besides these structural features, some environmental parameters and test conditions like face velocity, particle size, temperature, and humidity also significantly affect the filtration performance [39]. Recently, the electrospun nanofibrous membranes for air filtration have attracted great interest in both research and industry due to the outstanding surface characteristics of electrospun nanofibers, such as the excellent surface adhesion, high porosity, large specific surface area, and the low basis weight with the uniform fiber size, which result in the high performance filter media. Surprisingly, the filtration efficiency of some electrospun filtration membranes can be 99.9998% with117.5 Pa pressure drop for 300–500 nm fine particles. It is worth mentioning that a library of polymers including PAN, PVA, polyethylene terephthalate (PET), polyamide (nylon 66, nylon 6), polyurethane (PU), PEO, polysulfone (PSU), chitosan, cellulose acetate, and lignin has been used in highperformance electrospun nanofibrous membranes [39]. Furthermore, many efforts have also been allocated to prepare antibacterial membranes by incorporating different ingredients like inorganic compounds: Ag, Cu, CNTs, and TiO2, and some natural plant extracts (Melaleuca alternifolia extracts, Sophora flavescens extracts, eucalyptus extracts, and greensoy protein) [39, 41]. So far, different types of electrospun nanofibrous air filters such as composite, multilevel structured, thermal stability, antibacterial, reusable and self-cleaning air filter membranes have been developed. Although we have observed numerous advantages for electrospinning technique application in HEPA filters over the past decade, there are some challenges like enhancing the mechanical strength of nanofibers at industrial applications to prevent breaking or crack of filters and development of making process without use of the harmful organic solvents. Despite the challenges, we are very convinced that the air filtration media is mainly influenced by the electrospinning technique which paves the way for producing safe and clean environment with the air filtration systems [39].

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Protective Clothing Currently, polymer nanofibers as a protective obstacle on textile fabrics have attracted great interest in different fields including wound dressing, air filtration, tissue scaffolds, sensors, and fire-retardant fabrics. Many attempts have been made to integrate nanoparticles into spun fibers to improve features of fire-retardant and anti-microbial activity; polymers, for instance, polyamide (PA), polyvinyl alcohol (PVA), polyurethane (PU), polypropylene (PPy), and their composite are modified to increase flame retardant. On the other hand, PA or nylon 6 has been treated with nanoparticles of MgO, SiO2, TiO2, ZnO, and ZrO2 to enhance the physical, mechanical, and thermal characteristics. Similarly, nanometal oxides integrated in the polymer matrix as an additive were used for the multipurpose applications including anti-flammability, UV protection, and antimicrobial activities. Furthermore, the biodegradable polyelectrolytic nylon 6 resulting from other modifications has also been largely used in the textile industry because of its mechanical, antimicrobial, thermal, and physical properties. It is also worth mentioning that MgO/nylon 6 hybrid nanofibers coated cotton textiles led to increased flame resistance, antimicrobial activity, and finally proper physical features which provided a good candidate for protective clothing for soldiers [42]. It was found that water vapor transmission characteristics of ENMs are comparable with textile materials and thus they can be used in protective clothing applications. Reactive organic compounds ((3-carboxy-4-iodosobenzyl) oxy-bcyclodextrin) and nanoparticles were integrated into nanofibers by mixing with polymer solutions followed by simple electrospinning and tested for decontamination of chemical warfare agents (CWA). The disinfection efficacy of such ENMs was found to be much higher than conventional activated charcoal. Facini et al. examined nylon nanofibers as the potential candidates for filtering of nanoparticles in protective suits [41].

Energy Devices Regarding depletion of fossil fuels and the enhanced energy demands, development of renewable energy supplies is required for maintaining the economic growth. It is found that nanofibers due to their unique characteristics of large aspect ratio, low density, and high porosity have more benefits than common materials in devices for energy harvesting, conversion, and storage. In fact, these 1D nanostructures provide the excellent materials for applications in energy devices like solar cells (SCs), nanogenerator, and lithium-ion batteries (LIBs). For example, nanofibers in solar cells have demonstrated the large photoelectric conversion efficiency based on the effective charge transmission and separation, and the maximum light absorption which was primarily attributed to the large porosity and the high specific surface area. Moreover, the unique properties of nanofibers (NFs) affected by the large surface area to volume ratio (SVR) and the small diameter lead to the high specific capacity and better cycling stability in NFs-based electrodes in SCs.

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On the other hand, the hydrogen production was improved resulting from the photocatalytic activity of electrospun nanofibers as a photocatalysts in water splitting. Furthermore, it is worth mentioning that LIBs for their unique properties such as high energy density and long life cycle have become a milestone for the advancement of energy storage technologies, which have been used in many fields. However, nanofibers with good electrochemical function, high mechanical strength, and large specific surface area can be used as amazing materials in LIBs [43].

Melt Electrospinning In melt electrospinning, molten polymers are used instead of polymer solutions, which should be done in vacuum [18]. Melt electrospinning has its own advantages including no requirement to organic solvent, environmental safety, higher productivity without any reduction in the volume induced by the solvent evaporation, and the production of submicron fibers from polymers which have no suitable solvents at room temperature [8]. Although the melt electrospinning has many cons, it has been still in the early stages, because of the limitations including high viscosity, high processing temperatures, and their inability to obtain nanoscale fibers [7, 8, 20]. A list of some polymers which can be spun in molten form along with necessary temperatures has been shown in Table 5.

Solution Blowing or Air Jet Spinning Solution blowing is the most feasible techniques to spun nanofibers from solution polymers using high-velocity gas flow as a fiber-forming driving force. In a wellknown model, the system consists of concentric nozzle system where solution polymer is injected into inner nozzle while simultaneously a high pressure gas from outer nozzle is surrounding the polymer solution jet. The polymer solution jet into collector as multiple strands affected by stretching forces resulted from high speed gas. Evaporation of solvent occurs within jet process induced by shear forces at gas/solution interfaces, and finally polymer nanofibers solidified on the collector to form a no-woven mesh. Formation of spun nanofibers is affected by several Table 5 Molten polymers used in electrospinning [7] Polymer Polypropylene Poly(ethylene terephthalate) Poly-(ethylene glycol-block- ε-caprolactone Polyethylene Poly(methyl methacrylate) Polyamides (nylon) Polystyrene

Processing temperature ( C) 220–240 270 58.2 200–220 130–157 220 240

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Table 6 Parameters for the solution blowing process [9, 15] Solution parameters

Process parameters

Viscosity Polymer concentration

Molecular weight Surface tension Vapor pressure Air pressure

Nozzle collector distance

System parameters

Ambient

Solution flowrate Nozzle diameter Nozzle geometry Temperature Humidity Atmospheric pressure

Explained in “Viscosity” section The most influencial on the fiber diameter Strongly correlated with the fiber diameter Polymer concentrations >15 wt% ! " fiber diameter Low polymer concentration not enable adequate chain entanglement ! beads formation unless to be sufficient molecular weight to maintain the solution viscosity Explained in “Molecular Weight” section

The greatest effect on the web uniformity and defect density # air pressures! polymer droplets Not linearly influence on nanofiber diameter The optimal working distance: 30 cm; at lower and greater distance (5 cm and 50 cm) the nanofiber formation limited, formation of films occur because of solvent evaporation and insufficient drawing of fibers " flow rate! fibers with larger diameters and a greater amount of droplets

Explained in “Environmental Parameters” section

parameters that have been briefly described in the Table 6. A schematic of the solution blowing is also indicated in Fig. 11.

Solution Blown Nanofiber Applications Air jet spinning has numerous applications from energy to biomedical applications which are summarized in the Scheme 1. This technique due to the properties which is free of electrostatic restrictions and the solvent constraints caused by dielectric constant is applicable for voltage-sensitive polymers. An example of these nanofibers for biomedical applications has been demonstrated in Fig. 12.

Forcespinning or Centrifugal Spinning Forcespinning is another alternative approach to fabricate nanofibers from polymer solution or melt. It takes advantages of high speed, low cost, production safety, and large scale production. Centrifugal spinning has been designed to overcome

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Fig. 11 Schematic presentation of solution blowing system [16]

Solution Blown Nanofiber Applications

Energy Applications

as electrodes in fuel cells and supercapacitors

-SPEEK/POSS, SPES/PES nanofibre-nafion membrane -Activated CNF by PAN as a carbon precursor

Biomedical Applications

-Coating vascular prostheses -Antimicrobial activity -Scaffolds in clinical applications -As bandages for wound healing -Artificial heart valves and artificial heart implantations -Wound dressing for drug delivery

-PLA nanofibres -PLA/HPMC nanofibres containing THC -nHA/PLA composite nanofibre Mats -PLA/PVP containing Copaiba oil composite nanofibres -PDMAEMA nonwoven nanofibre mat -soy protein solution blown nanofibres with Ag and nylon 6 electrospun nanofibres doped with TiO2 nanoparticles -combination of biopolymers nanofibres and PET -BSA and PVA

Scheme 1 Applications of solution blown nanofibres [9, 44]

Filtration Applications

-Phenol adsorption -O2 adsorption

-PAN nanofibre as precursor for activated carbon nanofibres

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Fig. 12 Direct deposition of conformal PLGA nanofiber mats on piglet organs: (a) Lung resection; (b) Intestinal anastomosis; (c) Liver injury; (d) Diaphragmatic hernia. In all cases, nanofibrous mats fabricated over the defect in less than 1 min which ceased the liver bleeding and air leakage from the lung after segmentectomy [44] (Reproduced from Stojanovska et al. [9] with permission of The Royal Society of Chemistry. Copyright 2018)

Fig. 13 Schematic of centrifugal spinning device [45]

Spinneret Collector

Orifice

^

Ω

Nanofiber

Feed polymer

constraints of electrospinning consisting of low production rate and requirement to high voltage. Simple structure of forcespinning consists of a spinneret containing polymer solution or melt imbedded into rotating chamber with two or more pores which presented its schematic design in Fig. 13. Centrifugal force acts as a driving force to expel nanofibers out of the pores, when it exceeds the polymer surface tension. Determinant parameters in centrifugal spinning process have been summarized in Table 7.

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Table 7 Parameters on centrifugal spinning process [9, 14, 45] Process parameters

Centrifugal forces Angular velocity of chamber Orifice radius Distance of orifice to collector Evaporation rate for solution applications

Temperature for meltspun applications Solution parameters

Viscoelasticity Concentration of solution Surface tension

More increasing ! breaking jet and bead formation Low angular velocity ! bead formation #orifice diameter ! # diameter fibers and #beads

Low evaporation rate ! the solvent cannot evaporate completely and the fibers get collected as a thin film on the collector High evaporation rate! Suppression of jet elongation, increased fiber diameter "Temperature ! corrupted or burned polymer #Temperature! " fiber diameter or the jet cannot be formed #Viscosity ! bead formation "Viscosity !not jet formation Related to viscosity has to exceed the critical value for obtaining adequate chain entanglement

Applications of Centrifugally Spun Nanofibers Several applications of centrifugally spun nanofibers have been summarized in Scheme 2. It can also be used commercially for various polymers (Fig. 14).

Drawing or Spinneret-Based Tunable Engineered Parameters (STEP) Method A process like dry spinning in the fiber industry produces very long individual nanofibers separately. In the basic production process, a sharp probe tip such as micropipette is dipped into the edge of droplet that is previously deposited on the glass slide; then, the micropipette by a micromanipulator is withdrawn from polymer solution with a constant rate of 100 μm/S. Ultimately, the pulled nanofibers were deposited on the surface by touching the micropipette end. Drawing techniques with well-controlled fiber diameter, precise spacing, and orientation of fibrils has the ability to form 3D structures for biomedical applications such as scaffolds which mimic the native ECM. Several solution parameters such as polymer type and its molecular weight, solvent characteristics, and polymer concentration control the fiber dimensions and beads formation. It is also worth mentioning that, just a viscoelastic material which can undergo a strong deformation while maintaining its integration and tolerating the increased stress during the pulling-off is converted to nanofibers by drawing [1, 8, 18, 46].

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Centrifugally Spun Nanofibres Applications

Energy Applications

electrodes and separators for lithium ion battery

-tincarbon nanofibres by PAN as a precursor -PMMA/PAN membrane -PAN nanofibres

Biomedical Applications

-Tissue engineering -Drug delivery -Wound dressing

-PCL gelatin/collagen hybrid nanofibres -highly aligned PCL/gelatin nanofibres -C-spun PS and PLGA fibers -PLLA/PVP composite nanofibres -PVP/PCL nanofibres -PVP/iodine nanofibres

Other Applications

Fluid filters

Fe2O3/ poly (ethylene oxide) (PEO) nanofibers

Scheme 2 Centrifugally spun nanofibers applications

Template Synthesis Template synthesis is another common method. As the name offers, it utilizes a nanoporous membrane as a template to produce solid (fibrils) or hollow (tubules) nanofibers. Using this method, a variety of materials such as electricity conducting polymers, metals, semiconductors, and carbons could be converted to the tubules and the fibrils in nanoscale diameter which can be used in electronics, optoelectronics, chemical or gas sensors, and batteries. However, there is no possibility to produce continuous nanofibers by this technique [8, 18, 47]. A shematic design of template synthesis has been shown in Fig. 15.

Phase Separation Phase separation method includes five stages: polymer dissolution in a solvent to achieve a homogenized mixture, gelatinization, extraction by a different solvent,

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Fig. 14 (a) PEO Nanofibers (Solution) and (b) PS Mat (Melt) produced by the Forcespinning™ Method, (c) nanofiber webs and (d) free standing nonwoven mats are also produced by the presented method [14]

a

Hard template with isolated pores (e.g. AAO)

Impregnation

Scaffold

&Reaction

Removal

Species filling, nucleation and product growing

Nanoparticles/rods, or nanowires/tubes

b

Soft template (e.g. polymer, virus)

Linkage of species and functional group

Wire-like structures

Fig. 15 Schematic description of (a) hard and (b) soft template synthesis of nanofibrous structures [47]

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freezing, and freeze drying, which ultimately fabricated porous nanofibrous foam. Unfortunately, making a porous structure through this method is a time-consuming process [8, 18, 24]. Parameters such as solvents, polymer concentration, and phase separation temperature affect the nanofibers. For example, increased polymer concentration prevents the aggregation of large ice crystals, which allows the formation of porous nanofibers. Moreover, adjusting the freezing rate led to the adjusting fibers alignment which can be obtained by gradually freezing the polymer solution at constant rate or extruding the solution on a frozen rotating drum. Achieved porous nanofibrous mats can be utilized in drug delivery systems, as precursors for carbon nanofibers with high porosity, or as templates for synthesis of inorganic fibers.

Self-Assembly Self-assembly is a process in which amphiphile compounds consisting of customdesigned peptide-like amphiphiles, amphiphile peptides with balanced hydrophilic/ hydrophobic amino acid domains, and di-block or tri-block copolymers under physiological conditions spontaneously organize to nanofiberous structures and patterns. The mechanism underlying the spontaneous phenomenon is intermolecular forces which brings together the smaller units. In this method, designing peptide sequences, optimizing, and stabilizing of their structures also take a long time [1, 8, 18, 24].

Characterization The polymer characterization usually includes physical, mechanical, and chemical characteristics. In order to determine the structural and morphological characteristics of nanofibers as a function of process parameters, various studies have been done and demonstrated in Table 8.

Physical Characterization Physical or geometric characteristics include structural features and the sample morphology; therefore, the structure of nanofibers determines their physical and mechanical characteristics. Fiber diameter, diameter distribution, fiber orientation, and morphology of fiber such as the shape of cross section and surface roughness were considered as geometric characteristics of nanofibers. SEM, FESEM, TEM, and AFM will be applied as the common techniques for characterization of geometry. SEM technique has been used as the most common technique to determine the diameter and morphology of nanofibers. However, it has some limitations including

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Table 8 Characterization of nanofibers and nanofiber mats [8] Fiber or mat Nanofiber

Properties Physical and chemical

Geometric surface

Porosity

Roughness Young’s modulus, tensile strength, elongation at break, tenacity Pore size and size distribution

Permeability

Water vapor and gas diffusion

Tensile

Young’s modulus, tensile strength, elongation at break Biodegradability in vitro and in vivo Cell attachment and proliferation

Tensile Nanofiber mat

Details Molecular structure, molecular orientation, cross-linking, crystallinity Diameter, diameter distribution, orientation Chemistry

Biological

Instruments and techniques FTIR, NMR, optical birefringence, FTIR, WAXD, SAXC, DSC SEM, TEM, AFM XPS, FTIR-ATR, water contact angle measurement AFM Cantilever technique Mercury porosimeter, capillary flow porometer Dynamic moisture vapor permeation cell Tensile tester Mass loss, strength loss, surface morphology change Optical microscopy, confocal microscopy, Biological assays

low resolution at maximum zoom and the samples should be conductive, so a coating of gold or titanium is used for the most polymers that may alter indicated diameter in higher magnification. However, SEM is a quick way to check the nanofibers but the studied sample sizes should be very small. Moreover, TEM is also a suitable technique to determine the fibers with very small diameter (1 M Da). HA has the dramatic ability to attract and hold a huge quantity of moisture, which is critical for its function in the skin (elasticity) and cartilage (lubrication). Human bodies approximately contain 15 grams of HA, and it has been purified from various sources and extensively available in capsules, skin creams, and even injectables. Though HA has outstanding biocompatibility, the anionic and hydrophilic properties of many HA materials do not support the direct attachment of cells. Combining HA materials with other materials, such as collagen, makes them more cell-friendly. Otherwise, creating 3D or a porous scaffold can help for the proliferation of cells. Such scaffolds can be formed by electrospinning [27]. HA has been produced in the form of nanofibers for use in tissue engineering. HA nanofibers are very complex to fabricate, and the high viscosity and surface tension of HA makes it difficult to electrospun, as both are important parameters in the production of nanofibers. Recently, a combination of an acidic solution with heated air blown around the electrospinning jet was employed to obtain uniform HA fibers. The pure HA nanofibers (diameter = 110 nm) have been fabricated by electrospinning. The scaffolds are assembled and were recognized to have good in vitro cell interaction properties [28]. Brenner et al. [29] fabricated pure HA mats with an average fiber diameter of 40 nm using a new solvent system, i.e., aqueous ammonium hydroxide (NH4OH) solvent and NH4OH/DMF solution, they also successfully reported the electrospinning of HA nanofibers from NaoH/DMF system. Figure 10 shows the different morphology of HA nanofiber mats prepared from NaOH/DMF and NH4OH/DMF solution [29]. With using 2:1 NH4OH/DMF solvent system, no degradation effects were observed, and the continuous electrospinning of pure HA fibers was possible.

Inorganic-Based Nanofibers The fabrication of inorganic nanofibers based on metals, metal oxides, and ceramic materials has been of vast scientific and technological importance [30]. Inorganic nanofibers frequently reveal novel thermal, electrical, mechanical, and optical properties as their size approaches nanometer scale dimensions. For many advanced applications, ranging from energy production and storage, current research is progressively more focused on exploiting the high porosity and suppleness of nanofibers for the assembly of complex nanomaterials. For example, the exceptional electronic and optical properties of inorganic nanofibers can find future applications in flexible batteries, supercapacitors, fuel cells, and solar cells. Structures together with core-shell nanofibers and multicomponent hierarchical assemblies can demonstrate superior properties and new functionalities arising from the close proximity of chemically distinct, nanostructured components [30]. An extensive range of structural inorganic nanofibers was effectively developed by electrospinning technique.

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Fig. 10 SEM images displaying the morphology of HA nanofiber mats: (a) 3% HA solubilized in 4:1 NaOH/DMF mixture, (b and c) 1.5% HA solubilized in 2:1 NH4OH/DMF mixture, (d) 1.5% HA solubilized in 4:1 NaOH/DMF mixture, and (e) 1.5% HA solubilized in 2:3 NH4OH/DMF mixture. The electrospinning process was completed within 5 min to prevent degradation of HA. (Reprinted from [29], Copyright (2012), with permission from Elsevier)

Literature shows various types of inorganic nanofibers with different structures. By modifying the electrospinning process conditions, inorganic nanofibers of different shapes are obtained, for example, mesoporous nanotubes, and nanorods were grown to form nanofibers, hollow nanofibers, multichannel microtubes, nanowire-in-microtube, and core-shell nanofibers [31]. Wang et al. [32] developed a controllable synthesis strategy of hierarchical heterostructure metal oxide/TiO2 nanofibers using the electrospinning and hydrothermal method. Four typical metal oxides, namely, Co3O4, Fe2O3, Fe3O4, and CuO, are adopted as secondary nanostructures grown on primary TiO2 nanofiber to verify the feasibility and versatility of metal oxides/TiO2 hierarchical heterostructures. The lowand high-magnification SEM images (Fig. 11a and b) show the secondary Fe2O3 nanorods grown on the primary TiO2 nanofibers to form Fe2O3/TiO2 hierarchical heterostructures with diameters of about 290 nm. The structure is further investigated by TEM in more detail. Figure 11c shows that Fe2O3 nanorods are uniformly attached to the primary TiO2 nanofiber surface and the selected circular area is enlarged (Fig. 11c, inset). The diameter and length of Fe2O3 nanorods are estimated to be about 22 and 45 nm, respectively. TEM (Fig. 11d) further confirms the singlecrystalline structure of the Fe2O3 nanorods with a lattice fringe spacing of 0.37 nm from the (311) plane [32]. The hierarchical heterostructure metal oxide/TiO2 nanofibers are investigated as the Li-ion batteries anode materials, and the obtained electrodes showed excellent rate capability with respect to the pristine TiO2 nanofibers. The hierarchical heterostructures and synergetic effect between the metal oxide and TiO2 are probably responsible for the enhanced electrochemical performance.

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Fig. 11 Controllable synthesis strategy of hierarchical heterostructure metal oxide/TiO2 nanofibers with improved Li-ion battery performance. (a) Low- and (b) high-magnification SEM images of hierarchical heterostructure Fe2O3/TiO2 nanofibers. (c) Low- and high-magnification TEM images of hierarchical heterostructure Fe2O3/TiO2 nanofibers. (d) TEM image of the Fe2O3 nanorod surface. (Copyright 2012, Nature [32], This work is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Unported License)

Nguyen and co-workers [33] developed highly sensitive hydrogen sulfide (H2S) gas sensors from CuO-decorated hierarchical ZnO nanofibers by the following steps: (i) preparation of ZnAc-PVP nanofibers using electrospinning method, (ii) thermal oxidation of ZnAc-PVP nanofibers to obtain ZnO nanofibers (ZnO-Fs), (iii) preparation of hierarchical ZnO nanofibers (ZnO-H) by hydrothermal method using ZnO-Fs, and (iv) CuO decoration of hierarchical ZnO nanofibers by a wet chemistry method. Figure 12 shows images of ZnO and PVP nanofibers at high magnification and crosssection correspondingly. Figure 12a illustrates the ZnO nanofibers and PVP composite nanofibers with diameters of 100 nm and 250 nm, respectively, with relatively smooth surfaces due to the polymeric nature and amorphous characters of Zinc acetate dihydrate (ZnAc). Figure 12b illustrates ZnO nanofiber after the oxidation of ZnAc/PVP at 500  C. Figure 12c shows the SEM image of the hierarchical ZnO nanofibers obtained by the hydrothermal growth of ZnO nanorods with an average thickness of around 1.1 μm. Figure 12 shows the SEM of the hierarchical ZnO nanofibers coated with CuO NPs. In the process, the ZnO nanorods (Fig. 12c) were coated with a copper salt solution. The CuO were formed on the nanofiber surface by employing UV illumination followed by oxidation. Gas sensors made of CuO-decorated hierarchical ZnO nanofibers exhibited a significant improvement in its H2S sensing. This enhanced performance is due to the formation of p-CuO nanoparticle/n-ZnO nanofiber junctions [33].

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Fig. 12 Hierarchical CuO-decorated ZnO nanostructures as efficient and established sensing materials for H2S gas sensors. Morphological structure of the prepared nanofibers: (a) ZnAc-PVP nanofibers, (b) ZnO nanofibers(ZnO-Fs) produced by oxidation at 500  C, (c) hierarchical ZnO nanofibers (ZnO-H) produced by hydrothermal method using ZnO-Fs in (b) as seed template, and (d) hierarchical ZnO nanofibers coated with CuO NPs. (Copyright 2016, Nature [33], This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material)

Aluminum oxide has many applications in which its properties of extraordinary hardness and thermal stability are exploited. It is an extensively employed material in ceramics preparations. Al2O3 nanofibers were employed as fillers in thermoplastic polymers for fabricating the tested composites. The high surface area and chemisorption properties of Al2O3 nanofibers have been used to remove metal ions from the aqueous phase [29]. The Al2O3 nanofibers typically exhibit the desired adsorption capacity, cycle performance, and the ability to regenerate easily. Also, Al2O3 nanofibers have significant potential as support materials in heterogeneous catalysis, for example, methane reforming and Fischer-Tropsch reactions. Peng et al. [34] successfully fabricated porous hollow γ-Al2O3 nanofibers by the single-capillary electrospinning of an Al(NO3)3/polyacrylonitrile (PAN) solution, followed by sintering treatment. Figure 13 illustrates the structure of the fibers with different weight ratios of Al(NO3)3.9H2O to PAN. Figure 13 illustrates the image of γ-Al2O3 cylindrical porous nanofibers after

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Fig. 13 Fabrication of porous hollow γ-Al2O3 nanofibers by facile electrospinning and its application for water remediation. Low-magnification and high-magnification SEM images of the surface and a cross-section of the porous hollow γ-Al2O3 nanofibers sintered at 800  C with various weight ratios of Al(NO3)3.9H2O to PAN (a) 1:10, (b) 2:10, (c) 3:10, (d) 5:10, and (e) 10:10. (Reprinted from [34], Copyright (2015), with permision from Elsevier)

decomposition of Al(NO3)3.9H2O and the absence of PAN. The nanofibers, prepared with weight ratios of 5:10 and 10:10 of Al(NO3)3.9H2O/PAN, have exhibited much smaller pores compared with nanofibers obtained of other weight ratios. So the pores on the surface of the fibers can be adjusted by changing the weight ratio of Al (NO3)3.9H2O to PAN. Furthermore, the average diameter of γ-Al2O3 nanofibers was increased with the weight ratio of Al (NO3)3.9H2O to PAN, whereas the mean diameter was 172 nm for 1:10 and around 350 nm for 10:10, respectively (Fig. 13a2, c2) [34]. These porous hollow γ-Al2O3 nanofibers were employed as adsorbents to eliminate organic dyes (i.e., methyl blue, Congo red, and acid fuchsine) from aqueous solutions. The nanofibers exhibited excellent dye adsorption efficiency with a removal efficiency greater than 90% after 60 min of adsorption [34]. Stannic oxide (SnO2) is an oxide semiconductor material with a lot of applications in the areas of sensors and optoelectronic devices. The SnO2 is available in numerous forms like nanoparticles, nanowires, nanobelts, and nanofibers. In comparison with solid nanofibers, hollow and mesoporous nanofibers are more advantageous in practical applications to catalysts and gas sensors, owing to their high surface area to volume ratio. Normally the conventional methods for applications of

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hollow and mesoporous SnO2 nanofibers by self-assembly and templates directed process are often suffering from firm synthesis conditions or tedious procedures [35]. Lee et al. [36] have fabricated hollow porous SnO2 nanofibers using electrospinning technique. Generally, the formation mechanism of hollow nanofibers which were fabricated via the electrospinning process followed by heat treatment is accredited to the decomposition of the sacrificial template of the organic polymer. Xia et al. [37] fabricated hollow SnO2 nanofibers by annealing electrospun polyvinylpyrrolidone (PVP)/Sn precursor nanofibers. The composite core-shell PVP/SnO2 nanofibers have been prepared with a capricious diameter ranging between 50 and 300 nm and clear boundaries of a phase separation between the PVP and Sn precursor. The hollow SnO2 nanofibers were obtained by the calcination treatment of as-spun core-shell PVP/SnO2 nanofibers. The nanofibers produced have a tubular structure with dense shells, which consist of nanograins of approximately 17 nm in diameter [37]. Du et al. [38] synthesized composite SnO2/In2O3 nanofibers by employing a co-electrospinning system with positive and negative polarity electric fields with two jets, followed by treating with oxygen plasma at radio-frequency power of 450 W (Fig. 14). The diameters of SnO2 nanofibers are relatively uniform ranging between 200 and 250 nm, while the surfaces of In2O3 nanofibers are comparatively irregular and slightly rough. The diameter of In2O3 nanofibers was in the range of 100–150 nm (Fig. 14a, b). They contain many rod-like nanoparticles with 40–50 nm diameters. The surfaces of both SnO2 and In2O3 nanofibers suit moderately asymmetrical and rough (Fig. 14c, d). However, both SnO2 and In2O3 nanofibers still maintained hollow and hierarchical structure after treatment with oxygen plasma, and the diameters of both SnO2 and In2O3 nanofibers increased to 450 nm and 500 nm, correspondingly. Figure 14e and f illustrates the slight differences in the morphology of treated SnO2 nanofibers [43]. The oxygen plasma-treated SnO2/In2O3 nanofiber sensors were effectively identified in the formaldehyde concentration range of 0.5–50 ppm. Furthermore, these fibers revealed good selectivity to formaldehyde-interfering gases such as ethanol, ammonia, acetone, toluene, and methanol. The superior response of SnO2/ In2O3 composite nanofiber sensors to detection of formaldehyde may be due to the increased conducting electron concentrations, the porosity, and the specific surface area after treatment with oxygen plasma [38].

Carbon-Based Nanofibers Carbon nanofibers (CNFs) have been pursued for both fundamental research and practical applications. Vapor grown carbon nanofibers (VGCNFs) are cylindrical nanostructure with graphene layers arranged as stacked cones, cups, or plates. Catalytic chemical vapor deposition (CCVD) or simply CVD with other methods such as thermal and plasma assisted is the foremost efficient approaches for fabrication of VGCNF. CNFs can be also fabricated by the electrospinning method. CNFs have been extensively used in many fields such as hydrogen fuel production, electrochemical capacitors (EDLCs), Li-ion batteries (LIBs), supercapacitors, and fuel cells. Polyacrylonitrile (PAN) is a popularly known ancestor for fabrication of

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Fig. 14 Fabrication of SnO2/In2O3 composite nanofibers. SEM illustrate the (a) untreated SnO2 nanofibers with oxygen plasma, (b) untreated In2O3 nanofibers with oxygen plasma, (c) untreated SnO2/In2O3 nanofibers with oxygen plasma, (d) treated SnO2/In2O3 nanofibers with oxygen plasma, (e) treated SnO2 in composite nanofiber mat with oxygen plasma, and (f) treated In2O3 in composite material with oxygen plasma. (Reprinted from [38], Copyright (2015), with permission from Elsevier)

CNFs. CNFs are promising excellent material resources due to their superior strength, conductivity, flexibility, and durability characters. However, the synthesis process is complex, and its surface area is lower than other nanostructured carbonaceous nanomaterials, e.g., graphene and carbon nanotubes [39]. An exceptional concept of making nanocomposite paper from CNFs has been explored. Carbon nanopapers made of CNFs have been recognized as a promising platform to transfer the exceptional electrical, thermal, and mechanical properties of CNFs at the nanoscale to macroscopic engineering applications. The uniform

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network structure CNF papers were fabricated by filtration of well-dispersed CNF suspension under controlled process parameters. CNF papers can be also prepared by using liquid molding processes by integrating conventional fiber reinforced into composite laminates (Fig. 15) [40]. CNFs are well-established fillers employed for improving the mechanical properties of polymers. Because the strengthening capacity of nanofibers increases with decreasing diameter [41], nanofibers have greater strengthening potential compared with microfibers. Figure 16 shows different types of carbon fibers with different sizes and morphologies. Typically, as the CNFs diameter was decreased, the ultimate tensile strength of nanofiber was increased, due to the minimization of a number of defects. Furthermore, the surface area/volume ratio and flexibility of the CNFs was increased due to the enhancement of the contract area between the filler and the polymer matrix. Due to this, fiber can bend without breaking and maintain good mechanical strength [46]. Therefore, the extreme investigation is going on polymer nanocomposite based on carbon nanotubes (CNTs), clay platelets, and CNFs [42, 43]. Because of the smaller diameter and lower density of SWCNT and MWCNT than VGCNFs, they exhibit better mechanical properties than VGCNFs. However, due to the low price of VGCNFs, they have been employed as low-cost alternatives for CNTs [44]. The VGCNFs are also the substitute of traditional carbon fibers due to their nanoscale dimensions, unique properties, and economically feasible applications [45]. VGCNFs can be used as reinforcing, electromagnetic interference (EMI) shielding, as electrostatic discharge (ESD) protection applications, and as a catalyst and encapsulation of DNA for biological applications and many more areas [46]. For example, the EMI shielding can be prepared by employing a 2 mm plate of a

Fig. 15 Fabrication of carbon nanofiber (CNFs) composite flexible paper. (a) The aqueous dispersion of CNTs and CNFs. (b) A web film made of slurry in (a). (c) A freeze-dried conductive nanopaper (200 μm thick). (d)–(f) SEM of conductive nanopaper with different magnifications. (Reprinted from [40], Copyright (2013), with permission from Elsevier)

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Fig. 16 SEM images showing the representative morphologies of (a) commercial T300 carbon fabrics, (b) vapor grown CNFs (VGCNFs), and (c) graphene-based CNFs, as well as (d) electrospun CNFs after being shortened. (Reprinted from [44], Copyright (2014), with permission from Elsevier)

polymer composite with 7.5 Vol% VGCNF solutions. For the ESD applications, 0.5Vol% VGCNF solutions were used for making a conductive network for insulating polypropylene (PP) [45, 46]. VGCNFs have been fabricated by pyrolysis of a hydrocarbon feedstock (natural gas, acetylene, etc.) or CO on a metal catalyst such as iron. This method is the most popular, proficient, relatively low cost to obtain low diameter fibers [41]. In this process, iron nanoparticles are used as a catalyst, and these are obtained by the pyrolysis of reaction between organic and metallic compounds such as ferrocene Fe (C5H5)2 and iron pentacarbonyl Fe(CO)5 [47]. The average diameter of iron nanoparticles, operating parameters, and catalyst activity significantly affects the thickness of nanofibers. Table 1 shows the summaries of the major properties of vapor grown carbon fibers (VGCNFs), single-walled carbon nanotubes (SWCNTs), multiwalled carbon nanotube (MWCNTs), and carbon fibers (CFs) [48].

Structural Nanofibers Structural nanofibers with different size and morphologies have been gaining great interest due to their unique properties. The structure of nanofibers depends on the type of precursor used, and the method of production allows for controlling the shape

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Table 1 Shows a summary of major properties of various carbon fibers [48]. (Copyright 2002, American Institute of Physics) Property Diameter (nm) Aspect ratio Density (g/cm3) Thermal conductivity (w/m K) Electrical resistivity (Ωcm) Tensile strength (Gpa) Tensile modulus (Gpa)

VGCNFs 50–200 250–2000 2 1950

SWCNTs 0.6–0.8 100–10,000 1.3 3000–6000

MWCNTs 5–50 100–10,000 1.75 3000–6000

CFs 7300 440 1.74 20

1  104

1  103–1  104

2  103–1  104

1.7  103

2.92

50–500

10–60

3.8

240

1500

1000

227

and arrangement of nanofibers. The most common structures of nanofibers were hollow, mesoporous, nonporous, and core-shell types of nanofibers. Also, there are many common structures reported in the literature such as herringbone, platelet, and ribbon-structured nanofibers. In herringbone-structured CNFs, the graphite layers are arranged diagonally with reverence to the fiber axis. In the case of the plateletstructured CNFs, the graphite layers are arranged vertically to the fiber axis, and in the case of the ribbon-structured CNFs, the graphite layers are arranged parallel to the growth axis of a fiber [49]. The composition and arrangement of these extracellular fibers play a vital role in imparting the mechanical properties to the tissue. Sometimes the network of the fibrous material acts as a bone-like structure and provides the favorable environment for the osteogenic function of resident cells. Molecules of the nanofibers can arrange themselves into patterns or structures through the non-covalent forces such as intra- and inter-hydrogen bonding, hydrophobic forces, and electrostatic forces of attractions. Interestingly, recent studies showed that self-assembly of amphiphilic nanofiber can generally occur by providing the suitable pH environment [49].

Hollow Nanofibers Hollow nanofibers (HNFs) are largely gaining interest from the scientific community for diverse applications in the fields of environment, energy, sensing, and health. HNF walls can be made up of a wide range of materials including polymer, metal oxide, ceramics, or composite. Their unique characteristics such as the presence of the porous structure, large surface area, high tensile strength, and modulus depend upon the helicity and arrangement of rings in their walls [50]. Fabrication of HNFs can be made by electrospinning two immiscible liquids through a coaxial, two-capillary spinneret, followed by selective removal of the cores. Electrospinning is a versatile and efficient process to fabricate HNFs of metal oxides, carbon, metals,

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composites, and others. The diameter and helicity of the HNFs indeed promote the electronic properties of the nanofibers [51]. The structure of HNFs depends on parameters such as viscosity, conductivity, surface tension, polymer molecular weight, dielectric constant, and dipole moment [52]. HNFs have been fabricated from a wide range of organic and inorganic materials. TiO2/PVP hollow nanofibers were developed by removing the oil phase as core [53]. In another study, hollow-microsized TiO2 fibers were prepared by removing the organics and inner materials. The photocatalytic activity of such microsized TiO2 fibers was enhanced for degrading acetaldehyde gaseous by adding interior hollow channel numbers [54]. Electrospinning parameters such as feed ratio can have an effect on the size and wall thickness of these nanofibers. The successful synthesis of HNFs is likely to depend on choosing the right solvent and controlling the heating rate. HNFs are able to fill with different substances for expanding their applications. PCL nanofibers were fabricated for controlling the release of bovine serum albumin (BSA) or lysozyme. PEG was used as a core material and proved that the release rate could be controlled by adding PEG, water-soluble macromolecules in the sheath material [55]. Lee et al. [56] developed hollow CNFs by coaxial electrospinning of styrene acrylonitrile (SAN) and polyacrylonitrile (PAN) solutions. In this study, PAN was used as a shell and SAN as the core, where SAN was found to be a very suitable material for the sacrificial core. The intrinsic properties of SAN prevented the PAN shell from shrinking during the stabilization and carbonization process. Lee et al. [57] observed that the concentration of the solution and flow rate were effective in controlling the outer diameters and the wall thickness of hollow CNFs. Highly porous polymeric HNFs were prepared by the coaxial electrospinning method using silicon oil as the core material and poly(methyl methacrylate)(PMMA) as a polymer. The polycarbonate (PC) is used as the shell material. It was found that the nature and concentration of the solvent affect the diameter as well as the wall thickness of the developed HNFs. The electric insulating a material constant of the solvent was abbreviated the diameter of HNFs. Nanofiber wall width and average pore size were improved by increasing the molecular weight of the polymer, but the specific surface area is slightly decreased. Ahmed et al. [58] developed a highly proficient hollow CNF electrode for capacitive deionization produced by using coaxial electrospinning of PMMA(core)and PAN(shell)polymer solutions, followed by oxidative stabilization and carbonization process. The specific capacitance of the obtained hollow CNFs (222.3 F g1) was almost four times higher than that of solid CNFs (63 F g1). In addition, the surface area of the hollow CNFs (186 m2 g1) was almost ten times greater to the surface area of the solid CNFs (17.7 m2 g1). The developed hollow CNFs showed an excellent desalination performance (86%) and a better cycling ability [58]. Kim et al. [47] discovered the mechanism for the formation of hollow SnO2 nanofibers fabricated by one-step electrospinning technique followed by a heat treatment step, applied to decompose the sacrificial template of the organic polymer. The work mainly aimed at investigating the effect of calcitration and crystal growth formation of hollow SnO2 nanofibers. In this work, the hallow SnO2 nanofibers

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were fabricated by electrospinning through a single capillary from PVP/SnO2 using a calcination treatment during which astringent structure of core-shell provides the advantage of preserving the fibrous pore structures based on the sacrificial PVP template. The formation of hollow structural fiber was initiated by the Kirkendall effect followed by the enlargement of an interior to produce surface diffusion process [47]. A multi-fluidic coaxial electrospinning technique has also been used to produce ultrathin, core-shell nanofibers with a unique nanowire-in-microtube design, as shown in Fig. 17a–c. In this approach, a spinneret comprising three coaxial capillaries was used, in which a chemically inert fluid acts as a buffer between the outer and inner polymer solutions. The buffer middle fluid is then removed, creating a void between the inner solid nanofiber and the outer solid microtube. This approach was successfully demonstrated in fabricating a TiO2 nanofiber encased in a TiO2 microtube. In addition to its usefulness in fabricating hollow structures, the triple-coaxial electrospinning technique can be adapted to produce novel fiber architectures [67]. The basic coaxial electrospinning is illustrated in Fig. 17d–f and consists of the hierarchically assembled compound nozzle comprising two or more metal capillaries separately leading to a single blunted metallic needle. Careful selection of the outer shell polymer solution, middle fluid, and inner core polymer solutions in terms of miscibility is critical in the stable ejection of the multi-fluidic compound jet to produce multichannel microtubes wherein the middle wall can be further divided into two to four channels, proving the versatility and simplicity of this technique [59].

a

c

b

Inner fluid Middle fluid Outer fluid

High voltage

500 nm

500 nm

d

e

10 µm

f

100 nm

g

100 nm

h

100 nm

100 nm

Fig. 17 Schematic illustration of the multi-fluidic coaxial electrospinning experimental setup used to generate hollow fibers with the nanowire/nanotube structure; (b) SEM and (c)TEM images of TiO2 with nanowire/nanotube structure; (d) side view SEM image of the sample after the organics has been removed; (e–h) SEM images of multichannel tubes with varying diameter and channel number from 2 to 5. (Reprinted from [59], Copyright (2017), with permision from Elsevier)

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Porous Nanofibers A porous medium or a porous material is a material containing pores (voids). The porous materials are materials with pores (cavities, channels, or interstices). The skeletal portion of the material is often called the “matrix” or “frame.” The characteristics of a porous material vary depending on the size, shape, and arrangement of the pores as well as composition of the material itself. The porous materials can be mainly categorized into microporous, mesoporous, and macroporous. Microporous materials are categorized along with macroporous materials due to their pore diameters of greater than 50 nm and microporous materials having pore diameters of smaller than 2 nm. Mesoporous materials cover novel and important aspects of porous solids with pore sizes between 2 to 50 nm. Mesoporous nanofibers have attracted attention because of their unique structure and widespread applications. Mesoporous nanofibers with controlled diameter from 50 to 250 nm and tunable pore size range from 2 to 50 nm and length of millimeters range have been reported in the literature. Up to date, several methods have been invented to fabricate mesoporous nanofibers, such as template-assisted process, hydrothermal route, structure-selective synthesis, electrospinning technique, and so on. The different mesoporous nanofibers, such a circular, hexagonal column, a circular lamellar cylinder, and a parallel, hexagonal column, have been synthesized by using different preparation procedures [60]. However, it is still a great challenge to fabricate mesoporous nanofibers with high uniformity and purity in a simple manner. Nonporous nanofibers were the plain fibers without any pores; therefore the surface area for nonporous nanofibers is less when compared to porous surfaces. The method of fabrication includes nanomaterial incorporation onto a fiber structure after formation of the fiber structure. Nanofiber structure can be a part of a nanoparticle carrier material, a nanoparticle disposal medium, a lighting medium, and a catalysis medium. There are different fabrication methods for producing nanofiber structures with surface porosity and coating techniques for porous and nonporous nanofibers. Nanofibers with the porous membrane have higher surface area than smooth/nonporous nanofibers [60]. Mesoporous structure with abundant inner spaces enables electrolyte access easily for the nanofibers, which can lead to the improvement in charge transfer [60]. Sihui et al. [61] developed highly porous nanofibers using a PS mixture with the combination of DMF/tetrahydrofuran (THF) solution as a core material and PVP/TiO2 mixture in combination with ethanol as a shell liquid. These two, PS and PVP/TiO2, polymer solution combinations were aligned, and the PS phase was detached by calcining nanofibers to form highly porous nanofibers [61]. Kim et al. [62] prepared electrospun polymer nanofibers made of PLA, PS, and poly(vinyl acetate) (PVA) with a porous surface morphology. In this work, the surface morphology of the obtained nanofibers, e.g., pore size, depth, shape, and distribution of non-woven mats, was optimized by varying the collector temperature. Nayani et al. [63] developed highly porous and hollow PAN fibers using nonsolvent-induced phase separation (NIPS). A highly porous structure is obtained when the polymer is absorbed in a nonsolvent bath(water), and the specific surface

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area of porous PAN nanofibers was increased comparing with solvent-induced phase separation [63]. In another study, porous PAN fibers were fabricated with a ternary system of PAN/DMF/water. The porous structure was formed when the spinodal decomposition phase separation was occurring. In addition, the thickness of nanofibers was tuned by raising the surface tension and viscosity of PAN solutions [64]. Liangmiao et al. [65] fabricated small wire-based 3D hierarchy boehmite hollow spheres without any surfactants and templates. Size and internal structure and morphological characteristics of hollow spheres were optimized by altering the aggregation of boehmite clusters into spheres and their subsequent reactions such as dissolution and redeposition process.

