Electrospun Materials and Their Allied Applications 1119654866, 9781119654865

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Electrospun Materials and Their Allied Applications

Scrivener Publishing 100 Cummings Center, Suite 541J Beverly, MA 01915-6106 Publishers at Scrivener Martin Scrivener ([email protected]) Phillip Carmical ([email protected])

Electrospun Materials and Their Allied Applications

Edited by

Inamuddin, Rajender Boddula, Mohd Imran Ahamed and Abdullah M. Asiri

This edition first published 2020 by John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, USA and Scrivener Publishing LLC, 100 Cummings Center, Suite 541J, Beverly, MA 01915, USA © 2020 Scrivener Publishing LLC For more information about Scrivener publications please visit www.scrivenerpublishing.com. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, except as permitted by law. Advice on how to obtain permission to reuse material from this title is available at http://www.wiley.com/go/permissions. Wiley Global Headquarters 111 River Street, Hoboken, NJ 07030, USA For details of our global editorial offices, customer services, and more information about Wiley products visit us at www.wiley.com. Limit of Liability/Disclaimer of Warranty While the publisher and authors have used their best efforts in preparing this work, they make no rep­ resentations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of merchant-­ ability or fitness for a particular purpose. No warranty may be created or extended by sales representa­ tives, written sales materials, or promotional statements for this work. The fact that an organization, website, or product is referred to in this work as a citation and/or potential source of further informa­ tion does not mean that the publisher and authors endorse the information or services the organiza­ tion, website, or product may provide or recommendations it may make. This work is sold with the understanding that the publisher is not engaged in rendering professional services. The advice and strategies contained herein may not be suitable for your situation. You should consult with a specialist where appropriate. Neither the publisher nor authors shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages. Further, readers should be aware that websites listed in this work may have changed or disappeared between when this work was written and when it is read. Library of Congress Cataloging-in-Publication Data ISBN 978-1-119-65486-5 Cover image: Pixabay.com Cover design by Russell Richardson Set in size of 11pt and Minion Pro by Manila Typesetting Company, Makati, Philippines Printed in the USA 10 9 8 7 6 5 4 3 2 1

Contents Preface xv 1 Electrospinning Fabrication Strategies: From Conventional to Advanced Approaches 1 J.R. Dias, Alexandra I. F. Alves, Carolina A. Marzia-Ferreira and Nuno M. Alves 1.1 Introduction 2 1.2 Conventional Fabrication Approaches 3 1.2.1 Randomly Oriented Fiber Meshes 3 8 1.2.2 Aligned Fiber Meshes 1.2.3 Fibers With Core/Shell Structure 14 1.3 Advanced Fabrication Approaches 19 1.3.1 Melt Electrospinning 19 1.3.2 Near Field Electrospinning 22 23 1.3.3 Electroblowing 1.3.4 Hybrid Structures 25 1.3.5 Cell Electrospinning 30 1.3.6 In Situ Electrospinning 33 1.4 Conclusions and Future Perspectives 36 Acknowledgments 37 References 37 2 History, Basics, and Parameters of Electrospinning Technique Aysel Kantürk Figen 2.1 Definitions 2.2 Milestone of Electrospinning Technique 2.3 Setup and Configuration of Electrospinning Technique 2.4 Parameters 2.4.1 Polymer Solutions 2.4.2 Spin Parameters 2.4.3 Environmental Parameters

53 53 54 56 59 59 62 63 v

vi  Contents 2.5 Concluding Remarks References

64 65

71 3 Physical Characterization of Electrospun Fibers Anushka Purabgola and Balasubramanian Kandasubramanian 72 3.1 Introduction 3.2 Characterization Techniques 76 76 3.2.1 Scanning Electron Microscopy (SEM) 3.2.2 Field Emission Scanning Electron Microscopy (FESEM) 77 79 3.2.3 Transmission Electron Microscopy (TEM) 3.2.4 High-Resolution TEM (HRTEM) 80 3.2.5 Atomic Force Microscopy (AFM) 81 3.2.6 X-Ray Diffraction (XRD) 83 3.2.7 Nanoindentation 84 85 3.2.8 Differential Scanning Calorimetry (DSC) 3.2.9 Thermalgravimetric Analysis (TGA) 85 3.3 Physical Characterization of Electrospun Fibers 87 3.3.1 Electrospun Polymer Nanofibers 87 3.3.1.1 Polyacrylonitrile (PAN) Nanofiber 87 3.3.1.2 Polyvinylidene Fluoride (PVDF) Fibrous Nanofibers 91 3.3.1.3 Polydodecylthiophene (PDT) Core–Polyethylene Oxide (PEO) Shell Polymer Nanofiber 92 3.3.1.4 Polymethylmethacrylate 92 (PMMA) Nanofiber 94 3.3.2 Electrospun Metal (Oxide) Nanofiber 3.3.2.1 Polyvinyl Alcohol (PVA)/Nickel Acetate 95 3.3.2.2 Polyvinyl Pyrrolidone (PVP)/TiO2 Nanofibers 96 3.3.2.3 Polyethylene Oxide/Polyvinylpyrrolidone– 96 Iron Oxide Nanofiber 3.3.3 Electrospun Nanocomposite Nanofibers 97 98 3.3.3.1 TiO2/SiO2/C (TSC) Nanofibers 3.3.3.2 Polyvinylidene Fluoride (PVDF)/ZnO Nanocomposite Nanofiber 100 3.3.3.3 Polyvinyl Alcohol (PVA)/Cellulose Nanocrystals Composite Nanofibers 101 3.3.4 Electrospun Carbon Nanofibers (CNFs) 104 3.3.4.1 Polyacrylonitrile (PAN)/N-Doped CNFs 104 3.3.4.2 Lignan-Derived CNFs/PAN 104

Contents  vii 3.3.4.3 Poly(L-Laticide-Co- -Caprolactone) (PLCL)/MWCNTs Nanofibers 3.4 Conclusion References

105 108 109

4 Application of Electrospun Materials in Catalysis Bilge Coşkuner Filiz 4.1 Introduction 4.2 Type of Catalysts 4.2.1 Catalyst Supports 4.2.2 Template for Catalytic Nanotubes 4.2.3 Metal Oxide Catalysts 4.3 Catalytic Applications 4.3.1 Energy Field 4.3.1.1 Oxidation Reactions 4.3.1.2 Reduction Reactions 4.3.1.3 Hydrogen Generation Reactions 4.3.2 Environment Field 4.3.2.1 Oxidation Reactions 4.3.2.2 Reduction Reactions 4.3.2.3 Degradation Reactions 4.4 Conclusion References

113

5 Application of Electrospun Materials in Packaging Industry Samson Rwahwire, Catherine Namuga and Nibikora Ildephonse 5.1 Packaging Industry 5.2 Electrospinning 5.3 Nanofibers 5.4 Biopolymers 5.4.1 Nanoencapsulation 5.4.2 Methods of Encapsulation Application in Food Packaging 5.4.3 Drying 5.4.4 Nano-Enabled Packaging Solutions 5.4.5 Food Packaging 5.4.6 Active Food Packaging 5.5 Future Perspectives References

131

113 115 115 116 117 117 118 118 119 120 121 121 122 122 124 125

131 132 135 135 135 139 140 140 141 142 144 145

viii  Contents 151 6 Application of Electrospun Materials in Water Treatment Shivani Rastogi and Balasubramanian Kandasubramanian 152 6.1 Introduction 6.2 Heavy Metal Ion Removal From Wastewater 154 6.2.1 Cellulose/Camphor Soot Nanofibers 157 6.2.2 Spider-Web Textured Electrospun 158 Graphene Composite Fibers 6.2.3 Resorcinol–Formaldehyde Nanofibers 161 6.2.4 Ion-Imprinted Chitosan/1-Butyl-3162 Methylimidazolium Tetrafluoroborate Fibers 6.2.5 Molecular Imprinted Camphor Soot 164 Functionalized PAN Nanofibers 6.2.6 Iron Functionalized Chitosan Electrospun 166 NFs (ICS-ENF) 6.2.7 Cellulose/Organically Modified Montmorillonite 166 6.3 Dye Removal From Wastewater 167 6.3.1 Zein Nanofibers 167 6.3.2 β-Cyclodextrin Based Nanofibers 169 O NP 6.3.3 3-Mercapto Propionic Acid Coated Fe3 4 Immobilized Amidoximated Polyacrylonitrile 171 6.3.4 Functionalized Polyacrylonitrile Membrane 171 172 6.4 Oil–Water Separation 6.4.1 Wettable Cotton-Based Janus Bio Fabric (PLA/Functionalized Organoclay) 172 6.4.2 Camphor Soot Immobilized Fluoroelastomer Membrane 174 6.4.3 Polycaprolactone/Beeswax Membrane 174 6.5 Microbe Elimination From Wastewater 176 6.5.1 β-Cyclodextrin/Cellulose Acetate Embedded Ag and Ag/Fe Nanoparticles 176 6.5.2 Silver Coated Polyacrylonitrile (PAN) Membrane 177 6.6 Antibiotic Removal From Wastewater 178 180 6.7 Conclusion References 180 7 Application of Electrospun Materials in Oil–Water Separations 185 T.C. Mokhena, M.J. John, M.J. Mochane and P.C. Tsipa 7.1 Introduction 185 7.2 Oil Spill Clean-Up 187

Contents  ix 7.2.1 Hydrophobic–Oleophilic Polymer Nanofiber 7.2.2 Blends 7.2.3 Composites 7.3 Separation Membranes 7.4 Thin-Film Composite (TFC) Membranes 7.5 Three Dimensional (3D) Nanofibrous Membranes 7.6 Smart Membranes 7.7 Conclusions and Future Trends Acknowledgments References 8 Application of Electrospun Materials in Industrial Applications Anisa Andleeb and Muhammad Yar 8.1 Introduction 8.2 Technology Transfer From Research Laboratories to Industries 8.3 Industrial Applications of Electrospun Materials 8.3.1 Biomedical Materials 8.3.2 Defense and Security 8.3.3 Textile Industry 8.3.4 Catalyst 8.3.5 Energy Harvest 8.3.6 Filtration 8.3.7 Sensor Applications 8.3.8 Food 8.4 Current and Future Developments References 9 Antimicrobial Electrospun Materials Samson Afewerki, Guillermo U. Ruiz-Esparza and Anderson O. Lobo 9.1 Introduction 9.1.1 Electrospinning Technology 9.1.2 Antimicrobial Materials 9.1.3 Antimicrobial Electrospun Materials 9.1.4 Conclusions and Future Directions Acknowledgments References

187 191 194 195 202 203 204 208 209 209 215 216 218 220 221 227 227 228 229 230 232 234 236 237 243 244 244 246 246 254 255 255

x  Contents 10 Application of Electrospun Materials in Gene Delivery GSN Koteswara Rao, Mallesh Kurakula and Khushwant S. Yadav 10.1 Introduction 10.2 Gene Therapy 10.3 Cellular Uptake of Nonviral Gene Delivery 10.4 Vectors 10.4.1 Viral Vectors 10.4.2 Nonviral Vectors 10.4.3 Delivery of Genes through Vectors 10.5 Nanofibers/Scaffolds 10.6 Electrospinning 10.6.1 Steps Involved in the Electrospinning Process 10.6.2 Types of Electrospinning 10.7 Characterization 10.8 Applications of Electrospun Materials 10.8.1 Electrospun Materials in Gene Delivery 10.8.1.1 Tissue Engineering 10.8.1.2 Regenerative Medicine 10.8.1.3 Vascular Grafts 10.8.1.4 Bone Regeneration 10.8.1.5 Diabetic Ulcer Treatment 10.8.1.6 Cancer Treatment 10.8.1.7 Blood Vessel Regeneration 10.8.1.8 Wound Management 10.8.1.9 Carrier for Genetic Material Loaded Nanoparticles 10.8.1.10 Myocardial Infarction Treatment 10.8.1.11 Stem Cell-Based Therapy 10.8.1.12 Gene Silencing 10.8.1.13 Controlled Release of Gene 10.8.1.14 DNA Delivery 10.8.2 Electrospun Materials in Drug Delivery 10.8.2.1 Antibiotics and Various Antibacterial Agents 10.8.2.2 Anticancer Drugs 10.8.2.3 Cancer Diagnosis 10.8.2.4 Wound Management 10.8.2.5 Tissue Engineering 10.8.2.6 Bone Tissue Engineering

265 266 266 268 269 269 270 271 273 275 276 279 281 282 282 282 284 284 285 286 287 287 288 288 288 289 289 290 290 291 292 292 292 293 293 293

Contents  xi 294 10.8.2.7 Dental Growth 10.8.2.8 Therapeutic Delivery Systems 294 10.8.3 Electrospun Materials in Miscellaneous Applications 294 10.9 Future Scope and Challenges 296 10.10 Conclusion 296 References 297 11 Application of Electrospun Materials in Bioinspired Systems 307 Anca Filimon, Adina Maria Dobos, Oana Dumbrava and Adriana Popa 11.1 Introduction 308 309 11.2 Composite Materials Based on Cellulosic Nanofibers 11.2.1 Processing of Cellulose-Based Materials 310 11.2.2 Structure–Property–Biological Activity Relationship 310 11.2.2.1 Biosensors Based on Cellulosic Fibers 310 11.2.2.2 Delivery Systems and Controlled 312 Release of Drugs 11.2.2.3 Wound Dressing 316 11.2.2.4 Tissue Engineering 317 11.3 Chitosan Nanofibrous Scaffolds 322 11.3.1 Overview on Obtained Chitosan From Bio-Waste Source 322 11.3.2 Specific Applications of Chitosan Nanofibers in Bio Inspired Systems 325 11.3.2.1 Wound Dressing 325 329 11.3.2.2 Drug Delivery 330 11.3.2.3 Tissue Engineering 11.3.2.4 Antibacterial Activity 336 11.4 Conclusions 339 References 339 12 Smart Electrospun Materials Gaurav Sharma, Shivani Rastogi and Balasubramanian Kandasubramanian 12.1 Introduction 12.2 Smart Electrospun Materials in Biomedical Applications 12.2.1 Tissue Engineering 12.2.2 Controlled Drug Delivery 12.2.3 Wound Healing