Core-Shell Nanofibers Core-shell electrospinning is capable of using an electrospinnable material as a carrier to fabricate nanofibers for non-electrospinnable material (Fig. 18) [66]. Given that a coreshell fiber is prepared out of two independent materials, each material might impart exceptional and independent functionality to the composite fiber. The core is protected until it is time for its release. The core-shell nanofibers can be differentiated into core and shell with an overall diameter varying from 20 to 100 nm. Distribution and orientation of molecules and ions are influenced by several factors such as crystalline, interaction between the material mixture, and molecular mobility. The core-shell polymers produce flexibility of lightweight with the high mechanical strength, chemical stability, and heat stable inorganic particles [66, 67]. To bring the functional properties onto the surface of the nanofibers (shell), as keeping the intrinsic properties of the nanofibers (core), coreshell nanofibers are introduced. In this type of nanofiber, the external layer may include active agents for getting functional properties, such as shells holding immobilized specific enzymes. Various methods, together with the multistep template synthesis, surface-initiated atom transfer radical polymerization “ATRP,” and coaxial electrospinning, are introduced for fabricating core-shell nanofibers. Among them, coaxial electrospinning is usually counted as one of the most versatile methods for fabricating Fig. 18 Schematic diagram of the core-shell electrospinning setup. (Reprinted from [66], Copyright (2014), Elsevier)

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these kinds of nanofiber [68]. A coaxial jet is formed, when two different liquids simultaneously flow through outer and inner spinneret capillaries in the presence of a high-voltage power supply. Then, nanofibers are subjected for solvent evaporation and a stretching process. The inlet volume of two different liquids into spinneret capillaries is influencing the uniformity of nanofiber and stability of the core material [65]. Also, flow rates of liquids in the inner and outer capillary affect the thickness of core-shell nanofibers. Additionally, the opening capacity of the spinneret capillaries, electric field, miscibility of two liquids and conductivity, and their viscosity plays important roles in the formation of uniform core-shell nanofibers and morphology. Liangmiao et al. [65] developed core-shell nanofibers with two miscible and immiscible polymer solutions using phase separation process. Achieving continuous and uniform core-shell nanofibers can be ascertained by proper stretching of the droplet (Cone Taylor). Core deformation or its breakage into droplets may happen due to a viscous force obtained by the shell, transforming itself into droplets (due to the weakness of electric fields) or its rapid stretching, thus exerting strong viscous stress tangential to the core. Several studies have used a coaxial jet and produced special nanofibers through it [65]. Recently, a novel kind of shape memory polyurethane (SMPU) nanofibers with core-shell nanostructure is fabricated using coaxial electrospinning. Pyridine(Py)-courethane as a shell and caprolactone-co-urethane as the core were coaxially electrospun for fabricating shape memory nanofibers. In this study, the ratio of the core polymer and shell were customized for best shape revival [69]. The developed fibers exhibited high-dimensional stability and good shape revival under thermal-induced tests. Collagen as the shell and PCL as the core were applied for creating a non-woven mat. According to cell culture results, collagen-coated PCL nanofibrous mat was attuned with fibroblast cell migration and proliferation in assessment with other controls (pure PCL nanofibers and single collagen and PCL nanofibrous or their mixtures) [70]. Li et al. [71] developed PMMA-PAN nanofibers by using a conventional single-nozzle electrospinning technique. In this study, PMMA and PAN were applied as core and shell, respectively. The same technique was also used for PEO and chitosan. In this study, the fraction effect of each component in the solution was investigated. The core-shell structure transformation was caused by dissimilar phase separation mechanisms with a continuous decrease of PEO fraction. Uniform-sized and monodispersed boehmite core-shell and hollow spheres have been successfully developed by Zhang et al. [72] by applying a template-free solvothermal process. The various parameters like reaction duration, the trisodium citrate amounts, and solvents were shown to affect the formation of the AlOOH core-shell and hollow nanospheres. Weinqi et al. [73] developed hollow core-shell ZnO-SnO2 nanofibers via a two-step process. A ZnO shell with a thickness of 10–15 nm was effectively grown on hollow SnO2 nanofibers, resulting in an additional core-shell nanostructure. SnO2 sensor exhibited significantly improved ethanol sensing performance as compared to the ZnO-SnO2 sensor at below 200  C temperature. This type of performance can be ascribed to the exceptional hollow structure, oxygen vacancies, and the n-n heterojunction. Moreover, the energy band structure of the heterojunction between the SnO2 core and ZnO shell-core and the electron depletion theory was frayed to construe the gas sensing mechanism. Nair et al. [74] reported

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the fabrication of non-woven porous mats of PS-Py core-shell nanofibers by electrospinning polymeric solutions containing chemical oxidants. Polymers with high molecular weights are dissolved in solvents that produce polymeric solutions with optimum viscosity, evaporation rate, and dielectric constants. PS can be electrospun in various solvents; it is in combination with ferric oxide used as a template for polymerization of pyrrole to fabricate polymeric shells on the structural polymeric core. The morphology of nanofibers exhibits higher conductivity due to the growth of poly-Py shells over PS template fibers. From the obtained results, it was suggested that the use of ferric tosylate instead of ferric chloride produced faster growth and higher crystallinity, leading to higher conductivity [74]. Nanostructure materials play an important role in the automotive technology, especially in the development of high-performance supercapacitors and portable power devices. Particularly the nanofibers with mesoporous structures possess unique dimensional structure and high surface area to volume ratio which favors the electrode-electrolyte interface to provide high electrochemical properties [75]. Xinghong et al. [75] reported on the preparation of coaxial electrospinning titanium nitride-vanadium nitride core-shell-structured mesoporous fibers with the spinneret of coaxial capillaries for developing the supercapacitors. Results indicated that the mesoporous structures of nanofibers were a good candidate for highperformance supercapacitors and can be used in Li-ion batteries. Li et al. [76] developed tetradecanol/PMMA nanofibers by melt coaxial electrospinning process. The sheath consisted of optical transmission PMMA, and core contains 1-tetradecanol. The TEM image reveals the clear interface between 1-tetradecanol core and PMMA polymer shell with inner and outer diameters of 200 nm and 500 nm, respectively. The core material was completely encapsulated independently and phase separated from the shell wall of the polymer matrix. These types of nanofibers are most important in thermo-responsive, energy-storage, and phasetransformation applications [76].

Emerging Applications of Structural Nanofibers Structural nanofibers can be produced from various polymers, metal oxide, and ceramic materials and therefore have different physical properties and application potentials, such as in energy production and storage, sensors, automotive, aerospace, smart textile design, tissue engineering, medical implants, pharmacy, and cosmetics. Attention is given to the future of research in these areas in order to advance and increase the application of nanofibers and commercialization. Various potential applications of functional nanofibers have been described in detail.

Energy Production and Storage The potential applications of nanofibers have been demonstrated for energy production and storage applications. They provide solutions for energy crisis as they have

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the ability to convert different forms of energies into electrical energy. Presently, various types of fuel cells, like direct methanol fuel cells, proton exchange mat fuel cells, solid oxide fuel cells, and alkaline fuel cells, are available [77, 78]. It was reported that nanofibers have been applied in construction for various parts of batteries, supercapacitors, solar cells, hydrogen storage and generation devices, and piezoelectric power generators. The outstanding properties of nanofibers such as high surface area-to-volume ratio and high porosity are being utilized in electrolytes for long-term storage and rapid electron/ion transport. Figure 19 shows fabrication of highly porous Li4Ti5O12/carbon nanofiber electrodes that exhibit excellent cyclability, high capacity, and super-high rate capability in hybrid supercapacitors and Li-ion batteries [79]. The highly porous structure of the Li4Ti5O12/carbon nanofibers facilitates the electrolyte infiltration, enabling full utilization of Li4Ti5O12 and fast transport of Li+ and e.

Environmental Protection and Improvement With increasing harmful pollutions in recent years, the need for environmental monitoring and access to clean air and water has become important. To achieve this, the fabrication and applications of nanofibers with tunable physicochemical properties and features are required. Rapid developments have been demonstrated in the applications of nanofibers for water treatment and environmental protection, notably in ultrafiltration, photocatalysis, and chemical sensing. Nanofibers have typically high porosity, a controllable pore size, which is advantageous for

Gases

C LTO pores e–

e– Li+

Ar/H2

Air

800 °C, 10 h

350 °C, 2 h

As-spun fibers PVP

LTO/C fibers LTO precursor

LTO

PLTO/C fibers C

12 nm

Li+

e–

LTO/C

Fig. 19 Schematic presentation of the formation of the porous Li4Ti5O12/carbon nanofibers through electrospinning and a subsequent two-step heat treatment. (Reprinted from [78], Copyright (2014), Elsevier)

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purification of water and air. Nanofibers possess high adsorption capacity and surface area, thus enhancing the filtration efficiency and sensing performance to remove the inorganic pollutants such as heavy metals Hg, Pb, Cu, and Cd from the environment [80]. Environmental remediation includes the removal of industrial pollutants, agricultural pollutants, bacteria, germs, fungus, and hard-to-decompose organic compounds present in wastewater. Figure 20 illustrates the idea of environmental remediation using a metal oxide as photocatalysis [81]. In industry, nanofibers have been used as filter media for the past two decades for cleaning air pollutants such as volatile organic compounds (VOCs) and nitrogen dioxide (NO2). Nanofiber filters also provide higher filtration efficiency due to smaller fiber size. Thin-plate die technology of M/s Non-woven Technologies Inc. (Georgia) had developed submicron fibers for filtration products. They find applications in the pulse clean cartridges for dust collection and in-cabin air filtration of mining vehicles.

Biological and Healthcare Applications Polymeric nanofibers have found wide biomedical applications [82] with several US patents [83–86] describing techniques for making vascular prostheses and breast prostheses. Porous, thin film protein nanofibers were applied to a prosthetic device for implantation into the body [87]. Tissue engineering is a promising substitute for damaged or deteriorated tissues which cannot be repaired with common methods. The tissue-engineered nanofibers may possess many advantages like versatility for

Fig. 20 Representation of environmental remediation by metal oxide nanofibers as photocatalysis. (Copyright 2017, MDPI [81], This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0))

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biofunctionalization and promotion of desired cell behaviors. The future success of nanofiber will depend on the fabrication of nanofiber scaffolds at a reasonable cost [88–91]. The various naturally available biomaterials like keratin, viral spike protein, silk, collagen, tubulin and actin, cellulose, chitin, and mucin are established as nanofibrous materials in the form of the nm-to mm-scale. The goal is to design 3D scaffolds of synthetic biodegradable matrices that provide temporary templates for cell seeding, invasion, multiplication, and differentiation, thereby reviving the biological tissue. Biodegradable scaffolds from nanoscale nanofibers may hold the key in adjusting the degradation rate of a specified biomaterial in vivo [85–87]. It has been recently demonstrated that smooth muscle cells oriented themselves along the aligned nanofibers [87, 88]. Electrospun nanofibers of the poly(ethylene-co-vinyl acetate) and PLA loaded with the antibiotic drugs like tetracycline and Mefoxin exhibited promising results in various disease treatments. Thus, drug delivery with nanofibers can be expected in a clinical setting in the near future [92–97]. Nanofibers were promising in the treatment of wounds and burns. Recently, biodegradable electrospun nanofibers produced mat dressing when applied onto skin wounds. This dressing facilitates the growth of normal skin without the formation of a scar. Non-woven nanofibrous membranes protect the wound by aerosol particle capture mechanism against the bacteria [92]. The encapsulation of gene vectors within electrospun nanofibers for consequent diffusion through porous routes can result in the sustained release of gene vectors. Figure 21 shows the encapsulation of gene vectors into nanofiber [98]. Presently available skin care products may cause allergies and/or inflammation [99] due to the migration of the product to the more sensitive areas of the body. Therefore, polymer nanofibers are being tested as skin care products. Due to the high surface area, nanofibrous skin masks facilitate higher use and transfer rate of the additives to the skin. Such cosmetic skin products made from electrospinning can be softly and painlessly applied for treatment of the skin. During combat, electrospun woven nanofiber clothing may increase the chances of survivability of soldiers against harsh environmental conditions. Nanofibers have been identified as ideal candidates for protective clothing applications due to their lightweight, high porosity, large surface area, resistant to penetration of harmful chemical agents, and good filtration efficiency [100, 101].

Sensors, Electric, and Optical Devices Researchers are using nanofibers to make sensors that change color as they absorb chemical vapors. Piezoelectric nanofibers of polyvinylidenefluoride were used in developing functional sensors. They were found to be more sensitive owing to the high surface area [102, 103]. Recently, highly sensitive optical sensors based on fluorescent polymer nanofiber films have been established. Initial results indicate that the sensitivities of nanofiber films distinguish ferric and mercury ions and a nitro compound (2,4-dinitrotoluene) is two to three times more significant than

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a

Emulsion electrospinning

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Fig. 21 Preparation of core-shell nanofibers for controlled gene delivery using coaxial electrospinning process and emulsion electrospinning. (a) Preparation of nanofibers with two methods (b) shows the TEM images core-shell nanofibers prepared by using coaxial electrospinning. (c) Shows the encapsulation of gene vector encapsulation for controlled release into core-shell nanofibers. (d) Shows the avoiding completely contact of gene vectors with core-shell nanofibers, (e) controlled delivery of gene vector from core-shell nanofiber, and (f) improved delivery of nanofiber layer modified with the polycationic polymers. (Copyright 2014, Springer Nature [97], This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http:// creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated)

sensitivities obtained from thin film sensors. A single nanofiber coated with two metals forms a thermocouple to rapidly detect inflammation of coronary arteries. Such a nano-thermocouple scan also is inserted into a cell to monitor the metabolic activities [104]. Additional, nano-thermocouples can be incorporated into a catheter balloon to determine the arterial wall temperature. CNFs have a great perspective to create the next generation of electrochemical biosensors owing to their exceptional structural, mechanical, and electrical properties. Figure 22 shows the fabrication of active humidity sensors based on lead-free NaNbO3 piezoelectric nanofibers. The developed equipment could detect humidity at ambient temperature conditions as well [105]. Flexible electronics have become the focus of major research since they can be the next-generation devices with lightweight and portable electronics. Transparent conductive films made of nanofibers have played important roles in different flexible electronic applications, including electronic displays and solar cells. There are several ways in which electrospun nanofibers may be made conductive. One of the simplest methods is by blending conductive additive such as CNTs to the polymer solution to be electrospun. These nanofibers can be used in fabricating small

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Fig. 22 Piezoelectric active humidity sensors based on lead-free NaNbO3 piezoelectric nanofibers. (Copyright 2015, Hindawi [105], This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any original work is properly cited)

electronic devices such as Schottky junctions, sensors, and actuators. In highperformance batteries, conductive nanofibrous membranes are also suitable for use as porous electrodes due to more surface area. Researchers have developed piezoelectric nanofibers that are flexible enough to be woven into clothing. Photoelectric conductive nanofibrous membranes have been proposed to have significant application in corrosion protection, electrostatic dissipation, and electromagnetic interference shielding and photovoltaic devices [105]. The primary part of the liquid crystal device consists of a fiber/liquid crystal composite with a submicron thickness. The refractive index differences between the liquid crystal material and the fibers govern the transmissivity of the device. For this application, the potential and performance of nanofibers need to be further assessed.

Conclusion Nanofibers are fibers having dimensions of 100 nm or less. The surface and/or interior of such nanofibers can be further functionalized with molecular species or nanoparticles during or after an electrospinning process. In addition, electrospun nanofibers can be assembled into ordered arrays or hierarchical structures by manipulation of their alignment, stacking, and/or folding. Functional nanofibers, based on the nature of materials used for construction, are broadly divided into organic, inorganic, and inorganic carbon and hybrid nanofibers. Further, depending on structural features, nanofibers are classified into hollow, mesoporous, nonporous, and core-shell nanofibers. Nanofibers found a wide range of applications in our daily

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life. The properties of nanofibers have stimulated researchers and companies to consider using them in several fields, including controlled drug delivery, cosmetics, tissue engineering scaffolds, sensor devices, optical devices, wound healing, and protective clothing, to name a few. Numerous publications have appeared in recent years on specific functional nanofibers and their processing methods and uses. However, there are several areas that require attention for further development of the field. At the laboratory scale, potential applications of nanofibers have been identified. Significant efforts will be required to commercialize these applications so that research and development into nanofibers will continue to attract the attention of scientists in the future.

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Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Antimicrobial Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Alternative Antimicrobial Approach: Nanofiber-Loaded Antimicrobial Drugs . . . . . . . . . . . . . . . Antimicrobial Polymer Nanofibers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nanofibers Loaded with Antimicrobial Nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Fabrication of Antimicrobial Nanofibers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Smart Nanofibers with Antimicrobial Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biomedical Applications of Antimicrobial Nanofibers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion and Future Prospects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abstract

Microbial infections are a major threat to public health and a leading cause of death worldwide. New strains of pathogens, such as resistant strains of viruses, bacteria, pathogenic fungi, and protozoa, are causing serious concern. Conventional antimicrobial agents have not shown therapeutic efficacy against multidrug-resistant strains of these pathogens. This review introduces the most popular applications of nanofibers in antimicrobial drug delivery for infectious diseases. Recent investigations of microbial infections,

R. Rasouli (*) Department of Medical Nanotechnology, International Campus, Tehran University of Medical Sciences, Tehran, Iran e-mail: [email protected] A. Barhoum (*) Institut Européen des Membranes (IEMM, ENSCM UM CNRS UMR5635), Montpellier, France e-mail: [email protected]; [email protected]; ahmed.barhoum@science. helwan.edu.eg © Springer Nature Switzerland AG 2019 A. Barhoum et al. (eds.), Handbook of Nanofibers, https://doi.org/10.1007/978-3-319-53655-2_33

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microbial resistance, and the mechanisms of antimicrobial drug resistance are discussed. Furthermore, current developments and future challenges in nanofiber technologies and applications for effective antimicrobial treatment are addressed. Keywords

Nanofiber · Antimicrobial therapy · Drug resistance · Infectious diseases

Introduction Infectious diseases caused by bacteria, viruses, fungi, and parasites are leading causes of death worldwide. In 2015, an estimated 56.4 million deaths due to infectious diseases occurred worldwide. Lower respiratory infections were the deadliest communicable disease in 2015, with 3.2 million deaths worldwide. During the same year, diarrheal diseases and tuberculosis caused 1.4 million deaths, while human immunodeficiency virus (HIV) infections and acquired immune deficiency syndrome (AIDS) killed 1.1 million people (World Health Organization, Top 10 causes of death worldwide: 2015 update, Updated January 2017). Nanofibers have been investigated for use in antimicrobial drug delivery in many areas, including tissue engineering, wound dressing, and medical implants. Nanofibers have several favorable characteristics, such as a large surface area-to-volume ratio, flexibility in surface functionalities, and superior mechanical performance [1]. These unique properties may make nanofibers suitable for a variety of physicochemical functions, including the sustained and controlled release of antimicrobial drugs, passive and active targeted delivery, targeted drug-enhanced antimicrobial activity, reduced frequency of administration, reduced dosage, reduced side effects, and ability to combat intracellular pathogens. Nanofibers are ideal candidates to immobilize antibiotics, enzymes, antimicrobial peptides, and growth hormones or encapsulate them into fiber matrixes [2–6]. A variety of nanobiocides, TiO2 [7–10], ZnO nanoparticles (NPs) [11, 12], CuO NPs [13, 14], Fe3O4 NPs [15], Ag NPs [16–20], and carbon nanotubes (CNTs) [21] have been incorporated by various techniques into nanofibers that exhibit strong antimicrobial activity in standard assays. Nanofibers provide great flexibility in the selection of biodegradable or nondegradable materials, which allows for more precise control over the kinetics of antimicrobial drug release. Nanofibers can manipulate or control drug release via either diffusion alone or diffusion and scaffold degradation. The remarkable properties of nanofibers make them ideal candidates for a wide range of applications in medicine, especially the antimicrobial treatment of bacteria-related biofilms, tissue scaffolds [22, 23], orthopedic implant-related infections [24], and wound dressings [25–32]. This chapter discusses the current progress and future challenges in the use of nanofibers as a new generation of potential antimicrobials.

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Antimicrobial Drugs Antimicrobial agents are used to prevent infections and diseases caused by pathogens. Several types of antimicrobial drugs are commonly available [33]: 1. Antibacterial drugs are prescribed to prevent the pathogenic activity of bacteria (e.g., Zithromax). 2. Antifungal drugs are prescribed to stop fungal activity in the host (e.g., clotrimazole). 3. Antiviral agents are prescribed to inhibit the pathogenic action of a virus (e.g., Tamiflu). 4. Antiparasitic drugs are prescribed to stop the growth of pathogenic parasites (e.g., anthelmintics). The efficacy of antimicrobial drugs can be characterized by testing their bactericidal and bacteriostatic properties. Bactericidal drugs kill sensitive organisms, so the number of viable organisms decreases rapidly after exposure to the drug. In contrast, a bacteriostatic drug inhibits the growth of bacteria but does not kill them. In the presence of a bacteriostatic drug, the number of bacteria remains relatively constant; thus, immunologic mechanisms are needed to eradicate organisms during treatment of an infection with this type of drug (Fig. 1). Some drugs can be either bactericidal or bacteriostatic, depending on their concentrations and the bacterial species against which they are used. Conventional antimicrobial agents do not show therapeutic

Fig. 1 In vitro effects of bactericidal and bacteriostatic drugs [34]

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Fig. 2 The process through which microbes gain resistance to drugs. Schematic created by ThermoFisher Scientific and MeMed

efficacy in combating multidrug-resistant strains of pathogens. Indeed, a main challenge in the treatment of infectious diseases is overcoming microbial drug resistance. Bacteria exhibit logarithmic growth in a broth culture in the absence of an antimicrobial drug. The addition of tetracycline as a bacteriostatic drug inhibits further growth but does not reduce the number of bacteria. Penicillin as a bactericidal drug reduces the number of viable bacteria [34]. Most viruses, bacteria, and other microbes multiply rapidly; thus, they can quickly develop resistance to antimicrobial drugs. Figure 2 shows how microbes gain resistance to drugs. For example, bacteria may obtain resistance genes via direct uptake of the antibiotic resistance genes present in the environment, such as in water environments or by means of horizontal gene transfer, which happens directly between two bacteria. Antibiotic resistance microbes can potentially

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bypass water treatment facilities and eventually return into the environment and back into our bodies. Over time, many infectious microbes have adapted to the drugs designed to kill them. Misusing or overusing antimicrobial drugs can make resistance develop even faster. Therefore, it is imperative to find innovative therapeutic approaches to overcome microbial drug resistance or develop vaccines to prevent infections. The fundamental mechanisms of antimicrobial resistance are as follows: 1. Antibiotic modification via production of an enzyme that modifies the structure of the antibiotic, prevents binding to the target, and confers resistance (e.g., aminoglycoside-modifying enzymes). 2. Enzymatic degradation by the production of an enzyme that hydrolyzes the antibiotic. 3. Reduced drug penetration. Many microbes express resistance genes that allow for reduced uptake to prevent the concentration of antimicrobial agent from increasing to toxic levels within the microbial cell. For example, Gramnegative bacteria reduce the permeability of antibiotics by the downregulation of porins, mutant porin alleles, or the replacement of porins with more selective channels. 4. Increased drug efflux. All bacteria carry multiple genes that encode multidrugresistant efflux pumps, which prevents the concentration of antimicrobial agents from increasing to toxic levels within the microbial cell. 5. Increased competitive antibiotic inhibition by synthesizing molecules that are competitive inhibitors of the antibiotic. For example, para-aminobenzoic acid (PABA) is a competitive inhibitor that competes with sulfonamide drugs for the binding site of bacterial dihydropteroate synthetase. 6. Swarming, which is a multicellular form of bacteria created by the following steps: Planktonic bacterial cells differentiate into elongated cells with multiple flagella, called swarm cells. These swarm cells stay in close proximity to each other and migrate over the substrate, as a single unit. These multicellular forms of bacteria are tolerant to multiple antibiotics. 7. The accumulation of biofilm (a matrix consisting of an extracellular polymeric substance), which eventually surrounds the population of bacterial cells and hinders antibiotic penetration to the full depth of the biofilm. The matrix surrounding the bacterial cells protects them from very high concentrations of multiple antibiotic agents. Therefore, bacteria in biofilms are up to 1000 times more resistant to antibiotics than planktonic forms, often resulting in chronic infections despite antibiotic treatment. 8. Drug target modification, which may cause reduced affinity of the target site for antibiotic acquisitions. This mechanism can occur through genetic modification of the target site (e.g., mutation of the target site and recombination to produce mosaic alleles) or chemical modification (modification of the target site via addition of a chemical group without altering the primary sequence of the target site).

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Alternative Antimicrobial Approach: Nanofiber-Loaded Antimicrobial Drugs Recent developments in nanotechnology indicate that the superhydrophobicity of nanostructured surfaces reduces the contact area between bacteria and the surface, thus preventing bacteria adhesion; this is similar to the antimicrobial/antifouling effects of nature-inspired nanoscale topographies such as butterflies [35, 36], cicada wings [37], lotus leaves [38, 39], gecko feet [40], dragonfly wings, and shark skin [41]. The inhibition of bacterial colonization is strongly related to the geometry parameters of nanostructured surfaces, such as the size, spacing, and aspect ratio [42]. In an alternative approach to creating antimicrobial agents, a nanofiber may be modified with antimicrobial NPs. For example, antimicrobial NPs, such as noble metal and metal oxide NPs, have been integrated into polymer nanofibers [43, 44]. These integrated antimicrobial NPs have several benefits compared with typical organic compound-loaded polymeric analogs depending on the chemical nature of NPs, including higher thermal stability, improved mechanical performance, and improved biocompatibility [45–47]. Researchers in materials engineering have discovered novel materials with suitable properties for use in medicine, especially on the nanoscale [48–53]. The unique physicochemical properties of nanofibers allow for the sustained and controlled release of antimicrobial drugs, passive and active targeted delivery, new nanoformulations of antimicrobial drugs, encapsulation, interruption, and conjugation. These developments have improved drug solubility for intravenous administration, enhanced antimicrobial activity, and reduced the frequency of administration, required dosage, and related side effects. Various antimicrobial nanofibers containing antimicrobial agents have been developed to cure and prevent diseases. They also can be used in applications such as clinical wound dressings, bioadhesives, biofilm, and the coating of biomedical materials, implants, and devices. In particular, antimicrobial metal NPs (Ag, Au, and Cu NPs) and metal oxide NPs (ZnO, TiO2, and CuO NPs) have been investigated as antimicrobial agents due to their biocidal effectiveness and compatibility with human cells [54–57].

Antimicrobial Polymer Nanofibers Antimicrobial polymers were first introduced in 1965 with the fabrication of polymers and copolymers prepared from 2-methacryloxytroponones to kill bacteria [58]. Antimicrobial polymers are categorized into three general types: polymeric biocides, biocidal polymers, and biocide-releasing polymers (see Fig. 3) [59]. The polymeric biocide class is based on the concept that biocidal groups can attach to a polymer. Polymeric biocides are polymers that consist of bioactive repeating units. The polymerization of antibiotics is usually performed to prolong the activity and decrease the toxicity of antibiotics – a method that is very sensitive to the tethering method and the nature of the antibiotic. In biocidal polymers, the

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Fig. 3 Schematic representation of the design possibilities of antibacterial polymers based on the working principles of macromolecular systems [59]

activity is embodied by the whole macromolecule. These polymers may be polymerized cationic biocides, which are attracted to the negative charge of microbial cells. (A negative net charge is related to membrane proteins, teichoic acids of Grampositive bacteria, and negatively charged phospholipids at the outer membrane of Gram-negative bacteria.) If they have a proportionate amphiphilic property, they are able to destroy the outer membrane and the cytoplasmic membrane, as well as contribute to lysis of the cell, thus causing cell death. In addition to the polycationic antimicrobial polymers, quarternary ammonium groups, antimicrobial polymers with protonated tertiary, primary amino groups, and a class of antimicrobial polymers that have only one biocidal end group have been described recently. Biocidereleasing polymers act as a carrier for biocides and can release the biocides close to the cell in high local concentrations. The antimicrobial performance of nisin as a model bacteriocin into triaxial, coaxial, and single-blended nanofibers has been evaluated to determine the longterm antimicrobial activity using modified versions of the antimicrobial textile test AATCC 100 and AATCC 147 against Staphylococcus aureus. The AATCC 100 tests indicated that nisin-incorporated triaxial fibers have excellent biocidal activities for up to 5 days (>99.99% of bacteria were killed; 4 log-reduction) and then provide biostatic activity for
2 days. Coaxial fibers showed longer antimicrobial activity, but their biocidal activity killed only >99% of bacteria (2 log-reduction) after 1 day of exposure, which was much weaker than that of triaxial fiber membranes. Singleblended polycaprolactone (PCL) nanofibers with nisin (Fig. 4) showed relatively

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Fig. 4 Electrospun membranes encapsulating nisin in the core of multi-layer coaxial fibers, with a hydrophobic polycaprolactone (PCL) intermediate layer and a hygroscopic cellulose acetate sheath. These materials have been demonstrated to provide long-term antimicrobial activity combined with a hygroscopic outer layer. Long-term antimicrobial effects of nisin were released from electrospun triaxial fiber membranes. Qualitative overlay analysis of antimicrobial activity on different types of electrospun membranes is shown: (a) PCL/nisin single-blended fibers; (b) coaxial fiber with polyvinylpyrrolidone (PVP)/nisin core and PCL sheath; (c) triaxial fiber with PVP/nisin core, PCL intermediate, and cellulose acetate sheath; (d) zone of clearance, observed as a “dark halo” of growth inhibition around the membrane edges [60] (Copyright 2017, Elsevier)

weak activity and only for 1 day [60]. Table 1 lists other recent investigations in which antimicrobial polymer nanofibers were produced through electrospinning and the incorporation of various antimicrobial agents. Natural products have been a rich source of antibacterial drugs. The use of natural nanofibers (e.g., chitosan, cellulose) is growing fast due to the nontoxicity and environmentally friendly properties of these materials. Chitosan, a versatile hydrophilic polysaccharide derived from deacetylation of chitin, has a wide spectrum of

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Table 1 Recent investigation in which antimicrobial polymer nanofibers were produced through electrospinning and the incorporation of various antimicrobial agents Nanofiber Polycaprolactone (PCL)

Antimicrobial agent Gentamycin sulfate (GS)

Poly-l-lactic acid (PLLA)

Mupirocin

Poly (vinyl alcohol)/poly (vinyl acetate) (PVA)/PVAc

Ciprofloxacin HCL

Poly-l-lactic acid (PLLA)

Tetracycline HCL

Poly(lactide-co-glycolide) (PLAGA)

Cefazolin

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

Fusidic acid (FA)

Dextran, polyurethane (PU)

Ciprofloxacin HCL

Result PCL-GS nanofibers exhibited a sustained release for GS, with no burst release phenomenon at pH 7.4 Mupirocin exhibited only a 5% release in the first hour before experiencing a more sustained release to provide antimicrobial action against Staphylococcus aureus for over 72 h The rate and period of the drug (ciprofloxacin) release in the wound region was controlled via (PVA)/ PVAc blending A sustained release of tetracycline HCL from the membranes was observed By modifying process parameters, the feasibility of incorporating cefazolin (antibiotics) into the PLAGA nanofibers was demonstrated. Therefore, PLAGA nanofibers show potential as antibiotic delivery systems for the treatment of wounds Increasing FA loading enhanced the antimicrobial activity of PLGA fibrous mats against S. aureus ATCC 6538P (Sast), Ps. Aeruginosa ATCC 9027 (Psst), and a methicillin-resistant S. aureus clinical isolate (MRSA1) from an infected wound PU-Ciprofloxacin HCL nanofiber mat showed good bactericidal activity against both Gram-positive (Staphylococcus aureus ATCC25923 and Bacillus

References [81]

[82]

[28]

[83]

[84]

[85]

[26]

(continued)

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Table 1 (continued) Nanofiber

Antimicrobial agent

Polyvinyl alcohol/Poly (acrylic acid) (PVA/PAA)

Ciprofloxacin HCL and Aloe vera

Poly (lactic acid)/poly (ε-caprolactone (PLA/PCL)

Tetracycline hydrochloride

Poly (styrene sulfonic acidco-maleic acid)(PSSA-MA) blended with polyvinyl alcohol (PVA)

Neomycin

Gelatin (GE)

Anthraquinone2,6-disulfonic acid (AQS)

Electrospun nanofibrous polyurethane (PU) membrane

–

Result subtilis) and Gramnegative bacteria (Escherichia coli K12-MG1655, Salmonella typhimurium, Vibrio vulnificus CMCP6) Adding both ciprofloxacin HCL and Aloe vera in PVA/PAA nanofiber’s structure prevents penetration of bacteria (Pseudomonas aeruginosa ATCC 27853, Staphylococcus aureus ATCC 25923) Dressings made from PCL and PLA/PCL blends showed better performance compared with the commercial wound dressing sample (Comfeel Plus) Acceptable antimicrobial activity against both Grampositive and Gramnegative bacteria were obtained by PSSA-MAPVA nanofiber mats loaded with neomycin. In an in vivo wound healing test, these mats better performance than gauze and blank nanofiber mats in decreasing acute wound size during the first week after tissue damage The composite gelatin nanofibrous membranes assembled with AQS demonstrated excellent photoinduced antimicrobial properties by killing bacteria PU membrane as a wound dressing revealed controlled evaporative water loss and excellent oxygen permeability, as

References

[27]

[86]

[29]

[30]

[25]

(continued)

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Table 1 (continued) Nanofiber

Antimicrobial agent

Poly(vinyl alcohol)/poly (vinyl acetate) (PVA-PVAc)

Ciprofloxacin HCL

Silkfibroin/ polyethylenimine (SF/PEI)

Polyethylenimine (PEI)

Poly(lactic acid) (PLA) and ciprofloxacin conjugated PLA

Ciprofloxacin

Halloysite nanotubes/poly (lactic-co-glycolic acid) (PLGA)

Tetracycline hydrochloride (TCH)

Poly (acrylic acid)(PAA)

Doxycycline hyclate (DOXY-h)

Result well as promoted fluid drainage ability due to the nanofibers with porosity and inherent property of PU. The nanofibrous membrane exhibited neither permeability to exogenous microorganism nor toxicity The PVA-PVAc nanofibrous mats as a dressing matrix for controlled release of drugs revealed an appropriate and convenient method for electrospinning to control the rate and period of drug release in wound healing applications. The initial release and rate of drug release are strongly related to the thickness of the blend of nanofiber mats SF/PEI nanofibers showed strong antimicrobial activities against Grampositive S. aureus and Gram-negative P. aeruginosa The ciprofloxacin released from the drug-conjugated nanofiber possesses antimicrobial activity against S. aureus bacteria Composite Halloysite/ PLGA/TCH nanofibers are able to release the antimicrobial drug in a sustained manner for 42 days and display antimicrobial activity solely associated with the encapsulated drug According to the antimicrobial tests, the studied Gram-positive bacteria, S. aureus and Streptococcus agalactiae,

References

[28]

[31]

[87]

[88]

[89]

(continued)

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Table 1 (continued) Nanofiber

Antimicrobial agent

Polyacrylonitrile (PAN)/agar

Ampicillin (AMC)

Laponite (LAP)-doped poly (lactic-co-glycolic acid) (PLGA)

Amoxicillin (AMX)

Polyacrylonitrile (PAN)

Chitosan

Poly(caprolactone)/poly (vinyl alcohol) (PCL-PVA)

Thyme extract

Hydroxyapat/poly(lactic-coglycolic acid) (PLGA)

Amoxicillin (AMX)

Polyvinyl alcohol (PVA)

Allyl isothiocyanate (AITC)

Chitosan

Gentamicin loaded liposome

Result seemed to be more sensitive to PAA/DOXY-h nanofiber mats than the tested Gram-negative bacteria, P. aeruginosa Composite agar/PAN nanofiber showed a good biocompatibility and enhanced thermal properties, as well as longlasting antimicrobial activity against Gramnegative E. coli Antimicrobial activity and cytocompatibility assays verified that the antimicrobial activity of AMX toward the growth inhibition of S. aureus is not compromised after being loaded into the PLGA nanofibers PAN–chitosan nanofibers produced a 5-log reduction against E. coli, S. aureus, and Micrococcus luteus PCL-PVA-thyme nanofibers showed antimicrobial activity against two bacteria: Gram-positive Staphylococcus and Gramnegative Escherichia Hydroxyapat-PLGA-AMX nanofibers inhibited the growth of S. aureus PVA-AITC nanofibers have shown higher antibacterial activity against E. coli and S. aureus Modified chitosan nanofibers showed bactericidal activity against E. coli, P. aeruginosa, and S. aureus

References

[90]

[91]

[92]

[93]

[94]

[95]

[96]

(continued)

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Table 1 (continued) Nanofiber Poly(lactic acid) (PLA) and Polyvinylpyrrolidone (PVP)

Antimicrobial agent Copaiba (Copaifera sp.) oil

Poly(vinyl alcohol) (PVA)

Benzyl triethylammonium chloride (BTEAC)

Poly(lactic acid) (PLA) and ciprofloxacin conjugated PLA

Ciprofloxacin

Polyethylene oxide/ hydrophobic poly-L-lactic acid (PLLA/PEO)

Maraviroc (MVC),30 azido-30 deoxythymidine (AZT), acyclovir

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

Griffithsin

Poly(lactic-co-glycolic acid) (PLGA) and poly(dl-lactideco-ε-caprolactone) (PLCL)

Acyclovir (ACV)

Poly(vinyl alcohol) (PVA)

Tenofovir (TFV)

Polyvinylpyrrolidone/ poly (methyl methacrylate) (PVP/PMMA)

Cetylpyridinim chloride (CPC)

Poly-ε-caprolactone (PCL)

Egg lecithin and terbinafine hydrochloride (terbinafine)

Result PLA-PVP-copaiba nanofibers had a greater antimicrobial action against S. aureus BTEAC-PVA nanofibers successfully inhibited the growth of Gram-positive S. aureus and Gramnegative E. coli and Klebsiella pneumonia. The BTEAC-PVA nanofibers inactivated bacteriophages MS2 and PhiX174 The ciprofloxacin released from the drug-conjugated nanofiber possessed antimicrobial activity against S. aureus bacteria With tunable fiber size and controlled degradation kinetics properties of the fabricated nanofiber meshes facilitated the simultaneous release of multiple agents against HIV-1, HSV-2, and sperm PLGA-griffithsin nanofibers potently inhibit HIV infection in vitro PLGA-PLCL-ACV nanofibers provided complete and efficacious protection against HSV-2 infection in vitro The results support the potential for scale-up of TFV-loaded TFV fibers against HIV-1 PVP/PMMA-CPC nanofibers had an antifungal action against Candida albicans Modified PCL nanofiber showed antifungal efficacy against molds as well as dermatophytic fungus

References [97]

[98]

[99]

[100]

[101]

[102]

[103]

[104]

[105]

(continued)

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Table 1 (continued) Nanofiber Poly-ε-caprolactone (PCL)

Antimicrobial agent Ketoconazole

Polyethylene oxide and polycaprolactone (PEO-PCL)

Clotrimazole

Polycaprolactone (PCL)/ gelatin

Terbinafine hydrochloride (TFH)

Poly(D,L-lactic acid-coglycolic acid) (PLGA)

Fusidic acid (FA) and rifampicin (RIF)

Poly(d,l-lactide-co glycolide acid)–poly(ε-caprolactone)

Quercetin

Poly (acrylonitrile)

Commercial hydrolytic enzymes

Poly(E-caprolactone) (PCL)/ polyethylene oxide (PEO)

Vancomycin

Poly(lactic-co-glycolic acid) / poly(E-caprolactone) (PLGA/PCL)

Vancomycin (Van), linezolid (Lin), and daptomycin (Dap)

Result Functionalized PCL nanofibers showed antifungal activity against Aspergillus flavus, Aspergillus carbonarius, Aspergillus niger, Aspergillus sp. A29, Fusarium oxysporum, and Penicillium citrinum An in vitro antifungal study suggested its therapeutic effectiveness in the treatment of oral candidiasis PCL-gelatin-TFH nanofiber showed antifungal activity against Trichophyton mentagrophytes, Aspergillus fumigatus, and C. albicans All dual-loaded formulations showed direct antimicrobial activity in vitro against Staphylococcus epidermidis, and two strains of methicillinresistant S. aureus (MRSA) Fabricated nanofibers showed antibiofilm activity against C. albicans No biofilm formation was observed on the prepared nanofibers that were coated with the enzymes PCL-PEO-vancomycin nanofibers prevented MRSA biofilm formation on the surface of ossicular prostheses regardless of materials in vitro, and MRSA otitis media in vivo In a mouse model of biofilm-associated orthopedic-implant infection, three different combinations of antibiotic-

References [106]

[107]

[108]

[24]

[109]

[110]

[111]

[112]

(continued)

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Table 1 (continued) Nanofiber

Antimicrobial agent

Poly(lactic-co-glycolic acid)/poly-D, L-lactide (PLGA/PLLA)

Doxycycline (DOXY)

Poly(E-caprolactone) (PCL)/ gelatin

Metronidazole

Poly caprolactone(PC)

Biteral

Result loaded coatings were biocompatible with enhanced osseointegration and provided good results in preventing infection of the bone/joint tissue and implant biofilm formation In vitro antimicrobial tests showed the ability of scaffold to inhibit common bacterial growth (S. aureus and E. coli) for a prolonged duration The fabricated PCL-gelatin membranes significantly prevented the colonization of anaerobic bacteria. Until the drug content reached 30%, cells could adhere and proliferate on the membranes without cytotoxicity The antibiotic-embedded membranes significantly improved healing and eliminated post-surgery abdominal adhesions. Macroscopic and histological studies demonstrated that these barriers reduce the extent, type, and tenacity of adhesion

References

[22]

[23]

[99]

antimicrobial activities against Gram-negative bacteria, Gram-positive bacteria, and fungi. Chitosan is considered to be a desirable polymer for antimicrobial applications because of its nontoxicity towards mammalian cells and biodegradability. Three possible mechanisms have been suggested for the antimicrobial activity of chitosan; the most likely mechanism associates the interaction between positively charged chitosan and negatively charged microbial cell membranes. The adhesion of bacteria to chitosan results in the disruption of the cell membrane and leakage of intracellular components [61, 62]. Another proposed mechanism is the penetration of chitosan into the nuclei of the microorganisms, which leads to the inhibition of mRNA and protein synthesis [63–65]. The third mechanism is related to the excellent metal-binding capacities of chitosan, which leads to the suppression of spore

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elements and binding to essential nutrients for microbial growth [66–68]. The antimicrobial efficacy of chitosan depends on several factors, including environmental pH, the degree of deacetylation, and molecular weight [69–75]. Cellulose and its derivatives, such as cellulose acetate and cellulose hydroxyl propyl, also are used widely in the fabrication of electrospun nanofibers for antimicrobial applications [76, 77]. The cellulose nanofiber surface can be chemically modified by grafting functional groups to provide antimicrobial properties, such as immobilized quaternary ammonium groups, amino groups [78, 79], and amino silane groups [80].

Nanofibers Loaded with Antimicrobial Nanoparticles Many researchers have focused on evaluating the activity and application of nanofibers and nanoparticles as antimicrobial materials. The antimicrobial mechanisms of metal nanoparticles (M NPs) and their ions (MX+ ions) have been demonstrated to be identical [113]. The mechanisms associated with the antimicrobial behavior of metal nanoparticles are shown in Fig. 5 [114]. However, the effective antimicrobial concentration of metal ions on the micromolar level differs from the nanomolar

Fig. 5 Antimicrobial mechanisms related to metal nanoparticles: (1) “Trojan-horse effect” due to endocytosis processes; (2) attachment to the membrane surface; (3) catalyzed radical formation; and (4) release of metal ions [114]

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level of metal nanoparticles. Metal nanoparticles have greater biocidal ability than metal ions at the same concentration [115]. Recently, there has been an exponential increase in the use of NPs for fighting microbial pathogens (Table 2). However, it remains unclear whether microbial organisms can develop resistance to the intrinsic antimicrobial properties of nanoparticles. A good example of this issue is Ag NPs. The antimicrobial action of Ag NPs is similar to that of Ag+ ions. The efflux system is a known antimicrobial action of Ag+ ions [116]; bacteria may generate the same resistance against Ag NPs. Studies have shown that an individual mutation or a set of mutations in the genetic background of the bacterium Escherichia coli (K-12 MG1655) may improve Ag NP or Ag+ ion resistance [117, 118]. Because metallic and metallic oxide NPs are similar to Ag NPs, both may have multitarget sites inside the bacteria and thus affect many aspects of bacteria. It therefore may be difficult for bacteria to develop resistance to the broad and unspecific antimicrobial mechanisms of NPs [119]. Investigations of the antimicrobial activity of Ag NPs suggest the following: (1) Ag+ ions bind to the ATP synthesis enzyme molecules in the cell wall and thus inhibit ATP synthesis; (2) DNA denaturation occurs via Ag+ ion binding to DNA in a cell; and (3) the respiratory chain in the cytochrome oxidase and NADH-succinatedehydrogenase region is blocked [120, 121]. Nanofibers containing Ag NPs have improved biocidal efficacy via sustained release of Ag+ ions [122–124]. In addition, the nanofiber provides a large surface area for contact with microbial agents. Synthesized nanofibers containing Ag NPs are reported to have improved biocidal ability with a release of metal ions over a longer period of time [16, 19, 20, 125, 126]. A synthesized Ag/polyrhodanine nanofiber has been studied as an antimicrobial agent with enhanced antimicrobial efficacy compared with silver sulfadiazine against Gram-negative and Gram-positive bacteria. A modified Kirby-Bauer test verified that the Ag/polyrhodanine nanofiber (Fig. 6) had better antimicrobial efficacy than silver sulfadiazine [127]. Metal oxide NPs (e.g. (ZnO, TiO2, and CuO NPs) are relatively low-cost [128] antimicrobial agents against a wide range of bacteria [129, 130], including Klebsiella pneumonia [131], Listeria monocytogenes, Salmonella enteritidis [132], Streptococcus mutans, Lactobacillus [133], and E. coli [134] (Table 2). Metal oxide NPs have demonstrated an ability to prevent biofilm formation, with low toxicity to human cells [135, 136]. The antimicrobial efficacy of these metal oxide NPs, similar to other metal nanoparticles, is size-dependent [137, 138]. Based on recent findings, the antimicrobial mechanism may be related to the binding of ZnO NPs to membranes, which makes the outer membrane permeable and results in the leakage of cellular materials. Then, the ZnO NPs enter the inner membrane and inactivate thiol-containing enzymes via the formation of disulfide and ROS-dependent pathways with inducing oxidative stress [132, 134, 139]. Synthesized ZnO/TiO2 composite nanofibers have also been studied as antimicrobial agents, showing excellent antimicrobial activity against Gram-negative E. coli and Gram-positive S. aureus under ultraviolet irradiation and in the absence of light (Fig. 7) [140].

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Table 2 Antimicrobial nanofibers containing metal and metal oxide nanoparticles Nanofiber Alginate containing 5–20 nm Ag NPs

Carboxymethyl chitosan (CMCTS)/ polyethylene oxide (PEO) containing 10 nm Ag NPs

Microbe Staphylococcus aureus (ATCC 6538), Bacillus pumilus (ATCC 14884), Gram-negative Escherichia coli (ATCC 8739), and Klebisiella pneumoniae (ATTC 13047) S. aureus ATCC 25923, Pseudomonas aeruginosa ATCC 27853, and E. coli ATCC 25922 in addition to the fungus Candida albicans ATCC 10231

Chitosan (CTS) containing 9–10 nm Ag NPs

Gram-negative P. aeruginosa and Grampositive methicillinresistant Staphylococcus aureus (MRSA)

Gelatin containing 9–20 nm Ag NPs

S. aureus and P. aeruginosa

Poly (vinylalcohol) containing 6 nm Ag NPs

S. aureus and K. pneumoniae

Results Alginate/Ag nanofiber can eradicate more than 72% of Gram-negative and 98% of Grampositive bacteria

References [16]

CMCTS/PEO/Ag nanofibers are very effective antimicrobial materials against S. aureus, P. aeruginosa, E. coli, and C. albicans, in a comparison of CMCS/PEO nanofibers and pure Ag NPs The antibacterial treatments of CTS/AgNPs and CTS nanofibers against P. aeruginosa showed that the inhibition zones for the CTS/AgNPs at 100:0, 50:50, 67:33, and 83:17 (AgNP contents = 0, 2, 1.3, 0.7 wt. %) were 0 mm, 16.73 mm, 16.58 mm, and 16.07 mm, respectively. The inhibition zones for MRSA for CTS/AgNPs of 100:0, 50:50, 67:33, and 83:17 (AgNP contents = 0, 2, 1.3, 0.7 wt. %) were shown to be 0 mm, 15.75 mm, 15.42 mm, and 14.9 mm, respectively Antimicrobial efficacy was >99% after 24 h of incubation Numbers of colonies of S. aureus and K. pneumoniae were significantly reduced by >99.9% after 18 h of incubation

[17]

[18]

[19]

[20]

(continued)

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Table 2 (continued) Nanofiber Poly (methyl methacrylate (PMMA) containing Ag NPs

Microbe Gram-positive bacteria (S. aureus) and Gramnegative bacteria (E. coli)

Cellulose acetate (CA) containing 21 nm Ag NPs

Gram-positive S. aureus and Gram-negative E. coli, K. pneumoniae, and P. aeruginosa

Poly(vinyl alcohol) containing 21 nm TiO2 NPs

Gram-positive S. aureus ATCC 6538 and Gramnegative K. pneumoniae ATCC 4532 Gram-negative E. coli and Gram-positive S. aureus

Chitosan (CS)/poly (vinyl alcohol) (PVA) containing 100 nm TiO2 NPs Poly(3hydroxybutyrate) (PHB) and chitosan oligomers containing AgNO3 > ZrO2 > TiO2 > SrO2

References [15]

[21]

[141]

Fabrication of Antimicrobial Nanofibers The biomedical applications of nanofibers – especially electrospun nanofibers – are increasing rapidly due to the unique features and properties of porous nanostructures, including high drug loading and encapsulation efficiency, enhanced therapeutic indexes, localized delivery, reduced drug side effects, and the ability to modulate drug release by engineering and controlling the processing and solution parameters of synthesis [142–146]. In general, antimicrobial nanofibers are fabricated by incorporating a biocide in nanofiber mats. The active agent is evenly blended in the polymer solution before electrospinning, confining the active agent in the core of the fiber. Fabrication methods to produce nanofibers have been widely explored. Several processing techniques have been used thus far, including self-assembly of polymers [147, 148], template synthesis [149, 150], phase separation [151], drawing [152], and electrospinning [153, 154]. Of these, electrospinning (electrostatic spinning) is the most cost-effective and easiest method to fabricate large volumes of nanofibers with diameters ranging from several micrometers to tens of nanometers [1]. Various well-known active agents have been used, including chlorhexidine, antibiotics, triclosan, biguanides, and metal and metal oxide nanoparticles (e.g. Ag, Au, CuO, TiO2, ZnO NPs) [7–21, 155]. Electrospun nanofibers are ideal vehicles for antimicrobial drug delivery because of their simple and versatile fabrication method, high surface-to-volume ratio, interconnected porous structure, high permeability of electrospun nanofibers, and ability to incorporate different antimicrobial drugs. In many infections, the low intrinsic potency and short half-lives of antimicrobial agents require high dosages and frequent administration of antimicrobial agents [146]. The sustained release of antimicrobial agents from electrospun fibers can overcome these challenges.

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Fig. 6 Field emission scanning electron microscopy images (left) of fabricated silver/polyrhodanine nanofibers (inset transmission electron microscopy image). Photographs (right) of the Kirby-Bauer plates of silver/polyrhodanine nanofiber (upper right) and silver sulfadiazine (lower right) against Escherichia coli (Gram-negative) and Staphylococcus aureus (Gram-positive) bacteria [127] (Copyright 2008, American Chemical Society)

Drugs can be easily incorporated into electrospun nanofibers by techniques such as physical adsorption, chemical immobilization, blending, co-axial electrospinning, and emulsion electrospinning [156–160]. Table 3 lists some of the recent studies on drug incorporation methods using electrospinning. Surface modification techniques such as plasma treatment, wet chemical methods, and surface graft polymerization have been used to introduce new functional groups and help with drug loading [170]. Biodegradable polyesters (polylactic acid, polyglycolic acid, poly [lactic-co-glycolic] acid, and polycaprolactone), non-biodegradable polyesters (polyurethane, polycarbonate, and nylon-6), and naturally occurring polymers (silk, collagen, gelatin, alginate, and chitosan) have been used in electrospun fibers for sustained drug release [171, 172]. Drug release from electrospun fibers can be controlled in various ways [173–179], as summarized in Fig. 8. A combination of diffusion, polymer degradation, drug partitioning in polymers, and drug dissolution has been considered as a mechanism for drug release from fibers. The drug release mechanism for a nonbiodegradable matrix is driven by the concentration gradient and osmotic pressure or matrix swelling. In a biodegradable matrix with or without a conjugated drug, hydrolytic or enzymatic cleavage of the relevant chemical bonds are involved (Fig. 9) [179].

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Dark condition UV irradiation at 312 nm

100

% Survival

80 60 40 20 0 Control

Pure TiO2

Pure Zno

ZnO/ TiO2 composite

Fig. 7 (a) Field emission scanning electron microscopy and (b) transmission electron microscopy images of fabricated ZnO/TiO2 nanofibers. Energy dispersive spectroscopy mapping images of composite nanofibers with (c) Zn elements, (d) Ti elements, and (e) Zn–Ti elements. The survival percentages of S. aureus are shown after exposure to the control, TiO2 nanofibers, and ZnO/TiO2 nanofibers in the presence and absence of ultraviolet light irradiation at 312 nm for 30 s. The number of bacterial colonies on the untreated petri dish surface under the dark conditions is shown as 100% [140] (Copyright 2011, Royal Society of Chemistry)

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Table 3 Drug incorporation methods using electrospinning (Adapted from [161, 162]) Drug incorporation methods Blending electrospinning

Materials Poly(D,L-lactic coglycolide) (PLGA)

Surface modification electrospinning

Poly(dioxanone)(PDO)/ Ciprofloxacin hydrochloride (CiH)

[164]

Emulsion electrospinning

PLGA–chitosan mats functionalized with graphene oxide and Ag NPs

[165]

Coaxial electrospinning

Chitosan/poly(ethylene oxide)/Cinnamaldehye

[166]

Schematic diagram

References [163]

(continued)

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Table 3 (continued) Drug incorporation methods Coaxial electrospray

Electrospray

Materials Polycaprolactone chitosan/silver nanoparticles

Schematic diagram

Electrospun/ electrosprayed mats with poly(3-hydroxybutyrate) (PHB) containing ZnO NPs

References [167]

[168, 169]

Smart Nanofibers with Antimicrobial Properties Considerable progress has been made in the fabrication of smart nanofibers with antimicrobial properties and/or controlled drug release. In this method, physical and/or chemical stimuli cause the drug release, such as pH value, ionic strength, temperature, light, electric or magnetic fields, or combinations thereof. Smart electrospun nanofibers are gaining considerable attention as ideal candidates for oral drug delivery [180–182], transdermal drug delivery [183–185], vaginal drug delivery [100, 186], and as a scaffold for tissue regeneration due to their morphological similarities to a natural extracellular matrix, high surface-to-volume ratios, very high and tunable porosity, and good mechanical properties [187, 188]. Another remarkable application of smart electrospun fibers is their use against infectious diseases (Table 4). Encapsulated antibiotics or nanoparticles in electrospun fibers exert potent antimicrobial activity against infectious diseases [72, 126, 189].

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Fig. 8 Drug release from electrospun fibers can be controlled by these factors

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Fiber composition

Factors affecting drug release

Drug molecular weight

Fiber crystallinity

Fiber swelling Drug solubility in the release medium Drug state Drug–polymer–solvent interactions Fiber diameter and porosity Fiber construct geometry and thickness

Future efforts may be focused on the development of electrospun nanofibers that are responsive to multiple stimuli. More research is needed on the biocompatibility of this generation of nanofibers, which have great potential in the biomedical field.

Biomedical Applications of Antimicrobial Nanofibers The base materials for next-generation biomedical applications should possess biocompatibility, antimicrobial activity, and appropriate flexibility and toughness. Materials for biosensing applications, biomedical devices, and tissue engineering require antimicrobial properties to prevent microbial infections and biofilm formation, as well as electrical conductivity to send signals inside and outside of the human body. Novel antimicrobial nanofibers have been developed for biomedical purposes. Electrospun nanofibrous mats have a structure similar to a native extracellular matrix with high interconnected porosity (60–90%) [210], great absorbance, balanced

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Fig. 9 Schematic illustrations of diffusion, degradation, and swelling release mechanisms from nanofibers

moisture, and gas permeability, thus providing an appropriate environment to protect wounds from exogenous infections. Furthermore, the ability to load antimicrobial agents into nanofibers offers great potential for the development of an effective antimicrobial system that is able to treat infections in the wound region [25, 211, 212]. There is a need to attain smart nanofibers with the ability to provide optimal drug release profiles and rates according to the type and condition of a wound. The release of antimicrobial agents should occur with an optimum delivery profile only when needed to treat infections in the wound region. An initial burst effect is toxic to tissue cells [187, 213]. Many researchers have focused their efforts on creating these smart systems and translating them into an effective wound healing approach [214–216]. Table 1 lists some studies on the antimicrobial applications of nanofibers in wound healing [28, 81–85]. Cellulose nanofiber membrane is an emerging biocompatible nanomaterial that can carry and deliver a wide range of antimicrobial drugs. The biomedical applications of cellulose nanofiber membrane include repairing skin in cases of burns, wounds, and ulcers. This antimicrobial membrane accelerates the epithelialization process and prevents infections in several wound-healing treatments, including chronic wounds and diabetic foot wounds [217] (Fig. 10). Medical device infections are related to the formation of biofilms – communities of bacterial cells that adhere to the implant surface. Cells in these biofilms are

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Table 4 Antimicrobial applications of smart nanofibers Smart nanofibers pH-responsive electrospun nanofibers

Materials Poly[styrene-co-(maleic sodium anhydride)] and cellulose (SMA-Na/ cellulose) hydrogel nanofibers

Triblock copolymer PLA–POEP–PLA (PLAOEP) with 10% (w/w) of POEP

Poly(dl-lactide) (PLA)–poly(ethylene glycol) (PEG) Ibuprofen-loaded poly (L-lactide) (PLLA) fibrous scaffold with doped sodium bicarbonate

Polydopamine-coated PCL

Thermoresponsive electrospun nanofibers

Poly(N-Isopropylacrylamideco-N-(Hydroxymethyl) acrylamide)/polyurethane Poly (N -isopropylacrylamide) (PNIPAA)/ethyl cellulose

Results These nanofibers provided improved mechanical strength and were pH responsive. Their waterswelling ratio revealed a characteristic two-step increase at pH values of 5.0 and 8.2 An in vitro degradation study indicated that electrospun fibers containing acid-labile segments were stable in neutral buffer solutions, and the degradation was accelerated under acidic circumstances The degradation was enhanced in acid buffers with a two-stage degradation profile The acid-responsive fibrous scaffold showed a quick drug-releasing response at pH 5.0 and a slow drugreleasing response at pH 7.4 in vitro. In vivo, a rat muscle wound model showed that the acidresponsive ibuprofenloaded PLLA fibrous scaffold caused slight inflammation and an earlier reparation Drugs that were released in low-pH solutions killed significantly more cells than those released in high-pH solutions Temperature-dependent drug release was shown for the model drugs paclitaxel and 5-fluorouracil In vitro drug release studies demonstrated that the PNIPAAm/EC blended nanofibers were able to synergistically combine the properties of poly

References [190]

[191]

[192]

[193]

[194]

[195]

[196]

(continued)

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Table 4 (continued) Smart nanofibers

Materials

Double-hydrophilic glycopolymer (DHG), poly (6-O-vinyl-nonanedioyl-dgalactose-co-Nvinylcaprolactam) (P (OVNG-co-NVCL)) Poly (N-isopropylacryamide) (PNIPAM)/ egg albumen (EA)/poly(ε-caprolactone) (PCL) Poly(N-isopropylacrylamide)/ ethyl cellulose

Light-responsive electrospun nanofibers

Electric field responsive electrospun nanofibers

Copolymer poly(Nvinylcaprolactam-comethacrylic acid) (PNVCLco-MAA) Poly (methacrylic acid) (PMAA) nanofibers covalently modified with spiropyran (SP) or a derivate SP, which was first coupled to a cyclodextrin molecule (βCDSP) A block copolymer of vinyl-benzyl chloride (VBC) and glycidyl methacrylate (GMA) (PVBC-b-PGMA loaded with the R-CD-5FU prodrug Poly(3,4-ethylenedioxythiophene) (PEDOT) incorporated with examethasone

Polyvinyl alcohol (PVA) / polyacrylic acid (PAA) / multiwalled carbon nanotubes (MWCNTs)

Results (N-isopropylacrylamide)/ ethyl cellulose polymers, providing temperaturesensitive systems with sustained-release properties The drug-release properties of DHG P(OVNG-coNVCL) nanofibers are temperature regulated

The drug release studies recorded initial rapid release up to 10 h, followed by slow and sustained release for 696 h (29 days) The nanofiber was shown to be a temperature-sensitive drug delivery system with sustained-release properties The drug release characteristics were dependent on the temperature The kinetic results revealed a faster isomerization process for the βCDSP molecule than that for the PMAA-βCDSP and for PMAASP, the slowest one

References

[197]

[198]

[199]

[200]

[201]

The R-CD-5FU prodrug loaded inside the carrier provided a photo-controlled fast “on-off” release characteristic

[202]

The release of dexamethasone was precisely controlled by external electrical stimulation of PEDOT nanotubes Uniform distribution of the oxyfluorinated MWCNTs in the nanofibers was crucial to the electro-responsive swelling and drug-releasing behaviors of nanofibers

[203]

[185]

(continued)

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Table 4 (continued) Smart nanofibers Magnetic field responsive electrospun nanofibers

Materials Magnetite NPs in polyethylene oxide (PEO) and polyvinyl alcohol (PVA)

Cellulose derivatives, dehydroxypropyl methyl cellulose phthalate (HPMCP), and cellulose acetate (CA) incorporated with magnetite (Fe3O4) nanoparticles

Magnetoactive polyethylene oxide (PEO)–poly(l-lactide) (PLLA)

Maghemite nanoparticles covalently coated with polyethylene glycol

Multiple-stimuli responsive electrospun nanofibers

Poly (acrylic acid)(PAA) and poly (allylamine hydrochloride) (PAH) with methylene blue (MB) as a drug model were responsive to both temperature and ionic strength

Results The polymer/magnetite nanofibers showed superparamagnetic behavior and deflected in the presence of an applied magnetic field Presence of magnetite NPs did not have any effect on the drug-release profiles from the nanofibrous devices The possibility of controlled drug release in the target zone was obtained by the guidance of an external magnetic field The biocompatibility and biodegradability of PEO/PLLA and the tunable magnetic activity of the oleic acid-coated magnetite nanoparticles (Fe3O4). Fe3O4 NPs are combined in the same drug delivery system, with N-acetyl-paminophenol (acetaminophen) as a proofof-concept pharmaceutical The measured susceptibility spectra may be well reproduced model using a superposition of Néel and Brown loss processes under consideration of the observed narrow normal size distribution Temperature-controlled release of MB was achieved by depositing temperature sensitive PAA/poly(Nisopropylacrylamide) multilayers onto the fiber surfaces. The sustained release of MB in phosphatebuffered saline solution was obtained by constructing perfluorosilane networks on the fiber surfaces as capping layers

References [204]

[186]

[205]

[206]

[207]

(continued)

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Table 4 (continued) Smart nanofibers

Materials pNIPA/PVA copolymer fibers, which are both pH and temperature sensitive

Poly[styrene-co-(maleic sodium anhydride)] and cellulose (SMA-Na/ cellulose) hydrogel nanofibers

Triblock copolymer PLA–POEP–PLA (PLAOEP) with 10% (w/w) of POEP

Poly(Nisopropylacrylamide) (PNIPAAm) and poly (acrylic acid) were responsive to both temperature and pH signals Poly(acrylic acid) and poly (vinyl alcohol) was responsive to both electric field and pH

Ionic-strength and pHresponsive poly [acrylamide-co-(maleic acid)]

Results At room temperature and at a pH 4. In contrast, at elevated temperatures (70  C), the swelling degree of the fibers reduced from 15- to 2.6-fold These nanofibers provided better mechanical strength and were pH responsive. Their water-swelling ratio had a characteristic two-step increase at pH 5.0 and 8.2 The in vitro degradation study indicated that the electrospun fibers containing acid-labile segments were stable in neutral buffer solutions, and the degradation was accelerated under acidic circumstances The PVA-crosslinked hydrogel fibers, exhibited faster swelling kinetics and all hydrogel fibers showed a drastic increase in the swelling between pH 4 and 5 The swelling ratio of the fibrous hydrogels increased up to 31 times their dry weight with increasing pH from 2 to 7, and most significantly between pH 4 and pH 5. The fully swollen fibrous membranes could be triggered by an applied electric field to swell further The water-swelling ratio of the nanofibers decreased with increasing ionic strength of the solution. It showed a characteristic two-step increase at pH 2.5 and 8.5 in response to an increase of the solution pH

References [189]

[190]

[191]

[189]

[208]

[209]

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Fig. 10 Application of a bacterial cellulose (BC) membrane as a wound dressing (Copyright 2016, Elsevier [218])

embedded in a extracellular matrix that may include polysaccharides, proteins, and/or DNA. Biofilm provides strong protection against different environmental conditions and prevents antibiotic penetration [219–222], thereby resulting in therapeutically challenging chronic infections, especially in cases involving antibioticresistant bacteria and difficult-to-treat infections [222]. Thus, biofilms play an important role in the spread of antibiotic resistance. A common but expensive treatment for biofilm-associated implant infections is remove or replace the infected implants and administer prolonged systemic antibiotic therapy [223], at a cost of approximately $100,000 per patient [224]. To date, there has been no effective clinical solution that combines antimicrobial efficiency with excellent osseointegration. Most implanted medical device infections are caused by staphylococcal species, including methicillin-resistant Staphylococcus aureus (MRSA) [225, 226]. A clinical practice guideline recommends systemic administration of combination of vancomycin plus rifampin to treat these infections [112]. Newer antistaphylococcal agents such as linezolid and daptomycin may also be used to treat MRSA infections [227]. The prevention of biofilm formation can be achieved with antimicrobial surfaces that either repel or kill the living planktonic microbial cells in its surroundings. A nanofiber coating with low surface energy has the capacity to provide optimal antimicrobial release of two or more combinatorial antibiotics for the prevention of biofilm-associated infections via both suggested mechanism to combat biofilm formation (Fig. 11) [59]. In a preclinical animal model of orthopedic-implant infection, a tunable nanofiber composite coating demonstrated complete bacterial

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Fig. 11 Suggested mechanisms to prevent biofilm formation by antimicrobial surfaces [59]

eradication from the implant and surrounding bone/joint tissue while enhancing osseointegration. With further development, combinatorial antibiotics in a nanofiber coating with tailored release profiles for each drug may provide highly effective prevention of infections related to medical devices and biofilm formation in patients.

Conclusion and Future Prospects In recent years, new strains of pathogens have caused serious concern, including resistant strains of viruses, bacteria, fungi, and protozoa. Conventional antimicrobial drugs do not show therapeutic efficacy against multidrug-resistant strains of pathogens. Thus, innovative strategies are necessary to treat infectious diseases and overcome microbial drug resistance. Nanofibers are promising materials for treating resistant strains of pathogens. Nanofibers have unique physicochemical properties, such as a large ratio of surface area to volume, high loading capacity, sustained and controlled release of antimicrobial drugs, passive and active targeted delivery, reduced frequency of administration, reduced dosage, reduced side effects, and an ability to combat intracellular pathogens. More efforts are needed to address the possibility of microbial organisms developing resistance to the intrinsic antimicrobial properties of nanofibers, including in vivo studies. Researchers should investigate the in vivo performance of nanofibers. such as biocompatibility, stability, durability, and efficacy of immobilized or entrapped antimicrobial agents.

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Rana Imani, Maryam Yousefzadeh, and Shirin Nour

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Drug-Loading Mechanisms in Fiber-Based DDSs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Direct Drug-Loading Approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nanocomposite-Embedded Fibers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Drug-Releasing Mechanisms and Rate Control Approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Controlled Release Mechanisms in Nanofibers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Factors Affecting Drug Release Mechanism and Kinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Smart Active Drug Release Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . pH-Responsive Nanofibers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Thermo-responsive Nanofibers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Light-Responsive Nanofibers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Electric Field-Responsive Nanofibers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Magnetic Field-Responsive Nanofibers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Multiple Stimuli-Responsive Nanofibers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Applications of Nanofibers in Drug Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Anticancer Drug Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Antibiotic Drug Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Growth Factor and Protein Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nucleic Acid Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Miscellaneous Drug Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cell Delivery and Tissue Engineering . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Wound Dressing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Naturally Derived Nanofiber . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cellulose Nanofiber . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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R. Imani (*) · S. Nour Department of Biomedical Engineering, Amirkabir University of Technology (AUT), Tehran, Tehran, Iran e-mail: [email protected]; [email protected] M. Yousefzadeh Department of Textile Engineering, Amirkabir University of Technology (AUT), Tehran, Iran e-mail: [email protected] © Springer Nature Switzerland AG 2019 A. Barhoum et al. (eds.), Handbook of Nanofibers, https://doi.org/10.1007/978-3-319-53655-2_34

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Silk Nanofiber . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Self-Assembled Peptide Nanofibers (SAPNs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Future Trends . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abstract

Electrospinning is an appropriate process to fabricate nanofibers for various applications. Regarding the intrinsically high surface-to-volume ratio of electrospun fibers, they are suitable candidates for drug loading with enhanced mass transfer properties. The diverse therapeutic agents, e.g., proteins, DNA, RNA, as well as chemical drugs, could be incorporated to the nanofibers. By controlling the nanofiber morphologies, its type, and drug incorporating methods, the preferred drug release and diffusion can be adjusted depending on the intended application. In this chapter, an attempt is made to cover the most usable methods to incorporate the therapeutic agents into the nanofibers and investigate the release mechanisms, factors, and methods to control the drug releasing rate. Most usable polymeric materials to fabricate fiber-based drug delivery formulations will also be introduced. Keywords

Electrospinning · Nanofibers · Drug · Sustained release · Biomaterials

Introduction Drug delivery systems (DDSs) have great importance for medical applications. Traditional DDSs are often imprecise, as they cannot provide a desirable therapeutic effect due to the delivery of an insufficient amount of drugs to the site of action as well as fast removal of drugs from the body, which needs repeating the dosage administration. Nowadays, more advanced DDSs are aimed at improving pharmacological properties of conventional dosage forms (e.g., tablet, capsules, topical creams, and injections). Most of the advanced DDSs are aimed at delivering a sufficient amount of drug for a desired period of time, avoiding the degradation of non-released drugs within the body and controlling the release rate to avoid undesired fluctuations of drug concentration in the bloodstream [1]. Over the past few decades, researchers have developed numerous carriers for drug delivery applications. Among them, micro- and nanofibers have become an attractive prospective as drug delivery carrier [2]. The local delivery and controllable release profiles make electrospun ultrafine fibers potentially implantable drug carriers and functional coatings of medical devices. Electrospinning seems to provide the simplest approach to produce nanofibers and is the most economically viable. It could provide a loading drug into the fiber matrix at room temperature processing conditions with simple situations. In addition, the morphology of the electrospun fibers as well as controllability of their properties, such as fiber

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diameter, porosity, and surface properties, makes them ideal candidates for DDS application. This chapter mainly aims at reviewing recent developments in employing the electrospun fibers for drug delivery applications. The different drug-loading techniques are introduced, and further considerations in designing fiber-based DDSs with controlled release rate are briefly discussed. Smart nanofiber systems with stimuli-responsive drug release behavior are pointed out as advanced fiber-based DDSs. The main applications of drug-incorporated fibrous structures are categorized and briefly reviewed.

Drug-Loading Mechanisms in Fiber-Based DDSs The type of electrospinning process can greatly influence the properties of the resulting drug-loaded fibrous system. According to the characteristics and application of the drug-incorporated fibers, the loading approach is being chosen. In this section, the different electrospinning approaches for drug loading will be briefly reviewed.

Direct Drug-Loading Approaches Simple Drug Loading In this approach, drug molecules can be simply mixed with polymer solution before the electrospinning process. Subsequently, the homogenous drug/polymer/solvent solution forms the fiber structure through simple blending and electrospinning. In addition, the drug molecules can be physically immobilized on the preformed fibers via simple immersion of the electrospun mat into the drug solution or chemically conjugated onto the surface-activated fiber. Electrospinning of Drugs and Polymer The most predominant drug-loading method is dissolving or dispersing both the drug and polymer in the same solvent and electrospinning the mixture called co-electrospinning (Fig. 1). High drug-loading efficiency and ability to homogenously disperse the drugs within the fibers are the main advantages of this technique. It is also important to control the distribution of the drug molecules into the electrospun fibers as well as the morphology of the fibers because drug release behavior is dependent on them. In order to attain perfect encapsulation of drugs into electrospun fibers, the physicochemical properties of polymers and their interaction with drug molecules must be precisely considered. To prevent high attraction between the drug and polymer which limits the tendency of the drug molecules to migrate to the surface of the nanofibers and consequently release fast, it is necessary to determine optimized criteria [4]. According to the aforementioned reasons, one of

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Fig. 1 Schematic of drug loading via co-electrospinning method [3] (Copyright © 2013, The Pharmaceutical Society of Korea)

the main factors in co-electrospinning is the drug solubility in the polymer solution and homogeneity, which will be discussed later. Natural polymers (such as gelatin, silk fibroin, collagen, alginate, and chitosan) have received much attention to incorporate hydrophilic drugs homogenously as these polymers can completely dissolve in the aqueous phase. However, they have some limitations such as the collapse of nanofibers during posttreatment such as the cross-linking process and low viscosity of solution, which impede the electrospinning. To overcome these problems, additional hydrophilic synthetic polymers (like PEO) are required for increasing the solution viscosity. Due to the negative effects of exposure to organic solvents and high voltage, co-electrospinning would not be a suitable method for sensitive drugs, particularly bioactive molecules. Moreover, simple blending of drug-loading methods exhibits a short time of release with an initial fast release, termed the “burst release effect.”

Surface Immobilization on the Nanofibers Other simple direct methods of drug loading are physical or chemical surface immobilization with target biomolecules (Fig. 2). In physical methods, secondary forces such as hydrogen bonding, electrostatic, hydrophobic, and van der Waals interactions are usually responsible for retaining the drugs on the nanofibers surface. In addition, the therapeutic agents can be directly immobilized on the fiber surface via chemical modification of the fiber surface with functional groups such as amine, carboxyl, hydroxyl, and thiol. Compared to the co-electrospinning, one of the main advantages of physical and chemical surface immobilization of drugs on the fiber is that it can avoid drug denaturation caused by high voltage or organic solvents. Another advantage of the approach is the ability to control the amount of drugs immobilized by controlling drug feeding ratio. More importantly, this method exhibits slow drug release kinetics with reduced initial burst release, which can preserve the functionality of the surfaceimmobilized biomolecules for a longer period [3]. Hence, this approach is suggested

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Fig. 2 Schematic presentation of drug loading via surface immobilization method [3] (Copyright © 2013, The Pharmaceutical Society of Korea)

for gene or growth factor delivery, where a slow and prolonged release of the agent is required.

Core/Shell Nanofibers Despite being a simple approach, co-electrospinning has some limitations including problems with drug release kinetics and the immiscibility of drugs and polymers. The coaxial electrospinning technique has been developed for loading multiple drugs with different solubilities in polymers and controlling the release kinetics of each drug. This method uses a coaxial spinneret needle that consists of an inner and outer nozzle arranged in a concentric geometry and attached to a double-compartment syringe of polymer supply, for spinning two separate solutions to produce core/ sheath nanofibers, in which the biomolecule solution formed the inner jet and polymer solution formed the outer jet (Fig. 3). With the benefit of simultaneous electrospinning in this technique, electrospinning of two immiscible polymer solutions containing drugs in the core and sheath is possible [4, 5]. Feeding rates of the polymer solutions, applied voltage, compound concentrations, and molecular weights in the feeding fluids are controllable parameters for the formation of the core/shell with desired radius and thickness, respectively. Furthermore, the formation of a continuous fiber jet under the electric field in the coaxial electrospinning greatly depends on the solutions’ conductivity and viscosity [6]. Most of the core/shell nanofibers used in drug delivery systems are loaded with hydrophilic polymers (such as PEG, PVP, PEO, or PVA) and drugs (e.g., proteins) in the core and hydrophobic moieties in the sheath. Furthermore, hollow nanofibers can be constructed by selective removal of the cores after the coaxial electrospinning procedure [8]. Although drug-loading efficiency is still in high amount in this method, sheaths of the nanofibers result in decreased initial burst release. Indeed, shell materials with hydrophobic properties (e.g., PCL) can play a barrier role against diffusion of the

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Core solution Sheath solution

Sheath

Co-axial capillary Co-axial cone Whipping co-axial jet

High voltage supply

Core Grounded collector Fig. 3 A schematic of drug loading via coaxial electrospinning method [7] (Copyright © 2016 Wiley Periodicals, Inc)

drug molecules loaded in the core [7]. Since electric charges concentrate at the outer surface of the droplet, active agents incorporated in the core can be protected against electric charges. Apart from the mentioned advantages, there are some disadvantages including the complexity of the method and insufficient amount of released drugs, which may cause low local therapeutic concentration. There is also an opportunity for surface bio-functionalization of the electrospun core/shell fibers by simply selecting natural bioactive compounds for the spinning of the shell layer or immobilization of functional groups on the fiber surface. Coaxially electrospun fibers can be employed for sustained, local, and efficient genes and growth factor delivery to the desired location within the body.

Emulsion Electrospinning In coaxial electrospinning, there are a lot of factors, which should be considered in the design step. Nevertheless, only a limited portion of the produced fibers can form the proper core/shell structure. Emulsion electrospinning is a method whereby the drug or aqueous protein solution is emulsified within a hydrophobic polymer solution. At the end of electrospinning, the biomolecule-loaded phase can be distributed within the fibers (Fig. 4). The ratio of hydrophilic to hydrophobic solution is one of the parameters that affect the distribution of the biomolecules within the fibers. This parameter plays a key role in regulation of the releasing profile, stability, and bioactivity of the encapsulated drug. In addition to the coaxial electrospinning, it is shown that by using ordinary single-nozzle electrospinning and the emulsion electrospinning method, it is possible to construct core/shell nanofibers [5].

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Stretching

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Stretching

Moving inward and merged

Original emulsion Stretching and evaporation

Partially de-emulsified Stretching and evaporation

Final fiber

Fig. 4 Mechanism of drug loading via emulsion electrospinning method [5] (Copyright © 2014 Taylor & Franc)

The main advantage of the emulsion electrospinning is that the drug and polymer can be dissolved in appropriate solvents. Consequently, numerous hydrophilic drugs and hydrophobic polymeric combinations can be used, while during this process the drug in contact with the organic solvent is minimal. However, there would still be a possibility to damage or degrade sensitive biomolecules like nucleic acids, mainly because of the shearing force and tension between the two phases of the emulsion. Therefore, further modifications like condensation of carrier gene in gene therapy might be useful for more protection [9]. During the emulsification or ultra-sonication procedures in emulsion electrospinning, the contact of core materials with the solvent is increased, which may cause probable damage to the drug contents.

Layer-by-Layer (LBL) Nanofibers One of the most practical methods used in the synthesis of different biomedical devices such as nano-/microparticles, micelles, films, and fibers, for tissue engineering and drug delivery applications, is LBL assembly. As depicted in Fig. 5, the LBL fibrous structure could be produced using two separate nozzles, which usually electrospun two different solutions simultaneously. The LBL structure can also be produced using sequential electrospinning of different drug-loaded polymer mixtures to fabricate a multilayered electrospun nanofiber mesh. The nozzle systems can be either coaxial or single [9]. Similar to the coaxial electrospinning, LBL systems provide reduced initial burst release because of the control drug release by sheet barriers. Commonly, polymer solutions without drugs were electrospun between the different drug-loaded solution electrospinning steps to reach the purpose of timecontrolled drug release. Therefore, a sandwich-like structure will be created with different layers. LBL systems can provide a great opportunity for construction of multilayered fibrous structure, where each layer could include specific drug. In such structures, the

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Fig. 5 Schematic illustration of drug loading via layer-by-layer electrospinning method [3] (Copyright © 2013, The Pharmaceutical Society of Korea)

drug release rate and timing could be affected by layer thickness and fiber size. In fact, multilayer-coated nanofibers can be produced through electrostatic or hydrogen bonding or even acid–base pairing in order to create polyelectrolyte multilayer structures that are suitable for drug delivery applications [10].

Fiber–Hydrogel Hybrid Structure Electrospun nanofibers can be hybridized with hydrogels for efficient drug delivery or raising the properties of the tissue-engineered scaffold. Hydrogels have attracted considerable attentions in drug delivery and tissue engineering applications due to their high capacity of water retention and drug loading, ability of dual drug delivery, extending to a variety of shapes, and resembling native tissue properties [11, 12]. A combination of the electrospun nanofibrous structure with the hydrogels can merge both their advantages. Studies have demonstrated that drug incorporation in nanofibers hybridized in the hydrogel dramatically reduced the initial burst release because of the hydrogel effect on delaying the drug diffusion rate after being released from the nanofiber (Fig. 6). It is worth mentioning that in hydrogel–nanofiber hybrid systems, the electrospun polymer should maintain its fibrous structure in water with the hydrogel properties. Moreover, comprehensive swelling of hydrogel in body fluid environment can squeeze the incorporated nanofibers which may lead to fast release of loaded drugs. This phenomenon is almost a new approach in designing smart drug delivery systems [13]. Beaded Nanofibers It is important to point out that electrospinning process variables should be controlled in order to generate a flawless nanofiber and prevent beaded morphologies. Studies have shown that there is approximately a direct relation between both low and high flow rate of polymer solution and high applied voltage in increasing the beaded defect in fibers [14]. Despite being considered as an undesired phenomenon in electrospinning, the beaded nanofibers have interestingly acquired more attention in drug delivery applications nowadays. In fact, it is so challenging to encapsulate particle drugs (micron size level) into nanofibers. Employing the beaded nanofibers in the system

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Nanofiber and hydrogel Dropping of gelation solution

Hydrogel

Step 1. drug diffusion from nanofiber Step 2. drug release from hydrogel

Nanofiber

Fig. 6 Schematic of drug loading via nanofiber–hydrogel method [3] (Copyright © 2013, The Pharmaceutical Society of Korea)

called bead-on-string nanofibers (in which beads are connected to each other with continuous nanofibers) can be an effective approach for micron-sized drug loading and their sustained release, because the beads are usually in the range of 1–2 μm in diameter (Fig. 7) [15]. Investigation of the optimized condition to form the beaded nanofibers has illustrated that competition of surface tension and viscoelasticity as well as concentration of polymer solution are the key parameters in the formation of such beaded structures. In addition to electrospinning processing parameters and ambient conditions, the solution properties are the critical factors for adjusting the bead morphologies and diameters. The bead diameter is considered as an important parameter in evaluation of the encapsulation capacity of the electrospun bead-on-string nanofibers [16]. In order to synthesize the aforementioned structures, the microparticle drugs are initially dispersed in the same solvent of the electrospinning polymer solution to create a homogenous suspension. Then, the prepared suspension is gently added to the polymer solution and stirred. The final solution/suspension mixture is electrospun to produce the beaded nanofibers. From the results reported in different studies, the beaded structures would be created only in a certain range of polymer concentration depending on the type of polymer and its critical entanglement concentration. Indeed, lowering the concentration of polymer in the electrospun solution will result in smaller diameter beads. Moreover, an increase in stretching force on the jet, which comes from the high conductivity of the solvent or adding charged particles into the solution, can hinder the formation of the beads. Considering the release mechanism in bead-on-string nanofibers, the beads had bigger diameter representing reduced burst release than smaller ones, due to their thicker shell encapsulated in the drug particles [15].

Nanocomposite-Embedded Fibers During the past few decades, delivery of bioactive compounds, such as drugs, proteins, and genes, using nanoparticle (NP) encapsulation has been widely

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Fig. 7 Schematic illustration of beaded nanofibers encapsulating tetracycline hydrochloride (TCH) as particle drugs (BD bead diameter) [15] (Copyright © 2016 Elsevier B.V. All rights reserved)

investigated because NPs can be uptaken by cells and pass through cell membranes. Engineered NPs can provide an enhanced surface-to-volume ratio to load drugs on the surface or within particles and facilitate the delivery of payloads to the targeted cells [17]. Various nano-/micro-particulate drug delivery systems such as polymeric micro-/ nano-formulations (e.g., polymerosoms, micelles), lipid-based particles (e.g., liposomes, niosomes, solid lipid nanoparticle), inorganic nanoparticles (e.g., porous silica, carbon nanotubes, graphene, clays), and metallic nanoparticles (iron oxide, Au nanoparticle) have gained huge interest as engineered drug delivery carriers [9]. Regarding electrospun fiber unique properties, the fibrous structure offers several desirable features suitable for DDSs. However, control of the burst drug release is one of the most important challenges for nanofiber-based drug carriers. Direct electrospinning of the drug/polymer mixed solution results in nanofibers with dispersed drugs in the polymer matrix, which usually display the burst drug release behaviors via the Fickian diffusion effect [18]. Recently, incorporating functional particles within the electrospun fiber matrix serves as emerging topics in electrospinning researches. NP-embedded electrospun fibers exhibit various potential applications in many different fields such as supercapacitors, batteries, solar cells, catalysts, sensors, and biomedicine, since the NP fiber composite properties can be tuned by the polymer and the NP properties as well as NP ratio [19]. The NP incorporation into the electrospun structure mainly aims at improving the fiber performance, e.g., increasing mechanical, thermal, and electrical properties or preserving the NPs from corrosion and/or oxidation.

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Combining the nano-/micro-particulate drug delivery carriers with electrospun fibers enables merging the advantages of both as well as introducing new capabilities to the combined structure (Fig. 8). Prolonged drug release from electrospun fibers can also be achieved by incorporating drug-loaded nano-/microparticles in the electrospun fibers [20]. Electrospun fiber hybridization with other types of particular drug carriers such as polymeric nanoparticles, nanotubes, micelles, microspheres, and liposomes could improve drug-loading efficiency, release pattern, and drug safety. Nano- and microparticulate drug-embedded nanofibers almost resemble the core/shell nanofibers as they protect drug stability from organic solvents during the fiber forming and sustain the period of drug delivery [3]. Although the electrospinning process is convenient to incorporate therapeutic nano-/micro-carriers into the fibers, the parameter adjusting is important because adding the nano-/microparticles into polymer solution could change the viscosity of the solution. Regarding the size of the electrospun polymeric fiber, incorporation of the NPs seems more convenient than microparticles [19]. As mentioned before, studying the release behavior of embedding a single drug species into electrospun fibers demonstrated that most of the time, the release behavior is uncontrollable because considerable amounts of drugs are positioned on the surface of the nanofibers, which could release fast. Therefore, coaxial electrospinning was also proposed as a one-step process for producing core/shell nanofibers containing nano-/microparticles, which showed more prolonged release behavior for drugs embedded in the core part [21]. However, the single-nozzle electrospinning is more favorable, because it is a simple process with easier scaleup in production. For example, Jo et al. [22] developed a facile electrospinning method for producing the core/shell nanofibers composed of an array of different cross-linked polymeric particles loaded by different active agents (Fig. 9). The results demonstrated that by adjusting the physical properties of the colloids in the core, the process provides independent programmed control over the release of each agent. The core/shell electrospun fibers have good potential to embed nanoparticlebased carriers in the core part. The shell could be employed as a barrier to render Nanofiber and nano- and micro-sized devices Polymer Drug loaded carrier Step 1. drug release from carriers Step 2. drug release from nanofiber

Fig. 8 Schematic illustration of the nanofiber with nano- and micro-sized particles as DDS [3] (Copyright © 2013, The Pharmaceutical Society of Korea)

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Fig. 9 Schematic view of producing core–sheath nanofibers containing an array of colloids in the nanofiber core [22] (Copyright © 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)

drug diffusion rate and potentially provide a more sustained-release rate. However, in the dual drug delivery approach, the shell could also be directly loaded with the other drug at the same time. Multiple agents loading in different sites of the core/ shell nanofiber can provide independent control over the release of each agent. Wang and co-workers described the development of a novel controlled drug release system for Rhodamine B and naproxen, two model drugs, consisting of chitosan nanoparticles in PCL electrospun core/shell nanofibers [21]. They showed that the developed DDSs provided distinct release patterns for each drug (Fig. 10). Two main methods could be employed to fabricate NPs/fiber composite structure including direct blending approach and surface immobilization approach. In the direct blending approach, the NPs could be incorporated into the fiber matrix during the fiber formation. The NPs could simply mix with the polymer solution before electrospinning. However, the stability of nanoparticles during the electrospinning process seems a challenging issue [19]. To achieve a uniform distribution of the nanoparticles within the fiber matrix, they should be completely wrapped by the polymer solution. Nonuniform distribution due to the nanoparticle aggregation may result in a wide distribution of fiber diameter [23, 24]. Also, aggregation or sedimentation of the NPs during the process may disturb the fiber formation due to clotting of the nozzle tip. As mentioned, the hybridization of nano-/microparticles and the electrospun fibers can be utilized for multidrug delivery purposes, which is a very beneficial approach in combinatorial therapies [25]. The multiple drugs can be loaded into the NPs and the nanofibers separately using co-electrospinning, or two different drugs

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Polymer solution Naproxen

Taylor Cone

orange color sign

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Accumulated drug release (%)

Chltosan Nanoparticles loaded Rhodamine B Green color sign

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Naproxen Rhodamine B

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Diffusion pathway of Naproxen

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Diffusion pathway of Rhodamine B

Fig. 10 Up: Schematic representation of preparing core/shell nanofibers containing chitosan nanoparticles encapsulating Rhodamine (as core) and naproxen (as shell). Down: Release behavior of two loaded drugs regarding their distinct diffusion pathways [21] (Copyright © 2010 Wiley-Liss, Inc. Published by Elsevier Inc. All rights reserved)

can be loaded into the nanoparticles embedded within the electrospun polymer solution [21, 22]. Apart from the direct blending of nano-/microparticles into the fiber, the drugloaded particles could be immobilized on the surface of fibers. However, the drug delivery pattern of such systems shows faster release from the surface than bulk of the fiber. For example, Son and Yoo investigated the release rate of the micelleincorporated drugs which were introduced on the surface of nanofibers by surfaceimmobilized polymer chains for antiproliferation studies of smooth muscle cells [26]. Among various nano-/microparticles introduced as drug delivery carriers, polymeric ones have been commonly utilized in combination with electrospinning fibers [19]. For example, polymeric nano-/micro-micelles, which are usually synthesized by self-assembling of amphiphilic polymers [27], could be simply incorporated into the fiber during electrospinning. Hu et al. combined the advantages of

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chitosan/polyethylene oxide (PEO) composite nanofibers and methoxypoly (ethylene glycol)-block-poly(L-lactide) (MPEG-b-PLA) micelles and fabricated a novel DDSs by incorporating two different model drugs (Fig. 11), cefradine (hydrophilic) and 5-fluorouracil (5-FU) (hydrophobic), for dual drug delivery [28]. The micelleloaded nanofibrous membrane showed a significant sustained-release profile than the free drug encapsulated into the fiber matrix. Natural polymeric nano-/microparticles were also used to incorporate therapeutic agents into the fibers. Lai et al. developed nanofibrous inter-stacking wound dressing based on collagen (Col) and hyaluronic acid (HA) for staged release of multiple angiogenic factors for diabetic wound healing (Fig. 12). Four angiogenic growth factors (GFs) were either directly embedded in the nanofibers or encapsulated in the gelatin nanoparticles (GNs), subsequently embedded in the fiber matrix by the single-nozzle electrospinning process. The designed particle-in-fiber structure provided a sustained release of growth factors up to 1 month [29]. Sustained local release of bioactive agents, e.g., growth factors, peptides, and proteins, has been utilized for acceleration of tissue regeneration in tissue engineering approaches. Since these factors have a short half-life, they may lose their bioactivity over a short time. Therefore, direct incorporation of bioactive agents in

Fig. 11 Illustration of fabricating procedure used to loaded MPEG-PLA micelles into chitosan/ PEO/nanofibers [28] (Copyright © 2014 Taylor & Francis)

Collagen fiber

EGF mix with collagen PDGF loaded in gelatin nanoparticle

Collagen solution

Fig. 12 Schematic representation of loading four different growth factors into fibrous structure. GFs either directly embedded in HA and Col nanofibers or encapsulated in gelatin nanoparticles and then incorporated into nanofibers [29] (Copyright © 2014 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved)

Grounding wire

0.08 cc/hr

Grounding wire

Syringe pump

12 cm

High voltage power supply Voltage: +12 kV

0.1 cc/hr

8 cm

Collector Speed: 100 rpm

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tissue engineering scaffolds does not always exhibit efficacy in tissue repair in vivo [30]. NP-embedded electrospun nanofiber scaffolds show good potential for controlled multiple deliveries of these kinds of bioactive agents. Li et al. developed a dual-drug-loaded poly(ε-caprolactone)-co-poly(ethylene glycol) (PCE) copolymer nanofiber scaffold for the repair of bone defects in bone tissue engineering. Bone morphogenetic protein 2 (BMP-2) was encapsulated into bovine serum albumin (BSA) nanoparticles to maintain the bioactivity of BMP-2, while dexamethasone (DEX), another commonly used bioactive molecule in bone regeneration, was loaded directly within the fiber matrix [31]. In vitro release profiles of DEX and BMP-2 demonstrated that the dual-drug-loaded nanofibrous scaffold showed a slightly slower than the single-drug-loaded one. Surprisingly, the release profiles of BMP-2 exhibit a slower zero-order-like release pattern, while the DEX release profile displayed a typical burst effect. It was confirmed that BMP-2 protection is afforded by the multi-barrier structure that supported continuous release for more than 35 days. Compared with the single or core/shell electrospun nanofibers [32], the results of this study demonstrated that the nanoparticle-embedded BMP-2-delivering scaffolds performed more effectively due to the dual-drug-loaded system, showing a sequential release pattern. Inorganic NPs such as ceramic and metallic ones are widely studied as drug delivery carriers [33]. Loaded inorganic micro-/nanoparticles could also be incorporated into the electrospun fiber to improve the drug release pattern as well as tune the composite structure characteristics (e.g., mechanical properties). For instance, Chang et al. studied mesoporous silica nanoparticle (MSN)-incorporated poly(lactic-co-glycolic acid) (PLGA) electrospun mat. The composite fibrous mat was loaded by fluorescein (FLU) and Rhodamine B (RHB), as two model drugs, and their release profile was investigated [20]. Results showed that most of the FLUs (freely loaded in the shell part) were released rapidly, while RHB (MSN-loaded) showed a sustained-release behavior (Fig. 13). The nanotube in the fiber composite seems a promising approach, which utilizes the capability of nanotubes and electrospinning technology. Inorganic nanotubes like carbon nanotube (CNT) or halloysite clay serve as a potent nano-container for drug delivery applications [34, 35]. Halloysite clay nanotubes doped into PCL/gelatin (PG) microfibers have been utilized for sustained delivery of metronidazole (MNA) from guided bone regeneration membranes. This nano-embedded microfiber architecture provided an extended release of metronidazole that prevented colonization of bacteria over a period of 3 weeks [36]. Incorporation of MNA into the halloysite nanotube, then adding to the fiber matrix, drastically slowed the rate of release, whereas without halloysite, around 90% of MNA was released from the membrane during 4 days. Among the inorganic nanoparticles, carbon-based nanoparticles with high surface area like CNT or graphene have been successfully utilized to physically immobilize drugs [35, 37]. These kinds of particles show good potential to be embedded into the nanofibers during the electrospinning process. Shao et al. fabricated PCL/CNT composite electrospun nanofibers with green tea polyphenols (GTP) content of 0–10% for potential application in cancer therapy [38]. As depicted in Fig. 14, the in vitro GTP

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Fig. 13 A dual-drug-loaded electrospun composite fiber containing Rhodamine B-loaded MSN in the core and fluorescein in the shell [20] (Copyright © 2012 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved)

release study demonstrated that the cumulative drug release of PCL nanofiber containing GTP-CNTs (NCF) was significantly less than GTP-dispersed PCL nanofibers (CFs). Although NPs embedded into the electrospun fiber can improve the release rate of encapsulated drugs compared to freely fiber-loaded drugs, the fiber matrix can improve some common nano-carrier drug delivery potential. For instance, lipidbased NPs (e.g., liposomes, niosomes, and solid lipid particles) have received widespread attention as carriers of therapeutic agents in regenerative medicine, whereas their applications are hampered by their short half-life, inefficient bio-stability, and poor control of drug release over prolonged periods [39]. Such disadvantages could be significantly improved by their combination with nanofibers through electrospinning. Mickova et al. developed liposome-enriched nanofibers through two different electrospinning methods, blend and coaxial electrospinning, to incorporate liposomes into the nanofibers [40]. This study primarily aimed to investigate the delivery efficiency of horseradish peroxidase (HRP) as a model protein and delivered HRP enzymatic activity protection in samples prepared by blend or coaxial electrospinning with or without liposomes. The results demonstrated that in contrast with blend electrospinning, intact liposomes incorporated into nanofibers by coaxial electrospinning showed the highest potential for drug loading and sustained release. As the aqueous environment inside intact liposomes embedded in the nanofibers was retained during the release period, the fiber/liposome structure significantly enabled preserving HRP-specific activity. Moreover, nanofibrous scaffolds encapsulating recombinant GF (TGF-β) within the liposome were more potent at stimulating MSC proliferation than nanofibers without liposomes. In another study, Li et al. developed a liposomal naproxen (NAP) releasing nanofiber mat for potential application as a wound dressing [41]. NAP-loaded

Fig. 14 GTP release profiles from NFC samples and CF-10 nanofiber incubated in PBS (37
C) (Top); the schematic diagram of GTP controlled release from PCL and PCL/MWCNTs nanofibers (Bottom) [38] (Copyright © 2011 Elsevier B.V. All rights reserved)

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liposomes were embedded in the hyaluronic acid (HA) core, coated by cellulose acetate shell. NAP release behavior showed a specific pattern with a burst drug release at the initial stage and subsequently a sustained drug release for 12 days. Such burst release seems helpful to suppress the infection during the initial stage. In addition, the sustained drug release is necessary for efficiently supporting the wound healing for long periods without changing the dressing.