351 352 354 354 355 356

xii  Contents 12.3 Smart Electrospun Materials for Environmental Remediation 357 12.3.1 Water Pollution Control 357 12.3.2 Air Pollution Control 359 12.3.3 Noise Pollution Control 360 12.4 Smart Electrospun Materials in Electronics 361 12.4.1 Solar Cell 361 362 12.4.2 Energy Harvesters 12.4.3 Shape-Memory Polymers 363 12.4.4 Batteries and Supercapacitors 364 12.4.5 Sensors, Transistors, and Diodes 366 12.5 Smart Electrospun Materials in Textiles 368 368 12.5.1 Biomedical Parameter Regulation 12.5.2 Protection from Environment Threat 369 12.5.3 Energy Harvesters in Textiles 370 12.5.4 Smart Textile Project 370 12.6 Smart Electrospun Materials in Food Packaging 371 372 12.7 Conclusion References 373 13 Advances in Electrospinning Technique in the Manufacturing Process of Nanofibrous Materials Karine Cappuccio de Castro, Josiel Martins Costa and Lucia Helena Innocentini Mei 13.1 Introduction 13.2 Process 13.3 Important Parameters 13.3.1 Effects of the Applied Tension 13.3.2 Effects of Solution Eject Rate 13.3.3 Effects of Needle-to-Collector Distance and Needle Diameter 13.3.4 Effects of Solution Concentration and Viscosity 13.3.5 Effects of Solution Conductivity 13.3.6 Solvent Effects 13.3.7 Effects of Surface Tension 13.3.8 Humidity and Temperature Effects 13.4 Recent Advances in the Technique 13.4.1 Electrospinning Coaxial 13.4.2 Electrospinning Triaxial 13.4.3 Multiple Needle Electrospinning 13.4.4 Electroblowing

379 380 380 382 382 382 384 384 385 385 385 386 386 386 387 387 387

Contents  xiii 13.4.5 Magnetic Electrospinning 13.4.6 Centrifugal Electrospinning 13.4.7 Needleless Electrospinning 13.5 Coaxial Electrospinning as an Excellent Process for Hollow Fiber and Drug Delivery Device Production 13.6 Applications 13.7 Conclusions and Future Perspectives References 14 Application of Electrospun Materials in Filtration and Sorbents T.S. Motsoeneg, T.E. Mokoena, T.C. Mokhena and M.J. Mochane 14.1 Introduction 14.2 Morphology of Sorbents With Concomitant Sorption Capacity 14.3 Mechanistic Overview in Purification During Filtration 14.4 Conclusion and Future Prospects References

388 388 388 389 390 393 393 401 402 403 406 410 411

15 Application of Electrospun Materials in Batteries Subhash B. Kondawar and Monali V. Bhute 15.1 Introduction 15.2 Electrospun Nanofibers as Anodes 15.2.1 Carbon Nanofibers as Anode 15.2.2 Metal Oxide Nanofibers as Anode 15.3 Electrospun Nanofibers as Cathode 15.3.1 Lithium Metal Oxide Nanofibers as Cathode 15.3.2 Transition Metal Oxides Nanofibers as Cathode 15.4 Electrospun Nanofibers as Separator 15.4.1 Polymer Nanofibers as Separator 15.4.2 Polymer–Inorganic Nanofiber Separators 15.5 Conclusions and Outlook References

415

16 State-of-the-Art and Future Electrospun Technology Prasansha Rastogi and Balasubramanian Kandasubramanian 16.1 Introduction 16.2 Some General Smart Applications of Electrospun Membranes 16.3 Stimuli Responsive or Shape Memory Electrospun Membranes

441

416 418 418 419 423 423 424 425 426 430 432 433

442 445 454

xiv  Contents 16.4 Conclusion Acknowledgment References 17 Antimicrobial Electrospun Materials Rushikesh S. Ambekar and Balasubramanian Kandasubramanian 17.1 Introduction 17.2 Drug-Loaded Polymer Nanofibers 17.3 Drug-Loaded Biodegradable Polymer Nanofibers 17.4 Drug-Loaded Non-Biodegradable Polymer Nanofibers 17.5 Conclusion and Future Scope References

473 474 474 483 484 485 485 501 507 508

Index 515

Preface The electrospinning technique uses an electrically charged jet of polymer solution or melt of both natural and synthetic polymers to produce fibers of submicron to nanometer size. Fibers with various morphologies and structures can be easily prepared by electrospinning by altering the processing parameters. Electrospinning is a voltage-driven process by which a wide range of materials, including polymers, biomaterials, inorganic sol– gels, colloidal particles, additives like fillers, plasticizers, etc., can be spun into nanofibers. Electrospinning can be traced back to the 17th century, about 400 years ago, when William Gilbert observed the deformation of a liquid droplet into conical form when a piece of statically charged amber was placed closer to the liquid. Later, in the early 18th century, John Zeleny worked on the mathematical model of the effect of electric field on the liquid meniscus. In 1934, Formhals filed his first patent for drawing artificial threads. In the 1960s, Taylor expanded the work of William Gilbert by using conducting fluid and showed the conical shape of the droplet in the presence of the electric field, hence named a Taylor cone. After the 1960s, researchers started studying the morphology, structure, operation parameters, etc., of electrospun nanofibers, which are still being expanded upon for their applications as smart materials. Despite the fact of the technology having already been developed, the surge in the utilization of electrospinning for the production of fibrous materials by both academia and industry intensified during the last decade. A variety of nanofibers can be prepared by electrospinning technology for a wide range of applications in tissue engineering, drug delivery, biotechnology, wound healing, environmental protection, energy harvesting and storage, electronics and defense, and security purposes. The materials possess higher mechanical performance, large surface area-to-volume ratio, and functional properties. The aim of this edition of Electrospun Materials and Their Allied Applications is to explore the history, fundamentals, manufacturing processes, optimization parameters, and applications of electrospun xv

xvi  Preface materials. This book includes various types of electrospun materials such as antimicrobial, smart, bioinspired systems, and so on. The electrospun materials have applications in areas such as energy storage, catalysis, biomedical, separation, adsorption, and water treatment technologies. The book emphasizes the enhanced sustainable properties of electrospun materials, with the challenges and prospectives being discussed in detail. The chapters are written by top-class researchers and experts from throughout the world. This book is envisioned for faculty members and students of engineering, materials science, engineers, and materials designers who need to consider the morphological design of materials for versatile applications. Based on thematic topics, this edition contains the following 17 chapters: Chapter 1 discusses the current and advanced electrospinning fabrication strategies. The technological limitations of conventional strategies and their reduced ability to achieve 3D structures are also discussed. Advanced strategies, such as melt electrospinning, near-field electrospinning, electroblowing, hybrid structures, cell electrospinning, and in  situ electrospinning, are highlighted with respect to the way they may contribute to circumvent the limitations of conventional strategies. Chapter 2 discusses the development of electrospinning techniques and provides information about the theory of electrospinning. The setup and configurations of electrospinning are discussed in detail for the fabrication of nanofibers. The effect of processing conditions on geometry, morphology, and functionality of nanofibers are also presented. Chapter 3 briefly provides information about certain physical characterization techniques that are relevant with respect to electrospinning and the changes observed in the physical properties of the material. Chapter 4 focuses on the applications of electrospun materials in areas such as catalysis. Several reactions such as oxidation, reduction, and degradation in the field of energy and environmental applications are mentioned, in which the presence of heterogeneous catalyst is prepared by electrospinning technique. This chapter investigates recent approaches for these specific applications of catalysis. Chapter 5 discusses developments in the packaging industry, specifically food packaging; the science of electrospinning and parameters that

Preface  xvii influence the process are presented, and, after that, electrospun materials in the food packaging industry and their application thereof. Chapter 6 summarizes the advanced applications of distinct electrospun materials in the growing water treatment sector. Covered in this chapter are various organic/biomaterials as well as inorganic/synthetic materials with improved properties due to electrospinning procedure. It describes the power of electrospun materials for resolving the problem of hazardous water contaminants like heavy metal ions, dyes, microbial growth, and pharmaceutical waste (antibiotics), along with problems related to oil spills. Chapter 7 summarizes the design, manufacturing, and recent developments of electrospun nanofibers with tailorable surface wettability for oily wastewater purification. The chapter also discusses various electrospun nanofibrous materials having different mechanisms for oil-in-water separation and their challenges and prospects. Chapter 8 describes various industrial applications of electrospun materials, including the transfer of electrospun materials from research laboratories to industries for commercialization. The main focus is on the applications of electrospun materials in different industrial fields such as biomedical, filtration, textiles, sensors, protective clothing, energy harvesting, and storage devices. Chapter 9 highlights electrospinning technology for the fabrication of electrospun materials and their advantages and wide range of potential applications. Due to the fast-growing problem of infections and the prevalence of antibiotic-resistance microbes, the focus is on electrospun materials with antimicrobial property. Chapter 10 discusses the various applications of electrospun materials in gene delivery. It emphasizes the delivery of genes, DNA, RNA, peptides, antibodies, growth factors, and many drugs by electrospun materials, including nanofibers. The major applications that are elaborated on include their role in tissue engineering, bone regeneration, wound healing, stem cell treatment, blood vessel growth, dentistry, gene expression/­silencing, and controlled release of biomolecules/drugs. Chapter 11 presents information on the natural polymers and how they can be processed by electrospinning to obtain properties required by target

xviii  Preface applications. The role of methods in the development of electrospun materials is studied in correlation with the way in which they can be adapted for bioinspired applications. Chapter 12 discusses the various applications of electrospun materials in various sectors like air, water, and noise pollution control. Some of the important applications of electrospun materials in areas such as solar cells, energy harvesters, batteries, supercapacitors, and sensor diodes are extensively discussed along with their use in textiles and at industrial levels. The main focus is on the application areas of these materials for a wider explanation of the numerous studies reported in the literature and inventories. Chapter 13 details the main concepts involved in the electrospinning technique, discusses the parameters that influence the morphology of nanofibers, and presents the main advances related to the process and the applications that have been highlighted in recent years. Chapter 14 outlines the synthesis of sorptive mats by electrospinning methods for use in the filtration processes to eradicate contaminants predominantly in wastewater and terrains for the alleviation of environmental pollution. Recent developments in the manufacturing of new electrospun mats for use as sorbents in the purification processes and the in-depth mechanistic binding between sorptive mats and unwanted impurities during filtration are covered. Chapter 15 elaborates on the recent development of the electrospun nanofiber-based materials in terms of synthesis and application for lithium-ion battery components such as anodes, cathodes, and separators. A short overview of the challenges and prospects of electrospun nanofibers for lithium-ion battery components is also presented. Chapter 16 summarizes the employment of a robust electrospinning technique in membrane fabrication for varied applications. Performance of the same is diversified by utilizing stimuli-responsive/shape memory materials, which react to triggers from the external environment with a widened scope in biomedical treatment, fuel cells, filtration, etc.

Preface  xix Chapter 17 discusses the classification of antibacterial nanofibers based on biodegradability, which includes drugs such as synthetic drugs, natural drugs, or nanoparticle-embedded biodegradable and non-biodegradable nanofibers with applications. The ideal design of antibacterial nanofibers based on comparative study of recently developed antibacterial nanofibers is also reported in the chapter. Editors Inamuddin Rajender Boddula Mohd Imran Ahamed Abdullah M. Asiri December 2019

1 Electrospinning Fabrication Strategies: From Conventional to Advanced Approaches J.R. Dias*, Alexandra I. F. Alves, Carolina A. Marzia-Ferreira and Nuno M. Alves Centre for Rapid and Sustainable Product Development (CDRsp), Polytechnic Institute of Leiria, Leiria, Portugal

Abstract

Electrospinning is a widely used technique in several fields to produce micro-­ nanofibers due to its versatility, low cost and easy use. Moreover, electrospun meshes present some advantages like high surface area, small pore size, high porosity, and interconnectivity. Present, also, the possibility to control the nanofiber composition and orientation to achieve desired properties and/or functionalities. These outstanding properties make the electrospun nanofibers good candidates for many applications such as filtration, tissue engineering, wound dressings, energy conversion and storage, catalysts and enzyme carriers, protective clothing, sensors, drug delivery, electronic and semi-conductive materials. This chapter presents a comprehensive review of current and advanced electrospinning fabrication strategies. Recent advances have been mainly focused on the materials used rather than on sophisticated fabrication strategies to generate complex structures. The technological limitations of conventional strategies, such as random, aligned, and core–shell technologies, and their reduced capacity to achieve 3D structures will be discussed. Advanced strategies, such as melt electrospinning, near field electrospinning, electroblowing, hybrid structures, cell electrospinning and in situ electrospinning will be highlighted in the way they may contribute to circumvent the limitations of conventional strategies, through the combination of different technologies and approaches. The main research challenges and future trends of fabrication electrospinning strategies will be discussed.