Drug-Releasing Mechanisms and Rate Control Approaches Controlled therapeutic agent release technology represents one of the advancing areas of biomedical and pharmaceutical sciences. Compared to conventional drug dosage forms, the advanced dosage form with controlled release rate capability offers numerous advantages including improved drug efficiency, reduced drug

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toxic side effects, reduced number of drug administrations required during treatment, and tuned release rate based on the disease condition [42]. In many traditional dosage forms, a sharp increase of drug concentration at potentially toxic levels accrues at the initial step of drug administration, followed by a relatively short period at the therapeutic level, and then drug concentration eventually drops off until re-administration (Fig. 15) [1]. DDSs employ electrospun materials to achieve controlled drug release. Using electrospun fibers for drug delivery applications has some unique advantages including efficient drug loading and encapsulation, diversity of material selection to be compatible with various drugs, simple modulation of the release rate, and simple processability [43].

Controlled Release Mechanisms in Nanofibers Here, specific attention is given to common mechanisms of sustaining the release of drugs loaded in the fiber-based formulations. The release mechanism is simply defined as “the way in which drug molecules are transported or released” [44]. Understanding the release mechanisms is a key step to developing the DDS dosage form. Regardless of the dosage forms, different release mechanisms or ratecontrolling processes in the polymeric DDSs have been reported in the literature, mainly including dissolution of the drug (in combination with diffusion), diffusion

Conventional release

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Time Fig. 15 The drug release pattern of a traditional dosage form such as oral capsules or injection dosing (blue dashed curve) compared to a typical controlled release system (red continuous curve). Gray area indicates therapeutic windows [1] (Copyright © 2015, Springer-Verlag Berlin Heidelberg)

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through water-filled pores, diffusion through the polymer matrix, degradation, erosion, swelling, and osmotic pumping [45]. However, the three main release mechanisms associated with drug release from common dosage forms are diffusion (through water-filled pores or the polymer bulk), degradation/erosion, and osmotic pumping (Fig. 16). Among these mechanisms, the degradation/erosion does not require drug transport within the polymeric matrix, whereas in the other ones, the drug molecule transport is to be released. In diffusion-controlled rate systems (Fig. 17), the drug molecules randomly move out of the device through a difference of chemical potential (concentration gradient) as a driving force. The diffusion can occur within a polymer matrix (monolithic matrix-based DDSs) or across a polymeric membrane, which surrounds a drug reservoir core (reservoir-based DDSs) [1]. In contrast, in degradation-/erosion-controlled release systems, drug reservoirs are encapsulated by dissolvable/degradable polymeric membranes (reservoir DDSs) or dispersed/dissolved within dissolvable/degradable polymeric matrices (monolithic

Fig. 16 Common release mechanisms associated with various DDSs. Diffusion through waterfilled pores (a) and the polymer, (b), osmotic pumping, (c, d) degradation/erosion [45] (Copyright © 2011 Elsevier B.V. All rights reserved)

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matrix DDSs). In such systems, the drug molecules can be released from the reservoir core by dissolution of encapsulating membranes, whereas in matrix degradation-/ erosion-controlled systems, dissolution or degradation of the polymeric matrix drugs results in drug release (Fig. 18). If polymer undergoes a decrease in average molecular weight, the process is termed degradation, whereas if polymer undergoes a decrease in total mass, the process is termed erosion. Thus, usually degradation and erosion can occur at the bulk and surface of the polymers, respectively [46]. Convection, bulk water movement, is another way for transport into the polymeric DDSs through water-filled pores, which is mainly affected by the osmotic pressure-driven force. In osmotically controlled systems, it is necessary to have an osmotic agent (e.g., salts, sugars, PEG, PVA) within a semipermeable membrane reservoir [47]. The semipermeable membrane, which is permeable to water but not the loaded drugs, is a key component in osmosis-based DDSs (Fig. 19). However, this mechanism was rarely reported for the electrospun fiber-based-DDSs.

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Fig. 18 Schematic illustration of controlled release systems based on the matrix and reservoir dissolution mechanism [1] (Copyright © 2015, Springer-Verlag Berlin Heidelberg)

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Single-nozzle electrospun fibers usually serve as monolithic diffusion or degradation-based DDSs. In contrast, coaxial electrospinning typically produces a reservoir-like diffusion-type release system, where the drug molecules are encapsulated in the inner solution core and the outer shell forms the barrier layer surrounding core reservoir [49]. The release profiles of these systems are usually governed by diffusion through the shell membrane relative to the change of concentration gradient. Incorporating some porogen agents, e.g., salts, PEG, dextran, albumin, etc., can modify the diffusivity across the shell barrier [50]. The release profile is sometimes utilized for mechanistic evaluation of the studied dosage forms. Different release profiles due to diffusion, bulk degradation, and surface erosion for a typical uniform distribution of drug molecule in fibers are depicted in Fig. 20 [46]. The shape of the release profile does not often follow the pure diffusion or degradation pattern, where it consists of different phases.

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Since the drug release may proceed via a combination of two or more mechanisms, the release profile consists of different phases (Fig. 21) [45]. The first phase observed in the release profile is usually attributed to the burst release effect, where the non-encapsulated drug molecules on the surface or encapsulated drug molecules near the surface are easily released in a short time. However, sometimes, the observed burst release may be the result of cracks and the disintegration of formulation [51]. The release profile in the second phase often slowly proceeds, during which the drug gradually diffuses through the polymer matrix or through the pores or releases by slow polymer degradation. The last phase is sometimes called the second burst, during which the release profile shows acceleration due to onset of erosion or losing polymer integrity once again [45]. Besides studies that have experimentally worked on fiber-based DDSs, some studies utilized the modeling approach to investigate the release behavior of electrospun fibers with different fiber architecture or release mechanisms [49]. Developing an appropriate model to estimate the structural parameter effect on the release rate could be helpful to pre-adjust the electrospinning process variable or polymer characteristics, particularly when the dominant mechanism is diffusion.

Factors Affecting Drug Release Mechanism and Kinetics Besides the release mechanisms, understanding factors that affect drug release as well as physicochemical processes that influence the release rate is very important in order to be able to modify DDSs for a given application [52]. The properties of the

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Fig. 21 Typical drug release profiles including different phases. □: burst release and a rapid release phase II. ●: triphasic release pattern with a short phase II. : burst release followed by zero-order release. ◊: triphasic release pattern. : biphasic release pattern without the burst release [45] (Copyright © 2011 Elsevier B.V. All rights reserved)

DDSs and the surrounding environment, which dominantly impact the drug release pattern, are listed in Table 1. However, these properties are not independently associated with the drug release rate; thus, understanding their effects on the release behavior could be complex. For instance, the complex interactions of the various parameters that influence drug release from PLGA, one of the most frequently used biodegradable polymers in DDSs, are depicted in Fig. 22. Although the electrospinning process has various interconnected factors, which are simply tunable, polymer- and drug-related parameters must also be taken into account to achieve an optimized design for sustained drug release. Here, the most important factors discussed in the literature are briefly reviewed.

Polymer Composition Selection of a suitable polymer composition as well as altering the physicochemical properties of the selected composition is a simple mean to modify the release kinetics of a drug delivery system. Affecting the rate of water diffusion into the electrospun fiber network is a strategy to control sustained release of drugs. Water diffusion into the fiber is mainly dependent on hydrophilicity/hydrophobicity of polymer-formed fibers [53]. Tuning hydrophilicity/hydrophobicity of synthesized polymers can also be utilized to control water diffusion into the polymeric matrix. Hydrophilic drug molecules can diffuse faster within the hydrophilic polymeric matrix. In degradable-controlled release fibers, wetting properties and solubility of the polymeric matrix mainly impact the drug release rate [54].

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Table 1 Properties of the DDSs and the surrounding environment that influence drug release [52] (Copyright © 2011 Elsevier B.V. All rights reserved) The polymer Molecular weight L/G ratio End-group capping Semi-crystallinity Encapsulated substances The characteristics of the drug Drug load and location The characteristics of additives, such as salts, surfactants, and plasticizing agents The DDS Size Porosity Density Shape

In vitro conditions Temperature Stirring Composition of the release medium pH Osmolality In vivo conditions Sink conditions Enzymes Lipids Immune responses

Crystallinity of polymers is a key structural parameter which will affect the drug releasing rate [55]. Increasing the crystallinity of the polymer matrix retards the rate of water diffusion into these materials. Consequently semi-crystalline polymers are often used for sustained drug release and show slower release rate than the amorphous structure [43]. In addition, cross-linking of polymer chains can also impede water penetration as well as drug diffusivity, which makes them useful materials for some sustainedrelease applications [56]. Glass transition temperature (Tg), the temperature at which the polymer transitions from a hard, glassy material to a soft, rubbery material, serves as a structural property that controls the polymeric chain molecular motion at a given temperature. Consequently, Tg can impact molecular diffusion within the matrix polymeric chains in the release condition. In the high Tg polymers, the drug release rate can be sustained by hindering diffusion through the polymer chains. Some studies have investigated the effect of polymer Tg on drug release rate. In a study by Lyu et al. [57], two polyurethane (PU) fibers with low and high Tg were loaded by hydrophobic dexamethasone at 10 wt.% using uniaxial electrospinning. The results demonstrated that the PU fiber with higher Tg represented a lower drug release rate at the same condition. Interestingly, the intermediate release of dexamethasone was achieved by blending two PUs. Therefore, they could adjust the drug diffusivity using miscible polymer blends, where the drug diffusion coefficients were tuned from 7  1023 to 3  1019 cm2/s.

Drug Properties In addition to the polymer characteristics, properties of the loaded drug molecule as well as polymer/drug interactions effectively influence the drug release behavior.

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Fig. 22 Schematic illustration of the complex interactions of the various parameters that influence drug release from PLGA-based DDSs. Arrows indicate the effects of the properties of the DDSs and the surrounding environment on the processes [52] (Copyright © 2011 Elsevier B.V. All rights reserved)

Drug/polymer compatibility, which refers to the physical interaction between drug molecules and polymer chains, should be considered in designing the stage of fiberbased DDSs [43]. The drug/polymer compatibility will dictate how the drug molecules distribute in the final electrospun fiber matrix. Drug solubility in the polymer/solvent system will predominantly determine the compatibility. The lower solubility of drugs in the polymer solvent would cause some extent of phase separation during the spinning process that result in greater accumulation of the drug on the surface of the fibers, showing higher burst release. For example, paclitaxel is highly soluble in the organic solvent, whereas doxorubicin hydrochloride shows low solubility. Zeng et al. [58] utilized PLLA electrospun fibers to load these two anticancer drugs. They reported a preferable encapsulation of paclitaxel and doxorubicin due to their good compatibility with PLLA and solubility in the chloroform/acetone solvent. However, since doxorubicin hydrochloride has lower solubility in the solvents, it tended to accumulate on or near the surfaces of PLLA fibers. Consequently, an obvious burst release was found for doxorubicin than paclitaxel. Another important characteristic, which affects drug distribution within the finished fibers, is the ionization degree of the incorporated drug. The ionization degree refers to the proportion of neutral molecules that are ionized to charged molecules.

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The conductivity of the solution can be increased by the presence of ionized drug molecules [59], which increase the charge density of the jet resulting in the fibrous morphology. The drugs with higher ionic strength usually tend to be localized to the surface of the electrospun fiber. Particularly, during electrospinning of hydrophobic polymers, the majority of the drug molecules will migrate toward the surface of the nanofibers because the physical interactions between such polymer matrix and the drugs with high ionic strength are limited. Introduction of more hydrophilic parts such as amphiphilic block copolymers to the hydrophobic polymer structure can compensate the interaction and consequently lead to better drug distribution into the fiber matrix. Kim et al. [60] demonstrated that cefoxitin sodium salt, an antibiotic agent, incorporated into the PLGA nanofibrous scaffold showed more than 60% burst release in the first hour of incubation in the release media due to the high ionization degree of the drug and low compatibility with PLGA matrix. However, PLGA blending with the PEG-b-PLA amphiphilic copolymer improved the cefoxitin sodium dispersion into the fiber matrix and decreased the burst release effect. Since the ionized drug mixing with polymer solution provides higher conductivity and the diameter of the electrospun fibers decreases at higher drug-loading levels, the drug release rate increases [60, 61]. In addition, increasing the drug content may impact matrix polymer properties, e.g., interrupting crystallinity, thus resulting in a faster release rate. For example, Zamani and co-worker reported that increasing the amount of metronidazole benzoate in the semi-crystalline PCL nanofibers caused a reduction in the crystallinity and consequently an increase in drug dissolution rate [62].

Fiber Architecture Fibrous nature of fiber-based DDSs serves as the simplest rate-controlling parameter. Considering the unique properties of the fibers such as high specific area and high porosity, the drug release profiles of the fibrous structure differ from other common dosage forms (e.g., film, membrane, slab, sphere, or cylinder), even with the same chemical compositions [63]. Besides the traditional single-nozzle electrospinning technique, multiaxial (e.g., coaxial or triaxial) electrospinning, as a major advancement in electrospinning, resolves the limitations in the traditional drug delivery methods [49]. The unique advantage of multiaxial electrospinning is the ability to simultaneously load various therapeutic agents and modulate the release behavior by altering the fiber properties, e.g., thickness and drug localization (Fig. 23). Apart from the fiber composition, drug-loaded fibers with a multilayered structure offer unique opportunities to control the release profiles, including loading position, density of loaded drugs, and thickness of the fiber [6]. However, among the different fiber architectures, single uniaxial and coaxial fibers are most frequently used to develop fiber-based DDSs. Uniaxial Electrospun Fibers Architecture Uniaxial electrospun fibers represent a relatively simple method to disperse drug molecules within the polymer matrix and achieve rapid and sustained release of the

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Fig. 23 Schematics of drug (medications) loading within the electrospun fibers in various configurations [49] (Copyright © 2016 Elsevier B.V. All rights reserved)

encapsulated drugs. Processing parameters and injected solution properties such as polymer concentration, solvent type, electric field strength, and feeding rate can impact the drug molecules dispersion, which in turn can affect the release kinetics [43]. For example, fiber diameter, which can be simply adjusted by electrospinning processing and solution parameters, can impact the release rate of the drug encapsulated into the polymer fiber [64]. Xie and Buschle-Diller [65] studied tetracycline and chlortetracycline release from PDLLA fibers, prepared with different diameters by adjusting the cosolvent/solvent ratio. Release studies indicated that for tetracycline, smaller fibers (around 200 nm) yielded threefold faster release compared to larger diameter fibers (around 800 nm) after 24 h. Surprisingly, in the case of chlortetracycline, the result demonstrated that the release rate from thicker fibers was faster than smaller ones. These differences may be a result of swelling behavior and drug solubility in the different fiber formulations. For the same polymer/drug systems, it would be expected that for pure diffusional release, the thicker fibers would create a longer path length for the drug to diffuse. However, the drug release mechanisms are often very complex. Sometimes the drug release follows a combinatorial pattern due to different possible mechanisms such as swelling, degradation, and diffusion as well. Carson et al. developed antiviral fibers based on PCL/PLGA compositions safely releasing anti-HIV hydrophilic drugs to sustain the HIV inhibition effect [66]. This study focused on investigating the drug release patterns as a function of PCL/PLGA ratio (100:0, 80:20, 60:40, 40:60, 20:80, and 0:100) and drug molecule properties. The obtained release pattern showed that tenofovir (TFV)-loaded fiber (15 wt%) compositions containing higher PCL content resulted in more significant burst release, whereas fibers with higher PLGA content provided more sustained-release kinetics. The incremental tuning of TFV drug release was achieved by another composition in between. Furthermore, they examined three other highly watersoluble antiretroviral drugs, azidothymidine, maraviroc, and raltegravir, loaded into 80:20, 20:80, and 10:90, 5:95 PCL/PLGA fiber to investigate the effect of structural differences of the drugs, which have a similar molecular weight to TFV but have important physiochemical differences, including ionization state, functional groups, and solubility. Although the differences in the drug solubility or ionization

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state showed some differences in the drug release pattern, fibers with more than 90% PLGA content also sustained the release of all three drugs, where they did not show total drug release by 72 h. Coaxial Electrospun Fiber Architecture More recently, the coaxial electrospinning process to produce a core/shell fiber has been explored as an alternative strategy to provide a sustained drug release pattern from electrospun fiber. As discussed before, the coaxial electrospinning system ran different solutions (at least two) in separate nozzles as well as separate flow rate control to configure the core/shell fiber architecture [49]. Compared with uniaxial electrospinning, the integrity of the final core/shell fiber architecture is a challenging issue, which is influenced by miscibility of the polymers and the solvents used in the core and shell solution. Similar to uniaxial electrospinning, drugs are mixed with polymer solutions, while they are loaded into the polymer solution that forms the inner core. Therefore, the outer shell would be free of drug and serves as a diffusive barrier against the drugs transportation. The presence of such a barrier can help to delay the fast drug diffusion, and consequently burst effect. The shell thickness and core diameter, which are controlled by flow rate of the shell and core polymers, can determine the extent of the drug release delay. Although the core/shell fiber encapsulating drug can provide more prolonged release conditions, the electrospinning process may require more optimization than the uniaxial process to adjust the release rate [7]. An important factor associated with drug release behavior of coaxial fibers is distribution of the drug within the core or shell part, as well as final morphology of these hybrid fibers. Integrity of the core/shell structure and uniformity of fiber diameter and morphology are dependent on solvent volatility, evaporation rate, and solvent miscibility. For the immiscible core and shell solutions, if the shell solvent evaporates faster than the core solvent, it likely forms hollow fiber morphology [67]. Indeed, interfacial compatibility of the core and shell solutions plays a key role in the core/shell integrity, where insufficient compatibility may tend to delaminate at the interface, even in the absence of hollow fiber morphology. For immiscible core and shell solutions, if the evaporation rate of the shell solvent is faster than the core solvent, some portion of the solvent remains in the core part. The entrapped solvent may partially dissolve the shell polymer; consequently, the shell structure gets porous. The resulted porosity also affects the drug diffusion into the shell and increases the release rate compared to the nonporous shell. Therefore, choosing compatible solvents and polymer solutions is an essential step to form integrated coaxial fibers [43]. One of the weaknesses in the integrity of the core/shell architecture will take place when the core and shell part are partially mixed in the interface due to mixing of the core/shell solvents during electrospinning. As a result of such inconvenience, the shell layer often contains an amount of drugs from the core part. For example, Sohrabi et al. [68] reported 30% initial burst release from poly (methyl methacrylate)–nylon6 core/shell fibers encapsulating ampicillin in the core part. They anticipated that such burst release effect may be originated from the accumulation of drug

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molecules at or near the surface of the fibers during coaxial electrospinning due to core/shell mixing in the interface. Tiwari et al. [69] developed PVA–PCL core/shell fibers to deliver metoclopramide hydrochloride to investigate the factors that control the burst effect as well as the rate of subsequent release. Results of this study demonstrated that about 50% of the loaded drug released as the initial burst effect. This is most likely due to the presence of micron or nano-sized pores in the PCL shell, which allows easy penetration of water to the core, facilitating the rapid release of the drug. In coaxial fiber in which drugs are incorporated in the core, predominantly, diffusion through the shell polymer shows a rate-limiting effect [70, 71]. The shell thickness and composition play a key role and should be adjusted to achieve a desirable release rate. In Wang et al. [72], the release rates of dimethyloxalylglycine (DMOG) from PLA and poly (3-hydroxy butyrate) (PHB) core/shell electrospun fiber with various shell thickness were investigated. The DMOG release profile demonstrated that the fibers with PHB core and PLA shell showed a burst release, where about 60% of DMOG was released during 2 h. In contrast, the fibers with PLA core and PHB shell provided a two-phase sustained release over 30 days, where a small amount of DMOG release in the first stage is followed by the zero-release order of a majority of DMOG in the second stage. Comparing samples with various shell thickness demonstrated that the shell thickness did not have any significant effect on the burst release phase, whereas the linear release in the second phase was dependent on the shell thickness. Increasing shell thickness from 120 to 230 nm sustained DMOG release (70%) from 11 to >30 days. Besides the shell thickness, similar to uniaxial fiber, the hydrophobicity of the shell layer strongly impacts the release rate of hydrophilic small molecules. The surface hydrophilic–hydrophobic properties of the coaxial fibers can control the fiber wetting mechanism with which drug release is associated. For example, He et al. [73] investigated the release behavior of metronidazole, loaded in PCL core, gelatin shell fibers. They have changed the hydrophobic of gelatin shell by the cross-linking process, where more cross-linked gelatin resulted in less hydrophilicity, measured by the contact angle test. Interestingly, the cross-linked gelatin shell sustained the metronidazole release for up to 6 days, whereas for an uncross-linked gelatin shell, 80% of the loaded drugs were released after 1 day. However, in addition to increasing hydrophobicity, the degradation behavior of the gelatin shell may affect cumulative release results. Posttreatment and Release Media

The drug release kinetics could also be modified, even after fiber formation by physical or chemical posttreatment techniques such as cross-linking [74]. However, maintaining the chemical and physical stability of the drug during the treatments is a challenging issue. For example, Stephansen et al. [75] showed that release of insulin from fish sarcoplasmic protein fibers was affected by surfactants in the release media. Their study demonstrated that interactions between anionic surfactant (e.g., sodium taurocholate and sodium glycocholate) in the solution and the electrospun protein

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had a concentration-dependent effect on insulin release, so that the fiber stability, porosity, and fiber surface properties were significantly influenced in the presence of the surfactants. However, the addition of cationic and neural surfactants did not have any significant effect on the amount of released insulin.

Smart Active Drug Release Systems For more capabilities of electrospun nanofibers, there are some variant-reported ways to make the drug-loaded nanofibers responsive to its environmental stimuli for releasing. In particular, smart or stimuli-responsive or on-demand delivery polymers could be used as effective carriers with controlled release. Their ability to respond to small changes in the environment such as pH, temperature, light, electric field, magnetic field, or multiple stimuli makes them smart and intelligent nanofibers. Due to the exclusive properties of electrospun nanofibers, these are very promising candidates for drug delivery.

pH-Responsive Nanofibers The pH of the media is a common stimulus for drug release. The human body is regulated by acid–base homeostasis, which keeps the pH of the arterial blood between 7.38 and 7.42. Nevertheless, many tissues or cell compartments have their own distinctive pH environments for normal functioning [76]. In tissues and cellular compartments, the pH varies from acidic to slightly alkaline. For example, the gastrointestinal tract in the stomach is acidic (pH 2), while it varies to more basic in the intestine (pH 5–8). Endosome and lysosome are acidic (pH 4.5–6.5). pH-triggered DDSs have been clinically used, and recently, it has been a lot of research for gene delivery. Materials responding to pH variations mainly undergo two mechanisms: pH influences the protonation/deprotonation balance and pH-dependent hydrolysis kinetics. Protonation/deprotonation is strongly associated with pH variations. Therefore, polymers containing functional groups with the acid dissociation constant pKa close to the physiological/pathophysiological pH can be used as pH-triggered DDSs. Changing of water absorption, swelling ratio, and solubility of the polymers could result changing the pH [42]. Demirci et al. [77] synthesized poly(4-vinylbenzoic acid-co-(ar-vinylbenzyl)trimethylammonium chloride) [poly(VBA-co-VBTAC)] as a pH-responsive polymeric carrier for release study. The ciprofloxacin was chosen as the model drug to encapsulate into poly(VBA-co-VBTAC) by electrospinning. The nanofibers were found to be able to reversibly swell–deswell between a pH of 5.4 and 8.8, due to the protonation/deprotonation of 4-vinylbenzoic acid (VBA), and change the release profile of ciprofloxacin correspondingly. Chemical reactions like hydrolysis are dependent on the pH. Therefore, polymercontaining acid-labile bonds such as hydrazone or acetal groups are sensitive to speed degradation in acidic conditions [42].

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Increment of drug release rate in acidic media have been demonstrated for biodegradable pH-sensitive polymers containing ortho ester groups such as D, L-lactide. Qi et al. [78] electrospun biodegradable acid-labile polymers with the encapsulated paracetamol as a model drug. The total amount of drug released from these polymeric fibers was accelerated after incubation into acid buffer solutions in in vitro release study. For matrix polymers with hydrophilic acid-labile segments, the amount of initial burst release and sustained-release rate were significantly higher. It was indicated that the fibers containing acid-labile segments were stable in neutral buffer solution, but the molecular weight reduction of matrix polymers, the morphological changes, and mass loss of fibers were enhanced in the acidic environment. Yuan et al. [79] constructed an acid-responsive poly-L-lactide (PLLA) nanofiber via doping sodium bicarbonate (NaHCO3) for faster release of ibuprofen which are used to intelligently regulate the anti-inflammatory agent release with the change of acid microenvironment in regions where the pH is reduced below 7.4, leading to a good restrain of inflammation on the early stage and a scarless repair on the later stage. The in vivo study showed that nanofibers containing NaHCO3 resulted in skin scarless healing and prevented excessive inflammation compared to drug-loaded nanofibers without NaHCO3. The air–plasma treatment is also an alternative method for introducing pH-sensitive groups to electrospun nanofibers. The air–plasma treatment of PCL and PLA nanofibers can generate carbonyl, carboxyl, and hydroxyl groups on their surfaces. Jiang et al. [80] proposed that air–plasma-treated PCL or PLA nanofibers coated with polydopamine could be pH-responsive. In vitro release profiles demonstrate that the positively charged molecules are released slowly in neutral and basic environments than in acidic environments within the same incubation time. It was demonstrated that a mussel-inspired protein polydopamine coating, serving as a mediator, can tune the loading and release rate of charged molecules from electrospun PCL nanofibers in solutions with different pH values.

Thermo-responsive Nanofibers Some polymers are responsive to environmental temperature which will affect the drug release rate from its matrix. Polymers which exhibit changes at temperature close to the human body temperature of 37
C are particularly suited for temperatureresponsive drug release. These polymers undergo abrupt changes in solubility, that is, the affinity of water. This is the result of competition between hydrophilic and hydrophobic moieties on the polymer chain. The balance point is called the lower critical solution temperature (LCST), at which the polymer neither favors hydrogen bonding with the polymer nor with water. Thus, it could be stated that temperature can be manipulated and used as a stimulus to modulate the drug release. Among temperature-sensitive polymers, poly (N -isopropylacrylamide) (PNIPAM), PDEA, PVCL, and PMVE have been widely explored as components of the thermo-responsive system because their LCSTs are close to normothermia [76].

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PNIPAM is one of the most studied temperature-sensitive polymers, as it will exhibit thermal reversible volume phase transition at LCST. Due to intermolecular hydrogen bonding between the polymer chains and water molecules, PNIPAM is hydrophilic below the LCST. However, above the LCST, the hydrogen bonding along the PNIPAM chains is replaced by intramolecular hydrogen bonding between C=O and N–H groups as it is illustrated in Fig. 24, resulting in aggregation of the polymer in water. Simultaneously, as the polymer is not in the solution, the water is less ordered. As a result, the volume phase transition between the swelling and deswelling states of the PNIPAM as drug carriers will affect positively or negatively the release of the encapsulated drugs. The former is as at the deswelling state at high temperature, and the drug is expelled out quickly. The latter is explained as the heterogeneous deswelling of the carriers which induced formation of a less permeable and dense surface layer, described as a skin barrier for drug release [42]. The potential toxicity of this polymer has been tested subcutaneously, and results did not show any toxic effects. Azarbayjani et al. [81] used a mixture of polyvinyl alcohol (PVA) and biocompatible thermo- responsive PNIPAM to control the release of levothyroxine [3, 5, 30 , 50 -tetraiodothyronine (T4)]. T4 is a synthetic hormone used for the treatment of hypothyroidism and goiter, and it stimulates lipid metabolism and induces lipolysis. The co-electrospun technique can overcome the barrier of high aqueous solubility of PNIPAM. PVA is a hydrophilic polymer with distinct properties such as high degree of swelling, non-toxicity, and good biocompatibility, and PNIPAM is a thermally reversible hydrogel with a LCST of around 32
C. When heated above 32
C, PNIPAM undergoes a reversible phase transition from hydrophilic to hydrophobic, losing ~90% of its volume, resulting in the change of drug release rates. The PNIPAM nanofibers are soluble in water when the temperature is below LCST; however, it loses its fibrous feature at temperatures above LCST as well. The crosslinked gel of this material swells below this temperature and shrinks above it.

Fig. 24 Hydrogen bonding changes between LCST [42] (Copyright © 2014 WILEYVCH Verlag GmbH & Co. KGaA, Weinheim)

Pr

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The drug release is expected to be increased while the material shrinks. It was claimed that these polymeric nanofiber delivery systems may have potential use in skin formulations containing active ingredients that are meant to be concentrated on the skin surface and can help to increase the retention of the drug on the skin layers. However, due to the high water permeability of hydrophilic PVA, there were serious burst effects at 25
C and 37
C. Tran et al. [82] similarly used a combination of PNIPAM and hydrophobic poly (ε-caprolactone) (PCL) to control the release of ibuprofen (IP) from the nanofiber matrix and utilized it for controlled and on-demand release of the drug without burst effect. They study PCL, PNIPAM, and PNIPAM/PCL composite electrospun nanofibers containing IP. The release rates of IP from PCL nanofibers are not affected between 22 and 34
C, but in PNIPAM nanofibers, the release rate is very sensitive to the change in temperature. It was found that it is five times higher at 22
C compared to 34
C. At a temperature of 22
C, PNIPAM nanofibers showed a burst release while it demonstrates a gradual release at a temperature of 34
C. For a composite PNIPAM/PCL, the release of IP is gradual even at 22
C, although its release rate is faster than at 34
C. The presence of PCL effectively suppressed the burst release of IP at lower temperature, but the rate at 22
C is still 75% faster compared to that at 34
C in this composition (Fig. 25). The release rates of ibuprofen from three types of nanofibers were investigated in a pH of 7.4 deionized water at 22
C and 34
C as shown in Fig. 26. It is seen that in PCL/IP nanofibers, in the first 1 h at 22
C and 34
C, about 15% IP was released, and for both temperatures, there was less than 10% change in delivery rates. About 34% IP was released in 4 h, on average. For PNIPAM/IP nanofibers, 1 μmol of IP was quickly released in the first 1 h at 22
C, and then the rest was released at a much slower rate of 0.05 μmol/h, and it was found that 24% IP was released in 4 h. In comparison, when the temperature was increased to 34
C, IP released mode was more controllable, and it was released in the first 1 h, and only 17% IP was released in 4 h. In the case of PNIPAM/IP/PCL nanofibers at both 22
C and 34
C, the diffusion rates were linear and without burst effects. Compared to the IP release rate at 34
C, the average IP release rate from this composite nanofiber was 75% faster than at 22
C. Such kinds of controllable and switchable delivery systems could easily find many practical applications in both pharmaceutical and medical sciences, but still more studies should be done. The core/shell nanofibers were prepared with PNIPAM as core and hydrophobic ethyl cellulose (EC) as shell by coaxial electrospinning. Analogous medicated fibers were prepared by loading with a model drug ketoprofen (KET). Water contact angle measurements proved that the core–sheath fibers from hydrophilic were transformed into hydrophobic when the temperature reached the lower critical solution temperature. Compared to the blended nanofibers, the coaxial nanofibers have similar regular morphologies in drug sustained release and biocompatibility. However, the coaxial nanofibers show very clear thermo-sensitive drug delivery with sustained release than the blended nanofibers. Thus, the coaxial nanofibers have both thermo-sensitive and sustained-release properties, which could be good thermo-responsive carriers for the sustained release,

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Fig. 25 The schematic diagram to indicate the mechanism of reduced burst effects from PNIPAM/ IP/PCL composite nanofibers [82] (Copyright © 2015, Tran et al.; licensee Springer)

especially for poorly water-soluble drugs, and are potential biocompatible nanofibers in the biomedical field. The system reported was claimed to prevent the undesirable side effects that may sometimes arise from non-localized drug release [83]. Polystyrene (PS), PCL, poly(2-acrylamido-2-methylpropanesulfonic acid), poly (ethylene oxide) (PEO), and PLCL have been co-electrospun with PNIPAM to achieve a thermo-responsive effect. Many of them are considered biocompatible and biodegradable, which makes them excellent candidates for controlled release [76]. Another well-known thermo-sensitive polymer which was approved by US Food and Drug Administration (FDA) and has been applied in drug delivery systems is Pluronic or the PEG–PPG–PEG triblock copolymer. The gelation is considered to respond at elevated temperature by a 3D packing of micelles due to the hydrophilic–hydrophobic balance of the amphiphilic molecule [42]. Hydrogel nanofiber based on multiblock poly(ester urethane)s comprising poly (ethylene glycol) (PEG), poly(propylene glycol) (PPG), and poly(ε-caprolactone)

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b 22°C

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Fig. 26 Ibuprofen release profiles from (a) PNIPAM NFs, (b) PCL NFs, (c) PNIPAM, and PCL composite NFs, all containing 50 mg ibuprofen [82] (Copyright © 2015, Tran et al.; license Springer)

(PCL) segments were fabricated by electrospinning as thermo-responsive material. Under cold conditions, the hydrogel nanofibers absorbed more water and shrunk when exposed to higher temperatures. By changing the environment temperature, the rate of protein release could be controlled. The volume of water trapped reduced twice as low by increasing the temperature. That’s because at higher temperatures, the PPG segment in the copolymer is becoming more hydrophobic. The encapsulated protein, bovine serum albumin (BSA), was released with water, and a higher rate of release was observed at 37
C [84].

Light-Responsive Nanofibers Human bodies are often exposed to light (e.g., sunlight and artificial light). The wavelength of light encountered in daily life ranges from 3000 nm of the infrared heater to 315 nm of ultraviolet light A (UVA) in sunlight. Below 315 nm, the ultraviolet (UV) light is not suitable for therapeutic purposes since the high-energy photons directly start to damage DNA. Light-responsive drug-loaded electrospun

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nanofibers respond faster, avoiding chemical stimulants and by-products. For safety considerations, light-responsive nanofibers should be able to respond to light with a wavelength longer than 315 nm. The photo response of these materials is based on the photoisomerization of their constituent molecules which in response to the absorption of light at two different wavelengths undergo a large conformational change between two states. Typically, trans-cis-isomerization of azobenzene chromophores has been incorporated into different drug delivery systems which give rise to changes of the dipole moments, polarity, or shape of the molecules. Under UV light, these molecules switch from its trans- to cis-form and switch reversely upon exposing to light with a wavelength above 400 nm or heating [42]. Cyclodextrins (CDs) have been extensively studied mainly because of their wellhosting properties. This material is made of glucopyranose units with frustum structure. The CDs have unique combination properties, with their outer surface being hydrophilic; where the hydroxyl groups are located, the inner cavity is hydrophobic to host various hydrophobic molecules and form water-soluble inclusion complexes. Azobenzene can efficiently bind to CD in its trans-isomer but not in cis-configuration. The electrospun nanofibers showed well-controlled release of 5-fluorouracil upon the irradiation of UV light. The drugs were released quickly and reached the maximum of release amount after 30 min of UV irradiation. It was found that the delivery system had a quick and specific response to the UV stimuli and stopped immediately after exposure off, and it demonstrated that a CD drug could be used as photo-triggered effective and controlled release material [85]. The UV has quick attenuation in tissues, so the near-infrared (NIR) light could be an appropriate alternative light source for biological applications, which has low risk of damage to healthy tissues and a deep penetration depth into tissues. Usually, by incorporating photo-sensitive nanostructures which have intense absorptions in the NIR light range, the NIR light-responsive materials were synthesized. The electrospun polymer can be incorporated with light-sensitive additives like gold nanoparticles or nanorods to initiate changes in response to light. Au nanorods were able to strongly absorb near-infrared red light to generate heat, and this triggered a thermal transition in the polymer matrix [86].

Electric Field-Responsive Nanofibers The electrical field can lead to swelling, shrinking, or bending of the polymeric drug carriers, in some cases the process of ionization and trigger redox reactions. Based on the mechanisms, electric field-responsive polymers are mainly classified into the following categories: electroactive polymers, ion-doped conducting polymers, and polymer composites/bends/coatings. Electroactive polymers (e.g., piezoelectric polymers, electrostrictive, and dielectric elastomers) display a change in their size or shape when stimulated by an electric field, which has not been investigated for controlled release by an electric field. Ion transport

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takes place in conducting polymers during the electro- and/or chemical oxidation and reduction. The reversible intercalation motion of the ions results in a volume change of conducting polymers. The polymeric nanofibers incorporated with carbon nanotubes operating in electrolyte can lead to volume changes because of capacitive charging. Both conducting polymer-coated electrospun nanofibers and carbon nanotubeencapsulated electrospun nanofibers have been examined for controlled release under electrical stimulation [76]. Yun [87] prepared the electro-responsive transdermal drug delivery system by electrospinning of poly(vinyl alcohol)/poly(acrylic acid)/ multi-walled carbon nanotube (MWCNTs) nanocomposites. The MWCNT content and oxyfluorination that were used for improving the MWNTs dispersion played important roles in the swelling and drug release characteristics of nanofibers. Due to the variation of ionization of functional groups in the polymer structure depending on the electric voltage applied, swelling and drug release of nanofibers varied sensitively.

Magnetic Field-Responsive Nanofibers Substantial interests in magnetic materials have been devoted to their potential biomedical applications. The magnetic field has unmatchable advantages over other options. Living tissues are magnetically transparent since their compositions are mainly water, which is diamagnetic and negligibly repelled even in a powerful magnetic field, like a clinical magnetic resonance imaging machine, while applied light or heat can only reach up to 4 in. beneath the skin. In addition, the human body is able to tolerate a magnetic field of high strength. Humans can tolerate magnetic fields of up to 7 tesla, while a strong light or heat source usually leads to DNA damage and cell death [76]. Superparamagnetic nanoparticles could be incorporated into nanofibers during electrospinning. Superparamagnetism appears in small ferromagnetic or ferrimagnetic nanoparticles that randomly flip their magnetization direction under the influence of temperatures. This property guarantees SPNs to be aligned with the applied alternating current magnetic field (ACMF) without showing magnetic hysteresis that is not desirable by the magnetic field-responsive drug-loaded electrospun nanofibers. Liu [88] prepared magnetic nanofibers by electrospinning of polyacrylic acid (PAA)/polyvinyl alcohol (PVA) aqueous solutions with homogenously dispersed magnetite Fe3O4 nanoparticles. This nanofiber showed a soft ferromagnetic behavior. Wang [89] added Fe3O4 nanoparticles and indomethacin and aspirin to electrospun dehydroxypropyl methyl cellulose phthalate and CA nanofibers. They showed that the presence of Fe3O4 nanoparticles had no influence on the release profiles, though it was possible to move nanofibers to the target site under the guidance of an external magnetic field.

Multiple Stimuli-Responsive Nanofibers Multi-stimuli-responsive electrospun fiber systems that respond to a combination of two or more signals have been developed to extend the already broad tunability over

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the drug delivery. These combined responses can occur at the same time or in a sequential way. For instance, dual-stimuli-responsive drug-loaded electrospun nanofibers can activate the release of drugs to an infection site whenever the local pH or temperature shifts from the normal value [76]. Chen [90] generated electrospun nanofibers composed of PNIPAAM/PVA blends responsive to both temperature and pH. At room temperature and at a pH below 4, the fibers showed nearly no swelling, whereas at room temperature and at a pH above 4, a high degree of swelling was observed. In contrast, at a pH above 4 and at elevated temperatures (e.g., 70
C), the swelling ratio was reduced from 15- to 2.6-fold. Zhang [91] fabricated pH and temperature dual-responsive poly(methyl methacrylate/N -isopropyl acrylamide/acrylic acid) (P(MMA/NIPAM/AAc)). The fibers showed reversible and positive temperature-controlled release of Rhodamine 610 chloride as a model drug, and it was found that it had faster release above LCST. By decreasing the ratio of the two monomers, NIPAM and MMA, from 7:3 to 5:5, the LCST of the nanofibers was tuned from 38 to 52
C. The acrylic acid (AAc) and PAA molecules adjust their conformation in aqueous solutions because of the protonation/deprotonation equilibrium. These nanofibers shrunk upon both decreased pH and elevated temperature. The shrinkage pH thresholds could be adjusted by changing the ratios of NIAPM, MMA, and AAc. Although the concepts of smart nanofibers for controlled release have been demonstrated in some studies, translation of these smart nanofibers to clinical applications could take a long way to go. Future efforts may be devoted to the development of smart electrospun nanofibers that are responsive to multiple stimuli under normal physiological conditions.

Applications of Nanofibers in Drug Delivery Regarding the unique properties of electrospun fibers as well as controllability of drug-loading capacity and releasing behavior in the fibrous mat, the drugincorporated fibers have a wide range of biomedical applications. Biodegradable fibers are more biocompatible due to elimination of a second surgery to remove the implanted system. The vast spectrum of biodegradable materials from natural polymers (such as collagen, gelatin, zein, silk fibroin, chitosan, cellulose, alginate, etc.) to common synthetic polymers (including poly(D-lactic acid) (PDLA), poly(vinyl alcohol) (PVA), poly(lactic-co-glycolic acid) (PLGA), poly(L-lactide-cocaprolactone) (PLCL), etc.) are widely used in fiber-based drug delivery systems [7]. However, hybrid blends of natural and synthetic polymer are usually desirable. In this section, some common applications of electrospun nanofibers in therapeutic agent delivery have been reviewed.

Anticancer Drug Delivery Systemic administration of anticancer drugs commonly results in the inefficient therapeutic effect due to their poor solubility and instability in body fluid, low

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absorption and concentration in tumor site, and high rate of elimination. Therefore, using advance DDSs such as particulate base carriers for efficient targeted delivery of the anticancer drugs has attracted much attention with the great market acceptance. Considering multifarious parameters including limited drug-loading capacity, undesirable burst release, and targeting difficulties, the utilization of locally administrated drug-loaded nanofiber scaffolds can be suggested as an alternative approach, particularly for chemotherapy in the postoperative area [5]. Drug-loaded nanofibers conveniently cover the tumor site for prolonged release with maximized efficiency and minimized adverse effects. In fact, not only does this system provide high local dosage needless of the large amount of drug, but it also increases the patient’s quality of life because of the reduction in administration repetition and exclusive delivery to the cancerous tissues. Numerous drugs with different water affinities (including doxorubicin hydrochloride and paclitaxel) can be incorporated in nanofibers using blend or coaxial electrospinning for sustained release [92]. There is also a possibility to apply natural anticancer compounds such as green tea polyphenol [38], curcumin [93], etc., in order to decrease the side effect of usual chemical drugs. Moreover, a vast number of studies have represented the high efficacy, solubility, and compatibility of antitumor drugs in polyester-based nanofibers including poly(l-lactic acid) or PLLA and its copolymers [94]. For highly hydrophobic antitumor agents, overcoming poor solubility and instability can be provided by either usage of solubilizer compound in the electrospinning mixture or core–sheath electrospinning techniques to have sustained and sufficient release of the active drug. It is worth mentioning that in the case of the large or inaccessible tumors, which the delivery of drug into the site is hindered, the fibrousbased DDSs may be regarded as imperfect.

Antibiotic Drug Delivery Antibiotic biocides for either killing or inhibiting bacterial growth can play an important role in subsiding infections caused after surgery or by pathological cues. The electrospinning fibers containing antibiotics are considered as suitable systems for in situ and sustained release in the form of wound dressings or other implants. Until now, a significant number of antibiotic agents against Staphylococcus epidermis, Pseudomonas aeruginosa, Listeria innocua, and Escherichia coli such as levofloxacin, gentamicin, ampicillin, tetracycline hydrochloride, ciprofloxacin, silver nanoparticles (AgNPs), etc., have been encapsulated into nanofibers for multifarious applications [5, 7]. Several studies have utilized a mixture of hydrophobic and hydrophilic polymers for controlled release of antibiotic agents. For example, Torres et al. [95] made a coaxial PLA/collagen fiber containing gentamicin. Drug-loaded fibers showed sustained drug delivery instead of burst release (only 33% of gentamicin was released in the first 50 h, which is followed by 85% in 500 h). This result may be originated from the hydrophobic nature of PLA core.

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Among the aforementioned drugs, AgNPs have also attracted much attention in researches. Core/shell nanofibers, consisting of PLLA as a shell and AgNPs blended PVP as core, have been reported by [96] with high effectiveness. Moreover, there are some polymers (mostly polysaccharide based) representing the antimicrobial entity. For example, chitosan, a popular biodegradable polymer, has been applied in tissue engineering scaffolds and wound dressing with high drug-loading capacity as well.

Growth Factor and Protein Delivery Growth factors (GFs) are a group of protein-based biomacromolecules with the regulation capability of biological processes by binding the cell surface receptor and transferring signals between cells and their extracellular matrix (ECM), which pave the way for regulating growth, proliferation, migration, and differentiation of cells, thereby enhancing tissue regeneration. Thus, incorporation of GFs (from natural to recombinant sources) into tissue engineering scaffolds is recommended for fast and effective regeneration. From different properties of GFs affecting their delivery approach, their short half-life in a biological environment and fast rate of inactivation should be considered as the most important factors. Moreover, studies have proven that without both a slow and sequential releasing profile of GFs, the scaffold cannot perform effectively. For this reason, electrospun nanofibers have been employed in the scaffold’s structure for sustained and controlled release of GFs. Several techniques including blend electrospinning, coaxial electrospinning, emulsion electrospinning, and a combination of electrospinning with other conventional techniques were applied for GF incorporation alone in nanofibrous scaffolds (alone or in combination with hydrogels) [9]. In order to create efficient drug loading, and protection of GF molecule while exposing it to cell receptors, surface-modified nanofibrous scaffolds are more appropriate for GF delivery, which is economical and both morphologically and biochemically similar to native tissues. Among the different substances for conjugating GFs in a structure, polysaccharides and sulfated glycosaminoglycans (GAGs) (like heparin) should be regarded as the perfect choice, since not only do they provide a mimicked ECM composition but can also efficiently interact with GF via negatively charged sulfate groups on their backbones [97]. As mentioned before, the preservation of bioactivity of GFs and their controlled release are considered important factors, which can be provided by using protective strategies such as coaxial or emulsion electrospinning [98] and also combination of nanofibers with other existing forms of biomaterials (e.g., hydrogels). Another interesting technique for sustained release with high efficiency is immobilization of GFs onto nanofibers, which expose their active motifs to be targeted to a specific site. Moreover, only a small amount of GF is required to achieve similar

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results to its soluble form in the medium. Notwithstanding, it is so striking that the chemical immobilization of these molecules can damage second or third protein structures as well as their active domain, which is sometimes out of control. Thus, an efficient approach, which is appropriate with such applications, should be regarded.

Nucleic Acid Delivery Nowadays, with the benefit of gene therapy and delivering DNA or interfering RNA and short interference RNA (siRNA), we are able to adjust both cellular responses and signaling pathways by enhancing or preventing a specific protein, which is valuable in regenerative medicine. Commonly, gene delivery systems based on their carriers, can be categorized into two main groups: viral and nonviral delivery systems. Despite the high specific transfection and being needless for multiple dosages, viral delivery systems can transfer a limited size of the gene, while they may cause acute immune response and mutations. Hence, developing novel nonviral gene delivery systems is necessary. Electrospun nanofibers are a novel class of potent materials as a carrier or in the form of scaffold for delivery of nucleic acid base therapeutics because of their unique features such as high surface area and high porosity with interconnected pores. Several studies have investigated DNA-functionalized nanofibrous systems for gene delivery in tissue engineering. An influential factor in this field of research is proper encapsulation and protection of therapeutics, which would not come true via simple blending of DNA with electrospinning solution. Therefore, employing techniques such as incorporation of DNA-loaded particles into the nanofibers, coaxial electrospinning, and surface modification is considered to overcome low transfection efficacy and other problems [3, 9]. It has been represented in different studies that incorporation of therapeutic agents in the core with polymer sheath can extend their releasing period of up to several months. Thus, core/shell structures are necessary for the protection of nucleic acid from degradation and unwanted release as well as making it possible for multiple drug loading [99]. Among different nucleic acid-based therapeutics, siRNAs are in spotlight, particularly in the tissue-repair process prohibited by the secretion of inhibitory factors, or in cancer therapy, where specific genes can enhance tumor growth [100].

Miscellaneous Drug Delivery Drug-loaded nanofibers have also been employed for the delivery of miscellaneous therapeutics including neurotransmitter or receptor blocking, anti-inflammatory, and antiepileptic agents. For example, PLGA nanofibers with aqueous solution of levetiracetam were prepared and underwent solvent evaporation, which creates microcavities as drug reservoirs [101]. It was documented that alteration of the disperse-to-continuous

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phase ratio in electrospinning solution has a direct connection to the size of cavities and consequently both the diffusive length and order of release. This system, intended to be implanted into an adult’s brain for treatment of epilepsy, has shown linear and sustained release for over 21 days. Anti-inflammatory activity of both nanofiber-loaded non-/steroidal drugs like ketoprofen, ibuprofen [102], and DEX have been studied in several studies. For example, [103] incorporated DEX in silk fibroin/poly(ethylene oxide) (PEO) fibers via emulsion electrospinning without any organic solvent usage. In vitro results showed reduced porcine hip artery endothelial cells inflammatory damage. In another research work, a nanofiber patch for effective ocular drug delivery was synthesized by electrospinning poly(vinyl alcohol) (PVA) and poly(caprolactone) (PCL) incorporating timolol maleate and dorzolamide hydrochloride as drugs. Results suggested that the patch has great drug-loading capacity and prolonged duration of action in the intraocular area [104]. In the case of periodontal diseases, in which controlled local administration of antibiotics is crucial, and in viral infection and anti-HIV drugs, where pH-dependent solubility of fibers is determinant, the usage of nanofiber drug delivery systems is feasible [105].

Cell Delivery and Tissue Engineering Appropriate tissue responses to cell delivery treatments are mostly dependent on the type of carrier to transfer cells to the exact location. Thus, numerous materials and scaffolds, such as macroporous hydrogels, sponges, in situ gels, and nanofibers (especially self-assembling peptide nanofibers), have been studied for cellbased therapy. Moreover, these delivery systems should be flexible, smooth, and biodegradable [92]. The electrospun fibers have also been served as potent scaffolds for regeneration of tissues such as bones, cartilage, nerves, blood vessels, cardiac muscles, skins, etc. In addition to high surface-to-volume ratio, which is appreciated for biomolecule delivery, cell attachment, proliferation, and differentiation, their ECM-mimicking properties all along with the tailor-made ability make nanofiber-based scaffolds very interesting in the field of regenerative medicine. The coaxial fibers with controlled release potential of tissue regenerative agents demonstrated better performance than monolithic fibers on tissue engineering. Moreover, biocompatible, biodegradable, and hybrid materials are preferred in this field as well. Numerous studies have utilized the fibrous-based scaffolds with sustained controlled release potential to improve the tissue regeneration process. For instance, McCullen et al. [106] employed tricalcium phosphate (TCP) nanoparticle-loaded coaxial fibers, which provide sustained release of calcium ions at a constant concentration with no burst release, to improve bone tissue regeneration. In a study by Su et al., the bone morphogenetic protein 2 (BMP-2) to the accompaniment of a steroid, dexamethasone (DEX), has been loaded into a poly(l-lactideco-ε-caprolactone) (PLLACL) core/shell scaffold [107]. Controlled release of

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BMP-2 and DEX increased mineralization, and osteoblast marker expression was observed on in vitro and in vivo evaluations. Comprising striated active muscle fibers, cardiac tissue is another appropriate option for electrospun nanofiber-based scaffolds. Prolonged release of the bioactive growth factor can promote the angiogenesis response, which will be potential substrates for cardiac tissue regeneration. For example, Tian et al. [108] developed a dextran-protected VEGF-loaded poly(lactide-co-caprolactone) (PLCL) fiber, which can improve attachment and proliferation of bone marrow-derived mesenchymal stem cells. Another important application of electrospun nanofibers is in nerve guidance conduits (NGC), which have a tubular structure bridging the gap between damaged parts of the nerve. In this prospect, aligned PLGA coaxial nanofibers releasing nerve growth factor (NGF) were investigated by Wang et al. [109]. In another research, dual-gradient NGF-loaded silk fibroin nanofibers were successfully utilized for nerve regeneration applications [110]. Skin tissue engineering scaffolds are one of the most important fields of application of nanofibers due to their positive effects on wound healing from hemostasis to reepithelialization. Various GFs such as EGF, bFGF, VEGF, PDGF, etc., can be incorporated into the fibers in order to stimulate the proliferation and cell migration (keratinocytes, fibroblasts, and endothelials), angiogenesis, and accelerating skin regeneration [111].

Wound Dressing Among common skin products, advanced wound dressings have attracted great attention as they can protect the wound from infection, absorb exudates while moisturizing the wound bed, and accelerate wound healing. Electrospun nanofibers have shown great potential as wound dressing due to their high surface area and porous structure, which can absorb exudates, as well as their ability for incorporation of therapeutic agents (such as drugs and growth factors). Several studies showed the effective role of electrospun wound dressings in hemostasis, antibacterial properties, prevention of scar formation, and skin regeneration. On the other hand, transdermal drug delivery systems (TDDS), which are designed to support the delivery of target agents through the skin into the body, can also be fabricated from electrospun nanofibers. With the benefit of TDDS, researchers are able to administer sensitive drugs, which cannot be transferred orally [112]. However, considering the barrier-like nature of skin, a finite number of drugs limited to low molecular weight (up to a few hundred Daltons) and hydrophobic drugs can effectively pass through the skin. Therefore, the transdermal delivery of large hydrophilic drugs still remains problematic. There are numerous researches that have applied herbal pharmaceutical compounds (e.g., curcumin (from turmeric), aloesin (from aloe vera), thymol (from thyme), etc.) incorporated in electrospun nanofibers in order to develop TDDS and/or active wound dressings [9].

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Naturally Derived Nanofiber Besides electrospinning, which is a versatile method to produce fiber structure, nature also provided some fiber-based features that could be utilized for drug delivery applications. The naturally derived fibers entirely come from natural sources such as animal or plant. Unlike the electrospun fibers, properties of the naturally derived fibers are rarely tailored because they have preformed structure. However, using various modification strategies may help to adjust some properties such as surface functional groups, wettability, and charge. Among the naturally derived fibers, cellulose and silk are two main nanofiber structures which are, respectively, extracted from plant and animal sources and used in drug delivery applications. Self-assembled peptide nanofiber (SAPN) is a new class of fibers, which are inspired from the naturally derived fibers. Recently, the SAPNs are widely used in the biomedical applications. Here, we briefly introduced these naturally derived nanofibers and review their applications in drug delivery systems.

Cellulose Nanofiber Bacterial cellulose (BC) is one such biopolymer that fulfills the criteria for consideration as a drug delivery material. It has already been approved by the FDA as a component of other products used for various clinical indications. There are lots of cellulose sources in nature, and numerous applications are reported for this material especially in the pharmaceutical and biomedical fields. There are many variations of cellulose due to the availability of extremely heterogeneous sources. Cellulose is a polysaccharide with a β-1,4-glycosidic linkage which is formed after condensation polymerization of anhydroglucose units. The cellulose may exist as cellulose nanowhiskers (CNWs) and nanocrystalline cellulose (NCC), with negatively charged form. The purely synthesized BC is unlike the plant cellulose which is produced as lignocellulosic polymer, and its degree of polymerization, crystallinity, high surface area, wet tensile strength, purity, and nanostructured fibers make it different from plant cellulose. The BC shows resembling properties of collagen in the human body with biocompatible flexibility and porosity. That is why the BC has been shown to have been used in several studies to fabricate drug delivery systems [113]. Hydrogen bonding is the main parameter of the existence and properties of BC. It has achieved smaller diameters with more fibrils which lead to even stronger hydrogen bonding. Many ions, including calcium (mineralization), can chemically modify the surfaces of these fine fibers and can also be found beneath the surface [114]. BC has been used in several systems for drug delivery after some sort of physical or chemical modification or else in the form of nanocomposite materials with diverse polymeric matrices. Furthermore, these systems have been mainly tested in in vitro transdermal drug delivery, oral drug delivery, and tissue engineering [115].

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It is obvious that BC has been useful in wound healing for skin substitute products. The properties of this type of wound healing system can be oriented toward transdermal drug delivery, since it avoids external contamination, prevents moisture from evaporating, and maintains intimate contact with the exposed, inflamed, or diseased area which helps localized drug delivery to the target site. The use of BC with antibacterial materials such as silver nanoparticle has been used for fabrication of materials with antibacterial properties [116]. In composite layer of BC membrane with methacrylate, the S-enantiomer of propranolol, an antihypertensive drug, has been released. It applies to transdermal application where primary control of drug release came from the BC. Transdermal delivery systems that can work bilaterally, both to deliver drug and absorb exudates, represent a very exciting opportunity for the application of BC membranes [117]. BC could also be used as electrically stimulated drug delivery device in conjunction with a conducting polymer, such as polyaniline [118]. A series of cellulose hydrogels were made into membranes by the same investigators and examined for permeation of the lipophilic drug. BC can be used to generate multifunctional tissue engineering scaffolds (TES) from polymeric materials. A number of different methods can be employed, each of which depend upon the type of drug molecule and the features of TES [113]. In conclusion, the BC could be used for transdermal applications and as a pharmaceutical excipient in drug delivery systems and tissue engineering scaffolds, and it has the potential to couple tissue engineering with drug delivery for proteins and others.

Silk Nanofiber Silk is a fibrous high molecular weight (200–400 kDa) biopolymer naturally produced by Bombyx mori silkworm or spiders and identified by repetitive hydrophobic–hydrophilic peptide sequences. Representing biocompatibility, biodegradability, thermal stability, excellent mechanical properties (strength and toughness), and mild processing conditions, silk fibers have attracted much attention in the biomedical fields. The raw silk consists of two parallel fibroin fibers with a layer of sericin that held them together on their surfaces. Because of the immunogenicity of the sericin part, removing procedures should be done by degumming clean cocoons in boiling alkaline solution of sodium carbonate [119]. The resulting silk fibers are mostly used as suture or woven biomaterials. The structural composition of the natural fibroin mainly consists of glycine, serine, and alanine repeating sequence, which creates α-helix and β-sheet crystallites with strong disulfide and hydrogen bonds and raises the tensile strength of the fiber up to five times higher than steel but extendable as synthetic rubber [120]. The extracted silk fibroin fiber can be used either without any further processing (as mentioned before) or by regenerating the silk fibroin (solubilizing the degummed silk fiber in hot salt solution and then dialyzing out the salts) and electrospinning the fiber solution in order to make desired morphologies for different applications. However, electrospun fibroin shows weaker mechanical properties than natural fiber which can be attributed to the nonuniform micro-/macro-orientations [121].

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Silk fibroin unique properties lead to unfold numerous application for this fibrous protein, namely, surgical sutures; drug delivery carriers; tissue engineering scaffolds used for regeneration of the skin, corneal, and vascular and neural tissues; as well as load-bearing parts including the tendon, ligament, cartilage, and bone [122]. Studies demonstrated that the silk fibroin fibers as an ideal carrier can be applied for systemic/localized delivery of the variety of therapeutic agents including drugs, growth factors, genes, etc. Depending on the release kinetic pattern, amount of drugs, and the intended application, the drugs may be loaded onto the surface or inside the bulk of fibers. While in bulk loading, drugs are entrapped in the regenerated fibers by blending electrospinning or soaking native silk fibers in drug solution, surface loading includes direct coating or conjugating therapeutic agents onto the fibers. Sustaining the drug release, covalent conjugation of therapeutics such as proteins to the silk fibers can increase both their stability and half-life compared to simple adsorption [122, 123]. For example, [124] modified the silk fibers with sulfonated groups suggesting improved adsorption of fibroblast growth factor 2 (FGF-2) to the substrate. However, washing steps and harsh reaction condition may reduce the activity of drug in this type of loading, effectively. Not only dose bulk loading method prevents destroying therapeutic agent during the fabrication process, it is also more suitable for delivering high doses. On the other hand, studies have demonstrated that native silk can strongly absorb the low molecular weight therapeutics specially with positive charge, through the electrostatic interaction between the drug and the negatively charged side chains of the hydrophilic spacers of its heavy chain, which usually occurs above the isoelectric point of silk (3.5–4.4) [125]. In addition, hydrophobic interactions between silk fibers and hydrophobic drugs represent another drug-loading possibility appropriate for lipophilic anticancer drugs [126]. It is worth mentioning that the crystallinity of fibroin (i.e., amount of β-sheet crystallites) can play crucial role in lowering initial burst release effect; the more β-sheet crystallites in fibroin, the more sustainedrelease pattern will be created. Choi and co-workers used silk fibers to incorporate two antibiotics (doxycycline and ciprofloxacin) via different strategies including the simple loading (by dyeing fibers in various temperature, pH, and duration) and treatment of silk with NaOH solution for varied time leading to chemical and conformational changes [127]. It has been shown that the fibers can inhibit local growth of the Staphylococcus for more than 24 h. As an alternative route of drug loading, composite systems of silk fibers which are typically achieved by integrating multiple silk formats (fibers, yarns, particles, etc.) into the implants, combinations of silk with other natural or synthetic polymers, all together with therapeutic agent incorporation in to the composite structure, indicate promising approach for tissue engineering and controlled drug delivery.

Self-Assembled Peptide Nanofibers (SAPNs) Self-assembling peptides are a category of peptides which undergo autonomous assembling process into ordered nanostructures such as nanofiber, nanorods,

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nanotubes, nanospheres, nanofibrils, and nanotapes [128]. Molecular selfassembly is a spontaneous process in which the molecules are organized into an ordered structure, driven by free-energy. The main driving forces which are involved to start assembling process are van der Waals, electrostatic, hydrogen bonding, and π–π stacking interactions [129]. In this “bottom-up” process, peptides as simple building blocks interact with each other to form large and more complex supramolecular structure. Interestingly, the essence of this technology is to mimic what nature does: for instance, fibrin clot formation as a response of vessel injuries or actin microfiber assembly in various cellular biochemistry processes. The peptides undergo self-assembling process that could be formed from natural or synthetic amino acids. Synthetic polypeptides which are usually derived from natural amino acids are the more preferred building block for biomedical or pharmaceutical applications because they are physicochemically stable, have variety of sequence and shape, and are suitable for large-scale synthesis [129]. A specific type of peptide amphiphiles could be self-assembled into the supramolecular structures under physiological conditions, mainly nanofibers with a cylindrical geometry. PSANs are highly attractive nano-materials for many drug delivery applications. Drugs commonly are loaded during the formation of SAPNS by simple mixing of the drug molecules with the peptides. By modifying the amino acid sequence and adjusting the concentration of the peptide to form SAPNs, the proper drug loading and controlled release pattern then can be successfully achieved. Recently, the use of SAPNs as “smart” drug delivery platforms which can release the therapeutic components in response to environmental cues is very attractive. The amphiphilic peptide with pH-responsive self-assembling nature can be utilized as a pH-responsive drug delivery system that can release the drug content in response to environmental pH changing [130]. Furthermore, the SAPNs could be designed with novel peptide motifs, which are modified to make them stimuliresponsive [131]. Regarding the hydrogel applications in biomedicine, the SAPN hydrogels represent a promising alternative to current drug delivery approaches due to their encapsulation capability, water solubility, and biocompatibility [132]. Several studies have investigated SAPN hydrogels which were chemically conjugated with drugs, particularly anticancer drugs for chemotherapy applications [133, 134]. Based on the literature, SAPNs have been used to deliver the wide range of drugs and biomolecules such as anticancer agents, growth factors, and nucleic acids. For example, Ashwanikumar et al. developed a SAPN sustained-release DDS based on the RADA-F6 peptide with pH-responsive self-assembling nature to deliver 5-fluorouracil (5-FU) as an anticancer drug at basic pH [135]. Wang et al. developed a RGD peptide-based SAPN hydrogel for sustained drug delivery to the rabbit-eye posterior segment that was degraded gradually and exhibited great biocompatibility [136]. SAPNs are utilized to encapsulate the hydrophobic chemotherapy agent, e.g., camptothecin, to improve their solubility [137]. Studies also have reported the potential of SAPNs as the tissue engineering scaffold to deliver growth factors or bioactive biomolecules [138].

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Future Trends Undoubtedly, drug delivery methods have experienced rapid transition to advanced systems, increasing the efficacy of therapeutic agents by controlling the site, time, and rate of release in the body and alleviating drug side effects by sustaining drug concentration in blood plasma. Employing porous micro-/nanostructured devices have received much attraction in biomedical applications, particularly tissue engineering and drug delivery. The reasons behind this fact include high surface area-tovolume ratio (enhances drug dissolution rate), ability of surface functionalization, adjusting surface morphology, and structural similarity to the ECM. Considering its simplicity, cost-effectiveness, potential to scale up, and ability to spin a broad range of polymers from natural to synthetic and copolymers, electrospinning is one of the useful methods for micro-/nanofabrication in biomedical applications. Using this method, scientists are able to direct encapsulation of both hydrophobic and hydrophilic drugs (including anticancer drugs, antibiotics, etc.) and biomolecules such as proteins and nucleic acids into electrospun fibers. Compared with other approaches, electrospinning affords a facilitated drug release system (due to high surface area and porous structure of fibers) and the ability of controlling the distribution state of drugs within fibers while decreasing the required dosage of the drug, leading to a less systemic absorption. Moreover, due to the high porosity of fibers, degradation products will not accumulate in the device and electrospun membranes can be tailored into any size and shape. Despite being excellent drug carriers, electrospun fibers still have some limitations, which should be addressed. Initial burst release of the drug from fibers, which can occur in directly mixing drugs into the polymer solution, is considered a main problem due to the aggregation of drug molecules near the surface of nanofibers. Using super-hydrophobic polymers (i.e., doping electrospun fibers with hydrophobic agents) is suggested as an alternative approach to slow the burst release as well as prolong the sustained release of drugs. Although the sustained-release behavior has been usually achieved from uniaxial fibers with low loadings and hydrophobic molecules, optimization of the discussed designing parameters will increase the possibility of achieving sustained-release behavior for both hydrophilic and hydrophobic small molecule drugs at high loadings. Therefore, a deep understanding of the drug/polymer/solvent interactions at all stages of the electrospinning process is required to analyze the drug release behavior. Finally, fiber-based DDSs seem very promising combinatorial technology for biomedical applications.

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Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Medical Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Oral/Oromucosal Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Transdermal and Topical Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Intravenous Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ophthalmic Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Vaginal Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Wound Healing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Targeted Drug Delivery Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Smart Nanofiber-Based Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Coating on Implants and Stents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gene Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Theranostic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Photodynamic Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Veterinary Drug Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abstract

Nanofibers are fibers having dimensions in the nanometric range of few tens to 1000 nm. Advantages of nanofibers include their high surface-area-to-volume ratio resulting in enhanced drug solubility, high porosity, superior mechanical strength, versatile surface functionalization, and similarity to the extracellular matrix which promotes their use as wound dressings. Nanofibers have demonstrated their

P. Prabhu (*) Shobhaben Pratapbhai Patel School of Pharmacy and Technology Management, SVKM’s NMIMS, Mumbai, India e-mail: [email protected]; [email protected] © Springer Nature Switzerland AG 2019 A. Barhoum et al. (eds.), Handbook of Nanofibers, https://doi.org/10.1007/978-3-319-53655-2_48

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biomedical prowess in the fields of diagnosis as well as therapy. Nanofibers have been explored as ultrasensitive biosensors for point-of-care diagnosis of cancer, detection of circulating tumor cells in cancer patients, diagnosis of malaria, and detection of urea, glucose, cholesterol, bacteria, etc. Their huge surface area offers large number of binding sites thus endowing them with the capability for ultrasensitive detection. Nanofibers have also exhibited promising potential as drug delivery carriers and as wound dressings. Smart nanofibers which release the drug in response to stimuli such as pH, temperature, magnetic field, ultrasound waves, enzyme, and light have been studied to cater to the need for on-demand drug release systems. Nanofibers for photodynamic therapy have also been reported. Multifunctional nanofibers have also been developed for combined hyperthermia and therapy. Nanofibers may be fabricated using natural or synthetic polymers and using synthetic drugs as well as herbal molecules and extracts. Drug release from nanofibers can be modified based on the choice of polymer and the method of drug loading. Nanofibers have been developed for administration through various routes such as oral, oromucosal, periodontal, transdermal, intravenous, ophthalmic, vaginal, etc. The chapter showcases the potential applications of nanofibers in medical diagnosis and therapy.

Keywords

Nanofibers · Diagnosis · Therapy · Wound healing · Theranostic · Gene · Electrospinning

Introduction Nanofibers are defined as fibers having dimensions in the range of few tens to 1000 nm [1]. Their huge surface area and porous architecture facilitate excellent encapsulation of therapeutic agents [2]. Techniques employed for nanofiber fabrication include electrospinning, phase separation, self-assembly, template synthesis, and mechanical drawing [3]. Electrospinning is a quick and simple method [4]. It involves application of a high voltage to a polymer solution in a syringe [5]. It offers better control over morphology of the nanofibers [6]. Phase separation is a simple method and shows good batch-to-batch reproducibility [7]. It involves quenching of a single-phase polymer solution resulting in formation of a solvent-rich phase and a polymer-rich phase [5]. Self-assembly technique is more complicated than electrospinning and results in nanofibers of a smaller diameter [7]. It is a bottom-up method which involves extemporaneous organization of molecules into structurally welldefined stable networks via predetermined non-covalent interactions such as hydrogen bonding, Van der Waals forces, electrostatic interactions, and hydrophobic bonding [8]. Template synthesis involves utilization of nanoporous metal oxide membranes which serve as a template for generation of nanofibers. The process involves passage of a polymeric solution through the membrane into a non-solvent bath to yield nanofibers [7]. Mechanical drawing technique requires minimum

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equipment but suffers from poor productivity and is a discontinuous process. It involves contact between a sharp tip of a glass rod or a micropipette and a polymer solution droplet followed by slow withdrawal of glass rod/micropipette to generate nanofibers [7]. Detailed discussion of the methods is beyond the scope of the chapter. Polymeric nanofibers may be fabricated using natural or synthetic polymers. Natural polymers show lower immunogenicity than their synthetic counterparts, and some of them also possess inherent antibacterial activity. Synthetic polymers show higher degree of flexibility with respect to synthesis and modification but suffer from less cell affinity. Composite nanofibers containing a blend of natural and synthetic polymers have been fabricated to combine the properties of mechanical strength, cell surface affinity, and biomimetic nature [9]. Examples of natural polymers employed in fabrication of nanofibers include collagen, gelatin, chitosan, silk fibroin, hyaluronic acid (HA), etc. [10]. Examples of synthetic polymers employed in fabrication of nanofibers include polyglycolide (PGA), poly ε-caprolactone (PCL), poly(lactide-co-glycolide) (PLGA), and polylactide (PLA) [10]. The chapter summarizes a myriad of applications of nanofibers in medical diagnosis and therapy.

Medical Diagnosis Diagnosis plays a very important role in the management of any disease condition. Early and accurate diagnosis is imperative for proper therapy of any disease condition [11]. As per the World Health Organization, an in vitro diagnostic tool should be sensitive, specific, provide quick diagnosis, stable, user-friendly, reproducible, robust, portable, and cost-effective. The need of the hour is rapid point-of-care diagnostic tools for medical diagnosis [12]. Nanofibers are reported to offer greater number of binding regions resulting in better sensitivity and lower limit of detection [13]. The three-dimensional architecture of electrospun nanofibers results in huge surface area, increased enzyme loading, and reduced impediment to mass transfer [14]. Composite nanofibers have also been extensively explored owing to the synergistic effects observed when metal oxide nanoparticles/nanofibers are used in conjunction with polymer nanofibers. Zinc oxide, copper oxide, cobalt oxide, nickel oxide, and manganese oxide are few examples of one-dimensional nanostructured metal oxides which offer high electron mobility, huge surface area, chemical stability, electrochemical activity, and biocompatibility desirable for sensors [15]. This section encompasses various nanofibers which have been developed as diagnostic tools for detection of different substances like glucose, cholesterol, urea, and alkaline phosphatase and diagnosis of infections such as malaria, Candida albicans infection, etc. They have also been employed for detection of circulating tumor cells (CTCs) which are pivotal markers of metastatic cancer. There is an urgent need to develop cost-effective sensors for targeted detection of CTCs with adequate selectivity and efficiency [16]. Gomathi et al. developed composites of chitosan nanofibers and gold nanoparticles immobilized with cholesterol oxidase for the detection of cholesterol.

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Chitosan nanofibers were coated onto indium-doped tin oxide (ITO)-coated glass plate followed by electrochemical deposition of gold nanoparticles and immobilization with cholesterol oxidase. The developed biosensor showed a broad linear response to cholesterol in the range of 1–45 μM, excellent sensitivity, and good long-term stability. The nanofibers offered huge surface area for enhanced enzyme loading. The biosensor showed a very short response time of less than 5 s and was able to provide reproducible cholesterol detection with good selectivity [17]. Nanostructured titania (TiO2) has been employed in the fabrication of biosensors owing to its homogeneous structure, huge specific surface area, chemical stability, and good biocompatibility. The low isoelectric point of TiO2 hinders the direct attachment of biological such as antibodies, enzymes, etc. However, treatment with oxygen plasma can introduce functional groups such as –COOH and –CHO on the surface of TiO2 which will help in covalent binding to –NH2 group of the enzyme. Mondal et al. have synthesized mesoporous TiO2 nanofibers grown on ITO electrode by electrospinning technique and rendered their surface hydrophilic via introduction of –COOH and –OH groups by oxygen plasma treatment. Cholesterol oxidase and cholesterol esterase were immobilized onto the surface of modified TiO2 nanofibers via covalent interactions. The developed sensor demonstrated quick detection of esterified cholesterol with excellent sensitivity. It also exhibited excellent reproducibility and precision for detection of esterified cholesterol [13]. Sapountzi et al. developed polyvinyl alcohol (PVA)/polyethyleneimine (PEI) nanofibers at the surface of gold electrodes by electrospinning technique for enzyme-based detection of glucose. Glucose oxidase enzyme was immobilized onto the nanofibers. The nanofibers were coated with gold nanoparticles to enhance conductivity. Combination of metal nanoparticles and electrospun nanofibers is reported to enhance mechanical strength, thermal resistance, and optical and electrical properties. The nanosensor showed good selectivity for glucose and good operational and storage stability and provided a very low limit of detection for glucose [18]. Estimation of blood glucose levels is imperative in the diagnosis and therapy of diabetes mellitus [19]. Enzymatic sensors utilized for the detection of glucose provide quick, sensitive, and specific detection of glucose. However, enzymatic activity may be influenced by environmental features such as temperature, pH, humidity, etc. [15]. Electrochemical sensors based on glucose oxidase enzyme which are commonly employed for the purpose suffer from disadvantages such as low stability and reproducibility and are expensive [19]. Zhang et al. have developed a nonenzymatic sensor based on attachment of cupric oxide nanoparticles on carbon nanofibers for detection of glucose. Carbon nanofibers are inexpensive to produce on a large scale, amenable to surface functionalization, and possess better wettability as compared to carbon nanotubes and are therefore preferred for development of biosensors. The sensor showed excellent sensitivity and a low limit of detection. The sensor was able to analyze glucose with acceptable accuracy and precision. It also showed successful application to detection of glucose in human serum [19]. Ding et al. developed cobaltosic oxide (Co3O4)-polyvinyl pyrrolidone (PVP) nanofibers

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using electrospinning and calcination for nonenzymatic detection of glucose. Co3O4 fibers show excellent catalytic activity. The biosensor showed quick response time of less than 7 s, great sensitivity, selectivity, reproducibility, and low limit of detection. The sensor was able to estimate glucose levels in human serum samples with similar efficacy as that of the commercial glucometer [20]. Continuous monitoring of glucose would be beneficial to assess fluctuation in blood glucose levels. Implantable nanosensors are preferred for the purpose since their small size would allow minimally invasive implantation. Balaconis et al. developed nanofibers from plasticized PCL and loaded them with alizarin and boronic acid derivatives for continuous physiological monitoring of glucose. Alizarin contains a diol group that binds to boronic acids. Alizarin bound to boronic acid exhibits strong fluorescence. However, binding of glucose to boronic acid displaces alizarin from the boronic acid and quenches its fluorescence. The extent of fluorescence quenching depends on the concentration of glucose in the sample. The nanofibrous sensors when implanted subdermally showed greater residence time than spherical nanosensors which showed early diffusion within 3 h [21]. Su et al. developed a biosensor based on a combination of graphene oxides and polymer nanofibers for glucose sensing. The group co-electrospun chitosan, PVA, graphene oxide, and glucose oxidase on a platinum electrode. Graphene is suitable for biosensor development owing to its huge surface area, good electrical conductivity, high mechanical strength, amenability to functionalization, and biocompatibility. Graphene oxides may also help to preclude leaching of enzymes via binding through electrostatic interactions with the latter. The nanosensor showed good sensitivity for glucose, low limit of detection, and broad linearity range. The electrode also possessed good stability, enabled reproducible glucose detection, and was able to estimate glucose in the presence of interfering compounds such as uric acid and ascorbic acid. It was successfully utilized for detection of glucose in human serum samples [14]. Huang et al. fabricated manganese oxide (Mn2O3) and silver nanofibers using electrospinning and calcination and immobilized glucose oxidase onto them for glucose sensing. Manganese oxide and silver were utilized owing to their good catalytic and electrical characteristics which would facilitate electron transfer. The developed nanosensor exhibited high sensitivity, good selectivity, low limit of detection, and also enabled fast detection of glucose. It was also able to estimate glucose levels without any interference from uric acid and ascorbic acid [22]. Wu and Yin developed a nanofibrous sensor containing chitosan, PVA, and Prussian blue for detection of glucose. Prussian blue film was electrodeposited on ITO-coated glass plate followed by electrospinning of chitosan-PVA nanofibers and immobilization of glucose oxidase onto the system. Glucose oxidase catalyzed the oxidation of glucose to generate hydrogen peroxide. The sensor was based on the estimation of hydrogen peroxide which was oxidized by Prussian blue. Chitosan and PVA were used since they are biocompatible, biodegradable, and able to form long, straight, and aligned nanofibers. Chitosan-PVA nanofibers also retained stability of Prussian blue in alkaline conditions. The developed nanobiosensor showed good reproducibility and long-term stability and was able to estimate glucose without any interference from uric acid and ascorbic acid [23].

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Human epidermal growth factor (hEGF) receptor is an important biomarker expressed in around 33% of breast cancers. Zinc oxide nanofibers offer great promise as biological sensors owing to their high surface-area-to-volume ratio, eco-friendly nature, biocompatibility, good electron transfer, and chemical stability. Mesoporous zinc oxide nanofibers were fabricated via electrospinning technique by Ali et al. Zinc oxide nanofibers were electrophoretically deposited on ITO glass, treated with oxygen plasma, and conjugated with antibody for hEGF receptor via covalent interactions. The biosensor showed good selectivity, reproducibility, and femtomolar sensitivity. The sensor demonstrated sensitivity which was three orders of magnitude higher as compared to the enzyme-linked immunosorbent assay (ELISA) for breast cancer biomarker detection [24]. Malaria is a serious problem particularly in developing countries. Diagnosis of malaria is commonly done using microscopy which is unable to detect low blood levels of parasite. Other newer methods developed include ELISA, flow cytometry, mass spectrophotometry, polymerase chain reaction, etc. which are expensive. Hence, Brince Paul et al. developed a low-cost ultrasensitive nanosensor for diagnosis of malaria. The group fabricated copper-doped zinc oxide nanofibers by electrospinning technique and functionalized them with mercaptopropylphosphonic acid (MPA). Functionalization with MPA was done to facilitate antibody immobilization. Monoclonal antibody against histidine-rich protein-2 was immobilized. Histidine-rich protein-2 is released by Plasmodium falciparum into the blood. Copper doping helped to enhance the conductivity and preconcentrate the target analyte on the surface of nanofibers owing to the electric field generated at the copper oxide/zinc oxide interface. The high isoelectric point of zinc oxide (9.5) facilitates attraction and binding of the target analyte molecules via electrostatic interactions. The developed nanobiosensor was ultrasensitive with a limit of detection in attogram/ml and showed good selectivity for histidine-rich protein-2 [25]. Gikunoo et al. developed a nanosensor containing carbon nanofibers which were grown on glass microbaloons. Polyclonal antibody against Plasmodium falciparum histidine-rich protein-2 was immobilized onto the nanofibrous matrix. The amine functional groups of the antibody underwent covalent binding with carboxylated carbon nanofibers. The nanosensor enabled detection of extremely low levels (0.025 ng/ml) of Plasmodium falciparum histidine-rich protein-2 by a visual signal within 1 min. The high aspect ratio of carbon nanofibers resulted in a very low limit of detection. The sensor was also able to selectively capture both Plasmodium falciparum histidine-rich protein-2 and Plasmodium vivax merozoite surface protein-1 at two different capture areas within the same nanofibrous sensor [26]. Zhao et al. developed a ratiometric fluorescent nanosensor for the detection of alkaline phosphatase (ALP) in serum. Fluorescein was immobilized on to polyethylene terephthalate fibers via covalent interactions, and bisquaternary ammonium salt of tetraphenylethene (TPE-2N+) was electrostatically adsorbed. When there was no ALP, complex formation occurred between phosphorylated fluorescein and TPE-2N+ leading to fluorescence of TPE (blue color). However, in the presence of ALP, hydrolysis of phosphoesters resulted in gradual removal of TPE-2N+ and

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restoration of fluorescence of fluorescein (green color). The nanosensor showed detection of ALP without any interference from serum components. This nanosensor can be integrated into a self-test device to yield a simple ultrasensitive portable sensor for detection of ALP in serum [27]. Candida albicans infections are known to result in deaths in cancer patients. Currently available diagnostic modalities for the infection suffer from poor sensitivity and are time-consuming. Wang et al. developed viral nanofibers for quick ultrasensitive detection of serum antibody biomarker in cancer patients. Two functional peptides were genetically displayed on a single filamentous fd phage. One peptide (PTYSLVPRLATQPFK) served to bind to magnetic nanoparticles (Fe3O4) and the other to recognize the biomarker (antisecreted aspartyl proteinase 2IgG antibody) of Candida infection present in serum of cancer patients. The fd phage is a virus similar to nanofibers containing coat proteins enclosing a ssDNA genome that encodes the proteins including major proteins surrounding the wall and minor proteins at the tip. Insertion of DNA encoding peptides into the genes of the coated proteins results in the peptides getting displayed either at the tip via fusion with the minor coat protein or around the walls via fusion with the major coat protein. The phage contained magnetic nanoparticle binding peptide along the side walls and the peptide binding to serum antibody at the tip. The phage bound form of biomarker is magnetically enriched and detected by ELISA. The method showed a drastic decrease in the mean detection time (6 h) as compared to clinically used blood culture method (1 week) and showed a detection limit of 1.1 pg/ml [28]. Increased levels of urea are indicative of kidney and liver dysfunction. Sawicka et al. developed nanocomposite fibers containing PVP and urease enzyme by electrospinning technique for detection of urea. The advantages of the developed system included lesser response time and sensitivity [29]. Xu et al. developed a microchip embedded with HA-modified electrospun PLGA nanofibers for capture of CTC (Fig. 1). HA receptor CD44 is reportedly upregulated in breast cancer, epithelial ovarian cancer, leukemia, lung cancer, and head and neck squamous cell carcinoma. HA functionalization thus enabled the nanosensor to achieve targeted capture of CTC. HA being one of the principal constituents of the tumor extracellular matrix, HA-functionalized nanofibers not only promote in situ Fig. 1 Schematic representation of HA-modified electrospun PLGA nanofibers for capture of CTC (Modified from [16])

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culture of captured CTC but also allow their subsequent visualization using an optical microscope. HA was covalently bound to PLGA through bond formation between the carboxylic acid group and amino groups using PEI as a linker. The developed PLGA-PEI-HA nanofibers were able to capture HeLa cancer cells under flowing conditions even at a very low density of 20 cells per ml. The nanofibers demonstrated a higher capture of HeLa cells (high CD44 expression) as compared to L929 cells (low CD44 expression). The nanosensor also enabled growth of the captured cancer cells when perfused with cell culture medium. This feature would facilitate personalized drug screening by studying drug resistance of the captured cancer cells which will be a boon for patients with cancer metastasis [16]. Solid tumors exhibit high heterogeneity in oxygen distribution and show lower levels of oxygen as compared to their normal counterparts. Cancer cells exhibit lower degree of sensitivity to anticancer drugs and radiotherapy at extremely low levels of oxygen. Hence, there is a need to develop sensors for real-time continuous monitoring of cellular oxygen levels to facilitate better understanding of cancer biology in order to decide the best mode of therapy. Conventional Clark electrodes which have been the cornerstone of oxygen sensing have certain shortcomings such as their consumption of oxygen during measurement, invasive nature, and difficulty to miniaturize. Hence, oxygen sensors which show quenching of luminescence on exposure to molecular oxygen are preferred owing to their noninvasive nature, sensitivity, costeffectiveness, ability to be miniaturized, and no consumption of oxygen during measurement. Xue et al. developed polydimethylsiloxane-PCL core-shell nanofibers loaded with oxygen responsive probes by electrospinning technique for sensing of both gaseous and dissolved oxygen. Polydimethylsiloxane offers very high oxygen permeability and chemical stability. The nanofibers were fabricated with a PCL shell surrounding them which helped to maintain the morphology of fibers during slow curing and also provided biocompatibility. Tris(4,7-diphenyl-1,10-phenanthroline)ruthenium(II) (Ru(dpp)) and platinum octaethylporphyrin (PtOEP) were utilized as oxygen sensors. The porous nature of the nanofibers coupled with the enhanced oxygen permeability resulted in faster response (99 >99 >99 – 99.99 100 50.5

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1.5 0.23

–

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Commercial Millipore RA 1.2 membrane Commercial Millipore GS0.22 membrane [15]

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GSWP commercial membrane, Millipore [13]

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PAN/poly(VEVIMBr) [15]

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PAN/PET/cellulose [14]

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7

0.5 μm 0.2 μm

E. coli bacteria MS2 virus E. coli bacteria MS2 virus Polybead carboxylate microspheres 1 μm 0.5 μm 0.2 μm 1 μm 84

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98 90

99 98 90 99

99.9 99.99 99.9999 99.99

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resulting in very low rejection, the ENMs are commonly used for UF in the form of composite membranes (three or two layered) or as a coating layer in the membrane matrix [2]. In this case, the high porosity (>80%) of the ENMs compared to conventional membranes (5–35% porosity) provides increased water permeability, and the high surface-area-to-volume ratio offers increased addition of surface functionalities via modification [2, 6]. The UF membranes are also used to filter the microorganisms such as bacteria or virus due to their smaller pore sizes [16, 17]. ENMs have been widely used as thin-film composite (TFC) membranes. The UF TFC membrane consists of an electrospun nanofibrous (EN) mid-layer, a nonwoven microfibrous substrate layer, and a coated or interfacially polymerized barrier layer. Highly porous EN mid-layers offer higher permeability compared to the asymmetric porous phase and offer enhanced filtration efficiency for the TFC membranes [18]. Such three-tier composite membranes containing a nonporous hydrophilic nanocomposite coating top layer, an EN substrate mid-layer, and a conventional nonwoven microfibrous support were prepared [19]. The EN substrate was fabricated using cross-linked polyvinyl alcohol (PVA) scaffold with a nanofiber diameter of 130–300 nm and 83% porosity. As the hydrophilic barrier top layer, both crosslinked PVA hydrogel incorporated with surface-oxidized multi-walled carbon nanotubes (MWNTs) and PEBAX ® 1074 (a polyamide polyethylene glycol copolymer) were employed. This TFC membrane was employed to filter a mixture of soybean oil and polysiloxane polyethylene glycol emulsifier and gave high flux (up to 330 L/m2/h at the feed pressure of 6.9 bar) and 99.8% total organic solute rejection rate. The permeate flux and rejection rate were strongly dependent on the cross-linking density of the PVA barrier layer controlled by the amount of glutaraldehyde as the crosslinker due to the swelling of PVA layer by hydrophilic macromolecules that provide additional space for the water transport during ultrafiltration. Moreover, when oxidized MWNTs (10 wt% polymer) were incorporated to the barrier layer, the permeate flux improved by about five times for cross-linked PVA with 99.8% rejection and three times for PEBAX ®. The TFC NMs with MWNT incorporated barrier layer gave about ten times more flux than the UF TFC membrane. Another new type of high flux EN TFC membrane was prepared based on EN PAN scaffold coated by a thin, hydrophilic, water-resistant, but water-permeable chitosan top layer [20]. By varying the nanofiber diameter from 100 nm to a few micrometers via electrospinning, the interconnected porosity of the nonwoven nanofibers can be partially controlled. The hybrid membrane containing PAN nanofibrous scaffold (70% porosity and 124–720 nm nanofiber diameter) coated with 1 μm chitosan layer exhibited an order magnitude higher flux rate than that of NF commercial membranes in 24-h operation maintaining the same rejection efficiency (>99.9%) for oily wastewater filtration. Similarly, another high flux EN TFC membrane for UF applications based on PAN electrospun scaffold is coupled with a thin cross-linked PVA layer [21]. With 85% porosity of PAN nanofiber layer and 0.5 μm thick PVA coating, the composite membrane exhibited 12 times higher flux than that of conventional PAN UF membranes with >99.5% rejection for oil/water mixture (1500 ppm in water) over 190 h at a pressure range up to 9 bar. However, the antifouling properties of these three-tier membranes and the leaching of components

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or disintegration of the membranes were not investigated to show its long-term operation and stability. Also, the ENMs offer high flux (above threshold flux) compared to conventional UF membranes that may intensify the chance of fouling that increases the operational cost [22]. However, the fouling rate is a function of variables such as the characteristics of the membrane, flow rate, permeate concentration, filtration temperature, and character of feed and reentrant streams [20]. A novel class of thin-film nanofibrous composite (TFNC) membranes for UF was designed and fabricated by incorporating PAN EN scaffold mid-layer, cross-linked PVA barrier layer with directional water channels and a PET nonwoven support [23]. The membrane with pure PVA barrier layer had a permeation flux of about five times greater than that of the commercial PAN10 (Sepro) UF membrane at low pressures (2 bar) while maintaining a similar rejection ratio (99.7%). Further, oxidized MWCNTs and cellulose nanofibers (CN) were incorporated as nanofillers into the PVA barrier that increased the permeation fluxes about ten times higher than those of PAN10 while still maintaining 99.5% rejection. This increase was due to the directional water channels formed through the interface between the barrier layer and that of the incorporated nanofillers. The hydrophilic property and permeability of UF membranes were proved to be enhanced by the addition of electrospun nanofibers thus improving the antifouling property. The PSU and PSU/polyaniline (PANI) nanofibers blended membranes with different PANI-PSU mass ratios (1, 5, 10, and 15 wt%) by phase inversion process were prepared [24]. The blended membranes had high porosity (77%) and better hydrophilic property (60 water contact angle) showing improved permeability and less fouling with similar bovine serum albumin (BSA) rejections compared to PSU membrane (79 water contact angle). Pure water fluxes of the blended membranes were 1.6 and 2.4 times higher for PANI-PSU mass ratios of 1 and 15 wt%, respectively, compared to the PSU membrane. Recently, electrically conducting UF membranes were developed by blending single-walled carbon nanotube/polyaniline (SWCNT/PANI) nanofibers into a PSU matrix [25]. It was shown that by choosing the amount of nanofibers, the chemical structure, hydrophilicity, thermal stability, permeability, porosity, conductivity, and BSA rejection of the composite UF membranes were controlled. The initial water flux was improved by 2.5–7.3 times and BSA rejection enhanced from 39.8% to 73.7% by adding SWCNT/PANI nanofibers to the composite membranes. Similarly, hollow fiber UF membranes were prepared using dry-wet spinning technique by first synthesizing PANI nanofibers by interfacial polymerization technique, dispersed in N-methyl-2-pyrrolidone (NMP) solvent and blended with PVP/PSU [26]. The best membrane rejected 99.25% of RR120 hazardous dye with 55 L/m2/h at 2 bar of pressure due to the reduced pore size, adsorption of dye onto the membrane surface, and electrostatic repulsion (due to negative charge on the membrane surface). The antifouling property of this membrane was enhanced by 10% increase in hydrophilicity (6 decrease in water contact angle). Lately, the membrane performance was enhanced by UF membranes with electrospun nanofibers [27]. The high-porosity nanofiber layer provides a tailorable platform that does not affect the base membrane structure. The polymers, cellulose

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acetate, (CA) and PSU were electrospun into a layer that was 50 μm thick having fiber diameter of 1 μm. Fouling resistance was improved, and selectivity was retained by Biomax PES UF membranes enhanced with a layer of either CA or PSU nanofibers. The PSU ENMs demonstrated a higher pure water permeance across a greater range of transmembrane pressures than the CA ENMs due to better mechanical integrity. Another novel nanofiber-based composite UF membranes were fabricated via consecutive electrospinning of hydrophilic nylon-6,6/chitosan nanofiber blend and conventional casting of hydrophobic PVDF dope solution [28]. The optimized PVDF/nylon-6,6/chitosan composite membrane had 72% improved hydrophilicity compared to the pure PVDF benchmark, due to the incorporation of intrinsic hydrophilic hydroxyl and amine functional groups on the membrane surface. The integration of the nanofiber and cast layers has led to altered pore arrangements offering about 93% BSA rejection with a permeance of 393 L/m2/h/bar in cross-flow filtration experiments which is higher than the control membranes. The composite membrane exhibited high fouling propensity with 2.2 times higher reversible fouling and 78% decrease in the irreversible fouling compared to the PVDF benchmark after 4 h of filtration with BSA foulants. Hence, the nanofiber composite membranes for UF applications could potentially enhance the permeability and antifouling properties while maintaining a good rejection of contaminants. The TFNC membranes are also used widely in microfiltration applications. The ENMs for UF applications and its performance are summarized in Table 2. Overall, it is remarkable that the three- or two-tier membrane containing the ENMs could be potentially used for UF applications by offering high flux and more than 98% rejection of contaminants due to alterable pore size and high porosity. However, the pore size of the ENMs could be altered by changing the nanofiber diameter, and hence the pore size of the membranes can be altered in accordance with the contaminants. A good balance between the porosity and pore size of ENMs gave better flux with the same rejection for the composite UF membranes. Furthermore, the combination of ENMs with either coating or other hydrophilic functional layers enhanced the antifouling properties of the composite UF membranes.