*Corresponding author: [email protected] Inamuddin, Rajender Boddula, Mohd Imran Ahamed and Abdullah M. Asiri (eds.) Electrospun Materials and Their Allied Applications, (1–52) © 2020 Scrivener Publishing LLC

1

2  Electrospun Materials and Their Allied Applications Keywords:  Conventional/advanced strategies, hybrid fibers, hierarchical structures

1.1 Introduction Although the electrospinning technique is under growing development in several fields its principles emerged around the 1600s. However, since the 1980s, several research groups demonstrated that it is possible to produce electrospun fibers with organic polymers increasing, since then, the number of publications exponentially [1, 2]. Electrospinning is a technique allowing to create submicron to nanometer scale fibers from polymer solutions or melts and was developed from a basis of electrospraying, widely used for more than 100 years [3, 4]. It is also known as electrostatic spinning, with some common characteristics to electrospraying and the traditional fiber drawing process [5]. The conventional setup for an electrospinning system consists of three major components: a high voltage power supply, a spinneret, and a collector that can be used with horizontal or vertical arrangement [1, 3, 6]. The syringe contains a polymeric solution or a melt polymer, pumped at a constant and controllable rate. The polymer jet is initiated when the voltage is turned on and the opposing electrostatic forces overcome the surface tension of the polymer solution. Just before the jet formation, the polymer droplet under the influence of the electric field assumes the cone shape with convex sides and a rounded tip, known as the Taylor cone [5, 7, 8]. During the jet’s travel, the solvent gradually evaporates and charged polymer fibers are randomly deposited or oriented in the collector [8]. The electrospinning process can be influenced by several parameters, such as solution parameters (viscosity, concentration, type of solvent), processing parameters (flow rate, distance between needle and collector, voltage supply, type of collector), and ambient parameters (temperature and humidity). The technique is also highly versatile since, in addition to the conventional fiber configuration, it is possible to obtain a variety of other configurations, namely core/shell (co-axial) or emulsion configurations and, according to the fiber orientation, it is possible to produce aligned or randomly oriented fibers depending the type of the collector used. More recently emerged several advanced fabrication strategies that allow making structures more complex and multifunction. The present chapter intends to give an overview of the fabrication

From Conventional to Advanced Strategies  3 strategies used in electrospinning technique from conventional to the recent advanced strategies.

1.2 Conventional Fabrication Approaches 1.2.1 Randomly Oriented Fiber Meshes Conventional electrospinning setup configuration consists of fibers randomly deposited over the grounded collector, which is usually a metal plate [1, 9, 10]. The random deposition is a consequence of the jet instability resulting from the electric field applied to overcome the polymeric solution surface tension [7, 11]. There are several studies comparing random and aligned deposition strategies in terms of nanofibers morphology, hydrophilicity, mechanical properties, and cell adhesion and proliferation [12, 13]. In terms of biological response, numerous studies demonstrated that aligned fibers usually exert a more relevant influence on cellular behavior including cell morphology, cellular density and gene expression. In terms of mechanical properties, the elongation at break presents better results when fibers are randomly oriented [12, 14]. The electrospun fibers without defined orientation are often produced when using the electrospinning technique, due to the simplicity of the process and the collector type associated with this process, which is usually a planar and static collector as a standard [15]. The collecting method of electrospun nanofibers is one of the parameters that influence their orientation, and by consequence, their shape, size, and mechanical properties [15, 16]. The collector must be a conductive metal plate, to reduce the loads and avoid repulsive forces between the fibers themselves. Aluminum foil, copper plates, paper and water bath are some of collector types used by some authors to produce non-woven meshes with smooth surface and dense structure [15]. The electrospun meshes have certain characteristics, resulting from their unstructured deposition, such as high specific surface area to volume ratio, with high porosity (>90%), wettability, and appreciable mechanical properties [17–19]. Characteristics that make its use advantageous in several fields, such as biomedical applications, environmental protection, energy store cells, catalysts, defense clothes, among others [17–20]. Electrospinning serves as a popular technique for fabricating porous scaffolds with diverse properties for culturing cells to be used in engineer tissues [16]. In wound healing, electrospun fibers accurately mimic the in vivo environment of cells, such as fibroblasts and keratinocytes, allowing

4  Electrospun Materials and Their Allied Applications their adhesion, proliferation and growth. Thus, by reproducing the extracellular matrix (ECM), since it also has a disorganized structure formed by nanofibers of collagen and elastin, allows a rapid and efficient tissue replacement [21]. Sobhanian and colleagues [22], developed electrospun nanofibrous of poly(vinyl alcohol) (PVA)/gelatin and alginate grafted with collagen (extracted from rat tail) as a potential skin substitute. The results demonstrated that the structures grafted with collagen potentiate their functionality, hydrophilicity and cells adhesion and proliferation. Some mechanical properties have been improved with the addition of collagen, such as elongation at break, resulting in a successful technique and reasonable cost to repair damaged skin when compared to solutions that already exist in the market as autograft, allograft, or xenograft [16, 22]. In the wound healing process, the first procedures of the damaged tissue are crucial to ensure the organism hemostasis [23, 24]. The application of a wound dressing is an essential procedure to prevent infections and promote exudate absorption. The electrospinning technique allows creating more functional wound dressings than conventional ones since it is quite versatile in the materials and parameters that can be used [17–19]. Electrospun wound meshes can fit the ideal requirements such as gas permeation, wound protection, and prevent wound dehydration. For this reason, it is necessary to have a high porosity, which is only possible with nanofibers with random orientation. The great advantage of nanofibers is the possibility of incorporating drugs and other substances that potentiate their functionality [25]. To study the potential of electrospun meshes in wound healing, Li and his colleagues [26], produced nanofibers based on hydrophilic poly(vinylpyrrolidone) (PVP) and hydrophobic ethyl cellulose (EC). Fibers were, also, collected in aluminum foil and directly on gauze. Ciprofloxacin (CIF), a model antibiotic, was loaded into fibers to avoid bacterial infection [26]. The results obtained showed a faster CIF release, when compared with their hydrophobic analogs. While EC nanofibers in 3 days had a release to zero-order. Cell viability assays with human dermal fibroblasts (HDF) cells have close to 100% viability for all fibers types [26]. Fibers with EC formulations cell growth is assured, with cell adhesion and proliferation. The antibacterial tests with S. aureus, a gram-positive, and E. coli, a gram-negative showed that both polymers have antibacterial activity, although PVP fibers had greater activity. There were also no differences in the fibers when deposited in different collectors, allowing the application directly in gauzes for a smart fabric [26]. In terms of water and air purification, electrospun membranes serve as an alternative to non-membrane based purification methods, which often are not easily recycled or reused [20].

From Conventional to Advanced Strategies  5 In addition to the features already mentioned, nanofibers have good mechanical and thermal properties, that give them more resistance, when compared with other fibers like glass fibers, melt-blown and spunblowing fibers, and others materials for the same application [16, 20, 27]. The changeability of the technique allows several polymers to be used for this purpose, even if they are synthetic or organic. The most commonly used are poly(acrylonitrile) (PAN), chitosan (CS), cellulose, PVA, and polystyrene (PS) [16, 20–22, 24]. Bortolassi et al. [27] utilized PAN electrospun nanofibers containing different percentages of silver (Ag) to be used as air filters by removing nanoparticles from the air, and, evaluating their antibacterial activity against E. coli [27]. The results demonstrate that when 50 wt% silver nitrate AgNO3 (50AgF) was added to the PAN nanofibers, although, had the lowest filtration efficiency (>98%) comparing with other Ag concentrations, being the best candidate to be applied in air filter because had the best high quality factor with low-pressure drop as well the highest antibacterial activity [20]. To remove micropollutants, such pharmaceuticals, personal care products, radioactive or biologically harmful metals, pesticides or endocrine disrupters, from waters, Fan et al. [28] produced electrospun nanofibers with β-cyclodextrin (β-CD), CS, and PVA. They conclude that the randomly oriented nanofibers can rapidly remove organic pollutants and heavy metals by adsorption, like lead (Pb2+), mercury (Hg2+), cadmium (Cd2+), nickel (Ni2+), cooper (Cu2+), and dichromate Cr2O72− . These heavy metals are naturally present in the environment, but due to anthropogenic activity, their concentrations may exceed the desired limits, causing problems for the organism, the human being even [28]. In addition, random nanofibers can also be used in the desalination process. The range of electrospun meshes characteristics makes them indispensable in the membrane distillation since its reduced and sturdy structure increases hydrophobicity, which is necessary for this process [28–30]. An efficient separation membrane must present high porosity and hydrophobic character to not allow the passage of liquid water [28–30]. According to Woo et al. [29] study, polyvinylidene fluoride-co-hexafluoropropylene (PH) was loaded with different concentrations of graphene, between 0–10 wt%, to be used as membrane distillation via air gap (AGMD). The results presented show that graphene, at a concentration of 5 wt%, potentiates the structure of the fibers, increasing its roughness and thus improving its absorption/desorption capacity [29]. When exposed to salts, the superhydrophobicity of the membrane avoids the penetration of water, and due to its porous structure and high volume/ratio only water vapor passes through it (Figure 1.1).

(

)

6  Electrospun Materials and Their Allied Applications Graphene protrusions Effects of graphene incorporation

Graphene

SWV WW V W V W S W V SW W S S V S V WS W S S WV WS V V WW V WW V SW V S WW S V S S W WS V S WW S V S W VW WW V S S W W WWV S V W Water

G/PH electrospun nanofiber membrane

V

V V

S

Graphene/PH membrane V V properties V W V 5 1 Superhydrophobic V V V V V V W 2 Fast transport along V V V graphene surface V V V V W 4 V V 3 Direct permeation through V V V W membrane V V V VW 3 V W 4 Activated diffusion via V V adsorption/desorption V V W V on graphene surface 2 W V V V W V V 5 Highly porous surface V W V V V V V V VCondensed 1 pure water Salt ion V Vapor Condenser

Feed Flow

Nanofiber

− Provides surface roughness and hydrophobicity − Improves anti-wetting property − Provides diffusion path for water vapour (i.e., rapid adsortion/desorption capacity) − Improves thermal stability & mechanical properties of the composite membrane

Figure 1.1  Scheme of the effect of graphene nanofibers on AGMD process. Reproduced with permission from Ref. [29].

Although the technique still has some challenges to overcome, such as optimization of parameters, mechanical properties and scale-up production, the easy production of randomly oriented fibers through electrospinning, as well as the variety of materials that can be used to make the membranes more robust, makes the technique very attractive to purify air and water, compared to the traditional ones [30]. Electrospun nanofibers have been receiving more attention over the last few years in the chemistry sector since they are a more ecological and economical option than traditional ones that often-including hazardous chemicals. These characteristics are due to the possibility of using a vast range of natural and semi-natural polymers that are eco-friendly, and due to the possibility of reuse these electrospun nanofibers without losing their functionalities [16].

From Conventional to Advanced Strategies  7 In addition, the catalysis reactions are those that occur more frequently in the chemical processes, it is estimated that 90% of the processes use heterogeneous catalysts, especially in a more industrial component. Other nanostructures beyond nanofibers can play this role such as nanotubes, nanoparticles, and nanowires [31]. In fact, they can be used together, i.e., Xu et al. [32] used electrospun nanofibers with random orientation, to be introduced into a halloysite nanotube (HNts) with the function of absorbing dyes and catalyst support. The fibers are made of PAN and polyimide (PI), providing mechanical elasticity and stability, while PVA was utilized as a binding agent. The results demonstrated that using electrospun nanofibers as a skeleton of HNTs sponges allowing to remove 90% of dye after five cycles of adsorption/desorption and can be reused up to five times [32]. Recent studies have demonstrated the use of carbon nanofibers (CNFs), and other similar ones, such as graphene, in energy cells such as highrate batteries [33]. CNFs have good mechanical and conductive properties and can work as the anode to be applied at lithium-ion batteries (LIBs) [33]. In 2019, Bhute & Kondawar [34], produced by electrospinning poly(vinylidenefluoride) (PVDF)/cellulose acetate/silver-titanium dioxide (AgTiO2) nanofibers to loaded in lithium batteries (Figure 1.2). The ionic mobility and polymer segmental motion were increased with the aid of Ag–TiO2 in the membrane [34]. These are just a few examples of recent works that prove the diversity and applicability of nanofibers in this field, although its applications may still extend to other examples. Namely photochemical energy, by dye-sensitized solar cells, where electrospun nanofibers increased the surface area of photoelectrode and the overall performance [16]. Supercapacitors development is another example, those, are used as an energy store because possesses high power densities and lifetimes compared with LIBs [35]. The performance of supercapacitors with electrospun nanofibers composed by PAN and 40 wt% of manganese acetylacetonate (MnACAC) as precursors improved their performance from 90 Fg−1 specific capacitance to 200 Fg−1 [35]. Electrospun fibers demonstrated great potential as reaction catalysts, but especially their role in generating and storing energy in appreciable quantities, in view of the available commercial devices. At the same time, using electrospun nanofibers, become an environmental and economic solution, by reducing the need to consume energy from fossil fuels to store energy [16]. In the section were highlighted the topics that address the main applications of randomly oriented fiber meshes. However, they can also be applied in the textile industry, protective materials, sensors, agriculture, and food packing [16–18, 20]. Despite this technique has unique applications, some

8  Electrospun Materials and Their Allied Applications

Cellulose acetate PVdF

Ag+

Ag+ Ag+

Ag+

Solvent DMF: Acetone

Ag+

Ag+ Ag+

AgTiO2 Electrospinning

Li+

PVdF/CA-AgTiO2 Nanofibers Polymer electrolyte

PVdF/CA-AgTiO2 Nanofibers membrane

Figure 1.2  Diagram of production of electrospun nanofibers with (PVDF)/cellulose acetate/AgTiO2. Reproduced with permission from Ref. [34].

associated production challenges remain, such as method reproducibility, and large-scale production [16, 19, 20].