Nanofiltration (NF) and Reverse Osmosis (RO) Membranes NF and RO membranes are used for desalination to remove smaller size contaminants (0.01 μ to ionic sizes), such as salt ions or chemicals. Although ENMs cannot produce ionic pore sizes, they can be used for NF and RO applications in the form of TFNC membranes [2]. Recently, the use of ENMs to purify low salt content water by NF was investigated [29]. The TFNC membranes were reported to have the ability to control the top barrier layer thickness as well as selection of suitable nanofibrous substrate [30]. Thus, the optimization of these two layers with respect to structure and stability will lead to better NF performance. In addition, the TFNC membranes offer unique features including higher flux electrospun nanofibrous scaffold as porous substrate and nanocomposite barrier layer, containing interlocked water

4 5

3

2

Entry 1

Composite UF ENMs PVA/MWNT/ PEBAX 12% PEBAX 6% PEBAX PVA/MWNT/ PVA hydrogel 15% hydrogel 5% hydrogel [19] Chitosan/PAN/ PET [20] NF270 membrane (Dow) [20] PAN/PVA [21] Commercial PAN400 (Sepro) membrane Commercial PAN10 (Sepro) membrane [21]

85 10

–

–

153 –

73

160 –

–

–

39 17 2.8

8.7

Nanofibers for Membrane Applications (continued)

Oil/surfactant (vegetable oil 1350 ppm and surfactant 150 ppm in water)

99.4

>99.5 98 99

99.8

21

Oil/surfactant (vegetable oil 1350 ppm and surfactant 150 ppm in water)

98.8

65

Feed Oil/surfactant (soybean oil 1350 ppm and nonionic surfactant 150 ppm in water)

>99.95

99.8

15

19

98.3

Rejection %

45

Permeation flux Average porosity (%) Mean pore size (μm) (L/m2/h/bar) 82 –

124

Average nanofiber diameter (nm) 80

Table 2 UF ENMs, their properties, and performance

28 947

11

10

9

8

7

Entry 6

PANI (15%)/ PSU [24] SWCNT/ PANI/PSU [25] 10% nanofiber 50% nanofiber PANI/PSU hollow fiber UF [26] CA/PES [27] PSU/PES [27] PVDF/nylon6,6/chitosan [28]

Composite UF ENMs PVA/PAN/ PET [23]

Table 2 (continued)

60

0.9 1.0 196

–

43

Average nanofiber diameter (nm) 170

0.009 0.015 –

0.018 0.025

5.6

–

–

–

0.005

2.5

75

580 830 393

27

457

157

141

Permeation flux Average porosity (%) Mean pore size (μm) (L/m2/h/bar) 85.2 2.6 144

– – 93

99.25

39.8

73.7

96.3

Rejection % 99.7

1 g/L BSA solution in water

250 mg/L BSA solution in water

RR120 dye 300 ppm

1 g/L BSA solution in water

Feed Oil/surfactant (vegetable oil 1350 ppm and surfactant 150 ppm in water) 1 g/L BSA solution in water

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channels formed between the nanofibers and cross-linked polymer matrix, which can produce highly permeable or energy-efficient nanocomposite membranes for NF or RO operations [31]. The conventional barrier layer for RO involves cross-linked structures having low flux with nondirected water channels, whereas the TFNC barrier layer introduces directed water channels to significantly increase the flux with similar selectivity [2]. However, the barrier layer thickness influences the filtration performance of TFNC membranes directly. The interfacial polymerization technique is a common and effective method to prepare the thin barrier layer by employing two immiscible phases containing reactive monomers [32]. PAN ENMs have been used as scaffolds in place of the mid-layer to support interfacially polymerized polyamide barrier layer containing piperazine and bipiperidine at different proportions [32]. The membranes exhibited about 2.4 times higher permeate flux than conventional composite membranes having the same chemical compositions while maintaining the same rejection ratio (98%) to divalent salts (MgSO4). Further, the ionic liquids were used as additives in interfacial polymerization to improve the permeation flux of the barrier layer by two times in TFNC NF membranes than the commercial NF-90 membrane with comparable salt rejection ratio. However, the existence of small ion liquid molecules reduced the permeation flux but increased the salt rejection ratio, while the presence of larger ion liquid molecules could increase the permeation flux but only slightly reduced the salt rejection ratio. The good wetting ability of the porous support forms a thin and defect-free barrier layer by rapidly reacting with the subsequently cast organic solution. Since it is difficult for the hydrophobic support material to get wet and form uniform amine layer, the hydrophobic EN support could be modified by oxidant for a short period to improve the hydrophilicity. Other TFNC NF membranes were also fabricated by interfacial polymerization (IP) pathways (the organic phase on top of the aqueous phase and vice versa) of polyamide around the ultrafine cellulose nanofiber layer (Fig. 1) [33]. It was found that IP with the aqueous phase above the organic phase yielded better filtration performance and higher MgCl2 rejection due to a dense barrier layer formation on top of the nanofibrous substrate. The permeation flux was 71.7 L/m2/h with 98.5% rejection ratio against MgSO4, which was twice better than those of the commercial NF-270 membrane having similar barrier layer chemical compositions [34].

Oil/Water Separation (OWS) Membranes A rapid increase in the production of industrial oily wastewater and regular oil spills causes serious environmental pollution that threatens biological and human safety [35]. Membrane technology was considered as the most promising approach owing to reasonably easy operational method and high separation efficiency in treating oily wastewater. The oil/water separation depends on the interfacial phenomena, and materials with high wettability are the ideal candidates [36, 37]. Fabrication of ENMs with high surface area having selective high wettability achieved by alterations in the surface structure and chemical composition makes them good

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a

b

500 nm

c

500 nm

d Looser part Denser part Cellulose nanofibers Electro-spun fibers

Denser part Looser part Cellulose nanofibers Electro-spun fibers

Current Opinion in Chemical Engineering

Fig. 1 TEM cross-section images of (a) IP-based membrane, (b) IP-R-based membrane on the CN (cellulose nanofibers)/PAN (electrospun nanofibers)/PET (nonwoven substrate) composite scaffold, and their corresponding schematics are shown in (c) and (d), respectively [33]

candidates for OWS [38]. In general, the OWS membranes are classified into oil-removing, water-removing, and smart separation membranes. The “oil-removing” superhydrophobic/superoleophilic ENMs can repel water completely and allow oil to flow through freely, thus achieving high efficiency and selectivity. By introducing suitable multiscale roughness, a hydrophobic surface becomes superhydrophobic and an oleophilic surface becomes superoleophilic (per Wenzel and Cassie-Baxter model) by having low surface energy. Recently, an in situ polymerization method was developed to synthesize superhydrophobic/superoleophilic ENMs for effective OWS. The ENMs were fabricated by a simple layering of different ENs and an in situ polymerized functional fluorinated polybenzoxazine (F-PBZ) layer containing nanoparticles (NPs) (e.g., SiO2 NPs and Al2O3 NPs). Here, the electrospun nanofibers were CA [39], poly(m-phenylene isophthalamide) (PMIA) [40] and SiO2 nanofibers [41]. After F-PBZ/NPs modification, the pristine hydrophilic ENMs had a superhydrophobic water contact angle (WCA) of 161 and a superoleophilic oil contact angle (OCA) of less than 3 . Due to gravity-driven process, the fabricated membranes exhibited fast, significant, and efficient separation of oil/water blends. The OWS with high flux was driven by gravity, thus exhibiting good antifouling properties, thermal stability, and durability. Further, introduction of rough surfaces with low energies was achieved by incorporating silver (Ag) nanoclusters [42] or hydrophobic nanosilica [43] onto

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nanofiber surfaces. Here, the superhydrophobic/superoleophilic ENMs with good OWS efficiency were fabricated by merging the PAN nanofibers amination and immobilization of silver nanoclusters via electro less plating, followed by surface modification. These membranes showed significant OWS proficiency due to superoleophilicity in high saline environment (35 g/L NaCl) and under broad pH range (pH 1–11) with excellent recyclability. On the other hand, porous materials with super-wettability were also directly constructed to prepare oil-removing membranes without any modification. A super-wettable membrane was prepared by single-step electrospinning deposition of PSU nanofibers onto a stainless steel mesh for OWS [44]. This method can also be used for other hydrophobic polymers to prepare superhydrophobic/superoleophilic ENMs [45]. However, due to the oleophilic property, these membranes can be easily fouled or clogged by oils, which truly affects the separation efficiency preventing the membrane to be reused. An alternate route to overcome issues in OWS was provided by the recent advancement in fabricating “water-removing” membranes with superhydrophilicity and superoleophobicity. These membranes were designed based on the inspiration of the oil-repellent nature of fish scales having specific combination of roughness and surface energy. Superhydrophilic/superoleophobic ENMs were fabricated by coating CaCO3 mineral on poly(acrylic acid) (PAA)-grafted polypropylene (PP) ENMs [46]. The rigid mineral coating provides superoleophobic/hydrophilic properties by forming a hydrated layer on the membrane pores via trapping an abundant amount of water in an aqueous environment. Under pressure or gravity, these membranes could separate various oil/water mixtures and emulsions with high separation efficiency and water flux. Similarly, a hydrophilic polyester (P34HB) was incorporated into polylactide (PLA) nanofibers (90% porosity) to regulate the hydrophilicity with reduced membrane porosity (80%) of the composite water-permeable membranes exhibiting superoleophobicity [47]. Here, the hydrophilicity of P34HB/PLA membranes increased by 22% compared to hydrophobic PLA membranes. Also, the diameter of blend fibers is decreased with P34HB content because of increased conductivity and reduced relative viscosity which controls the porosity. Recently, superoleophobic cellulose/PVDF-co-hexafluoropropylene (PVDF-HFP) ENMs were developed, which can efficiently separate 99.98% water from oil by filtering motor oil at kPa using a dead-end apparatus [48]. Formation of smaller pores (0.3 μm) with narrower pore size distribution is achieved as the fibers are coated with cellulose matrix that aids in enhanced OWS. Compared with polymer-based membranes, inorganic nanofibrous membranes display potential advantages in terms of easy recycling, stability, and antifouling ability. A novel flexible porous silica nanomats (SNM) were prepared that are thermally stable and separating water from surfactant-stabilized oil-in-water microemulsions solely driven by gravity [49]. The pristine SNM was used as the template for the in situ polymerization, and the incorporation of SiO2 NPs did not change the flexibility of SNM while creating roughness revealing the positioning of SiO2 NPs on the membrane surface. The developed membranes showed superamphiphilicity in air

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and oleophobicity in water making it an ideal candidate for OWS. In a further study, water-removing ENMs were fabricated by incorporating NiFe2O4 NPs [50]. The as-prepared NPs incorporating SNM exhibited high separation efficiency, high flux up to 2237 L/m2/h, high thermal stability, good antifouling properties, and ease of recycling. However, the oil-removing and water-removing processes may not adapt to the complex composition of the oil/water mixture and different types of oil having varied densities. Hence, different smart materials with alterable wettability in response to external stimuli such as pH, temperature, light irradiation, and electricity were fabricated and used for OWS. More recently, Janus hydrophilic PAN ENM was fabricated with a single-side hydrophobic carbon nanotube (CNT) network coating, showing switchable separations of oil-in-water and water-in-oil emulsions [51]. The CNTs-PAN ENM exhibited asymmetric wettability on each side, i.e., the hydrophilic PAN ENM side had oleophobicity, and the hydrophobic CNTs side had oleophilicity. The CNTsPAN ENMs had highly efficient oil-in-water emulsion separation with the PAN ENM side and water-in-oil emulsion separation with the CNTs side. Lately, a smart tree-like nanofiber membrane was fabricated with pH responsivity by electrospinning PVDF-g-PAA [52]. Through realizing protonation and deprotonation in response to the pH of the aqueous media, the as-prepared membrane can alter its wettability and conformation, resulting in the switchable surface oil/water wettability. The separation is however using gravity alone by switching the pH of the medium. The temperature-responsive copolymer poly(methyl methacrylate)-block-poly (N-isopropylacrylamide) (PMMA-b-PNIPAAm) was used to fabricate two different smart membranes via solution casting and electrospinning methods, respectively, that exhibited temperature-dependent oil/water wettability [35]. Due to the porous structure of 3D network of entangled nanofibers, the ENMs possessed better switchability of oil/water wettability compared to the cast membrane. These membranes performed with more than 98% separation efficiency through the gravitydriven with switchable temperature. Here, the superhydrophilic/superoleophobic membranes are initially wetted by water before separation that allows the water to pass through and oil to retain on the membrane surface. Subsequently, the membrane wettability switches to hydrophobicity and oleophilicity by heating the membranes above the LCST (32–33  C) temperature. As a result, the retained water is slowly replaced by the oil that permeates through the membrane. The cast membrane exhibited a water flux of about 6200 L/m2/h and an oil flux of about 1550 L/m2/h. In contrast, the water fluxes were 50% higher and the oil fluxes were about 2.4 times more due to the ENM’s high porosity and large surface-to-volume ratio. Later, beads-on-string structured nanofibers were developed for smart and reversible OWS with excellent antifouling property by electrospinning TiO2-doped PVDF nanofibers [53]. As desired in OWS, the liquid superwetting/resisting ability of membranes was offered by the nanofiber structure and surface roughness. Switched simply by UV (or sunlight) irradiation and heating treatment, the smart membrane can realize reversible separation of oil/water mixtures (n-hexane (red)/D.I. water

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(blue)) by selectively allowing only water or oil to pass through and is confirmed visually. The photocatalytic property of TiO2 offers the antifouling and self-cleaning property of the ENM which was confirmed by FTIR analysis of the membrane surface using oleic acid as the oily pollutant. These provided a means for fabricating cost-effective, scalable, and recyclable membranes for use in versatile OWS that adds in to the green separation technology.

Membrane Distillation (MD) Membranes Membrane distillation (MD) is a temperature-dependent non-isothermal process, which permits only vapor molecules to permeate through a highly hydrophobic porous membrane [54]. Here, the driving force is the vapor pressure difference induced by temperature difference between the feed and permeate flows [55, 56]. During the MD process, the water heated to about 60  C is repelled by the hydrophobic membrane preventing it from reaching the pores. On the other hand, the vapor molecules are condensed and collected on the permeate side by vacuum or gas [57]. The major advantage of MD process is that it works below the boiling point of water, hence saving energy cost [57, 58]. The four types of MD processes include direct contact membrane distillation (DCMD), sweep gas membrane distillation (SGMD), air-gap membrane distillation (AGMD), and vacuum membrane distillation (VMD) [56, 59]. The use of PVDF ENMs for AGMD operations to produce drinking water (NaCl concentration 135 were fabricated and optimized [61]. Addition of inorganic additives was shown to improve the electrospinnability of polymer dopes and further decrease the membrane pore size. Heat-press posttreatment improved the ENM integrity with enhanced water permeation flux (21 L/m2/h for 15 h, 3.5 wt% NaCl solution as the feed and 323 K feed and 293 K permeate temperatures, respectively), thus preventing pore wetting in DCMD operation compared to the commercial PVDF membranes. Further, the effect of PVDF concentration on the properties of ENMs and the corresponding DCMD desalination performance was studied. The optimum beaded ENMs with 25 wt% PVDF concentration exhibited a DCMD permeate flux of 44 L/m2/h for distilled water and 39 L/m2/h for 30 g/L NaCl feed solution, respectively (the feed and permeate temperatures were 80  C and 20  C), where the NaCl rejection factor was higher than 99.99% [62]. Correspondingly, they performed a systematic experimental study on the effects of PVDF ENM thickness on the DCMD performance [63]. With an increase of the nanofiber thickness, liquid entry pressure of water, and electrospinning time, a decrease of the pore size was observed. However, no major changes were observed for the water contact angle (137.4–141.1 ), EN diameters (1.0–1.3 μm) and void volume fraction (0.85–0.93).

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In order to achieve more stable DCMD performance with high efficiency, the PVDF ENMs were improved by modifying using different methods including ENMs based on PVDF blended with clay nanoparticles [64], hot-pressed PVDF-HFP ENMs [65], ENMs based on PVDF-PTFE blends [66], nanocrystalline cellulose reinforced PVDF-HFP ENMs [67], and ENMs based on silver-coated PVDF/polydopamine electrospun scaffolds with thiol surface modification [68]. Recently, a self-cleaning composite nanofiber membrane system inspired by lotus leaf consisting of a superhydrophobic silica-PVDF composite selective skin on the PVDF nanofibrous scaffold was demonstrated (Fig. 2) [69, 70]. The PVDF ENMs exhibited a steady permeate flux of 18.9 L/m2/h over 50 h of testing time using a 3.5 wt% NaCl feed solution (the feed and permeate temperatures were 50  C and 20  C), which was better than conventional PVDF flat-sheet membranes tested under the same test conditions. Other reported researches include the fabrication of superhydrophobic ENMs for MD operation, such as dual-biomimetic superhydrophobic PSU micro-/nanofibrous membranes [71], aromatic fluorinated polyoxadiazoles, and polytriazoles membranes [72], PTFE ENMs [72] that showed improved desalination performance over conventional MD membranes. Thus, ENMs with superhydrophobic properties and suitable pore sizes are appropriate for MD applications for desalination of seawater or brackish water.

Bio-separation Membranes The ENMs used for bio-separation processes must possess the following properties: (1) small nanofiber diameter to offer high specific area (most significant for adsorptive processes and less significant for size-based separations); (2) well-controlled narrow pore size distribution between nanofibers to ensure homogenous flow distribution during adsorptive processes and lower cutoff for size-based separations; (3) excellent mechanical and chemical stability to withstand potentially high operating pressures and

Fig. 2 Self-cleaning composite ENMs prepared by Liao et al. (a) lotus-leaf-like superhydrophobic selective layer and a scaffold-like nanofiber support layer [69] (b) the liquid membrane interfaces on silica blended superhydrophobic membrane using different liquid types [70]

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harsh cleaning conditions; and (4) nanofibers should have a well-defined dimension and chemical composition. The varied morphologies (cylindrical, spindle-shaped, beaded, etc.) of the polymeric (synthetic and natural), carbon, and ceramic nanofibers are due to the electrostatic instability and the solvent evaporation during electrospinning that plays an important role in the formation of polymer nanofibers. One of the applications where ENMs are beginning to receive greater attention is in bio-separations. The ENMs are used for both adsorptive and size-dependent bio-separations.

Adsorptive Bio-separations One of the major purification methods for many industrial bio-separation processes is selective adsorption and removal of the target molecule. These membranes are developed to purify the molecules depending on the physical, chemical, or biological properties rather than the molecular weight/size [2]. The adsorptive membranes require ligand molecules to be introduced into the inner surfaces of the membrane to capture targeted molecules, and hence the high surface-area-to-volume ratio, porosity, stability, and interconnectivity of the ENs are preferably suited for this purpose [73]. Here, the fibers of the adsorption unit act as support for ligands during the selective adsorption process. Here, the flow is through micro-/macropores of the unit (as opposed to tightly packed resin beads), and the adsorption occurs on the fiber surfaces within the unit [74]. So far, adsorptive membranes based on surfacefunctionalized ENMs have been demonstrated as effective heavy metal adsorption, organic waste adsorption, or ion exchange media [75–77]. Thus, membrane adsorption capability is a factor to be considered while treating wastewater via membrane filtration processes such as UF, MF, NF, RO, OWS, and MD. However, the adsorptive membranes are likely to suffer rapid fouling. Size-Dependent Bio-separations Currently, the size-dependent separations are routinely used in downstream bioprocessing that involves depth filtration (e.g., clarification of fermentation broth), MF (e.g., removal of cellular debris from bioreactor slurry), NF (e.g., viral purification), and UF (e.g., protein purification) processes where a separation medium is desirable. The separation medium must have a well-defined size cutoff to obtain tightly controlled separations, must be highly porous for high-throughput processing to minimize operating time/area requirements, and must possess chemical and physical robustness for harsh cleaning conditions and operation under moderate pressures [74]. Nanofiber mats are considered for advanced size-dependent separation medium because of their low production cost for large quantity and wellcontrolled pore size [74]. Till now, the ENMs have been applied for isolation of nanometer and micrometer scale bio-particles (or surrogates) by a depth filtration mechanism. The high specific surface area of the nanofibers within a filtration mat provides for a more tortuous path and greater chance to capture a desired particle from solution while maintaining high porosity [2]. Polymer, carbon, and ceramic nanofibers have all been evaluated and were all able to separate the desired particle size from a mixture while maintaining high fluxes [9, 78, 79]. Specifically, PVDF and nylon-6 ENMs can remove PS particles

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between 0.5 and 10 μm [9, 10]. Furthermore, ceramic nanofiber meshes have been used most extensively. Composite titanate/boehmite ENMs were capable of very high fluxes (1000 L/m2/h) with relatively low pressure driving force (0.2 bar) and could remove virtually all particles larger than 60 nm from a solution [78]. It should be noted that many applications of micro- and nano-depth filtration depend on chemical adsorption of particles to the surface, which nanofibers are easily capable of and can be manufactured to specifically adsorb a desired impurity [74]. The use of electrospun nanofibers for size-based bio-separations using MF, UF, and NF processes involves the fabrication of different ENM patterns such as arrangement of substrates and functional layer, mixed matrix membranes, and coating functional layer that was explained in the previous individual sections. Furthermore, hollow nanofibers produced by electrospinning offer the potential to act as a size-based separation NF membrane. While no reports have been made to date regarding this application of electrospun nanofibers, nanotubes (which are produced differently but would have very similar properties to hollow nanofibers) have seen some application for size-based separations [74]. The nanotubes were optimized and studied to control the pore diameter, wall thickness, nanotube length, and connectivity of ceramic nanotubes and shown application for diffusion separation of different sized biomolecules [80–82].

Conclusions This review highlighted the advances of using ENMs for a wide range of membrane applications in water treatment and remediation. ENMs offer unique desirable properties to generate membrane materials, including high specific surface area, interconnected pore sizes, high porosity, and easy modification that makes it advantageous over conventionally prepared membranes. Highly porous nanofiber membranes were fabricated from electrospinning technique from a wide range of materials to be well suited for water treatment applications including MF, UF, NF, RO, OWS, MD, and bio-separation. The structural properties such as fiber diameter, thickness, porosity, and pore size of the electrospun nanofibers were found to greatly influence the membrane performance. Membrane fouling was found to be a critical problem during filtration processes due to high flux of ENMs and was effectively brought down by the ENM surface modifications using suitable antifouling materials/coatings. Therefore, the construction of ENMs by layering, coating, polymerizing, and blending electrospun nanofibers into different configurations stands to be the most significant step that allows them to be used for various water treatment applications.

References 1. Homaeigohar S, Elbahri M (2014) Nanocomposite electrospun nanofiber membranes for environmental remediation. Materials 7(2):1017–1045 2. Wang X, Hsiao BS (2016) Electrospun nanofiber membranes. Curr Opin Chem Eng 12:62–81

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Riyadh Al-Attabi, Y. S. Morsi, Jürg A. Schütz, and Ludovic F. Dumée

Contents Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Classification and Characterization of Air Pollutants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Capture Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Fundamental Benefits of Nanofiber Air Filters: A Theoretical Analysis . . . . . . . . . . . . . . . . . . . . . . . Properties of Nanofiber Filters and Parameters Affecting Performance: An Experimental Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Applications of Nanofiber Air Filters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions and Perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

962 964 965 968 970 973 975 976

Abstract

This chapter presents an overview of nanofiber-based materials fabricated for applications in air filtration. Air contaminants can be classified as gaseous or particulate matter, and the capability to capture these will strongly vary with the specifics of their chemistry, morphology, and agglomeration kinetics, as well as

R. Al-Attabi Faculty of Science, Engineering and Technology, Swinburne University of Technology, Hawthorn, VIC, Australia Institute for Frontier Materials, Deakin University, Geelong, Waurn Ponds, VIC, Australia Y. S. Morsi Faculty of Science, Engineering and Technology, Swinburne University of Technology, Hawthorn, VIC, Australia J. A. Schütz CSIRO Manufacturing, Waurn Ponds, VIC, Australia L. F. Dumée (*) Institute for Frontier Materials, Deakin University, Geelong, Waurn Ponds, VIC, Australia e-mail: [email protected] © Springer Nature Switzerland AG 2019 A. Barhoum et al. (eds.), Handbook of Nanofibers, https://doi.org/10.1007/978-3-319-53655-2_37

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with atmospheric conditions, such as humidity and temperature. The capture mechanisms of different design methods must therefore be adapted to achieve stringent capture efficiency targets. For one, the benefits of nanofibers over more conventional microfibers reside in the small fiber diameter facilitating more tuneable and finer pore sizes, narrower pore size distributions, and higher specific surface areas. The advantages of nanofiber media for filtration applications, such as extreme compactness, are highlighted in the chapter concerned with the specific properties of nanofiber filters. The challenges arising from the use of nanofibers that is contrasted by opportunities that may direct future trends of nanofiber filters for air filtration applications are discussed at the end of the chapter. Keywords

Air filtration · Nanofibers · Electrospun fiber membranes · Air pollutants · Air filtration performance

Background Air pollution endangers the health of a growing part of the human population and leads increasingly to public and politic concerns, especially those related to hazardous particulate matter (PM), gaseous emissions and smoke, as well as the spread of viruses and bacteria [1]. Commercial air filters are addressing significant challenges in hospitals, heating for offices and dwellings, kitchen range hoods, private and public air conditioning systems, as well as large-volume dust removal in manufacturing industries, leading to a growing air filtration market that is expected to reach a value of US $700 billion by 2020 [2]. High-efficiency particulate air (HEPA) [3] filters are the most widely utilized air filters for removing unwanted airborne particles from air [4]. These filters have the capacity to clean out fine particles from the most penetrating particles sizes (MPPS), which are particles for which air filters have the lowest filtration efficiency (or highest penetration); the diameter of these particles is typically in a range of 100–500 nm [5]. The emergence of nanoscale particles generated increasingly from foundries, diesel vehicle exhaust, nano-composite materials degradation, and industrial smoke requires novel filter structures to be investigated, offering adaptive tailoring of capture efficiencies for fine particles in air at low energy consumption, as represented by low pressure drop [6–8]. There is a growing need for more efficient filters offering better selectivity and lower energy consumption [6–8]. The first detailed investigation concerned with the principles of filtration using fiber felts was attempted in Germany by Albert Kaufmann for applications in respiratory protection [9]. However, filter materials for respirator masks appeared already as early as the late nineteenth century to protect people from disease and chemical warfare agents and, more specifically, to protect firemen from fumes [10]. In 1905, early concept respirators were tested against bacteria in the form of absorbing suspensions. A mixture of asbestos fibers and wool was first used to make efficient gasmask filters during World War I [10]. In the 1930s, such filters

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were replaced by the asbestos-free “Hansen filters” [11]. In the late 1960s, fiber media made from asbestos were found to lead to severe lung disease if fibers are inhaled. Nowadays, filtration efficiency is not the only relevant factor to evaluate filter performance and progress in new technology concentrates on minimizing pressure drop, since energy loss also increases with pressure drop [10]. Common commercial HEPA filters capture aerosol particles by means of either glass or polymeric microfiber media [12]. Although according to the air filtration theory it is necessary to consider slip flow when gaseous media are involved, the correction is generally small for micrometer-sized fibers. However, the slip flow mechanism has a more pronounced effect when nano-sized fibers promote a flow regime according to Reynolds that resembles that of micrometer-sized fibers under vacuum pressure [13]. In addition, although fiber structures allow efficient capturing of micrometer and nanoscale aerosol particles with relatively low resistance to the air flow, finer particles in the sub-500 nm range are removed with significantly poorer efficiency and are the known cause for growing health concerns [14]. To address these concerns, the production of fiber media must overcome several challenges related to the chemistry and structure of the raw fiber materials, as well as the homogeneity and diameter distribution of the fibers [15]. Natural fibers typically yield much broader size distributions, and for this reason man-made, calibrated fibers are often preferred for the manufacture of air filters. In addition, the uniformity in fiber distribution, thickness, and pore structure of the mats is critical to ensure reproducible high-level performance [15]. Current fibers used for the manufacture of many filter products used in the control of contaminants, however, offer limited scope for the capture of particles less than 2.5 μm (PM2.5) in size primarily due to the large interstitial gap between the typically coarse fibers. The design of filters made from nanofiber-based materials, on the other hand, offers attractive perspectives for high-efficiency filter media and products for the capture of fine particles with a high quality factor (QF) [16] . The key properties for such nanofibers are their high aspect ratio, a large surface area-to-volume ratio, an extremely wide range of fiber diameters leading to versatile pore size distributions, and a highly interconnected fiber network leading to excellent mechanical properties [17]. Such nanofibers may be synthesized by melt blowing and electrospinning [18], where the latter is typically considered to be more versatile and up-scalable than the former. In this chapter, the performance of micrometer-sized fiber-based air filtration systems and electrospun nanofiber materials will be compared and analyzed in terms of state-of-the-art filtration theories. In the first part of the chapter, the theory and mechanisms of air filtration in fiber media, concerning both micro- and nanofiber media, are being reviewed, while a comprehensive comparison of air filter properties is presented in the subsequent experimental section. Finally, specific characteristic features of nanofibers impacting the air filtration performance are discussed. The main objective of this chapter is to highlight the potential benefits of nanoscale electrospun materials over classical coarse fibers as well as to critically discuss the main parameters and factors impacting nanofiber fabrication and how this translates to air filtration performance.

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Classification and Characterization of Air Pollutants In order to introduce the theory and recent advances in the field of air filtration application, an explanation of the diversity of the different air pollutants and ensuing classification must be considered. Air pollutants are divided into particulate matter (PM) and gaseous contaminants. Such contaminants are present and ubiquitous both in outdoor and indoor environments, propagated by air flow systems such as air conditioning, and supplemented by everyday activities like heating [19], cooking, and indoor smoking. Inside closed, size-limited volumes, these activities can lead to the concentration and accumulation of PM. Major emissions in the outdoor environment [20] are produced by certain heavy industries, including foundries, cement works, petroleum processing, and energy plants [21], which can release relatively large quantities of chemicals and PM into ambient air [22, 23], but distributed emitters like passenger cars and heavy vehicles [24] in general traffic. The combination of such emissions with specific atmospheric and geographic conditions can lead to the occurrence of smog [25], which has become a major issue in various large cities globally, such as cities in China (Shanghai, Beijing), Europe (Athens, Rome), and historically London due to coal heating. PM capture capacity with air filters may be evaluated by means of the penetration (which is related to filtration efficiency) and pressure drop across the filter. HEPA filters can be tested by means of liquid or solid aerosols (e.g., using the sodium flame method of BS 3928:1969 [26] or the newer ISO 29463-1:2011 [27]) to generate relatively high concentrations of PM [28]. The setup is composed of an aerosol generator (e.g., polydisperse aerosol from an atomizer or a relatively monodisperse aerosol of PSL spheres), a charge neutralizer (radioactive source or corona discharge), a flame photometer or suitable optical particle counter (often in conjunction with a diluter) for particle detection, a holder for the filter medium, and a fan blower to maintain an air movement through the filter medium. The filtration efficiency of the tested filters can be calculated according to Eqs. (1a and 1b) [1]: P≔

Cdownstream Cupstream

  Cdownstream η≔ð1
PÞ ¼ 1
ð100%Þ Cupstream

(1a)

(1b)

where P is the penetration, η is the filtration efficiency, and Cdownstream and Cupstream are the respective particle concentrations of the aerosol in the airstream after and before passing through the test filter. Furthermore, the quality factor (QF) can be calculated according to Eq. (2) to evaluate the performance of air filters [29]: QF≔


lnðPÞ
lnð1
ηÞ ¼ ΔP ΔP

(2)

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where ΔP is the pressure drop across the tested filter. Higher QF is preferable for air filters, which means that the air filters should have high filtration efficiency and low pressure drop at the same time. The mix of airborne particles may also contain biological particles, such as viruses, bacteria, and spores [30]. Investigations reported were devoted to produce antibacterial filters, as well as means for characterization via setups capable of measuring the air filtration efficiency. Bacteria are dispersed into aerosols and dehumidified with a diffusion dryer, prior to being injected into the filtration module, which contains the antibacterial filter cartridge. An aerodynamic particle size is typically used to measure the concentration and size distribution of the bacterial aerosols, and the bacterial inactivation rates may be evaluated with Eq. (3) [1]:   CFUantimicrobial Inactivation rate ð%Þ ¼ 1
 100% CFUpristine

(3)

where CFUantimicrobial is a colony-forming unit number which can be measured after filtration and CFUpristine is the number of CFU which can be measured after filtration in the filter using a pristine filter. The filtration performance of air filters particularly differs according to the size of fibers contained in the filter, mainly in terms of where the MPPS is located, and the effect on particle size distribution is intimately linked to the combined effects of different capture mechanisms. The leading mechanisms relevant for PM capture are investigated by a comparison between nanofiber-based and microfiber-based filters in terms of theoretical predictions and the measured filtration performance.

Capture Mechanisms Air filtration mechanisms largely depend on the size and properties of particles in the aerosol but equally importantly on diameter and surface properties of the fibers used [1]. The filtration mechanisms control the fluid dynamics that leads to the capture of particles on fiber surfaces [7] where they are retained with very high certainty by Van der Waals forces [31]. Fiber filters can therefore physically retain particles much smaller than the pore size of filters. The main mechanisms of air filtration include (i) interception, (ii) inertial impaction, (iii) Brownian diffusion, (iv) the electrostatic effect, and (v) gravitational settling [32]. Figure 1 shows a general diagram highlighting the main capturing mechanisms for fiber filters. These mechanisms are characterized in more detail in the section below. The figure illustrates that the characteristics of the mechanisms is determined by the type of movements through which aerosol particles deviate from the gas flow lines in the vicinity of the fibers [1], and these movements also depend on the size of the aerosol particles [7]. (i) Interception effect: The fibers inside the filters are randomly distributed and irregularly arranged, and particles propagating around the fibers are following a streamline trajectory [33], according to principles of fluid dynamics.

966 Fig. 1 The main filter mechanisms of fiber material [33]

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Interception

Electrostatic deposition

+ fiber cross section

Inertial impaction

Flow streamlines

Diffusion

Particles are captured if they lie inside a trajectory, which is defined as the limit trajectory that is located at the distance of the particle size. If it is assumed that the center of mass of each aerosol particle follows such streamline and never deviates from it [34], the interception of fine particles occurs only when the particles contact the surface of fiber filter materials, where they stay due to the attraction from van der Waals forces [33]. Interception is typically the main capture mechanism for particles in the range of 100–1000 nm [33]. (ii) Inertial deposition: The streamline governed by fluid dynamics is tortuous due to the irregular arrangement of fibers in the filter medium. If the velocity of the flow is sufficiently high, the tortuosity can be responsible for particles not following perfectly their designated streamline due to the particle’s inertia and is slowed down by friction with gas molecules or collisions with other aerosol particles. Thus, particles may collide with fibers and be captured because they are unable to stay on their trajectory to avoid the fiber. This mechanism can explain why larger or heavier particles, in the range of 300–1000 nm diameter and with more inertial momentum, may yield higher filtration efficiencies compared to smaller particles. This effect tends to dominate at high airflow velocities and lead to increased filtration efficiency [33]. (iii) Brownian diffusion: Particles may collide with the fibers due to random diffusion, called Brownian motion [33]. Brownian motion is the result of fine particles colliding with gas molecules, which are swerving randomly with a speed distribution that is governed by Plank’s black body radiation according to temperature. These collisions move ultrafine particles away from the main air trajectory, which is particularly apparent at low face velocities. Deflected particles are captured by Van der Waals forces on impact with fibers [34]. The Brownian diffusion mechanism can capture particles smaller than 1000 nm, depending on their density, and works significantly better for particles smaller than 100 nm [1]. However, particles in the range of 500–1000 nm are less affected since the average thermal velocity is becoming smaller with increasing particle size [35]. (iv) Electrostatic effect: Electrostatic interactions, such as polarization and coulombic interaction, may change the track of aerosol particles away from the streamline when the particles and/or the fibers are electrically charged [33]. This mechanism

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may attract or repel particles, depending on the polarity of charges involved, and at times make them adhere more strongly onto the surface of the fibers where charges are located [1]. Electrostatically enhanced collection is widely utilized in different types of air filtration systems, which is particularly effective against submicrometer aerosol particles. An electrostatic field can be generated by conductive electrodes (e.g., precipitators) or using statically embedded surface charges on the fibers (electrets, triboelectric media, corona charged media). (v) Gravity effect: This mechanism is less important than the other mechanisms for fine particles [33], due to low mass [1]. Gravity sedimentation can be ignored if the average size of aerosol particles is less than 500 nm [1]. However, for large collection columns as well as for larger or denser particles or aggregates, this mechanism may lead to improved capture and less penetration in a pertinent filter. Different sizes of aerosol particles may therefore be captured through different types of filtering mechanisms. The separation of aerosol particles from an airstream by fiber media is thus governed by a combination of mechanisms, which change in magnitude with fiber diameter and particle size. These mechanisms can be investigated remarkably well by looking at the [1] collection efficiency of a single fiber in a parallel array of fibers separated by average distances. The efficiency in the “single fiber” model is defined by Eqs. (4) and (5) [33]: ηs ¼

Particles collected by fiber Particles in volume of air geometrically swept out by fiber (4) η ¼ 1
expð
ηsÞ

(5)

where ηs is the air capturing efficiency of a single fiber, S is the filter area factor (the projected area of fiber per unit filter area), and η is the overall filter efficiency. Interception and impaction are generally the dominant filtration mechanisms for aerosol particles larger than 200 nm; however, the diffusion is dominant for particles smaller than 200 nm. Individual contributions of the five filtration mechanisms to the total filtration efficiency dependence on particle size are shown in Fig. 2a [33]. The MPPS is also shown in Fig. 2a, which indicates that the pore size of filter does not completely indicate of filtration efficiency [7]. The figure shows the most common mechanisms for capturing particles in a size range of 0.01–10 μm. It should be noted that gravitational setting can make particles larger than 10 μm drop out of the aerosol before the gas flow reaches the filter [7]. Furthermore, Fig. 2b shows the particle size range for which each mechanism is active or dominant: very small particles (smaller than 300 nm) are efficiently captured by diffusion, while larger particles are captured more effectively by impaction and interception [7]. Recent research investigations have seen increasing focus on using the nanofiber filters for air filtration. Indeed, the unique properties of nanofibers that have given rise to this use, including key properties and typical performance advantages, are discussed in the next section of this chapter.

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a 100 Collection efficiency/%

Fig. 2 (a) Filtration mechanisms with particles size [33]. (b) Filtration efficiency for filtration mechanisms and total efficiency [7]

total filter settling impaction

50

diffusion Interception

MPPS 0.01

b

0.1 1.0 particle diameter/μm

10.0

Particle diameter (μm) 0.3

Diffusion + Electrostat

1

Interception

10

Inertial impaction Gravity+clogging Sieving

Fundamental Benefits of Nanofiber Air Filters: A Theoretical Analysis HEPA filters made of microfibers represent the commercial benchmark for this type of filter. HEPA filters are usually made of glass and polyolefin fibers [36, 37] and exhibit a minimum of 99.97% filtration efficiency for particles greater than 300 nm in size. The structure of HEPA filters is generally nonuniform in thickness and mass [37], which may negatively affect filtration performance. Furthermore, melt blown filters consisting of microfibers (in the range between 100 and 10,000 nm), which yields large pore size distributions ranging between 174 and 27,297 nm, and large basis weights (25 g/m2) compared to electrospun nanofiber filters. Typical parameter ranges for electrospun webs are 15–1500 nm for fiber diameter, 15–1200 nm pore size, and 0.2 g/m2 basis weight [12]. Specifically, synthetic commercial filters with 5.4 μm fiber diameter were shown to yield 0.8015 m2/g of specific surface area and 77.5027 g/m2 of basis weight [38]. While the filtration efficiency of nanofiber filters was between 90% and 97.5% for particles size less than 100 nm, the filtration efficiency for microfiber melt blown filters in comparison was ranging from 86.5% to 92.2% [12]. These results illustrate that the use of finer fibers (submicrometer) may offer interesting alternatives for air filtration in this space. Nanofibers particularly have been shown to achieve higher air filtration efficiency in comparison to microfibers under specific conditions [30]. Nanofiber filters offer small pore size distributions, low basis weight and thickness, as well as high permeability, which are advantages that can be useful to exploit for filtration applications. Fibers with diameters up to 300 nm can achieve filtration efficiencies over 99% for submicron particles up to 300 nm [22]. The reason for higher air filtration performance is that the nanoscale fibers have better filtration efficiency than the microscale fibers due to the difference in the flow of air across the material [13].