1.2.2 Aligned Fiber Meshes Depending on the field of application, highly aligned micro or nanofibers are often required in order to attend to specific needs, either in the biomedical field [36–38], energy and electronics [39–42], or reinforcement in composite materials [43–47]. Electrospinning comprises two regimes of jet movement upon jet emission from the Taylor Cone: a minor short-distance segment in a straight line (stable) followed by a dominant whipping motion (unstable) [48, 49]. Regarding unstable jet-based, electrospun fibers spatial orientation can be achieved through modification of the collector (rotating, parallel, water bath) or by manipulation of external forces (magnetic field, electric field, post-drawing, centrifugal force, or gas force) [50]. On the other hand, the use of stable jet region is highly desirable to align fibers and can be achieved

From Conventional to Advanced Strategies  9 with short or long range of stable jet electrospinning namely through near field electrospinning or melt electrospinning approaches [7, 50–52]. In both cases, the collector is moving in X and Y directions to induce filament orientation, and the process is characterized by short distances between the tip of the needle and the collector. To achieve a stable jet region for controllable deposition the average distance of near electrospinning lies between 500 µm and 3 mm and for melt electrospinning between 3 and 5 cm [53–55]. Due to the complexity of these two methodologies both will be discussed in detail in the section of advanced strategies. A widely used approach to align fibers is the customization of the collecting setup with either parallel, rotating, or water bath collectors (Figure 1.3) [38, 56, 57]. (a)

(b)

needle

Si

V Power supply Si

fiber

Collector Si

100 µm

Si 2µm

(c)

(d)

Spinneret with metal disk

Guide spring with insulating tube

High Voltage supply(+)

Winding Roller

Electrospun fiber mesh deposited on non-solvent

Electrospun Twisted Yarn Vortex Fluid (–)

Recycling Pump

Non-Solvent Reservoir

200.0µm

Figure 1.3  (a) Frame electrode used for obtaining parallel fibers and scanning electron microscopy (SEM) image of parallel PLA fibers obtained. Reproduced with permission from Ref. [127]. (b) Schematic illustration of an electrospinning setup with two conducting silicon stripes separated by a void gap and SEM of the PVP nanofibers collected on top and across the gap. Reproduced with permission from Ref. [209]. (c) Drum collector and SEM of electrospun nylon nanofibers collected on the copper wires. Reproduced with permission from Ref. [66]. (d) Schematic setup of continuous production of twisted nanofiber yarn by liquid vortex and SEM image of the structure obtained. Reproduced with permission from Ref. [81].

10  Electrospun Materials and Their Allied Applications Due to the fact of the electrospun solution is ejected at different velocities (from several hundreds of mm/s to 2 m/s) [58–62], the most common way to control the deposition pattern is through the use of a rotating collector moving at an equally high-speed rate [38, 57, 62]. Based on this, the rotation speed of the collector is known to affect the microstructure (orientation of polymeric crystals) and spatial distribution of the collected fibers [38, 63, 64]. However, thicker aligned electrospun meshes commonly present lower alignment degree and collection rate due to the repulsive effect of residual charges and the insulating effect of the deposited fiber [65, 66]. Moreover, rotating speed is inversely proportional to the diameter of electrospun fibers, i.e., increasing the mandrel speed results in a fiber diameter decrease between 15% and 40% (depending on the speed rate) [38, 57]. Nevertheless, an increment in rotation velocity increases fiber deformation, which can lead to fracture, resulting in decreased crystalline orientation within the fibers and reduction in fiber quantity and quality [62, 63, 67]. The application of rotating collector for the alignment of electrospun materials has been widely applied in in vitro and in vivo studies evidencing the positive effect of an aligned nanotopography in certain cells functions such as morphogenesis and differentiation, gene and protein expression, combined drug delivery and guided orientation [68, 69]. In optoelectronics, an ordered deposition of conducting/semiconducting fibers can be beneficial as a means to access and control anisotropic electronic properties [39]. Shim et al. [70] produced an arranged inorganic nanowire architecture consisting of planarly aligned TiO2 nanowire arrays comprising both uniaxially aligned and multiple layers of cross-aligned nanowire arrays with a conjugated polymer through electrospinning using a rotating collector. The nanowire architectures displayed an improvement of over 70% in power conversion than non-woven TiO2 nanowire, due to enhanced transport rate and charge collection [70]. In the electronic textiles area, Fu et al. [40] developed a portable, scalable and eco-friendly strain sensor composed of aligned cellulose acetate (CA) nanofibers with belt-like morphology and a reduced graphene oxide (rGO) layer. These researchers used a rotating collector for the alignment of the nanofibers that further functioned as a flexible substrate for graphene oxide (GO) sheets (Figure 1.4). The well-aligned CA nanofibers induced an enhanced capillary force responsible for drawing the GO solution downward, facilitating interaction between CA and GO (later rGO) and decreasing interface resistance [40]. Instead of resorting to mechanical stretching forces to align nanofibers with a rotating collector, the parallel collector technique allows the alignment of fibers through manipulation of the electric field in the collecting

From Conventional to Advanced Strategies  11 Syringe pump

High-voltage power supply

Syringe Metallic needle GO aqueous solution

V

Hot press

Spin-coating

Thermal reduction

Belt-like CA nanofibers

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Battery

LED bulb

RGO/CA membrane

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0.0 200

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Figure 1.4  (a) Schematic of the steps involved in the fabrication of RGO/CA fibrous membrane based on electrospinning and hot pressing. (b) Sheet resistance of the RGO/ CA mats against hot-press time at 130°C. Inset shows that the RGO/CA mat can light up LEDs with two 1.5-V batteries in a circuit, after hot pressing for 700 s. (c) Resistance of the strain sensor shows regular change in monitoring (c) the bending and (d) the pushing, respectively. Reproduced with permission from Ref. [40].

area [38]. The electrospinning jet is highly charged and sensitive to the surrounding electric field, thus aligning in certain field configurations. This can be accomplished using a rectangular collector or a parallel collector. The parallel collector consists of two grounded conducting parallel plates that are set up as the collecting target, creating an electric field that causes nanofibers to deposit and align perpendicularly to the plates across the air gap that stand between them. The void gap distance was proved to affect the degree of fiber orientation considerably as Liu and Dzenis [65] demonstrated that alignment improved substantially with the gap size increase. The electrical properties of a polymer solution affect the deposition of aligned nanofibers across conducting parallel plates [38, 57]. If the conductivity of a given solution is too low, the electrostatic forces will not be sufficient to stretch the fibers across the gap, on the other hand, if it is too high, then random whipping instability will be predominant in the jet’s motion, making it all too hard for an oriented deposition [71–73]. In the nanogenerators’ field, Ma et al. [74] produced high-output piezoelectric energy-harvesting nanofibers through electrospinning of a polyvinylidene fluoride (PVDF)/zinc oxide (ZnO) nanowires solution using two grounded electrodes placed 5 cm apart. PVDF and ZnO are both piezoelectric materials, capable of converting mechanical forces into electrical

12  Electrospun Materials and Their Allied Applications energy. PVDF is a uncommon ferroelectric polymer that exhibits great promise in energy harvesting, data storage and sensing applications [75, 76]. Additionally, this polymer is biocompatible and low-cost, and imparts some flexibility to composites with ZnO, a known direct band-gap semiconductor and photoconductor, naturally brittle and hard to manipulate [74]. This study demonstrated that the maximum output voltage generated by a single hybrid PVDN/ZnO nanofiber was, reportedly, over 300% of the voltage generated by a single nanofiber of pure PVDF. Moreover, the material demonstrated higher values of electrical conductivity when exposed to ultraviolet light, serving not only has a piezoelectric material but also as a photoconductive material [74]. Another approach to assemble aligned fibers or continuous uniaxial fibrous yarns is by employing a water bath collector in the electrospinning process. Smit et al. [77] reported a method for producing continuous uniaxial fiber bundle yarns by electrospinning a polymer solution onto a water reservoir. The nonwoven web of nanofibers formed in the water surface was then drawn, with the help of a glass rod, across the surface of the water and then scooped off into the air to a rotating collector [77]. The collection liquid can be either water or another non solvent with low surface tension for example, acetone, methanol, boric acid, or ethanol have also been used [71–73, 78, 79]. A liquid system may present the potential to address the current limitations of electrospun fibers, namely their manipulation without fracturing them, obtaining a considerably high degree of alignment with a significant production rate [80]. Nonetheless, this method reveals a great difficulty for the production of nanofibers and nano yarns of water-soluble materials, giving preference to water-insoluble or coagulated materials or to the establishment of a non-solvent solution for the coagulation bath [81]. This is a dangerous and complex operation (with an intricate apparatus) due to the proximity between electricity and water [82]. Teo et al. [82] used a vortex created by a dynamic liquid system for the manipulation of electrospun nanofibers into a continuous yarn. However, their approach was unable to produce twisted nanofibers and presented some weaknesses as to maintaining the feed rate at a minimum to avoid fiber breakage would mean the increase in diameters to more than 1 µm, with large deviations [82]. Collection of electrospun nanofibers with a water bath collector is an approach that allows the production of scaffolds with large pores due to increased fiber dispersion and decreased fiber bonding [83]. This method for 3D scaffold production can be advantageous in bone and cartilage tissue engineering, due to large porosity and increased fiber thickness [84, 85]. Yang et al. [85] fabricated loose, cotton-like PLGA/PCL scaffolds using

From Conventional to Advanced Strategies  13 an ethanol bath that exhibited a porosity of 99.0 ± 0.2%, compared to the 79.4 ± 2.8% of porosity for conventional scaffolds. After 4 weeks of chondrogenic differentiation, cell infiltration of rat bone marrow cells (RBMCs) and plentiful cartilage matrix deposition were observed throughout the scaffolds. The cell-seeded scaffold was subcutaneously implanted into nude rats, exhibiting new bone formation through the remodeling template after 8 weeks, although without total ossification of the construct [85]. Through electrospinning, it is possible to tune many properties of the nanofibers and assemble them into aligned arrays with anisotropic mechanical properties, improved strength, Young’s modulus and toughness in the alignment direction [36, 86]. Additionally, the electrospinning technique also allows post-functionalization of nanofiber surface with bioactive molecules or ECM proteins [87]. This type of topography changes improves interactions with cells, translating in the modulation of cellular behaviors such as selective endocytosis, adhesion, migration, orientation, proliferation, matrix deposition and integrin expression [88–90]. Many tissues, such as the nervous [91, 92], cardiac [93, 94], tendon [69, 95], and vascular [96, 97] have unique anisotropic structures and architectures, exhibiting different conductivity, tensile and optical properties in different directions, whose regeneration benefits greatly with aligned nanofibers. In comparison to randomly aligned fibrous scaffolds, aligned electrospun nanofibers provide a more adequate microenvironment (in vitro and in vivo) for spatial orientation of cells and tissue regeneration [68, 98–100]. However, the overall development of oriented or aligned nanofibers with adequate topographical features remains a challenge due to the polymer jet’s trajectory which translates into a very complex 3D whipping rather than a straight line, caused by bending instability [101, 102]. In the electronics field, conductivity is a decisive property for the production of nanofibrous devices [103]. Laforgue and Robitaille [104] have demonstrated that aligned nanofibers possess higher conductivity than random ones and this property increases with the decrease of fiber diameter, which is in accordance with more recent studies [105]. This is due to the fact that aligned structures present thinner fibers, less porosity and higher surface area that translates into higher conductivity, while thicker fibers increase void space in the mesh and reduce the contact of conductive segments [103]. In contrast, conventional fiber manufacturing methods, such as dry spinning and wet spinning, allow the facile controlled fabrication of patterned and aligned fibers. These processes rely on the mechanical extrusion of fibers rather than the use of electrostatic forces, which results in fibers with bigger diameters than those obtained by electrospinning (tens of micrometers versus tens of nanometers to several microns), thus easy to align.

14  Electrospun Materials and Their Allied Applications

1.2.3 Fibers With Core/Shell Structure The core/shell approach emerged among the most promising setups in the field of electrospinning since it is based on the combination of, at least, two different materials or substances. Using this approach, the same filament may have distinct inner and outer layers, allowing different compositions such as a material surrounded by another material or by a matrix loaded with dispersed particles [106, 107]. This design was developed to incorporate substances (e.g., drugs, enzymes, growth factors, or other biomolecules) inside the nanofibers. It presents two main advantages [108]: i) substances can be incorporated in the inner layer being protected from environmental factors, such as the organic solvents usually used in the electrospinning technique; ii) and the incorporated substance can be released from the inner layer and past the outer shell layer in a more controlled and sustained way [106]. The design parameters, selected materials, thickness and microstructure of the shell will directly influence the release profile of the substance contained inside of the fibers. The core/shell design is also being widely explored to improve the fibers surface properties, such as the hydrophilicity, which influence the biological response [106]. There are two different processes to produce core/shell fibers: co-axial electrospinning and emulsion electrospinning. Co-axial electrospinning consists of a capillary concentrically inserted inside the other capillary, resulting in a co-axial configuration in which each capillary is connected to a reservoir containing a given material. Similarly, to the conventional electrospinning setup this approach can work in the vertical or horizontal positions [107]. Through this process, several structures can be produced, such as bicomponent fibers, hollow fibers, and fibers with microparticles (Figure 1.5). Bicomponent fibers with core/shell configuration can be obtained from two electrospinnable materials or the combination of a spinnable material with other non-spinnable. This approach presents as major advantages the production of a final fiber presenting unique properties and the use of materials that on their own could not be used in the electrospinning process. Using this approach, the range of materials used in electrospinning considerably increases, overcoming the limitation to obtain electrospun fibers from specific materials due to their low molecular weight, limited solubility, unsuitable molecular arrangement, or lack of required viscoelastic properties [107]. Since, can be produced with more types of polymers and other non-polymeric materials, such as ceramics, metal oxides, and also semiconducting materials [109]. One of the applications of core-shell electrospun nanofibers is to act as the drug delivery system, where the compound with functional properties

From Conventional to Advanced Strategies  15

127 nm 278 nm

5kV

100 nm

(a)

X100 100µm 3939 21/AUG/11

(b)

(c)

Figure 1.5   Core/shell fibers. (a) Transmission electron microscopy (TEM) image of Core/shell CS/PVA electrospun composite nanofibers produced using a co-axial approach. Reproduced with permission from Ref. [210]. (b) SEM image of a cross-section of a polycaprolactone (PCL) hollow fiber in the water coagulation bath. Reproduced with permission from Ref. [211]. (c) Confocal microscopy image of a PVA(core)/PCL (shell) nanofiber mesh with encapsulated liposomes (in the core) stained with fluorescein. Reproduced with permission from Ref. [212].