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The filtration theory assumes a continuous flow and nonslip flow conditions around the fiber surface. However, the latter assumption is not necessarily valid when the fiber size is reduced beyond a certain threshold, at the nanoscale, and the fiber dimensions become small enough so that air molecules flow and interactions with the fibers become more significant per surface area [13]. The importance of the movement of air molecules can be described using the Knudsen number (Kn) for nanofiber diameter up to 500 nm [13]. The Knudsen number is derived as shown in Eq. (6): Kn ¼

λ rf

(6)

where λ is the mean free path of gas molecules and rf is the fiber radius. Kn needs to be taken into consideration when its value is more than 0.1. In slip flow, the speed of air molecules on the fiber surface is assumed to be nonzero as shown in Fig. 3 [13]. Due to the slip flow at the fiber surface, the drag force on a fiber is smaller than in the case of nonslip flow, which translates into lower pressure drop [13]. The slip flow makes the portion of the air flowing near to the surface of fibers larger than that in the case of nonslip flow, which means that more particles will transit near the fiber, resulting in higher inertial impaction, interception, and diffusion efficiencies [13]. Therefore, the slip flow mechanism is dominant when small fiber diameter materials are used [39]. This mechanism can be explained by the pore morphology generated by the nanofiber assembly. Figure 4 shows the fractional efficiency of nano- and microfiber filters versus nanoparticles in the range of 10–500 nm. It can be observed that the fractional efficiency increases with decreasing fiber diameter [5]. The MPPS is shifted toward smaller aerosol particle size suggesting a change in the penetration depth [5]. The MPPS were 366 nm, 199 nm, 140 nm, and 54 nm for filters η1, η2, η3, and η4, respectively, corresponding to diameters in the range 10 μm, 2 μm, 0.7 μm, and 0.1 μm, respectively. The shift of MPPS is stronger for finer nanofibers and leads to significant decrease in the penetration of submicrometer-sized particles due to direct interception at the fiber surface. Furthermore, the maximum penetration of aerosol particles was found to be decreased for filters composed of the fine fibers. As can be seen in Fig. 4, the maximum penetrations were 0.747, 0.293, 0.022, and 3.28  10
4 for filters η1, η2, η3, and η4, respectively, corresponding to diameters in the range of 366 nm, Fig. 3 Velocity profile at the surface of fiber for (a) nonslip flow mechanism and (b) slip flow mechanism [13]

a

Air velocity is zero at the fiber surface

Cross section of fiber

b

Air velocity is not zero at the fiber surface

Cross section of fiber

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Fractional efficiency, η [-]

1.0 0.9 0.8 0.7 0.6 0.5

h1

0.4

h3

h2 h4

0.3 10

100

500

Particle diameter, dp [nm] Fig. 4 Fractional efficiency versus aerosol particle size for filters with fibers with different fiber diameter (η1 = 10 μm, η2 = 2 μm, η3 = 0.7 μm, and η4 = 0.1 μm) [5]

199 nm, 140 nm, and 54 nm, respectively [5]. Thus, the use of nanofibers is therefore a sustainable solution to improve the filtration efficiency, especially for very fine aerosol particles, which are more difficult to remove with commercial HEPA filters. However, the structural parameters of nanofiber filters in the experiment have been found to impact the air performance of nanofiber filters [1]. Relevant parameters include generally (i) basis weight, relying on measurement of thickness and density, (ii) fiber diameter distribution, (iii) pore size distribution, and (iv) the combination of tortuosity and porosity, which describe the degree of pore interconnectivity in the structure. Submicron fiber diameters, a narrow range of fiber size distribution, and a highly interconnected structure of pores are advantageous for filtration applications. Although fine fibers offer higher pressure drops due to low stiffness that facilitates physical compaction more easily, inertial impaction and interception efficiencies were found to increase rapidly and become the dominant capture mechanisms [1]. The next section is devoted to investigating the impact of structural parameters of air filtration performance of nanofiber air filters.

Properties of Nanofiber Filters and Parameters Affecting Performance: An Experimental Analysis In order to investigate and evaluate the performance of nanofiber air filters, the impact of structural properties and the effect of test conditions on filtration performance must receive due consideration. Air filtration performance is significantly

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influenced by nanofiber parameters, such as fiber diameter, fiber surface area, pore size, basis weight, as well as the thickness of the filters [1]. In addition, test conditions like the air flow speed are also impacting air filtration performance by compacting the fiber web via the pressure differential across the medium. This section will go through and discuss these parameters one by one to provide a general scope of their impact on the performance. The fiber diameter was found to impact the air filtration efficiency. For example, using nanofiber diameter up to 300 nm can yield higher air filtration efficiency as high as 99% of 300 nm particles size [22] compared to 48.21% for 1000 nm fibers under similar conditions [40]. As an example, the decrease of polyacrylonitrile (PAN) fiber diameter from 1000 to 200 nm significantly increased the air filtration efficiency from 48.21% to 98.11% [40]. Indeed, the smaller diameter increased the filtration efficiency but simultaneously led to higher pressure drops. The decrease in the fiber diameter from 185 to 94 nm increased the pressure drop from 5.36 to 20.91 Pa [41]. Small fiber diameters will generate smaller pore distributions, which shall lead to enhanced direct interception impact for particle filtration [42]. It therefore appears that combining various pore size distributions in a structure would be a good strategy to enhance the QF of the filter medium. To illustrate this, identical polyurethane (PU) nanofibers with different pore size distributions were stacked on each other to generate an asymmetric sandwich structure [43]. The filters with small and large pore size distributions offered higher air filtration efficiency than the filter with a uniformly small pore size. The latter case is due to the less tortuous path of the airstream in comparison to the less porous filter. The pore size can be tuned with special additives to the electrospinning polymeric solution or by manipulating the electrospinning parameters during the electrospinning process [44]. Table 1 shows how the pore size can be altered via the fiber diameter. The table shows also that the submicrometer fiber diameter can generate submicrometer pore sizes; however, an increase of fiber diameter up to 2.6 μm leads to the generation of higher pore size (up to 8.273 μm). A higher specific surface area and an interconnected structure can also help to incorporate surface functionalities across the fibers and generate active sites, by forming rough or porous structures or by grafting functional particles or moieties across the surface of the fibers [49, 50]. Such examples include TiO2 [49]. For example, adding titania (TiO2) to polysulfone (PSU) solution increased the Brunauer–Emmett–Teller (BET) surface area of the electrospun fibers from 16.96 Table 1 The impact of fiber diameter on the pore size formation No. 1 2 3 4 5

Polymer and solution PA/FA+PAN/DMF PVA/distilled water Nylon 6/formic acid PA6/FA PVC+PU/THF+DMF

Fiber diameter (nm) 138–303 200 100–730 177 960–2600

Pore size (nm) 65–785 740 240–940 147.4–239.6 3524–8273

Reference [45] [46] [28] [47] [48]

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to 39.93 m2/g [49]. A small fiber diameter can also exhibit higher specific surface area compared to a larger fiber diameter [50, 51]. The increase of fiber diameter from 1 to 1.88 μm helped to increase the BET surface area from 5.28 to 18.45 m2/g [50]. A large surface area increases the deposition probability of aerosol particles on the surface of fibers, which delays the saturation and increases the filter life [22], and then enhances the filtration performance and potentially can help to remove biological contaminates by adsorption and interaction between the surface of fiber and the contaminates. The direct relationship between the specific surface area and the filtration efficiency has not been systematically investigated. The filtration efficiency and pressure drop are both increasing with the thickness of a filter and its basis weight, while air permeability follows an indirect relationship to these parameters [22]. For example, the filtration efficiency for γ-alumina electrospun nanofiber filter has increased from 99.848% to 99.97%, when the basis weight of the filter was increased from 9.28 to 11.36 g/m2 [52]. Regarding pressure drop, it was shown that increasing the basis weight from 0.042 to 0.333 g/m2 for electrospun nanofiber filter has contributed to increasing the pressure drop from 5.36 to 74.33 Pa [41]. A larger basis weight can increase the filtration efficiency but not the QF because of a corresponding increase in the pressure drop [41]. For example, the QF decreased rapidly when the basis weight increased from 0.042 to 0.085 g/m2 and dropped slowly from basis weight of 0.085 g/m2 onward to 0.333 g/m2 [41]. The QF decreases nonlinearly with the increase of the basis weight of the electrospun nanofibers. Thus, a higher filtration efficiency and QF need to be considered and optimized for better air filtration performance. The filtration conditions are also largely impacting the filtration performance of both the microfiber and nanofiber filters [53]. For example, the increase in face velocity leads generally to increase the pressure drop and decrease the filtration efficiency for the ultra-fine non-woven in the fibre range of 80-200 nm and HEPA filter [53]. The filtration efficiency of nylon 6 with diameter range of 80–200 nm decreased from 99.97% to 99.96% when the face velocity increased from 5 to 10 cm/s. However, the pressure drop increased simultaneously from about 90 to 290 Pa [53]. Last, humidity and temperature will also have an impact on the air filtration performance since they affect the material properties such as the surface tension, viscosity, and density, but no systematic studies have been conducted to date [1]. Filtration efficiency, pressure drop, and QF were tested in different relative humidities for porous poly(lactic acid) (PLA) nanofiber filters with fiber diameter in the range of 1–1,88 μm and pore size in the range of 4.67–5.35 μm [50]. The filtration efficiency of the membrane decreased from 99.38% to 98.45% as the relative humidity increased from 15% to 30% [50], then the filtration efficiency increased to 98.64% as the relative humidity increased to 45%, and after that, it dropped to 97.44% after the increase of the humidity to 60%. The pressure drop has decreased from 228.7 P to 143.8 Pa as the relative humidity increased from 15% to 60%. It was believed that the reasons for these phenomena could be attributed to the change in the BET surface area [50]. No more information is available so far about the impact of the temperature and the humidity on the air filtration performance for nanofiber- and microfiber-based filters.

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Applications of Nanofiber Air Filters The improvement of nanofiber filters has allowed to produce nanostructures that can satisfy higher air filtration requirements and provide lower pressure drop than the commercial HEPA filters media. For example, high performance masks have been commercially used as a protective tool for efficient capturing of fine particles and biomaterials such as bacteria and viruses, as well as particulate matters in air [1]. Some promising examples of nanofiber filters already used for commercial applications include: (i) Individual protection: nanofiber media can be used as facial masks. They have been adopted to prevent inhalation of small aerosol particles. These masks were known to exhibit high filtration efficiency and good breathability. Nanofiber facial masks have properties such as higher porosity, specific surface area, and lighter than the commercial media at the same pressure drop. The advantage of the nanofiber facial masks is that they have a small fiber diameter (about half a micrometer) which can contribute to increase the slip flow around the fibers and finally increase the interception, diffusion, and inertial impaction efficiencies, which leads to increase of the filtration efficiency without having to sacrifice the permeability. Recently, polymeric electrospun nanofiber gauze mask was designed from a polysulfone (PSU) solution to prevent the inhalation of PM2.5 from haze pollution [54]. The nanofiber masks were compared with commercial masks. Most the commercial masks were made of microfibers. The thin microfiber mask (disposable mask) exhibited 32.9% of PM2.5. However, the thick microfiber masks rejected more than 80% of PM2.5 but with higher pressure drop upward to 655 Pa. Likewise for R95 mask, it showed 99.9% of rejection ratio of PM2.5 but with 625 Pa of air resistance. The electrospun nanofiber mask rejected 90% of PM2.5 with just 410 Pa of pressure drop which can keep a comfortable breathability with high rejection ratio of PM2.5 [54]. The efforts for improvement of electrospun respirators should not only focus on the capture of PM but also on the problem of re-aerosolization and bioaerosol. (ii) Building air filters: several health hazards are related to the recirculation of contaminated air in buildings. Specifically, the recirculation in hospitals is a challenge, and it should address efficient filters to prevent pathogenic viruses and bacteria from air. Air cleaners made of electrostatic filters were employed to enhance the recovery of air into indoor spaces. Nanofiber filters have been suggested recently to remove bioaerosol, dust, and volatile organic gases. For example, electrospun PAN nanofiber media were functionalized with β-cyclodextrin (βCD) for removal of formaldehyde that might diffuse from fresh paints [55]. The fiber diameter of the functionalized electrospun PAN/βCD filter was in the range of 432–647 nm. The functionalized filter adsorbed the formaldehyde in the range 1.1, 2.03, and 2.35 mg/m2 at exposure time in the range 4, 8, and 12 h, respectively, which may have potential as molecular filters and indoor air purification materials [55].

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(iii) Dust collection and vehicle cabin: The air filter is one of the major parts of automobile engines. Recently, the industrial dust is one of the significant factors to cause air pollution. The filters at engines exhaust can purify the air before it is released. For example, a high efficient polyimide (PI) nanofiber filter was developed to remove PM2.5 from car exhaust [56]. The PM concentration was measured before and after filtration using particle counter. The filter was stable under the strong blowing of the car exhaust. Figure 5a, b shows the measurement of the PM concentrations before and after using the nanofiber filter, respectively. The filtration efficiency after using the filter was shown in Fig. 5c for particles size in the range of 0.3–10 μm. The filter can efficiently remove about 97.5% of particles of the PM from car exhaust at 80–90  C. The long-term service has also been tested for polyimide (PI) nanofiber filter, and the results revealed that the filter can continuously work for more than 120 h for PM2.5 and maintain a high PM2.5 filtration efficiency; the filtration efficiency was as high as 97–99% and 99–100% for removal of PM2.5 and PM2.5–10, respectively [56]. The electrospun nanofibers are therefore promising filter media with high filtration performance and low air resistance, which can work in a range of experimental conditions such as high temperature or long-term service [56]. The recent advances in the improvement of the nanofiber fabrication methods mean that the nanofibers have the potential to develop greater design than before for air filtration application. Various types and applications of nanofiber air filters have been designed and improved using nanofiber fabrication techniques and advantages. Air filters based on nanofibers offer excellent filtration performance such as selectivity, permeability, and pressure drop but sometimes lack mechanical flexibility and strength [1]. For example, the feasibility for developing composite structured filter by blending various weight ratios of different polymeric solution has been demonstrated to enhance the mechanical properties of electrospun nanofiber filter [48]. Electrospun polyvinyl chloride (PVC)/polyurethane (PU) fibers were deposited onto a

Fig. 5 (a) Measuring the concentration of PM of car exhaust without the filter. (b) Measuring the concentration of PM of car exhaust with the filter. (c) Filtration efficiency of PM from car exhaust [56] (Reproduced with permission [56]. Copyright 2016, American Chemical Society)

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commercial HEPA (?) filter. The best blend ratio demonstrated good tensile strength which reaches to 9.9 MPa with abrasion resistance approaching to 134 cycle. This multilayer composite however offered very high filtration performance, with 99.5% of air filtration efficiency and 144 Pa of pressure drop, respectively. Nanofiber filters using two different solutions were electrospun together at the same time to form composite structure [44]. Oil and non-oil aerosol particle filtration and superior antifouling properties were achieved using a novel synthesized fluorinated polyurethane (FPU) and were incorporated with the polyacrylonitrile/polyurethane (PAN/PU) composite nanofiber filter. One hundred fifty-four degree Celsius of contact angle with water (superamphiphobic) and 151  C of contact angle with oil (superoleophobicity) were endowed [44]. The filtration efficiency for the latter design was 99.9%, which may have the potential for various applications including respiratory protection and HEPA filters. Furthermore, flexible and self-standing nanofiber filter was fabricated using electrospinning technology [52]. γ-Alumina electrospun filter was formed of randomly oriented nanofibers with 330 nm of fiber diameter. A high thermal stability and tensile strength were shown, which reaches up to 900  C and 2.98 MPa, respectively. The filtration efficiency was 99.848% with pressure drop of 239.12 Pa at 9.28 g/m2, and the filtration efficiency could reach to 99.97% at 11.36 g/m2 of basis weight. The γ-alumina electrospun filter could favor their applications in fine particle removal applications and could be suggested for high temperature conditions. Introducing and developing other nanofiber fabrication techniques and materials will not only improve air filtration efficiency but can also contribute to create other nanofiber filtration media that could work in different conditions and circumstances.

Conclusions and Perspectives The recent advances in the improvement of the nanofiber fabrication techniques mean that it is now possible to combine functionalities and greater improved design for efficient air filters. The advantages of using nanofibers rather than microfibers for air filtration applications have been highlighted in over 43 publications, demonstrating the maturity of the field. A nanofibers addition to an air filters medium can be helpful filters, if used in combination to with HEPA filters, to better capture the nanoscale fractions of aerosol contaminants and with a resistance for the increase protection against microorganisms. Research in the direction of that is targeting the development the filters structure, and by assessing the impact of their fiber diameter, pore size, the specific surface area, as well as coverage mass basis weight of the electrospun web would likely help to achieve a higher quality factor and better filtration performance. Although nanofiber filters can efficiently capture particles less than 1 μm in diameter, their effectiveness to filter particles in the range of 1–100 nm has not been established yet. With the recent advances in the improvement of the nanofiber fabrication technologies, especially with regard to electrospinning technology, the nanofiber filters might effectively be able to capture the nanoscale of aerosol

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contaminates more effectively than current commercial media. Nanoscale aerosol particle capturing has not been explored and reported yet. Further improvements to the other nanofiber properties, such as the specific surface area, the interconnectivity of the fibers, and the thermal and mechanical properties, would likely help to optimize the air filtration performance of the nanofiber filters and support the development of the next generation of nanofilters.

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Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 981 Composite Membranes with Electrospun Inorganic Nanofibers Embedded in a Polymer/Ionomer Matrix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 985 Composite Membranes with Electrospun Ionomer Nanofibers Embedded in a Polymer/Ionomer Matrix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 992 Composite Membranes with Electrospun Polymer Fibers Embedded in an Ionomer Matrix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 998 Concluding Remarks and Future Trends . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1004 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1005

Abstract

Many fuel cell membranes are highly heterogeneous systems comprising mechanical and chemical reinforcing components, including porous polymer sheets, nanofibers or nanoparticles, as well as radical scavengers or hydrogen peroxide decomposition catalysts. In the last 10 years, great attention has been devoted to 1D nanomaterials obtained by electrospinning. Several chemistries and compositions from aliphatic or aromatic polymers to metal oxides and phosphates and morphologies from nanofibers to nanotubes have been employed to prepare nanocomposite membranes. Despite the significant advances realized, further improvements in ionomer membrane durability under operation are still required. In particular, it is crucial to control the heterogeneity induced by the nanofiber component and to strengthen the interface between them and the matrix. Specific interactions have been demonstrated to improve the fiber/matrix M. Zatoń (*) · S. Cavaliere · D. J. Jones · J. Rozière Institut Charles Gerhardt Montpellier, UMR CNRS 5253, Agrégats Interfaces et Matériaux pour l’Energie, Université de Montpellier, Montpellier Cedex 5, France e-mail: [email protected]; [email protected]; [email protected]; [email protected]; [email protected] © Springer Nature Switzerland AG 2019 A. Barhoum et al. (eds.), Handbook of Nanofibers, https://doi.org/10.1007/978-3-319-53655-2_32

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interface with overall improvement of dimensional and mechanical properties. In this chapter we review the different approaches to fuel cell membrane reinforcement based on electrospun polymers and inorganic nanofibers. Keywords

Fuel cell · Proton exchange membrane · Proton conductivity · Electrospinning · Ionomer · Composite membrane Abbreviations

(s)PAES (s)PEEK (s)PEEKK (s)PES (s)PFEK (s)PI (s)PPESK (s)PSU 1D 3D ADL BPPO CDP CNF CNT C-PAMPS Cys DMAc DMD DMF DMFC DMSO EW FER Gly LSC Lys MEA MW NT OCV PA PAA PAN PBI PBz

(Sulfonated) Poly(arylene ether sulfone) (Sulfonated) Poly(ether ether ketone) (Sulfonated) Poly(ether ether ketone ketone) (Sulfonated) Polyethersulfone (Sulfonated) Poly(fluorenyl ether ketone) (Sulfonated) Polyimide (Sulfonated) Poly(phthalazinone ether sulfone ketone) (Sulfonated) Polysulfone One-dimensional Three-dimensional Acid doping level Bromomethylated polyphenylene oxide Cesium dihydrogen phosphate Carbon nanofibers Carbon nanotubes Poly(2-acrylamido-2-methylpropane-sulfonic acid) Cysteine Dimethylacetamide Direct membrane deposition Dimethylformamide Direct methanol fuel cell Dimethyl sulfoxide Equivalent weight Fluoride emission rate Glycine Long side-chain Lysine Membrane electrode assembly Molecular weight Nanotubes Open-circuit voltage Phosphoric acid Polyacrylic acid Polyacrylonitrile Polybenzimidazole Polybenzoxazine

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Design of Heterogeneities and Interfaces with Nanofibers in Fuel Cell. . .

PEI PEMFC PEO PFSA PPA PPSU PTFE PVA PVB PVDF PVDF-HFP PVP RH SEM Ser sPOSS sPPO sPS SSC sZrO2 TEM TEOS Tg vol% wt% ZCCH ZrP

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Polyetherimide Proton exchange membrane fuel cells Polyethylene oxide Perfluorosulfonic acid Polyphosphoric acid Polyphenylsulfone Poly tetrafluoroethylene Polyvinyl alcohol Polyvinyl butyral Poly vinylidene fluoride Polyvinylidene fluoride-hexafluoropropylene Polyvinylpyrrolidone Relative humidity Scanning electron microscopy Serine Sulfonated polyhedral oligomeric silsesquioxane Sulfonated poly(phenyleneoxide) Sulfonated polystyrene Short side-chain Sulfonated zirconia Transmission electron microscopy Tetraethylorthosilicate Glass transition temperature Volume percent Weight percent Zinc-aminotriazolato-oxalate Zirconium phosphate

Introduction Proton exchange membrane fuel cells (PEMFC) convert the chemical energy of a fuel into electric energy and heat. Fuel cells can generate electricity continuously, with low or zero pollution emission as long as the fuel and oxidant are supplied. The key electrochemical reactions of hydrogen oxidation and oxygen reduction at the electrodes, as well as proton transfer from the anode to the cathode, take place in the core component of the PEMFC – the membrane electrode assembly (MEA) – which consists of an ionomer (proton-conducting polymer) membrane and anode/ cathode catalyst layers as schematically represented in Fig. 1. For low-temperature fuel cells (60–90
C), the fuel is hydrogen (or alcohols as in, e.g., direct methanol or ethanol fuel cells, DMFC, DEFC) and the oxidant is oxygen from the air (or gaseous O2). One major factor impeding large-scale commercialization of the PEMFC is the durability of the MEA components, in particular the electrolyte membrane [1–3]. It must not only be impermeable to the direct transfer of reactants and electronically

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Fig. 1 Schematic representation of a proton-exchange membrane fuel cell (PEMFC)

insulating, but it also needs to demonstrate high proton conductivity while being mechanically and chemically robust during the fuel cell lifetime [4]. Although these requirements have triggered development of many types of fuel cell electrolytes based on polysulfones (PSU), poly(benzimidazoles) (PBI), poly(imides) (PI), or poly(aryletherketones) (PAEK) [5–22], so far the state-of-the-art materials are perfluorosulfonic acid (PFSA) polymers. The PFSA membrane microstructure comprises two well-defined components: ionic clusters with hydrated sulfonic acid groups well percolated and phase separated from the hydrophobic backbone (polytetrafluoroethylene, PTFE) [23, 24]. The heterogeneity of the ionomer structure provides mechanical integrity and high stability in very harsh (electro)chemical environments due to the presence of the PTFE backbone and high proton conduction properties ensured by the presence of ionic domains [25]. The parameter that well describes transport properties of the PFSA ionomers in relation to its mechanical integrity is the equivalent weight (EW), defined as the ratio between the dry mass of the polymer in the acid form in grams and the equivalents of exchangeable groups. The EW can be tuned, and as a first approach, the lower the EW, the higher the proton conductivity of PFSA ionomers. Different membrane properties often closely related to polymer structure heterogeneity in terms of spatial organization of hydrophilic/hydrophobic domains were widely studied [25–27]. Based on this improved understanding, two main families of PFSA ionomer compositions are now classified: long side-chain (LSC) and short side-chain (SSC) structures (Fig. 2). In the SSC polymer structure,

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Design of Heterogeneities and Interfaces with Nanofibers in Fuel Cell. . .

Fig. 2 Chemical structures of LSC – Nafion ® structure (a) and SSC perfluorosulfonic ionomers (b) and (c)

a

CF2CF2

x

CF2 CF

Long Side Chain

OCF2 CFOCF2CF2SO3H CF3

b

CF2CF2 y

c

CF2CF2

z

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CF2 CF OCF2 CF2SO3H

CF2 CF OCF2 CF2CF2CF2SO3H

Nafion® EW 1100, x = 6.6

Short Side Chain Aquivion® EW 830, y = 5.5

Short Side Chain 3MTM

there is no -O-CF2CF(CF3)- unit in the pendant chain, and the length of the perfluoro vinyl ether side-chain is 2 (Aquivion® type) or 4 (3M™ type) CF2 units. One of the main constraints of PEMFC membranes is their loss of proton conductivity at temperatures above 100
C in a non-pressurized cell. In such membranes, the acidic functionalities of the polymers dissociate when solvated with water allowing proton transport. Thus the high conductivity of proton exchange membranes is directly related to the amount of ionic domains in the polymer structure and to their degree of hydration. Another factor to be considered for direct fuel cells is the fuel crossover. Methanol crossover occurs by diffusion through the water channels in hydrated PFSA as well as a consequence of electroosmotic drag (active transport among with hydronium ions during DMFC operation). The permeated alcohol is chemically oxidized at the cathode, which causes electrode depolarization or mixed potential resulting in lower performance and lower fuel efficiency of the DMFC, as well as cathode catalyst poisoning [28]. Constantly forward-moving performance and durability targets have driven the design of novel heterogeneous fuel cell membranes. First of all membrane thickness was reduced down to one tenth or one twentieth of that of first-generation Nafion®-like membranes in order to decrease the electrical resistance and improve water back transport. Thus the >200-μm-thick PFSA membrane of the 1990s gave a way to an ultrathin composite membrane system in which the well-documented heterogeneity of the ionomer membrane, at the microscale level, is further enhanced by incorporation of a mechanical [29] and/or chemical [30, 31] reinforcement. Reinforcement processing and membrane casting are usually separated steps, which create countless possibilities for different material designs. The nature of the ionomer or functionalized polymer, the chemical and mechanical reinforcing components, as well as the membrane thickness and any gradient of composition across it can be possibly developed or tuned for an engineered fuel cell membrane. For PFSA, ionomer development continues to be pursued in the direction of high proton conducting materials [32, 33]. These or other newly developed polymers/ionomers can be further associated with different types of mechanical supports in order to achieve membranes with outstanding performance and durability. The main role of the mechanical reinforcement in such a

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membrane design is to mitigate structural aging of the material and to extend MEA lifetime by constraining dimensional changes of highly conducting but mechanically fragile ionomer membranes. In contrast to thin self-standing pristine ionomer membranes, the reinforced electrolyte is able to withstand compression stress created by hydration and dehydration cycling that accompanies operation under variable load. Furthermore, some of the supports can be or can contain radical scavengers, which prevent radical attack and the ensuing ionomer defragmentation. Although the role of a mechanical support in macrocomposite membranes is clear, parameters such as material choice, desired architecture, and most importantly the interface between the support substrate and ionomer are all crucial for fuel cell performance and durability. Membrane reinforcements are often prepared using thermostable and mechanically robust polymers or inorganic materials [34–40]. The latter bring enhanced water retention, which significantly facilitate fuel cell operation at low relative humidity and high temperature conditions. Some of the most well-established substrates are expanded PTFE sheet from Gore® Fuel Cell Technologies [29], laserdrilled polysulfone or polyimide from Giner Electrochemical Systems [41], or polysulfone/microglass fiber fleece [42]. These materials fulfill their role as mechanical reinforcements; however, the use of each of them poses unique challenges: high processing cost, low flexibility in architecture design, and poor interface between substrate and ionomer to name but a few. Electrospinning with its versatility is attracting attention for the potential it has of introducing targeted architectures and interfaces into composite membrane systems [43–45]. Indeed, the variety of morphologies that can be achieved, from solid, hollow, porous, or core-sheath nanofibers or tubes to inorganic or hybrid fibers embedding nanoparticles, gives a tremendous freedom in engineering new materials. Furthermore, electrospinning technology allows control of the crucial parameters of porosity, fiber diameter, and their distribution in the matrix, which in terms of elaboration of composite membrane means the possibility of fine tuning interface and spatial organization between inert and conducting phases as well as pore interconnectivity. Many researchers have recently recognized these emerging opportunities for individualized products. The aim of this chapter is to describe the most relevant advances in the use of electrospun materials for the preparation of heterogeneous nanocomposite protonconducting membranes. For the sake of clarity, the chapter is organized into three sections based on material design criteria: – Composite membranes with an electrospun inorganic component embedded in a polymer/ionomer matrix (paragraph 2, approach C in Fig. 3) – Composite membranes with electrospun ionomer nanofibers embedded in a polymer/ionomer matrix (paragraph 3, approach A in Fig. 3) – Composite membranes with electrospun polymer fibers embedded in an ionomer matrix (paragraph 4, approach B in Fig. 3)

For a detailed explanation of the electrospinning technique and principles, the reader is invited to refer to published books or reviews [46, 47]. The effect

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Fig. 3 Types of membrane architectures based on electrospun materials: (a) inert material/ionomer surrounding a 3D interconnected nanofiber web of a proton-conducting polymer (paragraph 3), (b) proton-conducting polymer matrix surrounding an electrospun web of nanofibers of an inert or proton-conducting or cross-linked electrospun polymer (paragraph 4), (c) electrospun (protonconducting or inert) inorganic web embedded in a (proton-conducting or inert) polymer matrix (paragraph 2)

of electrospinning parameters on nanofiber membrane properties and performance is still difficult to evaluate and rationalize due to their numerous compositions and architectures. However, some endeavors may be found in literature [48].

Composite Membranes with Electrospun Inorganic Nanofibers Embedded in a Polymer/Ionomer Matrix As discussed above, among the challenges to tackle for proton exchange membrane fuel cells are retention of proton conductivity at high temperature and low relative humidity and suppression of direct crossover of the fuel to the cathode. Other concerns of great importance are mechanical stress in particular during wet-dry cycling and the free radical-induced chemical degradation of the polymer structure. The formation of radical species during fuel cell operation occurs through the decomposition of hydrogen peroxide in the presence of trace metal ions originating from the corrosion of system components. In particular hydroxyl, hydroperoxyl, and superoxide (HO•, HOO•, O•2) radicals attack vulnerable polymer sites, which leads to structure defragmentation and membrane thinning and consequent MEA failure.

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In this context, inorganic materials such as metals and metal oxides, zeolites, metal hydrogen phosphates, and heteropoly acids are of special interest when it comes to composite membrane development. The main advantages of adding an inorganic component are the improved proton conductivity [17, 49], water retention, thermal stability, and reduced fuel crossover in the resulting hybrid inorganic/ organic systems [5, 50]. Additionally, some inorganic additives are recognized as effective radical scavengers or hydrogen peroxide decomposition catalysts [4]. Embedded in the polymer structure, they efficiently mitigate radical attack and consequent ionomer defragmentation and significantly increase fuel cell durability [51]. Finally, some inorganic moieties with specific morphologies and interaction with the matrix ionomer can play an essential role in improving mechanical strength and dimensional stability of composite membranes. A range of approaches for the incorporation of inorganic moieties has been employed [52]. Among them electrospinning not only allows the preparation of 1D inorganic nanostructures with tuned compositions and morphologies [53–57] but also offers the possibility to build and control interfacial interactions between membrane components. It should be emphasized that the properties of hybrid membranes largely depend on the nature of the polymer matrix bearing acidic (e.g., PFSA) or basic groups (e.g., polybenzimidazole). However, no less important to successful material design are the homogenous dispersion and/or orientation of inorganic species in the ionomer, their morphology/shape control, and their propensity to favor interactions between organic/inorganic constituents. This section treats all these aspects as well as the development of novel hybrid inorganic-organic membranes. The strategy to improve membrane performance in dry and hot operating conditions through incorporation of hygroscopic metal oxide particles such as SiO2, TiO2, SnO2, and ZrO2 has been widely studied. The key challenges of this approach are the homogeneous distribution of the inorganic filler, the reproducibility of membrane processing, and the membrane homogeneity. All the issues can be addressed by electrospinning of inorganic additives. For instance, the approach of highly dispersed silica fibers embedded in electrospun sPEEK polymer nanofibers was used by Lee et al. [58] to develop a PFSAsPEEK/SiO2 composite material for medium-temperature (>100
C) fuel cells. Clearly the purpose of this work was to improve membrane water retention by incorporation of a hygroscopic oxide. Silica was formed in situ, during nanofiber formation, and was uniformly distributed through the sulfonated poly(ether ether ketone) web that was impregnated with Nafion® ionomer to prepare a dense membrane with good adhesion between the nanofiber and ionomer components. The presence of hygroscopic silica increases the water uptake capacity of the composite system, whereas sPEEK nanofibers provide its mechanical integrity and significantly reduced membrane swelling in the membrane in-plane directions. Thiam et al. developed a composite membrane of Nafion ® and electrospun palladium-silica nanofibers (Pd/SiO2) with the aim of reducing methanol crossover in DMFC [53]. A mixture of tetraethoxysilane, polyvinylpyrrolidone, and Pd nanoparticles was electrospun and the nanofiber web impregnated with the ionomer. The

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role of Pd nanoparticles in the composite membrane is to facilitate the oxidation of permeated methanol [59]. The final Pd/SiO2/Nafion® composite membrane indeed demonstrated excellent fuel barrier properties. Furthermore, a significant increase in membrane water uptake and proton conductivity was related to the participation of Si-OH groups in the construction of 3D proton conduction pathways. In other studies, in order to improve the efficiency of proton transport, SiO2 nanofibers were synthesized with immobilized amino acids such as cysteine (Cys), serine (Ser), lysine (Lys), and glycine (Gly) [60]. The proton conductivity of pristine and composite membranes decreased in the following order: Nafion®-Cys (242 mS/cm at 80
C) > Nafion®-Ser > Nafion ®-Lys > Nafion®-Gly > Nafion ®. Another strategy that introduces SiO2 nanoparticles in Nafion ® bulk was based on the dip-coating of an electrospun polyimide (PI) nonwoven web in SiO2/polyetherimide (PEI) [61]. The presence of silica particles interconnected by PEI in the PI nonwoven substrate enabled its facile impregnation with PFSA ionomer and significantly improved its mechanical strength. The composite membrane demonstrated higher water retention and suppressed dimensional change between waterswollen and dry states. In another approach, a PI nonwoven web was integrated into a proton-conducting silicate glass electrolyte fabricated via in situ sol-gel synthesis of 3-trihydroxysilyl-1-propanesulfonic acid/3-glycidyloxypropyl trimethoxysilane mixtures [62]. The high proton conductivity of the resulting glass electrolyte in nonhumidified conditions makes of this material an interesting alternative membrane type for further investigation. In another study, electrospun sulfonated zirconia (sZrO2) nanofibers were combined with a cross-linked poly(2-acrylamido-2-methylpropane-sulfonic acid) (C-PAMPS) [63]. sZrO2/C-PAMPS hybrid membranes with 30% fiber content showed exceptionally high proton conductivity of 340 mS/cm at 100
C. Clearly, continuous sZrO2 nanofibers served as interconnected channels capable of anchoring water molecules and providing facile hopping pathways for proton transfer. Moreover, thinner fiber diameters gave rise to higher proton conductivities most probably due to increased surface area and density of sZrO2 nanofibers. A different strategy toward novel thermostable high-performing inorganicorganic membranes is the incorporation of ordered mesoporous solids. For instance, mesoporous metal oxide (TiO2, CeO2, and ZrO1.95) nanotubes (NT) have been embedded into a Nafion® membrane to increase water retention in dry conditions [64]. The tubular structure in which metal oxide particles form a porous shell as displayed in Fig. 4 was achieved by calcination of metal precursors homogeneously dispersed in electrospun polyacrylonitrile nanofibers. This unique architecture of inorganic nanotubes not only increased water retention capability but also enhanced water diffusion in composite PFSA-based membranes. Indeed the amount of the water strongly bound to sulfonic acid groups was found to be two times higher in the nanotube-filled membranes than in the Nafion® 212 membrane at subzero temperature. Similarly, the water self-diffusion coefficient of TiO2 NT/Nafion ® was remarkably high in comparison with pristine Nafion ® (3.527 109 and 2.003 109 m2/s, respectively). Such improved water capacity and diffusion resulted in low ohmic and mass transport resistance of composite

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Fig. 4 SEM images of TiO2 TNT (a), CeO2 NT (c), ZrO1.95 NT (e) and TEM images and corresponding lattice fringes (inset) of TiO2 TNT (b), CeO2 NT (d), ZrO1.95 NT (f) (Reprinted with permission from [64]. Copyright (2014) American Chemical Society)

materials and led to higher PEMFC performance than with Nafion ® 212. For instance, the maximum power density values of MEAs operating at 18% RH and 80
C were 641 mW/cm2 with a 1.5 wt% TiO2 NT membrane, 449 mW/cm2 with a membrane comprising 0.5 wt% CeO2 NT, 546 mW/cm2 with a membrane containing 1.5 wt% ZrO2 NT, and 186 mW/cm2 with Nafion ® 212. The best results in terms of performance in both dry and fully humidified conditions were obtained with the membrane containing TiO2 nanotubes. Further studies revealed that nanotubes with smaller diameter (and thus high surface area) demonstrated greater water retention,

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which the authors related to an expanded ionic cluster size in the Nafion ® ionomer [65]. Also the durability of an MEA prepared using a hybrid nanofiber membrane was much improved, which was ascribed to enhanced water back diffusion [65, 66]. We earlier proposed the use of zirconium phosphate/zirconium oxide (ZrP/ZrO2) in the form of nanofibers, rather than nanoparticles, to introduce a reinforcing effect in a composite membrane [56]. The preparation of a nanofiber architecture required the use of “reactive” coaxial electrospinning: a zirconium precursor and a phosphorus source were spun together from separate solutions in order to delay formation of zirconium phosphate gel. The synthesis of the inorganic material occurs in situ, at the core/shell interface in the jet. The resulting web was then calcined, treated with phosphoric acid, and finally impregnated with SSC PFSA ionomer to form a composite membrane. It was demonstrated that the fiber length and high aspect ratio provide an extended interaction with the proton-conducting matrix. ZrP prevented membrane dehydration at elevated temperature and ensured high proton conductivity. Indeed, the ZrP/ZrO2 enriched membrane demonstrated improved elastic modulus, yield point, and proton conductivity in comparison with pristine PFSA membranes [56]. Solid acids are of particular interest due to their high proton conductivity (1–100 mS/cm) at the intermediate temperature range (200–300
C). These compounds undergo a phase transition from a low-temperature phase to a superprotonic phase, characterized by a dynamically disordered hydrogen-bond network. We proposed a different approach to electrospinning a highly interconnected protonconducting fiber web from an aqueous solution of thermally treated cesium dihydrogen phosphate, CsH2PO4 (CDP) [67]. CDP heat-treated at a temperature higher than its superprotonic phase transition temperature undergoes dehydration and partial polycondensation, and its dissolution in water leads to a viscous solution, which can be electrospun without a carrier polymer. SEM micrographs of freshly synthesized CDP particles, polymeric CDP, and electrospun polymeric CDP are shown in Fig. 5. The CDP-polymer nanofiber web showed a maximum proton conductivity of 80 mS/cm at 250
C. Carbon nanofibers (CNFs) are also receiving attention as a component of fuel cell membranes especially for direct methanol fuel cells [68, 69]. CNFs possess high aspect ratio and specific surface area and can be easily functionalized. For instance,

Fig. 5 SEM micrographs of (a) CDP, (b) polymeric CDP, and (c) electrospun polymeric CDP (Reprinted from [67] with permission of The Royal Society of Chemistry)

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Liu et al. used sulfonated CNF to create a hydrogen bonding interaction between the sulfonated fibers and sPEEK [69]. CNFs sheared into short length could be uniformly dispersed in composite membranes to generate tortuous methanol permeation pathways as illustrated in Fig. 6. Choi et al. combined the electrospinning of sPEEK with a carbon nanotube (CNT) forest [70]. The resulting aligned and interconnected nanofiber web was compressed and exposed to DMF vapor to eliminate the porosity, giving rise to dense and hierarchically organized CNT/sPEEK membranes with improved mechanical stability and performance over recast Nafion ® and sPEEK membranes. Original organic-inorganic hybrid membranes have been developed in LabertyRobert’s group [71, 72] with a design intent to mimic Nafion ® with its phase separation between hydrophobic and hydrophilic domains at the nano- and macroscale (see paragraph 1). The hybrid membranes prepared by electrospinning a sol-gel-based solution containing PVDF-HFP (polyvinylidene fluoridehexafluoropropylene) and 2-(4-chlorosulfonylphenyl)ethyltrichlorosilane with tetraethylorthosilicate (TEOS) [72] showed proton conductivity of 15 mS/cm at 120
C and 50% RH as well as an exceptional modulus above 80
C. These properties were related to the particular microstructure of the organic-inorganic membrane, consisting of bundles of assembled small polymer fibers surrounded by functionalized silica domains. In conclusion, all composite membranes comprising metal oxide 1D nanomaterials are characterized by improved water retention and fuel cell performance in low RH and high temperature conditions. Furthermore, the presence of some of the inorganic components reviewed so far enhanced water back diffusion and mechanical stability of the composite membranes. This long list of benefits provided by inorganic additives should be completed by radical scavenging activity and mitigation of chemical membrane decomposition [4].

H+

H+ CH3OH

CH3OH

SCNF/SPEEK composite membranes

SPEEK Backbone Carbon Nanfibers

Proton Channel Proton Transport Pathway Methanol Permeation Pathway

Fig. 6 The proposed mechanism of proton transport and methanol crossover prevention of sPEEK and sulfonated CNF/SPEEK composite membranes (Reprinted from [69]. Copyright (2017), with permission from Elsevier)

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The effective approach to mitigate PFSA membrane degradation is the incorporation of inorganic radical scavenger species such as SnO2, TiO2, CeO2, or MnO2. The scavenging ability of different additives largely depends on the rate constant of the redox reaction of the radical quencher with the hydroxyl radical HO•, as well as on the rapidity of regeneration of its active sites. Fast kinetics of hydroxyl radical quenching makes ceria one of the most efficient radical scavengers. Other factors such as ceria morphology, its distribution in the polymer matrix, or stability in highly acidic environment can be modified and further improved using electrospinning. Ketpang et al. investigated the influence of incorporation of mesoporous cerium oxide nanotubes on composite membrane durability [66]. The CeO2 NT/Nafion® not only outperformed pristine Nafion® membrane when operating under hot and dry conditions but also exhibited remarkable durability. After 100 h of accelerated stress test in open circuit voltage (OCV) conditions, the fluoride (product of the PFSA membrane decomposition) emission rate (FER) of the composite membrane was 20 times lower than that of the commercial PFSA membrane. Beyond the possibility of tuning ceria morphology, electrospinning was developed as a strategy for optimal ceria distribution within the polymer matrix. This approach was first considered in our work [31], in which we developed a thin protective composite layer of PFSA nanofibers embedded with CeOx that was incorporated into the MEA at the desired anode/cathode interface [73]. The lifetime of MEAs with asymmetric composite membranes comprising such a PFSA/CeOx layer was eight times longer than an unmitigated MEA, and the FER and OCV decay were significantly reduced. Interestingly, this approach was more effective when the PFSA/CeOx enriched side of the membrane was oriented to the anode side. This finding was related to enhanced regeneration of active Ce3+ sites in the reductive environment and to the partial dissolution of CeOx at the anode interface and further migration of cerium ions through the membrane. In contrast, cerium species created after CeOx dissolution at the cathode side are potentially easily leached from the MEA and so do not contribute to the prevention of membrane degradation. Indeed, the main problem associated with the integration of CeO2 into PFSA membranes is the dissolution and migration of cerium ions into both catalyst layers of the fuel cell. This instability of ceria in PFSA ionomer prompted further study, and a new approach of ceria immobilization on an electrospun polymer web has been investigated. The purpose of the electrospun support is to suppress the leaching of free radical scavengers. The additives were co-dissolved or dispersed in the polymer solution used for nanofiber web preparation. The integration of nanofiber-supported ceria in PFSA membranes was claimed in recent patent application [74]. The effectiveness of this solution has been confirmed also by recent work from Breitweiser et al. where PVDF-HFP nanofibers embedding CeO2 nanoparticles were directly electrospun onto gas diffusion electrodes and impregnated with a Nafion® dispersion [75]. The resulting reinforced membrane after 100 h aging showed at least three times lower voltage decay rate (0.39 mV/h) compared to that of a Gore-Select ® membrane (1.36 mV/h). Furthermore, energy dispersive X-ray spectroscopy did not reveal any significant migration of cerium into the catalyst layers during degradation after 100 h, thus corroborating that the nanofiber web provided anchorage to ceria.