maintains itself at the core, while shell wraps it [109]. Electrospun fibers surface can also include active agents as enzymes to transmit other functional properties. In fact, due to their high surface area to volume ratio, it is possible encapsulated in single-step a large proportion of dual drugs. In 2019, core–shell nanofibers were produced by Zhu et al. [110] for drug delivery in melanoma treatment by coaxial electrospinning. The fibers are composed of PCL/CS as shell layer and PVP as the core layer encapsulating 5-fluorouracil (5-FU). The results showed that the release of 5-FU significantly inhibited melanoma skin cancer cells (B16F10 cells), and the sustained release provided by core-shell structure exhibited “remedying effects” on normal skin cells (L929 cells) after suffering adverse effects from 5-FU treatment [110]. Bonadies and colleagues [111], developed core–shell electrospun nanofibers, where the core was fabricated with artemisinin (ART) and poly(butylene adipate) (HB) and the shell was constituted by PVP. Artemisinin is a drug system used in treatments for malaria and prostate cancer, and by world health organization, it is one of the best natural treatment against multidrug-resistant plasmodium species. In this study, in vitro assays, showed inhibition of P. falciparum parasites revealed that ART encapsulation into the PVP/HB fibers has the potential to replace traditional antimalarial drugs. Furthermore, in vitro analysis showed that the fibrous systems effectively reduced prostate cancer cell viability [111]. Coaxial electrospinning not only serves to release drugs but also other important molecules with bioactivities, such as proteins, hormones, growth factors, which undergo alterations in some organic solvents and whose

16  Electrospun Materials and Their Allied Applications long-term exposure results in denaturation and loss of bioactivity [112]. A good example is the proteins present in the food nutraceuticals, which lose their activity when exposed to gastrointestinal acid. To combat this problem, Wen et al. [113] produced core–shell nanofibers using alginate as shell, and chitosan loaded with bovine serum albumin (BSA). They conclude that the protein, BSA, keep their structural morphology and integrity and 75% of this protein are released in simulated colon fluid. Despite the release follows a complex mechanism by erosion, core–shell nanofilms demonstrated a great potential for food nutraceuticals field [113]. Recent works have demonstrated new practices using coaxial electrospinning, by employed copolymers, such as styrene and isoprene, with thermal compounds [114, 115]. Material interactions have resulted in peculiar structures, such as spheres, rods, micelles, stacked lamellae, vesicle tubules, that can be directed to the optical area photonics, optical waveguides, wearable power, sensors (Figure 1.6) [15]. The possibility of using mixtures of materials, even some of them do not form fibers by themselves or others that are immiscible, in coaxial electrospinning make this approach attractive with great applicability in several areas, compared to conventional electrospinning. Some of these applications are included in the field of electrochemical, environmental, biomedical, thermoelectrical, and many others [109].

(a)

(b)

(c)

(d)

Figure 1.6  TEM of coaxially spun fibers with 53% isoprene: (a) An as-spun fiber. (b) Stacked PS lamellar structure (c) transition to alternating concentric-cylinder morphology and (d) parallel morphology. Reproduced with permission from Ref. [15].

From Conventional to Advanced Strategies  17 Core/shell fibers can also be produced using emulsions. This approach does not require a special needle with a physical separation between the core and the shell solutions neither such a careful selection of operation parameters as in the co-axial approach. In this case, the dispersed drop in the emulsion turns into the core and the continuous matrix become the shell [107, 116, 117]. Co-axial electrospinning can also be used to produce hollow fibers without the need for a template to be coated. In this strategy, the core material is dissolved by a specific solvent, at the end of the process or the core interacts with shell forming a hollow fiber during the processing. Hollow structures can also be produced by chemical vapor deposition (CVD), in this case, the polymer is stretching to form nanofibers by a conventional electrospinning method. After, the meshes would be coated with a proper polymer or metal, for finally, the initial polymer used in this point is dissolved and drying with centrifugal rotation dryers or by calcining in furnaces [15]. The use of these type of structures is more suitable for nanofluidics and hydrogen storage [15]. As aforementioned, electrospun nanofibers had an enormous application in the energy storage field, as well as the hollow structures. Fu and colleagues [118], developed for the first time titanium–niobium oxide (Ti2Nb10O29) hollow nanofibers using co-electrospinning, followed by low-temperature calcination in the air for being used as the anode in LIBs. According to the results this structure have a good electrochemical performance such as high reversible capacity (307 mAh.g−1) at 0.1 cycle, safe working potential (1.66 V), high initial Coulombic efficiency (90.8%), superior rate capability (136 mA h g−1 at 20°C) and advanced cyclic stability. Thus, can be successfully used for energy storage devices [118]. In another work, nickel oxide (NiO) fibers with a hollow structure were obtained after a heat treatment at 350°C to be used at LIBs, where they have excellent performance like the previous study [119]. Weiwei et al. [120] study enhanced the selective detection of nitric oxide (NO2) and sulfur oxide (SO2) using ultraviolet light-activated gas sensor based on reduced graphene oxide (rGO) functionalized with hollow tin dioxide (SnO2) nanofibers (Figure 1.7). The results demonstrated that the structures enhanced selective detection to NO2 (102%) and SO2 (11%) and show how the intensity of excitation light affects gas detection. Efficient gas sensors are very important due to their detection of hazardous gases in daily life, and carbon materials such as graphene are an excellent candidate due to their high mobility of load and low electrical noise [120]. Multi-co-axial electrospinning is a recent approach, which allows, the production of multilayer and/or multichannel nanofibers with tailored

18  Electrospun Materials and Their Allied Applications (a)

(b)

200 nm

20 nm

Figure 1.7  (a) TEM images of microstructures rGO/SnO2 composites. (b) TEM of SnO2 grains with rGO nanosheets. Reproduced with permission from Ref. [120].

layers having different properties [109, 121]. The properties of individual layers can be varied from hydrophilic or hydrophobic, to electrically conductive or insulating and electrochemically active or inactive. Is a useful method because more than one bioactive molecule can be encapsulated, and thus improving their biocompatibility, mechanical properties, ­filament-forming ability, and functional properties [109, 112]. Tri-axial electrospinning is commonly used as multi-co-axial electro­ spinning method and is widely used in the biomedical field for drug delivery [38]. The way to produce fibers with this technique resembles the co-axial electrospinning, although in this procedure only one of the liquids must be able to electrospun alone [109, 112, 115, 121]. A study developed by Liu et al. [122] explored a new modified tri-axial electrospinning process to tune with precision drug release from nanoscale formulations. The authors used two un-electrospinnable liquids as the outer and middle working fluids, with only the core solution being individually electrospinnable into fibers. The outer liquid comprised a mixture of solvents, while the middle fluid was a dilute solution of cellulose acetate (CA). The core fluid was an electrospinnable co-dissolving solution of ferulic acid (FA) and gliadin. By processing these in tri-axial electrospinning, were possible create FA-gliadin fibers coated with a thin but even and continuous coating of CA. The CA coating eliminated the initial burst release seen with uncoated FA-gliadin fibers and led to close to zero-order release profiles, which could be incrementally adjusted by varying the thickness of the coating. The aim is to develop a new drug delivery system, especially, with zero-order release capable of applied in nutraceuticals field to reduce some cancer incidence or diabetes [122]. This approach is not yet well developed, thus its application to other fields is still restricted. The growing need to develop increasingly functional structures, and with new materials, allows exploring deeply the electrospinning technique, as well as the creation of new structures by this

From Conventional to Advanced Strategies  19 procedure, opening a new range of functionalities and applications in the most diverse areas.

1.3 Advanced Fabrication Approaches 1.3.1 Melt Electrospinning Melt electrospinning is similar to other melt-based additive manufacturing approaches, such as fused-deposition modeling (FDM), in which the nozzle mainly determines the final filament diameter. For very small nozzle diameters (90%) [72].

2.5 Concluding Remarks The chapter focused on history, basics, and parameters of electrospinning technique and the following remarks concluded: 1. Theory: Polymer solution or melt of both natural and synthetic polymers were electrically charged to produce fibers with nano and micro sized. Melt electrospinning, is alternative for polymer solutions, alleviate the using of solvents. 2. Set up: The basic setup for electrospinning consists of four parts: injection pump, spinneret, a nozzle, a high-voltage power supply, and a collector. 3. Configuration: The electrospinning mainly has two types of configuration as horizontal and vertical respect to geometrical arrangements of spinneret and collector. Other classification based on the number of nozzles. Electrospinning technique was also classified based on number of axial units as mono-axial, co-axial, and multi-axial. 4. Process parameters: Parameters classified into three main groups as solution, processing and environmental. 5. Applications: Fiber and its composites in varied structures as core shell, hollow, yarn, porous currently used in biomedical science, catalytic process, filtration applications, and biosensors. Emerging applications in energy and environmental technologies, and in healthcare related engineering are developing day by day.

Electrospinning Technique  65

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Electrospinning Technique  67 32. Yang, L., Yang, P., Yang, R., Wang, J., Hao, Y., Zhao, X., Low-temperature fabrication of carbon nanofibers with improved graphitization via incorporating carbonaceous inclusions. Polyhedron, 164, 13–16, 2019. 33. Kanjwal, M.A. and Woon-Fong Leung, W., Electrospun nanofibers of p-type CuO/n-type TZB-Gr heterojunctions with enhanced photocatalytic activity. Mater. Chem. Phys., 2019. 34. Kanjwal, M.A., Shing Lo, K.K., Woon-Fong Leung, W., Graphene composite nanofibers as high-performance photocatalyst for environmental remediation. Sep. Purif. Technol., 215, 602–611, 2019. 35. Vafania, B., Fathi, M., Soleimanian-Zad, S., Nanoencapsulation of thyme essential oil in chitosan-gelatin nanofibers by nozzle-less electrospinning and their application to reduce nitrite in sausages. Food Bioprod. Process., 116, 240–248, 2019. 36. SalehHudin, H.S., Mohamad, E.N., Mahadi, W.N.L., Muhammad Afifi, A., Multiple-jet electrospinning methods for nanofiber processing: A review. Mater. Manuf. Processes, 33, 5, 479–498, 2017. 37. Kobayashi, S. and Müllen, K., Encyclopedia of polymeric nanomaterials, Springer-Verlag, Berlin, 2015. 38. Zheng, Y., Cao, H., Zhou, Z., Mei, X., Yu, L., Chen, X., He, G., Zhap, Y., Wu, D., Sun, D., Concentrated multi-nozzle electrospinning. Fibers Polym., 20, 6, 1180–1186, 2019. 39. He, J. and Zhou, Y., Multineedle electrospinning, in: Electrospinning Nanofabrication and Applications, pp. 201–218, Elsevier Inc, Netherlands, 2019. 40. Zheng, G., Jiang, J., Chen, D., Liu, J., Liu, Y., Zheng, J., Li, W., Multinozzle high efficiency electrospinning with the constraint of sheath gas. J. Appl. Polym. Sci., 136–22, 47574, 2019. 41. Zhang, Y., Cheng, Z., Han, Z., Zhao, S., Zhao, X., Kang, L., Stable multi-jet electrospinning with high throughput using the bead structure nozzle. RSC Adv., 8, 11, 6069–6074, 2018. 42. Kim, G., Cho, Y.S., Kim, W.D., Stability analysis for multi-jets electrospinning process modified with a cylindrical electrode. Eur. Polym. J., 42, 9, 2031–2038, 2006. 43. Rezazadeh Tehrani, S.P., Hadjianfar, M., Afrashi, M., Semnani, D., An investigation on quilled nozzle-less electrospinning in comparison with conventional methods for producing PAN nanofibers. Fashion Text., 5, 1, 24 2018. 44. Mit-uppatham, C., Nithitanakul, M., Supaphol, P., Ultrafine electrospun polyamide-6 fibers: Effect of solution conditions on morphology and average fiber diameter. Macromol. Chem. Phys., 205, 17, 2327–2338, 2004. 45. Schiffman, J.D. and Schauer, C.L., A review: Electrospinning of biopolymer nanofibers and their applications. Polym. Rev., 48, 2, 317–352, 2008. 46. Beachley, V. and Wen, X., Effect of electrospinning parameters on the nanofiber diameter and length. Mater. Sci. Eng.: C, 29, 3, 663–668, 2009.

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3 Physical Characterization of Electrospun Fibers Anushka Purabgola1 and Balasubramanian Kandasubramanian2* Centre for Converging Technologies, University of Rajasthan (UOR), Jaipur, India 2 Department of Metallurgical and Materials Engineering, Defence Institute of Advanced Technology, Deemed University (DU), Pune, India

1

Abstract

With emerging technologies and recent fabrication methods, researchers have concentrated their studies on nanoscale materials and more precisely on nanofibers. The unique properties possessed by these nanofibers have gained interest in wide range of applications in the fields of nanotechnology, biology, chemistry, and material sciences. Electrospinning is one of the most versatile processes used for the fabrication of nanofibers utilized in pronounced applications including biosensing, wound-dressing, drug-delivery, and tissue engineering. Now-woven nanofibrous mats are delivered onto a grounded-metal coated collector when a strong electric field is applied across the polymer solution. The size of electrospun fibers ranges in few microns to sub-microns whereas the structural morphology is studied using physical characterization techniques such as SEM, TEM, AFM, and XRD. Moreover, the physical properties exhibited by these as-spun nanofibers can be evaluated by using thermal and mechanical characterization techniques (DSC, TGA, nanoindentation, etc.). This chapter provides a brief information about certain physical characterization techniques that are relevant with respect to electrospinning and the changes observed in the physical properties of the material. For instance, there was 20%, 18%, and 60% increase in tensile strength, elastic modulus and hardness, respectively, when 0.1 wt% of ZnO was doped with pure PVDF polymer. Keywords:  Electrospinning, nanofibers, polymer solution, physical characterization, non-woven nanofibrous mats

*Corresponding author: [email protected] Inamuddin, Rajender Boddula, Mohd Imran Ahamed and Abdullah M. Asiri (eds.) Electrospun Materials and Their Allied Applications, (71–112) © 2020 Scrivener Publishing LLC

71

72  Electrospun Materials and Their Allied Applications

3.1 Introduction Electrospinning [1], an electrohydrodynamic phenomena, is a voltagedriven process used to create fibers, of diameters ranging from few tens of nanometers to few micrometers, termed as electrospun fibers. With the emergence of nanotechnology and the interest toward studying unique properties of nanomaterials, electrospinning has gained popularity due to its versatility and diversity. Due to the simplicity of the process, diversity of electrospun materials and the unique features demonstrated by the electrospun fibers increases its potential for a variety of applications in the fields including tissue engineering [2], biosensors, filtrations, drug-delivery [1], protective clothing and smart textiles, electronics, etc [3]. The electrostaticdriven technique involves the fabrication of electrospun fibers through a polymer solution. Typically, electrospinning system consists of a polymer solution, a blunt needle/spinneret (in needle-based electrospinning), and a grounded collector plate. The complete dispersion of a polymer into a solvent generally give rise to a polymer solution which may smell unpleasant or are even toxic, therefore the overall process is carried out in a ventilatedchamber. The so formed polymer solution is subjected into a capillary tube/ syringe which is held due to its surface tension placed under an electric field. The applied electric field generates an electric charge on the liquid (polymer solution) surface and the repulsive electric forces overwhelms the surface tension forces when the applied field reaches a critical value [3, 4]. As a result, a charged solution jet starts ejecting from tip of the Taylor cone which leads to the volatile and rapid whipping of the jet between spinneret and the collector followed by evaporation of the solution leaving the polymer fiber behind as shown in Figure 3.1. It can be therefore concluded that the jet is stable only before ejection, i.e., on the tip of spinneret, and becomes unstable afterward. Electrospinning is a process that uses a variety of polymers to form fibers within a few microns range used in varied applications. Moreover, polymers used in the process include natural and synthetic polymers or copolymers comprising blends of proteins, nucleic acids or even polysaccharides. Normally naturally occurring polymers exhibits excellent biocompatibility and clinical functionality and low immunogenicity. Silk fibroin, chitosan, gelatin, collagen, etc., are widely used as a natural polymer [3]. Although natural polymer offers better biocompatibility and functionality as compared to synthetic polymers, mechanical properties and suitable degradation rate makes synthetic polymers more advantageous than natural fibers and can be utilized for various application including biomedical applications as well. Polyglycolide (PGA), polylactide, polylactic acid,

Characterization of Electrospun Fibers  73

Syringe Polymer solution

Taylor cone Needle

d

V

Voltmeter

Non-woven mat Grounded-metal coated collector

Figure 3.1  Schematic diagram of electrospinning process.

polyurethane, etc., are some of the synthetic fibers used for wound dressing, bone tissue engineering and cardiac grafts [3]. Some of the polymers used for electrospinning along with its basic properties and applications are shown in Table 3.1. Several parameters such as solution parameters, processing parameters, ambient parameters and type of solvent used often affects electrospinning. Figure 3.2 represents parameters affecting electrospinning. Each of these mentioned parameters significantly affects the morphology and the diameter of the electrospun fiber. A brief description about the parameters and their effect on the fiber is listed in Table 3.2. Solvent used in the process also significantly affects electrospinning, particularly influencing its spinnability as dissolution of the solvent in a solution serves to the first step in the process. Therefore, it is necessary for a solvent to have better volatility, vapor pressure, and to maintain coherence of the polymer solution. Electrospun fibers can further be classified into four different categories based on the starting material used for electrospinning: electrospun polymer nanofiber (EPF) [5], electrospun metal nanofiber (EMF) [6], electrospun CNFs (ECNF) [7] and electrospun composite nanofibers (ECF). Moreover, for electrospun polymer fiber, typically one or two polymer/s is/are dissolved into a solvent. Furthermore, EMF and ECNFs exhibits unique properties such as magnetism and electronic conductivity respectively. However, ECF being the most complicated type of fiber due to its complex structure and morphology also exhibits unique properties [8].

74  Electrospun Materials and Their Allied Applications Table 3.1  Basic properties and applications of different materials. Polymer

Properties

Applications

Silk fibroin

High SSA, potential strength and surface energy, significant thermal and electrical conductivity

Nanofibrous scaffolds for wound healing

Chitosan/polyethylene oxide

Physicochemical properties, biocompatible, biodegradable

Tissue engineering scaffold, drug delivery, wound healing

Gelatin

Biocompatible, biodegradable

Scaffold for wound healing

Hyaluronic acid

Biocompatible, biodegradable

Medical implant

Polystyrene

Biocompatible, biodegradable

Skin tissue engineering

Polyurethane

Good barrier properties and oxygen permeability

Nonwoven tissue template wound healing

Polyglycolide (PGA)

Bioresorbable polymer

Nonwoven tissue engineering scaffolds

Poly l-lactide (PLLA)

Mechanical strength, biocompatible, biodegradable

3D cell substrate

Ambient Parameters

Humidity

Temperature

Type of collector

Concentration Surface tension

PARAMETERS Solution Parameters

Conductivity

Viscosity

Applied voltage

Molecular weight

Figure 3.2  Parameters that affects electrospinning.

Processing Parameters Tip-to-collector distance

Feed rate/flow rate

Characterization of Electrospun Fibers  75 Table 3.2  Parameters and their effect on fiber morphology. Parameters

Description

Fiber morphological effect

Concentration

Increase in conc.

Increase in fiber diameter

Molecular weight

Increase in mol. wt.

Reduces bead and droplet number

Viscosity

Low viscosity

No continuous fiber formation/bead generation

High viscosity

Increases fiber diameter

Surface tension

High surface tension

Fiber morphology—NA, instability of jets

Conductivity/surface charge density

Increased conductivity

Decrease in fiber diameter

Applied voltage

Increased voltage

Decreased fiber diameter

Feed rate/flow rate

Low flow rate

Decreases fiber diameter

High flow rate

Formation of beads

Type of collector

Conductive

Varies with the material used

Tip to collector distance, d

Too small d

Bead formation

Solution parameters

Processing parameters

Too large d

Ambient parameters Humidity

High humidity

Circular pore formation on the fiber

Temperature

Increase in temp.

Decreases fiber diameter

Furthermore, the characterization of electrospun fibers is the most difficult task because of rare possibilities of getting single fibers. The characterization of these fibers has attracted many researchers due to their high surface area, smaller pore size and probability of making 3-D structures which enables the formation of advanced materials possessing revolutionary

76  Electrospun Materials and Their Allied Applications applications. Moreover, the characterization of these fibers can be divided into two main categories including physical and chemical. Physical characterization of a fiber corresponds to the structure and the morphology whereas the internal nanofiber structure determines the physical as well as mechanical properties. Furthermore, geometrical characterization of a fiber deals with the diameter and size distribution, orientation, and its morphology (surface roughness and cross-section). Scanning electron microscopy (SEM), transmission electron microscopy (TEM), field emission scanning electron microscopy (FESEM), and atomic force microscopy are amongst the main characterization techniques used for classifying fiber structure and its morphology. SEM is mainly used to determine the diameter and the morphology of the fiber and requires a sample to be electrically conductive. However, SEM suffers from a drawback of having low resolution at extreme magnification. Alternatively, TEM is successively used to determine the diameters of extremely small fibers (~ less than 300 nm). AFM is yet another characterization technique used to detect fiber diameter and labeled as a successful instrument to examine different morphology and appropriate description of the fiber surface. Other techniques such as X-ray diffraction (wide angle (WAXS) and small angle (SAXS)) and differential scanning calorimetry (DSC) have also been taken into account to determine the degree of crystallinity of the prepared fibers. The surface chemistry of electrospun fibers can be further resolved by utilizing X-ray photoelectron spectroscopy (XPS) and attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR). Although the main focus of this chapter is on the physical characterization of an electrospun fiber, surface chemical properties can also be examined through the molecular structure characterization using Fourier transform infrared (FTIR) and nuclear magnetic resonance (NMR).

3.2 Characterization Techniques 3.2.1 Scanning Electron Microscopy (SEM) SEM [9] is an electron microscopy that produces sample images by scanning the surface with a focused beam of electrons (see Figure 3.3). The interacted atoms produce a variety of signals that provides information about the sample’s topology and composition. Images are scanned in a raster scan manner where the beam position is combined with the intensity of the detected signals. The excited atoms emit secondary electrons which are detected by using Everhart–Thornley detector. Moreover, the number

Characterization of Electrospun Fibers  77 Electron source Monitor Condenser lens

Scanning coil

Objective lens

Secondary electrons

Scanning circuit

Primary electrons

Photomultiplier

Detector Specimen

Specimen holder

Figure 3.3  Working principle of SEM.

of emitted secondary electrons (SE) and the signal intensity produced depends on specimen topography. Back scattered electrons and X-rays are also emitted by electron beam and other instruments are employed to detect the compositional analysis. The electron beam of energy range between 0.2–40 KeV is focused using the condenser lenses. The focused beam is passed through scanning coil or pair of detector plates and finally passed through objective lens which deflects the beam in x and y axes to scan in a raster pattern over rectangular area. The emitted electrons produced are recorded using a detector. SEM is typically used to evaluate high resolution images in material science for research such as investigating nanotube and nanofibers [10]. In 2013, Bala et al. fabricated PLA/AgNO3 (Polylactic acid/silver nitrate) non-woven polymer nanofibers to evaluate antibacterial properties of these electrospun fibers against gram positive bacterial [11]. The surface characterization was done using SEM at a voltage of 20 kV (see Figure 3.4).

3.2.2 Field Emission Scanning Electron Microscopy (FESEM) FESEM is a microscopy technique used to observe small structures typically in the range of few nanometers ( 1 mm

100 µm

50 µm

4. Bonded FIBER aerogels

Minor pores 50 µm

(f)

(e)

10 µm

5 µm

5 µm

1 µm

300 nm

SiO2 NPs

100 nm 40 nm

1 µm

5 nm

Size scales Whole samples

Major pores

Minor pores

Nanofibers

Nanoparticles

Figure 7.6  (a) Schematic showing the synthetic steps for designing, processing, and cellular architectures of FIBER aerogels. (b) A FIBER aerogel (2.5 L). (c–e) SEM images of FIBER aerogels having hierarchical cellular fibrous structure (at various magnifications). (f) The scales for relevant prepared fibrous structures. Reprinted with permission from Ref. [46].

first requirement, while the last two are directly dependent on the materials used, i.e., polyacrynonitrile (PAN), crosslinking agent, and SiO2 nanoparticles as shown in Figure 7.6 [46]. The latter were introduced to enhance the porous structure and separation efficiency, with crosslinking agent cementing the adjacent fibers by forming Mannich-bridged bi-functional benzoxanine in-between the fibers. The obtained aerogel composite membrane was capable of withstanding compression; and had ultra-low density, and high porosity for effective oil–water emulsions separation driven solely by gravity (flux reached values of 8140 ± 220 L m−2 h−1 by gravity). In addition, the FIBER aerogel displayed high separation efficiency with superior antifouling property, excellent recyclability/ reusability which is applicable cleaning oil spills, oily wastewater and fuel purification.

7.6 Smart Membranes Stimuli-responsive wettability membranes for oily wastewater separation have been one of active research field due to the impact of these

Electrospun Materials in Oil-Water  205 membranes on the advancements on oily wastewater treatment [48]. These membranes are able to switch from one surface wettability to the next (i.e., between superhydrophobic/superoleophilic and ­superhydrophilic/ underwater superoleophobic) to afford one liquid to pass while the other is completely restrained depending on the exposure to external stimuli, such as electric field, pH, temperature, and light irradiation. Numerous researchers have been actively working on different materials toward smart surface materials for oily wastewater separation because of the practicality application which include remotely operatable, filtration manipulation, and on demand automation oily wastewater purification [48–50]. Among them, Ma et al. created a dual pH- and ammonia-vaporresponsive polyimide-based nanofibrous membrane by electrospinning [48]. Electrospun polyimide (PI) was modified via successive dipcoating in decanoic acid (DA)–TiO2 solution as well as silica nanoparticles to give highly superhydrophobicity in air and superoleophilicity in neutral aqueous environments. The pH-responsive wettability of the membrane was tested by assessing the changes of the contact angles of water and oil droplets values at various pH values, and it was found that superhydrophobic (WCA = 121°) and superoleophilic properties were observed at pH value of 6.5 ascribed to the nanoscale roughness provided by silica nanoparticles. However, under basic conditions the superhydrophobicity changed to superhydrophilic (WCA = 0°) due to the presence of the titaniumcarboxylate coordination bond breaking. The exposure to ammonia vapor resulted in spherical water droplets on the membrane spreading out indicating that the ammonia vapor effectively facilitated the transition of the membrane surface from superhydrophobic to superhydrophilic. In addition, the membrane showed the maximum of 6500 100 L m−2 h−1 was achieved for 1,2-dichloroethane-water mixture which was reported to be more than 30 times than those achieved by commercially available membranes (20–200 L m−2 h−1). Liu and Liu from Hsinchu reported on the fabrication pH-responsive electrospun nanofibrous mats for oil/water purification [51]. In this regard, they electrospun polybenzoxazine followed by thermal crosslinking to afford chemically and thermally stable overlapped hydrophobic fibers. Besides showing switchability with varying pH, the membrane displayed high flux rate of 21,750 Lm−2 h−1 for toluene and water flux rate of 14,950 Lm−2 h−1. Elsewhere, a switchable pHresponsive membrane was produced by electrospinning poly(methylmethacrylate)-block-poly(4-vinylpyridine) (PMMA-b-P4VP) onto stainless steel [52]. The three-dimensional structure of the fibers offered the strength for oil/water wetting property. It was shown that at the initial state, oil was able to pass through easily with water being retained by the membrane;

206  Electrospun Materials and Their Allied Applications and wetting with acidic (pH = 3) water the reverse prevailed (Figure 7.7a and b). Li et al. fabricated pH-responsive membrane from PDMS-blockpoly(4-vinylpyridine) (PDMS-b-P4VP) using electrospinning [53]. The obtained membrane afforded excellent pH switchability with WCA of 155 at pH of 7; and the water droplet wetted and spread over the mat when pH value is 4 over 480 s, i.e., superhydrophilic nature, while oil was absorbed by the mat. The membrane showed good separation efficiency by varying pH and achieved high flux rate, viz., 9000 L m−2 h−1 for n-hexane (as model oil) and 27,000 L m−2 h−1 for water. The inclusion of silica nanoparticles SiO2 enhanced thermal stability and pH-responsiveness of the membrane, hence the separation performance, i.e. flux rate of 9000 L m−2 h−1 for oil and 32,000 L m−2 h−1 for water. Temperature-responsive membrane surface wettability was also studied by numerous researchers [50, 54]. Among them, Li et al. demonstrated the fabrication of thermo-responsive electrospun nanofibrous membrane using temperature-responsive copolymer PMMA-b-PNiPAAm for oil/ water separation [54]. It was found out that the electrospun nanofibers with their three-dimensional structure exhibited extended transition range when compared to membrane prepared using solution casting. In addition, the nanofibrous membrane displayed a separation efficiency of 98% and flux rate of about 9400 Lm−2 h−1 for water and 4200 Lm−2 h−1 for oil. The incorporation of the nanoparticles serves as suitable strategy to improve the properties of the resulting composite materials [55, 56]. A smart composite membrane composed of TiO2 nanoparticles and PVDF was demonstrated by Wang, and co-workers [55]. The authors fabricated nanofibers consisted of beads-on-string structures for oily water separation. Such (a)

(b)

Water

Oil

Oil

Water

Figure 7.7  Photographs of pH-controllable oil/water separation device: (a) n-hexane (colored with iodine) was allowed to pass through the membrane, whereas water was retained (right). (b) When wetted with acidic water, water passed freely, while oil could not (right). Reprinted with permission from Ref. [52].