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Composite Membranes with Electrospun Ionomer Nanofibers Embedded in a Polymer/Ionomer Matrix In this approach, fuel cell composite membranes comprise a highly protonconducting nanofiber web usually impregnated with an inert component to provide its mechanical stability. In such a scenario, the nanofibers, as a novel ion transport material, have to be very well interconnected in order to ensure a continuous protonconducting path through the membrane. The membrane micro-/nanostructure can be greatly influenced by the processing methods used. The electrospinning technique offers an opportunity to influence polymer chain conformation and organization at the nano-/microscale, thus determining membrane properties such as water uptake, proton transport (refer to section “Introduction”), or thermal and mechanical stability (refer to section “Composite Membranes with Electrospun Polymer Fibers Embedded in an Ionomer Matrix”). In the context of the approach of electrospun ionomer nanofibers embedded in a polymer/ionomer matrix, the elaboration of a nanofiber web with an adequate proton conduction pathway is crucial. Indeed, the first study on entirely electrospun/sprayed sulfonated poly(ether ether ketone ketone), sPEEKK, fiber mats exhibited a channelshaped network of ionic groups and, according to small-angle X-ray scattering results, improved phase separation compared to dense membranes [76]. PFSA and sPI polymers showed fast ion transport [77–80] when spun into 1D nanomaterials. Numerous investigations were performed to shed more light on the phenomena occurring in the polymer structure during the electrospinning process (polymer discharging and fiber formation). It was suggested that long-range ordered arrangements of polar groups in the polymer chains form proton-conducting channels [76–80]. Sulfonated polyimide nanofibers were unidirectionally aligned using electrospinning [79–81], giving rise to ultra-high single-fiber proton conductivity values >1 S/cm at 30–90
C and 95% RH. These fibers displayed a separation of hydrophobic and hydrophilic domains on the wall and in the core of the fiber, respectively, with the formation of a quasi-one-dimensional narrow conduction pathway that facilitated proton transport (Fig. 7). Additionally, since the polymer chains within the nanofiber were oriented in the axial direction, the mechanical strength of the nanofibers was significantly improved. The authors related such directional properties to the electrostatic forces between the collector and the electric charge present on a given nanofiber [79]. Similarly, outstanding proton conductivity (1.5 S/cm) was described for a single Nafion ® nanofiber with diameter of 400 nm [77]. Interestingly, electrospinning of Nafion® fibers with diameters >2 μm did not present any advantage in terms of proton conductivity as the measured values were similar to that of bulk Nafion ® (100 mS/cm). However, once the fiber diameter decreased to less than 1 μm, a sharp increase in the conductivity has been observed. Once again, these results were linked to a confinement effect in thinner fibers, which assists the alignment of the ionic domains in the longitudinal direction, a conclusion supported by information deduced from X-ray scattering experiments. Similar results were reported on ionomer nanowires which were incorporated into a microfuel cell [78].

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Fig. 7 Temperature dependence (at 95% relative humidity, RH) and (b) RH dependence (at 90
C) of proton conductivity of sPI nanofibers prepared using different electrospinning conditions (applied voltage, V2, of 0.5, 1.0, and 3.0 kV), a cast sPI membrane, and Nafion ® membrane (Reproduced from [80] with permission of The Royal Society of Chemistry)

Undoubtedly, molecular orientation within the polymer chains is a critical factor in determining the intrinsic proton conductivity of nanofibers. Although most studies focus on the preparation of highly conducting fibers for a specific application, there has been some research on the influence of electrospinning conditions on fiber properties. For instance, polymer orientation in electrospun nanofibers can be induced by electric field [82–84], nature of the collector [85], solvent relaxation time [83], as well as electrospinning solution and polymer properties. Orientation itself is a result of two competing processes, namely, the extensional forces, which orient polymer chains along the filament direction, and orientation relaxation. The latter is strictly connected to the polymer flexibility, its molecular weight, and glass transition temperature (Tg). In other terms, molecular orientation parallel to the fiber axis occurs during electrospinning; however, chain relaxation usually caused by residual solvent promotes the return of the polymer structure to the isotropic state, unless chain relaxation is hindered (e.g., through the use of charged collectors) [84]. Two main conclusions could thus be drawn. The electrospinning process itself induces molecular orientation of the ionic domains of the ionomers along the fiber, which can be further enhanced by addition of a polar solvent [86]. Furthermore, ionomers may be able to retain such created orientation through ionic bonding between domains, thus locking in the oriented structure and preventing relaxation. After this brief overview of the properties of ionomer nanofibers, the following part will focus on the preparation of fibrous ionomer substrates and composite membranes from them. As already mentioned, the principal role of an electrospun ionomer web in this approach is to ensure high proton conductivity in heterogeneous membranes. Due to their outstanding properties, PFSA ionomers are undoubtedly the most used electrolytes in fuel cell applications and therefore excellent candidates

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for nanofiber preparation. However, the electrospinning of these materials is very challenging [87, 88]. Indeed, PFSA exhibits formation of aggregates or micelles in aqueous and nonaqueous media [89]. As a colloidal dispersion, PFSA ionomers lack adequate entanglement of the polymer chains, indispensable property for the electrospinning of a polymer solution. PFSA thus tends to give rise to electrosprayed particles rather than electrospun fibers. It should be noticed that chain entanglement also closely depends on the molecular weight of the polymer and its concentration in the electrospinning solution [90]. This hurdle was overcome by the addition of high molecular weight polymer carriers such as polyethylene oxide (PEO) [91–93], polyvinyl alcohol (PVA) [93], polyvinylpyrrolidone (PVP) [94, 95], polyacrylic acid (PAA) [96], and polyacrylonitrile (PAN) [97]. Among these, PEO is the most commonly used, due to its good compatibility with PFSA dispersions and low amount required to obtain uniformly sized electrospun nanofibers. The incorporation of such carrier polymers increases the entanglement of polymer chains as well as the solution viscosity. Therefore, the choice of an appropriate carrier with adequate molecular weight can significantly improve the outcome from electrospinning. On the other hand, the main drawback of this approach is the lower proton conductivity of the composite fibers due to the presence of nonconducting carrier, strongly interacting with the ionomer and probably disrupting the conductive pathways it formed. For instance, Laforgue et al. electrospun 5 wt% Nafion ® dispersion with 200 kDa PEO [93]. At this molecular weight, 5 wt% of PEO was not enough for Nafion® nanofibers to form. Fibers with diameters of 80–180 nm could only be collected when the PEO content in the electrospinning solution was increased to 16 wt%, which significantly lowered the proton conductivity [92]. Two principal approaches can be followed to limit this undesirable effect. The first involves electrospinning using a high molecular weight carrier, which significantly reduces the concentration needed for fiber formation. In such a scenario, Nafion® nanofibers can be electrospun to a very high volume fraction [77]. Another approach consists of reducing the amount of polymer carrier required by using short side-chain and low EW ionomers. The influence of the side-chain length on the electrospinning process was investigated in earlier work in our group [98, 99]. Interestingly, the effect of the molecular weight of PEO was very pronounced for electrospun LSC ionomer, which demonstrated a sharp transition between bead formation (when PEO of molecular weight Mw 400 kDa was applied) and fiber deposition (when using PEO of Mw 1000 kDa). On the other hand, the morphology of electrospun SSC ionomers changed progressively from beads to uniform fibers when using PEO of increasing molecular weight. Finally, the total amount of polymer carrier required for fiber stretching was found to be significantly lower for SSC ionomers, other conditions being equal. These observations were interpreted in terms of weaker interchain interactions in LSC PFSA, which leads to a dispersion of lower viscosity. Pintauro et al. also investigated electrospinning of LSC and SSC PFSA polymers with different equivalent weights, namely, Nafion ® EW 1100 [100], EW 1115 [101], and 3M™ EW 825 and 733 [92]. These authors observed that beadfree nanofibers of 3M PFSA could only be achieved using 1 wt% of PEO (Mw = 300 kDa) and 10 wt% of ionomer dispersion. However, increasing the

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molecular weight of the carrier from 300 to 1000 kDa resulted in bead-free nanofibers with only 0.3 wt% PEO. Finally, electrospinning of both LSC and SSC ionomers using solvents with high dielectric constant and dipole moment (e.g., dimethylformamide, DMF, and dimethylacetamide, DMAc) resulted in a more stable polymer jet and nanofiber homogeneity [101]. In contrast to PFSA ionomers, most sulfonated polyaromatic hydrocarbon polymers can be spun into nanofibers without addition of a carrier, since they do not form colloidal dispersions but solutions in common aprotic solvents such as DMF, DMAc, dimethyl sulfoxide (DMSO), etc. The spin ability of these polymers is simply related to their molecular weight and their volume fraction in the electrospinning solution [90, 102]. Indeed, it was demonstrated that by carefully adjusting polymer physical properties along with processing parameters, nanofibers of sulfonated polysulfone (sPSU), sulfonated polystyrene (sPS), sulfonated poly(arylene ether sulfone) (sPAES), and sulfonated poly(ether ether ketone) (sPEEK) could be elaborated [76, 80, 102–108]. Sulfonated polyimides containing fluorinated groups to enhance their solubility in N,N-dimethylformamide were also successfully electrospun into nanofibers [80]. The next step after the elaboration of such proton-conducting nanofibers in the form of a two-dimensional web is their integration into a matrix to form a dense composite membrane. The incorporation of nanofibers with extremely large surface area, remarkable mechanical strength, and proton conductivity are expected to confer unique properties to the final materials. The resulting membrane characteristics do not simply result from the sum of the individual contributions of their components but also from the synergy created by an extensive nanofiber/matrix interface (see also paragraph 4). Changing the types of interactions between membrane components, the surface energy and the existence of labile bonds can lead to modification of membrane properties including fuel permeability, ionic conductivity, chemical, mechanical, and thermal stability. Indeed, using the same ionomer (e.g., poly(phthalazinone ether sulfone ketone)) in the fiber web and in the matrix [109] significantly increased proton conductivity, swelling resistance, and mechanical and thermal stability and decreased gas permeability compared to the corresponding “homogeneous” cast membranes. A similar strategy was employed for composite membranes based on sulfonated polyimide where aligned sPI nanofibers were embedded into a matrix of the same polymer, showing improved proton conductivity, durability, and gas barrier properties in comparison with non-reinforced sPI cast membranes (see paragraph 4). It is worth noting that the authors avoided the dissolution of the nanofiber mat while impregnating it in the matrix of the same polymer, by dissolving the latter either at high temperature [109] or in a non-protonated form [81]. Chemical cross-linking will be another option further discussed in paragraph 4. In another approach, ionomer fibers have been embedded into non-functionalized, non-proton-conducting polymers. Pintauro’s group developed composite membranes containing PFSA or sulfonated aromatic polymer nanofibers impregnated with an inert cross-linkable monomer [92, 100, 104, 110]. In order to ensure a proton-conducting interconnected network, the mat was densified to

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increase the volume density of the nanofibers and weld them. Such membranes demonstrated better mechanical properties than monocomponent membranes, due to the mechanical strength of the nanofiber structure as well as the reinforcing effect of the inert robust polymer matrix. In addition, the proton conductivity was outstanding due to the formation of an interconnected 3D network of proton channels. The dependence of the proton conductivity at 80
C on RH and the experimental stress-strain curves are shown in Fig. 8. This approach has been widely employed by many other research groups as summarized in Table 1 [58, 63, 79, 111–120]. The methods initially developed to embed nanofibers into a matrix are impregnation/casting with a polymer (or prepolymer followed by cross-linking) to fill the voids of porous webs [45]. Recently, a single step strategy based on simultaneous

Proton conductivity (S/cm)

a 100 733 EW PFSA-0.70 fiber volume fraction 825 EW PFSA-0.74 fiber volume fraction Nafion 212 10-1

10-2

10-3 30

40

50

60

70

80

Relative humidity (%)

b 35

e

30 25 Stress, MPa

Fig. 8 (a) Dependence of in-plane proton conductivity on relative humidity at 80
C of EW 733 PFSA and EW 825 PFSA nanofiber composite membranes embedded within cross-linked NOA 63 and Nafion ® 212; (b) Stress-strain curves of wet membrane samples at 25
C; a: EW 733 PFSA homogeneous membrane, b: EW 825 PFSA homogeneous membrane, c: EW 733 PFSA nanofiber network membrane (0.70 fiber volume fraction), d: EW 825 PFSA nanofiber network membrane (0.73 fiber volume fraction), and e: UV-crosslinked NOA 63 (Adapted from [92] with permission of The Royal Society of Chemistry)

20

b

15

d

10

c a

5 0

0

20

40

60 80 Strain, %

100

120

140

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Table 1 Overview of composite membranes comprising electrospun nanofibers of protonconducting electrolytes and a matrix of inert polymer Electrospun material 3M™ ionomer EW 733 3M™ ionomer/ PPSU sPES

Matrix material Norland Optical Adhesive 63

Membrane processing Web impregnation

Proton conductivity (mS/cm) 160 (80
C; 80% RH)

References [92]

PPSU/3M™ ionomer

Dual electrospinning

93 (120
C; 50% RH)

[121]

Nafion ®

Web impregnation

[118]

Norland Optical Adhesive 63

Web impregnation

87.5 (25
C; 95% RH) for 70 wt% nanofiber content 94 (30
C; 80% RH) for 70 vol% nanofiber content

Norland Optical Adhesive 63

Web impregnation

sPFEK/PES

–

sPI

sPI

Coelectrospinning layer by layer Web impregnation

sPS

Nafion ®

sPS/PEO (70/30 w/w)

Vinyl-terminated poly (dimethylsiloxane) sPEEK/PVA

sPAES/ sPOSS (60/40 w/w) sPAES

sPEEK/ PVB (70/30 w/w) sPEEK/ PVB (70/30 w/w) PVDF/PVA

(65/35 w/w) sPEEK/PVA (65/35 w/w) Chitosan

sPPESK/ ZCCH

–

sPPESK EW 500 sPEK EW 1380

sPPESK EW 580 PEK

86 (25
C; 100% RH) for 70 wt% nanofiber content 61 (80
C; 100% RH)

[111]

[104]

[115]

ca. 100 (80
C; 98% RH) for 10 wt% nanofiber content 180 (80
C; 100% RH) 100 (25
C; 98% RH)

[122]

Web impregnation

13.5 (60
C)

[120]

Web impregnation

38 (120
C)

[123]

Web impregnation Coelectrospinning followed by hot pressing Web impregnation Dual electrospinning

23 (25
C; 100% RH)

[124]

82 (160
C)

[106]

186.4 (80
C; 100% RH) 112 (80
C; 100% RH)

[109]

Web impregnation Web impregnation

[116] [119]

[125]

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electrospinning of charged and inert polymers has been developed, referred to as “dual electrospinning” [101, 121, 125–127]. This approach does not require a further impregnation step as the matrix polymer is already present within the dual electrospun composite, and instead membrane processing is finalized by hot pressing of the nanofiber web. Moreover, this method is not limited by dispersion/compatibility issues that often plague blended membrane systems. Ballengee et al. demonstrated the versatility of dual electrospinning by designing two distinct membrane structures: (1) Nafion ® nanofibers embedded in inert/uncharged polyphenylsulfone (PPSU) and (2) a Nafion ® film reinforced by a PPSU nanofiber network [126]. Both membranes were prepared from the same dual nanofiber mat of Nafion® and PPSU, which was submitted to different posttreatments. Both membrane types presented similar proton conductivities directly related to the Nafion ® content, while the membrane type (1) presented superior mechanical properties.

Composite Membranes with Electrospun Polymer Fibers Embedded in an Ionomer Matrix Another complementary strategy for preparation of composite nanofibrous electrolytes for PEMFC involves embedding a nanofiber polymer web into an ionomer matrix that ensures the proton conductivity of the system. The electrospun web is thus a robust nonconducting polymer, mainly playing the role of mechanical support in an approach at one level similar to that of ePTFE impregnated with PFSA (e.g., Gore-Select ® membrane; see paragraph 1) [29, 128–130]. However, in recent years the use of proton-conducting materials or polymers functionalized with acidic or basic moieties has been developed, instead of an inert polymer, so demonstrating the versatility of the approach and the panoply of possible materials declinations and associations (as schematically depicted in Fig. 3). To accompany the increased complexity and multifunctionality of the composite nanofiber-reinforced membranes, their preparation process, initially based on simple impregnation or casting, has evolved to be further combined with other methods such as dual electrospinning, in situ functionalization and pore filling, and direct membrane deposition. Polymers that have been used to produce electrospun reinforcing mats include polyvinylidene fluoride (PVDF), polystyrene (PS), polyvinyl alcohol (PVA), polysulfone (PS), and polyimide (PI) [57, 62, 131–143]. When these polymers (e.g., PVDF) were associated with Nafion ® in blend membranes, poor mechanical strength and high cell resistance were observed [144–148]. However, when PVDF was introduced in form of electrospun fibers embedded in Nafion ®, the properties of the resulting membranes were improved. MEAs comprising these nanofiber-based membranes demonstrated better DMFC performance than those using Nafion ® 115 at 65
C in 2 M methanol, which was ascribed to improved interfacial contact with the electrodes and lower membrane thickness [132]. In general, the introduction of a nanofiber mat of robust inert polymers has been demonstrated to be beneficial in particular on membrane mechanical properties, even in the absence of specific interactions between the reinforcement and the proton-

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Design of Heterogeneities and Interfaces with Nanofibers in Fuel Cell. . .

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conducting polymer. Arguably, the interactions operating in these composite systems are hydrophobic. A step further has thus been the optimization of the compatibility of the interface between fibers and matrix with chemical functionalization that leads to increased durability of the membranes. Strong interactions between the reinforcing and matrix components, such as between basic polymer nanofibers and PFSA or sulfonated polyaromatic polymers have thus been employed to further improve composite membrane properties. In such acid/base systems, a distinct induction effect takes place, by which protonation and deprotonation are promoted, resulting in superior low-energy-barrier proton hopping pathways [149]. In our group we have exploited acid/base and ionic cross-linking in PBI-PFSA composite membranes. Poly[2,20 -(m-phenylene)-5,50 -dibenzimidazole] (PBI) webs were prepared by electrospinning and embedded into low equivalent weight (EW = 700 g/mol) short side-chain Aquivion®. The membrane mechanical properties showed significant improvement over those of non-reinforced Aquivion® of the same EW: Young’s modulus increased from ca 40 MPa to ca 160 MPa. The membrane proton conductivity exceeded 30 mS/cm at 110
C, 50% RH and 160 mS/ cm at 80
C, 95% RH. PBI/Aquivion® membranes have shown exceptional stability and durability in fuel cell tests designed to accelerate chemical and mechanical degradation mechanisms, including open circuit voltage hold testing at 85
C and 13% RH and wet-dry cycling at OCV [150]. These results are ascribed to the ionic cross-linking with proton transfer from the ionomer to the surface basic sites of electrospun PBI nanofibers. Additionally, the PBI nanofiber web may also confer chemical stabilization (see paragraph 2) to the composite membrane. Other acid/base interactions between electrospun fibers and matrix have been exploited in composite membranes, such as sPEEK and chitosan [151] or polydopamine-modified graphene oxide [152]. They result in the improvement of dimensional stability and the proton conductivity. A systematic study on the effect of different types of interfacial interactions (acid/acid, acid/base, acid/neutral, base/ base, base/neutral) between electrospun nanofibers and secondary polymers was reported [149]. Among them, acid/base interaction was confirmed as the most effective in enhancing the membrane tensile strength and proton conductivity in hydrated and anhydrous conditions. Further proof of the crucial role of ionic interactions is the improvement in mechanical and proton transfer properties when SSC PFSA was reinforced by pure polysulfone (PSU) nanofibers (weak hydrophobic interaction) [143] and 1,2,3-triazole-functionalized PSU [153] (strong acid/base interaction) [154]. Figure 9 clearly shows the lack of compatibility between PSU fibers and PFSA after drying the membrane (b) in comparison with the strong interaction achieved when the same fibers are functionalized (b). Other work consisted of the functionalization of the fibers with acidic groups similar to those present in the ionomer. For example, PVDF nanofibers were functionalized with Nafion® [134, 136] and impregnated into a Nafion ® matrix. The resulting membrane presented superior mechanical strength (Young’s modulus = 1840 MPa) to recast Nafion® (Young’s modulus = 1280 MPa). Its proton conductivity (60 mS/cm) surpassed that of Nafion ® 117 or recast Nafion ® (42 and 22 mS/cm, respectively). This result was attributed to the aggregation of Nafion®

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Fig. 9 Details of SEM micrographs of PFSA membranes embedding (a) 1,2,3 triazole functionalized and (b) bare PSU [154]

chains on the nanofiber surface inducing the formation of proton-conducting channels. The power density in DMFC and H2/O2 single cells for an MEA based on the functionalized PVDF fiber/Nafion ® membrane was higher than with MEAs comprising Nafion ® [134]. The presence of Nafion ®-PVDF nanofibers also reduced the methanol permeability of the membrane allowing DMFC operation with 5 M methanol. In other studies, polybenzimidazole nanofibers were doped with phytic acid and embedded into Nafion® [155]. The resulting composite membranes showed higher proton conductivity than a pristine recast Nafion ® membrane at 80
C and 40% RH (3.1 mS/cm vs 1.2 mS/cm) that was attributed to the formation of 3D network nanostructures able to effectively transfer protons and water through acid-condensed layers at the fiber/matrix interface. Gas barrier and mechanical properties were also improved upon the introduction of PBI-phytic acid fibers enabling the preparation of ultrathin membranes ( 0.999). This graph aims to show the influence that conditions such as initial dye concentration, adsorbent dose (affecting the saturation of dyes), and pH (influencing adsorbent surface charge and dye solubility) can have on the relation between adsorption capacity and specific surface area. The higher slope coefficient observable for nanostructures suggests a greater adsorption rate from the nanomaterials, which could be linked to their enhanced contact surface area.

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Adsorption capacity (mg/g)

a

MB IC 15-30 mg/L, AD 0.25 g/L, pH 7 IC > 60 mg/L, AD 1g/L, pH 7 1000

GAC from pods GAC from bamboo GAC from tea

BN nfs

100 Carbon nts

CoxOx nfs

10 10

100

1000

10000

2

Specific surface area (m /g)

Adsorption capacity (mg/g)

b

MB

600 500 400 300 200 100 0 0

100

200

300

400

500

600

Fiber diameter (nm) Fig. 2 Graphs showing the adsorption capacity related to adsorbent specific area against Methylene Blue MB in similar conditions of initial dye concentration IC, adsorbent dose AD ( 0.2 g/L), and pH ( 0.5) (a). Graph showing adsorption capacity related to nanofiber adsorbent diameter against MB (b)

Figure 2b shows the relation between adsorption capacity and nanofiber diameter for MB adsorbents. Assuming a similar fiber morphology and surface texture between the nanofiber adsorbents, fiber diameter can be assimilated as an indication of the adsorbent contact surface area with the dye. No specific trend could be observed regarding the possible influence of the nanofibers diameter onto the adsorption

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performance. This absence of relationship may suggest that other physical properties of the nanofiber adsorbents play a more important role in the adsorption of dyes, including the surface chemistry and functional groups or charge density [33].

Influence of Adsorbent Pore Size The impact of adsorbent pore size onto the adsorption capacity against MB, MO, CR, and RhB respectively is illustrated in Fig. 3a–d. The same trend can be observed in the four graphs and is characterized by an exponential-type decrease from a specific pore size range in the adsorption capacity with the increase of adsorbent pore size. In the case of MB adsorption (Fig. 3a, adsorbent pore size was reported from 1.9 nm (commercial AC, Table 2- n
33) to 1.0 μm (fresh diatomite, Table 2- n
32). This pore size corresponded to an adsorption capacity of 23.9 and 4.95 mg/g. Maximum adsorption capacities were observed for a pore size in a range between 2.05 and 3.5 nm (Table 2- n
41, n
1). Similarly, the best performance was obtained for a pore size range from 3 to 4.26 nm in the case of MO (Table 4- n
18, n
2 – Fig. 3b). In the case of CR, pore size ranged between 15.2 and 16.7 nm (Table 7- n
8, n
6 – Fig. 3c). Finally, in the case of RhB, pore size ranged from 19.5 to 22.95 nm (Table 5- n
17, n
13 – Fig. 3d) for the best adsorption performance. The pore size ranges themselves can be noticed to be of a relatively similar size for MB, CR, and MO (1.5 and 1.25 nm ranges), while twice the size for RhB (3.5 nm range), although less adsorptive data was reported in the case of RhB. This optimum pore size range of the adsorbent can be linked to the kinetics of pore blocking (i.e., dye diffusion rate), adsorbent pore geometry, and the single orientation of MB, MO, CR molecular chains (Table 1). Indeed, mesopores (from 2 to 50 nm) allow the diffusion of dye molecules in the adsorbents [31]. In the case of MB, with a hydrodynamic radius of 0.5 nm (e.g., 1 nm diameter), an adsorbent pore size of 1.9 nm would result in pore blockage in the event 1 MB molecule get adsorbed to opposite sides of a pore, assuming a cylindrical pore geometry. On the contrary, for an adsorbent with an average pore size of 3.5 nm, the adsorption of 1 MB molecule to opposite sides of a pore still allows the dye diffusion through a 1.5 nm channel [31]. On another hand, higher pore sizes (over 5 nm for MB and MO) can insufficiently promote contact between adsorbent/adsorbate, thus resulting in a potentially lower performance depending on the adsorption mechanisms at stake (Table 2- n
8, n
11). The suitability of the pore geometry (size and volume) regarding the orientations of the adsorbate molecule (one direction for MB, MO, and CR, and three for RhB) may explain the difference in the width of the pore size range leading to higher yields of dye diffusion and hence dye adsorption. Beside the adsorbent morphology, voids between the nanofibers in the case of fibrous mats could also impact on the diffusion of the dye molecules; however, over 85% of the studies reported a nanofiber web fabrication by electrospinning process, hence ensuring webs of high porosity and of suitably large pore sizes to enable dye diffusion. This last aspect is critical as to the hydrodynamics of the solution diffusion, and therefore the impact of the webs wettability is critical to the design of nanofibrous adsorbents.

Fig. 3 (continued)

0

200

400

600

800

1000

0

200

400

600

800

c 1000

Adsorption capacity (mg/g)

Adsorption capacity

0

0

200

20

60

600

Pore diameter

400

Pore diameter (nm)

40

100

800

1000

MB Particles Nanoparticles Nanotubes Nanofibers

80

MO Particles Nanoparticles Nanosheets Nanofibers

b

d

Adsorption capacity Adsorption capacity (mg/g)

a

0

50

100

150

200

0

100

200

300

400

500

0

0

2

6

40

Pore diameter (nm)

20

4

Pore diameter

60

80

100

RhB Nanoparticles Nanotubes Nanosheets

8

CR Particles Nanotubes Nanosheets Nanofibers

1064 E. des Ligneris et al.

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Nanofibers for Water Treatment

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Nanofiber adsorbents with average pore size in the above-defined ranges showed among the highest adsorption capacities against CR (Table 7- n
8) and RhB (Table 5n
18) when compared to other adsorbents reported in this study, and among the average performance compared against MB (Table 2- n
21) and MO (Table 4- n
1).

Comparison of Adsorption Equilibrium Time Figure 4a, b show the relationship between adsorption capacity and adsorption reaction equilibrium time for different adsorptive structures against MO and MB. These graphs aim to show the average shorter equilibrium times (under 5 h) reported for nanostructures compared to macro-adsorbents, as can be easily noticed in Fig. 4b, as well as the yield of higher adsorption capacities (over 200 mg/g) for nanofibers compared to other nanostructures, as can be seen in Fig. 4a. The difference in adsorptive performance can be explained by the stability of nanofibers in water, while the nanoparticle adsorbents tend to agglomerate under the effect of surface interactions such as van der Waals, hence hindering the adsorption reaction. The difference in kinetics between nanofibers and macro-structures can be the result of the higher surface to volume ratio of nanofibers. Figure 4c shows the reported equilibrium times for MB, CV, and RhB adsorption by nanofibers. Basic dyes show affinity for adsorption on selected carbon nanofibers, cationic polymers such as polyacrylonitrile, and protein nanofibers. The highest adsorption capacity, of 580 mg/g, has been reached by carbon nanofibers after 2 h of adsorption experiment (Table 2- n
14), and two cationic polymer nanofibers reached capacities over 200 mg/g in less than 3 h of adsorption duration (Table 2n
10, n
22). Although insufficient data has been reported to identify a clear trend in similar test conditions, it can be suggested that electron interactions as preponderant adsorption mechanism lead to faster kinetics than ionic binding with cationic polymers, itself faster than chemisorption on proteins. In the case of acid, direct, and reactive dyes (MO, CR, RB5), they have shown preferential affinity for adsorption on ceramic nanofibers, anionic polymers, and protein nanofibers, as shown in Fig. 4d. Two anionic polymer nanofiber adsorbents delivered higher adsorption capacities (up to 633 mg/g) yet reached a plateau after 22 h (Table 4n
10, n
9). Several ceramic nanofiber adsorbents showed capacities over 200 mg/g in less than 3 h, which is a higher performance than that delivered by proteins and anionic polymer nanofibers for the same reaction duration (Table 4- n
1 and Table 7- n
2). These kinetics comparisons suggest that electron interaction is a preferable adsorption mechanism for its time/performance ratio for both basic and acid dyes.

ä Fig. 3 Graphs showing the adsorption capacity related to adsorbent pore size for different adsorptive structures against Methyl Orange MO (a), Congo Red CR (b), Methylene Blue MB (c), and Rhodamine B RhB (d). Insufficient data reported for Crystal Violet CV and Reactive Black 5 RB5

Fig. 4 (continued)

c

10

15

1

2

Protein nanofibers

2

Cationic polymer nanofibers

25

d

200

300

400

500

600

Equilibrium Time

0 1

20

Basic dyes Carbon nanofibers

Equilibrium time (h)

0

200

400

600

800

1000

0

5

5

b

100

0

0

MO Particles Nanoparticles Nanotubes Nanofibers

100

200

300

400

500

600

0

200

400

600

800

1000

Adsorption capacity (mg/g)

Adsorption capacity

Adsorption capacity (mg/g) Adsorption capacity

a

5

10

0

5

15

1

Equilibrium Time

1

Equilibrium time (h) Acid, direct, reactive dyes Ceramic nanofibers Anionic polymer nanofibers Protein nanofibers

0

2

20

2

25

MB Particles Gel and foams Nanoparticles Nanotubes Nanofibers

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Nanofibers for Water Treatment

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Influence of Adsorbent Surface Charge and Solution pH Adsorbent isoelectric point IEP (here reported under pHPZC) and pH test conditions of adsorption are reported in the below adsorptive data tables. The adsorbent IEP was usually reported after being determined using the zero point of charge method in an aqueous medium with only H+/OH possible surface adsorption. Where adsorption pH was not reported, it may be assumed that solution pH is close to neutral pH, as dyes are relatively weak acids (Table 1) and adsorptive test was carried on model solutions. The isoelectric point of an adsorbent corresponds to the pH at which the adsorbent carries no net electrical charge and is used to determine adsorbent global surface charge in aqueous medium in function of the solution pH. The adsorbent surface charge can significantly enhance the dye adsorptive performance with the attraction of two opposite charges between adsorbent and adsorbate. Indeed, when the system is below the pHPZC, adsorbent will react with more H+ than OH groups, resulting in a positively charged adsorbent surface, therefore attracting anionic dyes (MO, CR, RB5, Table 4- n
6). On the other hand, for a system over the pHPZC, the adsorbent surface will become negatively charged, thus attracting cationic dyes (MB, CV, RhB, Table 2- n
7). As UV-Visible (UV-Vis) spectroscopy is often reported as the most appropriate technique to evaluate dye concentration, the range of initial dyes concentration reported is hence predefined by the UV-Vis detector limits. High-pressure liquid chromatography (HPLC) could be considered for the adsorptive study of low-contaminated effluents (initial dye concentration below 1 mg/L). In the case of MO, CV, and CR, initial adsorption pH and pH variations during adsorption can possibly lead to poor precision via UV-Vis as these dyes undergo an absorbance shift from orange (pH < 3.1) to yellow (pH > 4.4), from yellow (pH < 0.1) to violet (pH > 1.8), and from violet (pH < 3.8) to red (pH 4.8), respectively.

Nanofiber Performance Comparison Regarding Initial Dye Concentration and Adsorbent Dose Figure 5 shows bar charts representing the adsorption capacity with the corresponding test conditions of initial dye concentration and adsorbent dose for each dye, nanofiber adsorbent, and selected benchmark adsorbents. It can be noticed from all the charts that nanofibers delivered an adsorption performance on average in the range of other benchmarked adsorbents, from 1.5 to 580 mg/g (Table 3- n
2 and Table 2- n
14). The test conditions of initial dye concentration were in a similar

ä Fig. 4 Graphs showing the adsorption capacity related to the equilibrium time for different adsorptive structures against Methyl Orange MO (a) and Methylene Blue MB (b). Graphs showing the adsorption capacity related to the equilibrium time for selected adsorptive nanofiber compositions against basic (cationic) dyes (c) and acid, direct, reactive (anionic) dyes (d)

3 100

0 0

fib

np s

/PA M

an

Ch ito s

fs

nfs

en

Ce llu .n fs

Al2 PV O3 A/P nfs AA /G O/ PD An fs

3

so zim

4

Ly

5

fs

6

Ze in n

Po lya nil ine nfs

ers PE I/C hit os an be ad s

PE I-P VC

NiO

T/M IP nfs

Ox im e/

PE

Pa lm fib er PP /M IP fib er Du oli te res in

gh att i/F e3 O4 np s SiO 2n an os he ets

Mo S2 np s

T/C oF e2 O4

C/T iO 2n ts

PA Nn fs ED A/P AN nfs ED A/P AN PV nfs A/P AA /G O/ PD An fs

Gu m

CN

ter hy

nth

ac y

er

lym

po

nfs e/P VD Fn fs

DF

PV

Mo dif .C ell u./ PV DF nfs Hu mi ca cid /Ce llu .n fs Hu mi ca cid /PA Nn fs Gr ap he ne /h yd rog el nfs

Ce llu los

Ce llu los en fs

Wa

CD

Cu -sa lt h yd rog el Ch ito sa n/G O/ PU foa m

30

Pp yn fs

5

ps

e

e

nit

lig

40

SiO 2n fs Zn O/ Sn O2 nfs

4

O2

nit

ton

m

fro

Fe 3O 4/b ioc ha r

AC

50

PE In fs

5

2n

en

15

Ce llu ./C hit ./T i

-b

Co mm erc ial AC Bi2 O3 /be nto nit e Bla ck tea lea ve s AC /M nO 2n ps

PV

BN PD A/P nfs VA /PA A/P An AA fs /G O/ PD An fs

GA Cf rom co fro al m sa wd us t 3D GO ge Cr l us he db ric k Ch itin np s Mo S2 np s Ca rbo nn Po ts lya nil Gr ine ap nts he ne /PA M nfs ED A/P AN nfs Zn O/ TiO Sn O2 2/P nfs AN /M on tm .n fs Ke rat in ß-C nfs Dba se dn Fe fs /PV A/P AA nfs GO /PA Nn fs Ce llu los en At fs ta. /Ce llu .n fs Gr Ca ap rbo he nn ne fs /Hy Hy dro dro ge ln ge fs n/T ita na MI te L-5 nfs 3(F e)/ PA Nn Ox fs im e/P AN nfs GA C

1,5

TiO

Na nO

3-S

2O

Fe

nto

CN T

ith

C

20

PA Am /Si O2 np s Sta rch /PA NI np s

15

-be

ir p

PA

25

MW CN Ts

20

Ca

co

ial

2,0

PA Nn PA fs N/P AM AM nfs PA NI/ PA M nfs

d m

erc

0

ite 2n an oro ds na no BiO sh Cl ee /Ti ts O2 na no Mn pla /Fe tes 3O 4n an ow ire s Zn O/ Sn O2 Ca nfs lix a re ne /P AN nfs Mo dif .P ET fib ers Pp y/ PA NI nfs Mn O2 na no wi res ZIF -8@ PV An Ke fs v la r-b as ed nfs PA NI/ Fe nfs Cu O/ Zn O nfs

c fro

d

PA C

Co mm

c

AC

b

Pin en ee dle sb ioc ha r Be nto nit ep art icl es GO na no str uc tu r es

Co mm erc ial

a

Cn Ca fs rbo na ce ou sn PD fs A/P VA /PA An fs Co 3O 4n fs ED TA /PA Nn fs

ph rag mi te AC fro m fru it Co Ch rk ito pa sa rtic n/A les l2O 3/F e3 O4 np Al2 s O3 nfs film s Cu @C u2 Fe O 3O np 4/C s na no po wd er MW Pa lyg CN ors Ts kit en an oro ds Ch ito sa nf lak es Al2 O3 nfs

AC fro m

1068 E. des Ligneris et al.

MB Adsorbent dose (g/L) Initial dye concentration (mg/L) Adsorption capacity (mg/g)

1,0 400

0,0

CV Adsorbent dose (g/L) Initial dye concentration (mg/L) Adsorption capacity (mg/g)

20

RhB Adsorbent dose (g/L) Initial dye concentration (mg/L) Adsorption capacity (mg/g)

5

0

CR Adsorbent dose (g/L) Initial dye concentration (mg/L) Adsorption capacity (mg/g)

2

1

0

RB5 Adsorbent dose (g/L) Initial dye concentration (mg/L) Adsorption capacity (mg/g)

10 500

400

300

200

MO Adsorbent dose (g/L) Initial dye concentration (mg/L) Adsorption capacity (mg/g)

800

600

600

0,5 200 400

0 200

0

400 300

10 200 200

0

100

0

400

300

200

100

10

100 0

50

0

300 300

200 200

100 0

100

0

800

600

400

200

0

1000

800

2

400

400

1

200

600

200

0

0

0

Fig. 5 Bar charts showing the reported adsorbent dose (column, striped blue, g/L), initial dye concentration (column, green bar, mg/L), and adsorption capacity (scatter, red, mg/g) for all nanofibers adsorbents and selected benchmark adsorbents. Case of Methylene Blue MB (a), Crystal Violet CV (b), Rhodamine B RhB (c), Congo Red CR (d), Reactive Black 5 RB5 (e), and Methyl Orange MO (F)

32

Nanofibers for Water Treatment

1069

range, between 1.5 and 200 mg/L (Table 3- n
6 and Table 4- n
11). However, the adsorbent dose was reported on average below 1 g/L (Table 6- n
3). The lower adsorbent dose required for nano-adsorbents compared to macrostructures should be taken in consideration when calculating the material fabrication cost and regeneration volume. It can be noticed from the graphs that higher adsorbent doses, above 3 g/L, result on average in poorer adsorption capacities, falling below 20 mg/g (Table 3- n
11). Similarly, for an average adsorbent dose around 1 g/L, a lower initial dye concentration below 20 mg/L tends to result in a lower adsorption capacity (Table 2- n
13). These tendencies can be explained by the equations used to calculate the adsorption capacity, which will ultimately become lower for a higher adsorbent dose or lower initial dye concentration, yet for the same removal efficiency. The optimal adsorbent dose required for a given initial concentration and a target removal efficiency could be more consistently investigated among the adsorptive studies to enable a rigorous performance comparison between adsorbents. Adsorption capacities against basic dyes MB, CV, and RhB are presented in Fig. 5a, b, c. As previously discussed, basic dyes showed a preferential affinity for dyeing with protein fibers and cationic polymers. The best nanofiber adsorption performance against MB reported in this study goes to carbonaceous (580 mg/g, Table 2- n
14), polydopamine coated with poly(vinyl alcohol)/ poly(acrylic acid) polymer blend (356.1 mg/g, Table 2- n
22), β-cyclodextrin composites (250 mg/g, Table 2- n
10), and keratin (165 mg/g, Table 2- n
7) nanofibers. In the case of CV, graphene-embedded hydrogel (170 mg/g, Table 3- n
7) and humic acid-modified polyacrylonitrile (45 mg/g, Table 3- n
6) nanofibers are the best performance here reported, and in the case of RhB, ethylenediamine-modified polyacrylonitrile (65 mg/g, Table 5- n
2) nanofibers. These results show that the preferential chemical affinity for fiber dyeing via ionic binding and H-bonding with cationic polymers and proteins can be transposable to preferential chemical affinity for adsorption onto nanofibers and therefore play an important role in the adsorption performance. To further illustrate, humic acid-modified polyacrylonitrile nanofibers revealed a higher adsorption capacity than humic acid-modified cellulose nanofibers in lower conditions of adsorbent dose and initial dye concentration, against CV (Table 3- n
5, n
6). Adsorption onto carbon nanofibers via electron interaction showed to be most efficient adsorption process against this class of dyes. The highest adsorption capacities reported for nanofibers against direct dye CR as shown in Fig. 5d were obtained with para-aramid (340 mg/g, Table 7- n
8), ceramics such as manganese oxide (282 mg/g, Table 7- n
6), cellulose (158 mg/g, Table 7- n
11), and polyaniline (99 mg/g, Table 7- n
9) nanofibers. The dye preferential affinity for cellulosic and anionic polymer fibers via -H and ionic bonding is also here transposable to the adsorption by nanofibers. Contrary to basic dyes, polyacrylonitrile and graphene composite nanofibers gave lower performance, such as 35 mg/g (Table 7- n
3) and 12.94 mg/g (Table 7- n
12). Electron interaction as the most efficient adsorption mechanism also prevailed for direct dyes, as shown by the para-aramid and metal oxides adsorption capacities.

1070

E. des Ligneris et al.

Nanofibrous adsorbents against reactive dye RB5 presented in Fig. 5e showed higher capacities for polyaniline (434 mg/g, Table 6- n
1), lysozyme (160 mg/g, Table 6- n
3), and polyamide (119 mg/g, Table 6- n
4) nanofibers. Lysozyme nanofibers are protein nanofibers. Cellulose nanofibers as adsorbents for RB5 have not been found in the literature. As anionic dye (CR, RB, MO), the chemical affinity has been conserved for anionic polymers and proteins via ionic bonding. Finally, adsorption against acid dye MO shown in Fig. 5f delivered higher capacities in the case of nanofibers adsorbents for polyethyleneimine (633 mg/g, Table 3n
10), silica (607 mg/g, Table 3- n
12), carbon (558 mg/g, Table 3- n
2), and polyaniline–polyamide composite (370 mg/g, Table 3- n
9) nanofibers. This result further confirms the above trends.

Adsorption Mechanisms of Nanofiber Adsorbents Over 90% of the presented studies reported the nanofiber adsorption to follow a Langmuir isotherm model over the Freundlich isotherm model, suggesting a homogeneous and monolayer process of adsorption [20]. Furthermore, pseudo-secondorder kinetics were reported to fit the data well (compared to the pseudo-first-order model), thus suggesting chemisorption as the rate-limiting process of adsorption [20]. These behaviors suggest that functional sites are homogeneously distributed on the nanofiber surface, and that surface interaction forces such as Van der Waals do not significantly affect the adsorption on nanofibers. Figure 6 shows the correlation between the theoretical maximum monolayer adsorption capacities based on the Langmuir model and the demonstrated adsorbent capacities. It can be noticed that nanofiber adsorbents do not perfectly follow a linear

Methylene Blue Methyl Orange Congo Red

600

Adsorption capacity (mg/g)

Fig. 6 Graph showing the theoretical maximum monolayer adsorption capacity based on Langmuir isotherm models for nanofiber adsorbents related to the demonstrated adsorption capacity against Methylene Blue MB, Methyl Orange MO, and Congo Red CR. Insufficient data reported for Crystal Violet CV, Rhodamine B RhB, and Reactive Black 5 RB5

500 400 300 200 100 0 0

200

400

600

800

1000

1200

Maximum monolayer adsorption capacity (mg/g)

32

Nanofibers for Water Treatment

1071

trend, although studies consistently reported a correlation coefficient R2 above 0.98. This can firstly be explained by the temperature of the test, which has been reported for over 90% of the capacities shown in the graph below between 20
C and 30
C, hence possibly affecting the linear alignment of the data. A slight variation of temperature in that range would strongly affect Brownian motion of the dye molecules and their interactions with the surfaces [34]. This relationship may also be explained by a significantly slower dye diffusion step once the reported equilibrium time has been reached, resulting in a higher value of the theoretical adsorption capacity. This nonlinear trend might also be impacted by a change in the prevailing of the different adsorption mechanisms contributions depending on the equilibrium dye concentration.

Adsorption Data Tables Methylene Blue See Table 2.

Crystal Violet See Table 3.

Methyl Orange See Table 4.

Rhodamine B See Table 5.

Reactive Black 5 See Table 6.

Congo Red See Table 7.

9

8

7

6

5

4

20

14

39

220

240

250

225

0,04

0,66

14,5

4–4.5

0,18 0,32

25

73,4

0,1

1,25

0,25

40

250

20

10

400

130

165

15,68

39,2

39

9

6

10

25

25

25

25

50

5

6

5

0,67

4

0,17

Freundlich

Langmuir 826,45

Langmuir 167

Langmuir

Langmuir 94,07

[40]

[39]

[13]

[38]

[12]

[37]

[36]

[35]

[31]

Max. monolayer adsorption capacity (mg/g) Ref

Freundlich 0,75

Langmuir

0,7

2,5

0,19

24

200

3

1

22

5,26

0,016

85

220

124

2

3,5

1

0,29

200

583

N
Adsorbent

Lignin carbon nanofibers Nylon-6 nanofibers with entrapped graphene flakes PES nanofibers containing V2O5 nanoparticles Ethylene diamine-grafted PAN nanofibers ZnO/SnO2 nanofibers PAN/ montmorillonite nanofibers coated with TiO2 nanoparticles Keratin nanofibers β-cyclodextrinbased nanofibers PVA/PAA nanofibers decorated with Fe nanoparticles

Pore Pore Adsorption Initial dye concentration Adsorbent Temperature Equilibrium Isotherm Diameter volume diameter capacity (cm3/g) (nm) pHPZC (mg/g) (mg/L) dose (g/L) pH (
C) (nm) time (h) model

Adsorption experiment

BET (m2/ g)

Adsorbent properties

Table 2 Nanofibrous adsorbent properties and adsorption conditions for the removal of Methylene Blue

1072 E. des Ligneris et al.

10 Sericin/ β-cyclodextrin/ PVA nanofibers 11 PAN yarn waste/ graphene oxide nanofibers 12 Cellulose nanofibers 13 Attapulgitecellulose coreshell nanofibers 14 Carbonaceous nanofibers 15 Co3O4 nanofibers 16 Grapheneembedded hydrogel nanofibers 17 Hydrogentitanate nanofibers 18 MOF MIL-53 (Fe)/ PAN nanofibers 19 MnO2/cellulose nanofibers 20 Oxime-grafted PAN nanofibers 21 Porous boron nitride nanofibers

515

10

167

55

5

0,566

2,7

3,2

107,3

20

0,25

1

80

79,84 400

1

5

4,2

41

0,5

2

0,5

0,2

1,25

1

0,5

0,2

10

320

32

100

12

80

1

20

18

150

307

32

12,8

580

126