Electrospun Materials in Oil-Water  207 membrane displayed good antifouling and self-cleaning properties due to the presence of TiO2 having photocatalytic properties. Nanocomposites were found to be responsive when exposed to UV (sunlight irradiation) and heat treatment, thereby allowing either water or oil to pass through (Figure 7.8). A smart membrane responsive of being exposed to CO2 was also demonstrated in [57]. In this regard, amidine containing polymers is recognized to be CO2-reponsive since this compound reacts with (a) Transmittance (a.u.%)

C

(d)

1712

A UV

A

4000

(b)

2923,2852

B

3500

B 3000

C 2500

2000

1500

Wave number (cm–1) (c)

Stained T-P nanofiber

1000

Organic compounds O2

UV

CB

e–

O2–

VB

h+

OH+

TiO2

H2O CO2,H2O Self-cleaned T-P nanofiber

Figure 7.8  Antifouling and self-cleaning behavior of the prepared T–P nanofiber membrane. (a) FTIR spectrum showing the chemical component difference among the T–P membrane before being stained and after being stained by oleic acid and the stained T-P membrane treated by UV irradiation; the top surface of the membrane before (b) and after (c) UV irradiation. (d) Schematic showing the self-cleaning behavior of the prepared nanofibrous membrane under UV and the photocatalytic mechanism of the incorporated nanoparticles (TiO2). Reprinted with permission from Ref. [55].

208  Electrospun Materials and Their Allied Applications CO2 resulting in a charged amidinium bicarbonate which can be reversed by purging with inert gas (e.g., N2 or argon). A copolymer of PMMA-co-poly(N,N-diethylaminoethyl methacrylate) (PDEAEMA) having tertiary amine was electrospun and tested for oil/water separation as membrane with adjustable wettability between hydrophobicity/ oleophilicity and hydrophilicity/oleophobicity by alternating CO2 and N2. The authors synthesized PMMA-co-PDEAEMA copolymers via radical polymerization followed by electrospinning to afford fiber having diameter of 700 nm. In order to establish the switchability of the as-prepared nanofibrous membrane static water contact angle (WCA) measurements were conducted, and WCA of 140° was obtained for electrospun nanofibers due to their roughness. It was found that membrane can switch depending on the gas used, i.e., either CO2 or N2. When purged with CO2 for 15 min the membrane wettability changed from hydrophobicity to hydrophilicity, viz., WCA values changed from 140° to 36°. Therefore, oil passed through the membrane easily while water was retained and the bubbling with CO2 for 15 min led to the opposite behavior. In addition, the membrane displayed a flux of 17,000 Lm−2 h−1 for oil and 9554 Lm−2 h−1 for water after CO2 treatment.

7.7 Conclusions and Future Trends Electrospinning technique offers a new platform to design novel materials for effective oily wastewater separation. It renders opportunity to fabricate novel materials by either incorporate new functional components or changing surface topography, hence tailoring the surface wettability of the fibers toward effective oil–water separation as either sorbents or filtration membrane. Electrospinning technique is capable of generating hierarchical structures, i.e., a combination of nanofibers and different shapes of micro-/ nano-particle which can be fine-tuned to improve the selectivity and permeance of the resulting composite material. Over the past years, there is a lot that has been achieved in modification and production of nanofibrous membranes of different designs toward oily wastewater treatment. In this chapter, recent trends and challenges of oil/water separation using electrospun nanofibrous membranes taking advantages of different architectural structure that can be obtained using electrospinning techniques were discussed. Although the membranes showed high separation efficiency due to the super wettability introduced on the surface of the fibers there are few difficulties that need to be addressed in the near future. Besides the opportunity for surface modification and roughness using

Electrospun Materials in Oil-Water  209 electrospinning techniques, the resulting membranes are delicate making them easily damaged or contaminated upon external influences. Therefore, the modification of the fibers such that it improves the overall stability of the resulting nanofibrous membrane is of significant importance. On the other hand, some of surface modifications to afford different wettability are only applicable in laboratory scale, further studies to afford the industrial applicability will be of essence. Moreover, the investigations using real life oily water separation scenarios is of significant in order to be conclusive how far are these membranes to reach market. It can be concluded that the electrospun nanofibrous membrane have a great potential to address some of the issues facing conventional membranes due to its attractive attributes, such as interconnected porous structure, a large ratio of s­ urface-to-area, controllable mechanical properties, tuneable wettability, and porosity. In future, we foresee the electrospun nanofibrous membranes revolutionizing the current oil-separation techniques such that they can be used together with other techniques to afford highly effective oil–water separation membranes.

Acknowledgments Funding from Department of Science Technology (DST, South Africa)Biorefinery Program is gratefully acknowledged by the authors

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8 Application of Electrospun Materials in Industrial Applications Anisa Andleeb and Muhammad Yar* Interdisciplinary Research Centre in Biomedical Materials (IRCBM), COMSATS University Islamabad Lahore Campus, Defence Road off Raiwind Road Lahore, Pakistan

Abstract

Over the past few decades, electrospun materials have been widely studied and their applications in various industrial level fields are largely exploited. The simplicity of electrospinning process, the unique features, and diverse nature of electrospun fibers make this technique attractive for different applications. Recently, significant progress was observed in the area of electrospun fibers applications, as demonstrated by the number of recently published patents and research work on the electrospinning technique. At present, electrospun materials, electrospinning apparatus, and their technological solutions are rapidly moving toward commercialization. Dedicated companies are making efforts to commercialize electrospun products, laboratory and industrial-scale apparatus and equipment for electrospinning. The main focus is on the modification of electrospinning apparatus and conditions for the development of electrospun fibers with various morphologies, shapes, structures, and sizes, so that the resultant nanofibers should possess broad functionalities to get commercial interest. This chapter mainly focus on the present potential applications of electrospinning and electrospun materials in various industrial fields such as biomedical (tissue engineering, medical prostheses, wound dressing, drug delivery and cosmetics), filtration, sensors, textiles, protective clothing and energy harvest and storage devices (batteries/cells, capacitors). Although, in the current stage some of these applications are still limited to ­laboratory-scale production, but the rate at which the interest in electrospun nanofibers is growing, it is evident that electrospinning technique has a bright future in industrial applications.

*Corresponding author: [email protected] Inamuddin, Rajender Boddula, Mohd Imran Ahamed and Abdullah M. Asiri (eds.) Electrospun Materials and Their Allied Applications, (215–242) © 2020 Scrivener Publishing LLC

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216  Electrospun Materials and Their Allied Applications Keywords:  Electrospinning, electrospun fibers, large scale production, industrial applications, electrospun products

8.1 Introduction Electrospinning is an efficient and versatile method for large scale production of continuous and uniform nanofibers with diameter ranging from submicron to nanometer, by using a high speed electric field [1]. A variety of nanofibers can be prepared by electrospinning technology for their wide range of applications in tissue engineering, drug delivery, biotechnology, wound healing, environmental protection, energy harvest and storage, electronics and defense, and security purposes, because of their higher mechanical performance, large surface area to volume ratio and functional properties [2]. Nanofibers can be produced using several methods such as high-­volume production methods (island-in-sea [3], melt fibrillation [4], and gas jet [5] techniques) and highly precise methods (nanolithography [6,  7] and self-­assembly [7]). Moreover, various spinning technologies for fibers production are being developed to manufacture fibers with diverse specificity range. These spinning technologies results in the continuous and constant preparation of materials either single or multi-filament with diverse properties depending on the specificity of parameters and methods adopted. These spinning methods may be categorized as solution spinning, emulsion spinning, and melt spinning, with respect to the state or condition of the material to be spun. Polymer melt spinning possess unique advantages in term of process safety whereas solution spinning are advantageous in term of higher optical, mechanical, and electric properties and lower energy consumption. While emulsion spinning is best for polymers processing which exhibit high melting point like those from which flame-retardant fibers are produced. Due to their typical morphology, the electrospun fibers have ability to mimic the structure of extracellular matrix and hence are considered suitable for fabrication of biological scaffolds for tissue engineering purposes [1]. In 1930s, Formhals was the first who filed patents in US for electrospinning of plastics [8] but these initial patents could not be finalized for industrial applications due to lack of the characterization equipment. However, by the end of 1930s experiments by I. V. Petryanov-Sokolov and coworkers are regarded as first industrial application of electrospun materials, where they have employed Petryanov filters for production of gas masks [9]. The factory production of these filters was increased during the 1950–1960s

Electrospun Materials in Industrial Applications  217 but the actual production capacity was never revealed outside because of their likely use in defense against radioactive aerosols and they were considered as military secrets. In the early 1980s, the first commercial products were introduced by Donaldson Co., Inc. in the United States. In 1984, DuPont spun microdenier fibers [10]. In 1995, nano-scale nature of fibers were introduced by Reneker and co-workers and this method of fiber production is still used today with great success [11]. Presently, research on electrospun materials is growing continuously at higher rate as evident by scientific work published every year. In last decade, around 2500 research articles have been published related to electrospun nanofibers (especially of polymer based) and the current peak is reaching about more than 1.4 × 104 citations per year. The publication data from 2001 to 2011 [1] revealed that number of publications was ten times higher in 2011 than in 2003. About 70% of these published research items were contributed from USA, China, and South Korea whereas Japan, Germany, and Singapore come next in this list. On the other hand, the quantity of issued patents has tremendously increased from 2003 to 2011. Among these 75% were of international applications (Patent Cooperation Treaty, PCT), while the others were predominantly of Europe and South Korea contributing (17%) and (7%). DuPont (6%) and Donaldson (4%) were among the top patent owners companies and other includes mainly universities. However, these overall patent groups mainly focused on the development of filtration apparatus and media [1]. Importantly, various developing countries are also participating now in this research by entering in advance nanotechnology fabrication approaches. Among all applications of electrospun nanofibers, filtration is the best developed area where the particularities of nanofibers had been successfully shifted toward industrial products. As compared with conventional air-filter media these nanostructures show higher filtration efficiency and are easy to clean. The market of nanofiber based on air-filters has developed very quickly especially of liquid filtration such as desalination and treatment of waste-water and energy harvest and storage devices such as battery separator. After DuPont has introduced a new nanofiber based battery separator (Energain), the battery life and performance has been improved and there is a great interest in future for market of electric vehicles. Biomedical related applications are likely to be ready for industry for a long period, but still it requires time to get international authorizations and authentications in order to take these products in the market. However, several developing companies in the biomedical field are low enterprises and belongs to specific pharmaceutical companies or academic institutes,

218  Electrospun Materials and Their Allied Applications which are only producing copyrighted products [1]. Moreover, in context of industrial scale production, the price and production scale requirements greatly depends on the specific application which is under consideration. Usually, the technically complex or advanced end products like consumer electronics or medical devices demands higher prices in the market while needs lesser production volumes [12]. In order to be employed by the industry, the electrospinning process should be robust and be able to produce nanofibers continuously with uniform diameter and thickness. The production process should be safe for environment, workers, and end users. In order for electrospinning methods to be commercially valuable, they must be able to manufacture nanofibers for cheap cost and at large volume when comparing with current alternative products or technologies. For nanofibers to be compete with present textiles specially films, they must offer improved porosity, surface area, and reduced weight. Moreover, membranes must be small so that they can be effectively employed in miniaturized devices such as implantable biomedical devices, electronics, etc. [12]. From industrial viewpoint, there are several representative companies which are supplying or commercializing electrospun products for appli­ cation in various fields. These companies include DuPont (www.dupont. com), Espin Technologies (www.espintechnologies.com), Donaldson (www.donaldson.com), Esfil Tehno AS (www. esfiltehno.ee), Ahlstrom Corporation (www.ahlstrom.com), Hollingsworth and Vose Company (www.hollingsworth-v ose.com), Yflow (www.yflow.com), Finetex Techno­ logy (www.finetextech.com), Nano109 (www.nano109.com), Japan Vilene Company (www.vilene.co.jp), Hemon Medical Technology, Inc (www.hemcon.com), SNS NanoFiber Technology (www.snsnano.com), JohnsManville (www.jm.com), Polynanotec (www.polynanotec.com), Nanofiber Solutions (www.nanofibersolutions.com), Soft Materials and Technologies (www. smtnano.com), Kertak Nanotechnology (www.kertaknanotechnology.com), and NanoSpun (www.nanospuntech.com) [1].

8.2 Technology Transfer From Research Laboratories to Industries Although the benefits of electrospinning technologies and their associated applications have been extensively explored in many fields but still this technology requires further improvement to carry out the maximum production in an effective manner, in order to tackle the issues concerned with

Electrospun Materials in Industrial Applications  219 reproducibility, huge volume processing and safety and environmental aspects of electrospinning. Due to lack of affordable and reliable electrospinning methods, many advanced applications of electrospun fibers are still limited. During processing, certain ambient conditions largely affect the properties of electric field jet and in this way even a small environmental distress can cause complex variation in the fiber properties. To tackle these issues many companies have developed temperature and humidity controlled electrospinning systems [13]. From the commercial perspective, due to a growing interest in electrospinning an increased competition was seen among the laboratory scale equipment suppliers. At present, a wide variety of electrospinning equipment exists in the market which can work on laboratory-scale. Most of these laboratory-scale equipment are manufactured with concept of needle type electrospinning having low production rate. Moreover, in academic research, equipment flexibility and multi-functionality is very important in regard to be able to carry out different research projects. As most of the customers are from government institutions and academia, their requirements include price reduction, multifunctional set-up, and compactness to be installed in limited space of laboratories [1]. According to the latest count more than 100 companies are selling electrospun nanofiber-based products or electrospinning equipment but majority of them facilitates the laboratory-scale research market. while only a limited number of companies exist on the market of industrial scale equipment that are supplying large electrospinning equipment or machines such as BioInicia (Spain), Elmarco (Czech Republic), Inovenso (Turkey), and Fuence (Japan), while others are manufacturing ­nanofiber-based materials for commercial application like DuPont, Donaldson, 3M, Arsenal Medical, Hollingsworth & Vose, and many more. A large number of companies are also offering contract manufacturing services or personalized nanofiber production with the aim to bridge the gap between a commercial product and R&D outcome. Some of these evolving companies include BioInicia, FineTex Technology, E-Spin Technologies, Revolution Fibres, SNS Nano­ fibre Technology, Kertak Nanotechnology, YFlow, Electrospunra, Soft Materials and IME Technologies. A well-established industry Hills Inc. (USA) is leading in the field of polymer electrospinning technologies. They have established various melt processing techniques which are capable of submicron fibers production [12]. For an equipment to be effectively used on industrial-scale, the key issues required to be tackled are productivity, multi-functionality, well-established monitoring capacity, and quality ­control [1].

220  Electrospun Materials and Their Allied Applications

8.3 Industrial Applications of Electrospun Materials Despite the marked applications of electrospun nanofibers as exhibited by many peer-review journals in the field of filtration, electronics, medical devices, sensing, energy generation and storage devices and composites, excluding few, the commercialized products using electrospun nanofibers are extremely limited. Majority of the current market for nanofibers is based on polymeric electrospun nanofibers, finding applications in water and air filtration, batteries, medical devices, textiles, and composites. Inorganic nanofibers have been found to be valuable for high temperature filtration applications. Carbon nanofibers have applications in number of industries including energy (batteries, fuel cells, and catalysts), electronics (EMI shielding, heat management, and conductors), life sciences and medicine (tissue engineering, drug delivery, and implants) and composites (polymers, ceramics, glass, plastics, and resins). Carbon nanofibers also exhibit the fastest growing market in Li-Ion battery applications. Figure 8.1 shows leading potential industrial applications of electrospun materials.

Sensors

st ly ta Ca

W dr ou es nd sin g

ies

ter

Energy stora ge cells

Bat

Applications of Electrospun Nanofibers

Sea

Fuel Cells

lds

ffo So ce lar lls

Fi lt

er s Protective clothing

Figure 8.1  Diagrammatic illustration exhibiting the practical applications of electrospun nanofibers. Reproduced with permission from Ref. [32]. Copyright ©2017 Elsevier.

Electrospun Materials in Industrial Applications  221

8.3.1 Biomedical Materials Nanofibers are considered suitable for medical applications because of their unique structure that is capable to mimic the structure of natural extracellular matrix present in the tissues in our body. For regenerative medicine, when these nanofibers are used in the body, their high porosity allows the transport of nutrients and waste and growth of cells. Various natural and synthetic polymers as well as many FDA-approved materials can be spun by electrospinning, including incorporation of functional additives like growth factors or antimicrobials [12]. Electrospun nanofibers find their promising applications in several biomedical areas including tissue engineering, drug delivery, wound dressing, medical prostheses, and cosmetics [14]. Tissue engineering is amongst the most encouraging and mainly studied biomedical application of electrospun fibers. The basic purpose of tissue engineering includes repairing, maintenance or replacement of specific tissue or organ of the body. A wide variety of biodegradable polymers can be electrospun in the form of mats with structural integrity and specific arrangement of fibers. Moreover, surface of nanofibers can be functionalized to exhibit specific biochemical properties [15]. In tissue engineering, the main challenge is to design such scaffolds that are capable to mimic the structure of extracellular matrix present in the tissues of the body [16]. Scaffolds prepared from electrospun nanofibers have shown efficient cell adhesion and proliferation properties in both in-vitro and in-vivo studies. For tissue engineering applications, electrospun scaffolds can be prepared using a wide variety of material, including natural or synthetic polymers. Electrospun fibrous scaffolds are preferably fabricated by using naturally occurring polymers such as chitosan, silk protein, dextrin, collagen, fibrinogen, gelatin, hyaluronic acid, alginate, and starch. Among the synthetic polymers, poly (lactic acid) (PLA), poly (caprolactone) (PCL), and poly (glycolic acid) (PGA) are extensively employed in biomedical applications as they are biodegradable and biocompatible [15]. Biodegradable electrospun fibrous scaffolds are considered as a suitable template for cell seeding, proliferation, and differentiation and later their application on the body tissue for their regeneration [17]. In order to deliver active biomolecules, electrospun scaffolds are specifically fabricated using various techniques. Thereby, through physical adsorption, the biomolecules are loaded or incorporated into the scaffolds by dipping the scaffolds in an aqueous phase which contain biomolecules. While in case of blend electrospinning, the biomolecules are initially

222  Electrospun Materials and Their Allied Applications mixed in the polymer solution and subjected to electrospinning process, to construct a hybrid scaffold. Coaxial electrospinning offer a great promise in protein delivery field, through production of core-shell fibers having a unique ability to preserve proteins [18]. Electrospun nanofibers are also considered as an effective substrate for nerves tissue repair. Lee et al. [19] have fabricated conductive nanofibrous scaffolds by introducing electrical stimulations during cell growth on polypyrole (PPy) containing PLGA nanofibers. It was observed that electrically stimulated nanofibers were resulted in more neurite formation and longer neuritis than the nanofibers without simulation. For bone tissue engineering PCL based nanofibers were extensively studied [20]. Sun et al. [21] have reported coaxial electrospinning technique to prepare coreshell nanofibers to encapsulate nanocomposites and biomolecules whereas Zhang et al. [22] used PCL nanofibers to encapsulate a model protein via coaxial electrospinning. Due to higher porosity and large surface area, the nanofibers developed via electrospinning have been efficiently used for treatment of human skin wounds. The porosity of electrospun nanofibers permits gas exchange while the fibrous structure shields the wound from dehydration and infection. Non-woven membranes produced from electrospun nanofibers used as a wound dressings, have pore sizes from 500 to 1,000 nm and this pore size is small enough to ovoid bacterial infiltration into the wound. On the other hand, electrospun nanofibers are proved effective for dermal delivery and fluid absorption [16]. By using electrospinning, Chong et al. [23] have developed a composite wound dressing, consisting of a scaffold filter layer which also act as a semi-permeable barrier for skin. In this composite Tegaderm polyurethane (TG) which is impermeable to moisture but permeable to oxygen was used as a semipermeable barrier. On the surface of TG, PCL nanofibers were specifically electrospun to generate a TG-nanofiber (TG–NF) composite. For human dermal fibroblast, this TG–NF composite was considered an effective host substrate. The (Figure 8.2a) illustrates a structure and form of PCL/gelatin nanofibers based scaffold, prepared directly by electrospinning it onto polyurethane to prepare an impermeable wound dressing and (Figure 8.2b) shows SEM micrographs of the scaffold [23]. In another study, gelatin was electrospun with Norsocryl XFS to design a wound dressing. The designed material was useful for treatment of wounds mainly of chronic nature. Lee et al. [13] made a chitosan based non-woven web having soft texture and ability to moisturize the skin. The prepared web showed biocompatibility, biodegradability, good air permeability, quick antibacterial activity, and moisturizing properties.

Electrospun Materials in Industrial Applications  223 (a) Nanofiber scaffold

Tegaderm™ Wound Dressing

(b)

50µm

WD Mag Sig HV 8.0 kV 2000x SE 10.0 mm

50.0µm PCL Gelatin

Figure 8.2 (a)  A photograph of a scaffold (Tegaderm, 3M Medical) prepared from poly (caprolactone) (PCL)/gelatin nano-fibers that are electrospun onto polyurethane for wound dressing. (b) SEM micrograph of this construct. Reprinted with permission from Ref. [23]. Copyright ©2007 Elsevier.

A multilayered non-adherent dressing was made by coating of hyaluronic acid, PCL, PLG, and PLA which are hydrophilic polymers, on the base layer made primarily of hydrophobic, biocompatible and biodegradable polymers like poly(sebacic anhydride), poly(1,3-dioxan-2-one), poly-L-glutamic acid, polydepsipeptide, PLA, polyphosphazene, PLG, poly(1,4-dioxan-2-one), and polyglycolide. The multi-layered dressing also act as a barrier and has solved various shortcomings such as poor flexibility, adhesion to tissues or skin, etc., that are associated with the conventional sponge, gel or films. Moreover, this multi-­layered dressing was not broken when rolled and was easy to handle using smaller surgical instruments. Furthermore, it can block the blood infiltration, have

224  Electrospun Materials and Their Allied Applications ability to reduce a foreign body reaction while use in the surgical procedures and may encourage the wound healing [24]. Electrospun nano-­ fibers produced by electrospinning can be sprayed on the injured skin to get a function of wound dressing. Another study demonstrated that by using electric field, the ultrafine nano-fibers can be sprayed directly on the injured skin, where the fibers assemble in the form of fibrous mat dressing [15]. Electrospun nanofibers are emerging as promising materials for dental applications. Biodegradable electrospun nanocomposites have been reported as a good candidate for localized delivery of drugs such as piroxicam [25] and meloxicam [26] for periodontal regeneration or treatment of periodontitis. Another study by Khan et al. [27] have reported hydroxyapatite and carbon nanotube based electrospun fibers for dental and biomedical applications. Electrospun nanofibers have been proposed to be a good candidate in soft tissue prostheses such as vascular graft, blood vessel, breast, etc. A number of polymeric nanofibers have been designed as a porous film and placed on hard tissue prosthetic device intended for implantation into the human body. Kim et al. [28] have established a nanofibrous biomimetic nano-composite through electrospinning. These nano-­composite fibers were capable to significantly increase the bone-derived cellular activity than the pure gelatin equivalent. Electrospun nanofiber can also be used to develop bilayer structures that have potential to mimic the structure of native blood vessel. This bilayered scaffold have good mechanical properties comparable or equivalent with native vessels [29]. In order to study tissue engineering on vascular grafts, Zhang et al. [30] have seeded and cultured bone marrow mesenchymal stem cells (MSC) after genetic modification on the poly (propylene carbonate) based graft. This construct made a three-dimensional cellular network. For clinical use, various functional vascular grafts can be fabricated using protein electrospinning. Tillman et al. [31] have constructed PCLcollagen based scaffolds and studied there in-vivo biocompatibility through surgical implant using an aortoiliac bypass model in a rabbit (Figure 8.3). These electrospun scaffolds have supported the growth of vascular cells and cell adhesion and when exposed to blood, these endothelialized grafts had ability to resist the adhesion of platelets. In the biomedical field, nanofibers are promising carriers for controlled delivery of therapeutics, drugs, body-care supplements, and  molecular medicines. While using electrospun nanofibers for drug delivery it is generally considered that drug releasing rate will be enhanced when the surface

Electrospun Materials in Industrial Applications  225 (a)

(b)

Aorta

Scaffold

Native Aorta

Iliac

Iliac Artery

Pelvic Collaterals

Figure 8.3  The picture shows rabbit aortoiliac bypass procedure using a composite graft prepared from electrospun poly (caprolactone)-collagen. (a) The grafts were sutured between native aorta and iliac artery (b) shows a representative post-operative image. Reprinted with permission from Ref. [31]. Copyright ©2008 Elsevier.

area of both the carrier and the drug is increased. The work of Belenkaya on electrospun nanofibers led to the first patent on drug delivery system [14]. At present, many new drugs are developed having ability to cure cancer disease effectively. Several limitations are associated with common cancer treatments such as toxicity offered by radiotherapy and chemotherapy to normal healthy cells and insufficient distribution of drugs in the blood circulation in case of chemotherapy. In this context, electrospun nanofibers plays an important role as an efficient drug carrier in cancer therapy [32]. A new device based on core-shell nanofibers was developed by Shaobing Zhouand and co-workers which can serve as an effective and safe implant material for cancer treatment. For this nanofibers were prepared using co-axial E-spin technique and loaded with drug (doxorubicin) and combine with folate-conjucated PEG/PCL copolymer coated micelle. The therapeutic effect of these nanofibrous mats containing micelle revealed effective killing of tumor cells even with minimal drug loading and thus enhanced the survival rate of affected individuals [33]. However, there exist certain limitations with core-shell model, such as inadequate solubility, unable to cross the blood vessels and non-specificity for drugs. Zong et al. [34] carried out in-vitro studies by loading antibiotic drug into nanofibrous mats and studied its release or delivery pattern. They developed mefoxin loaded nanofibers and have optimized some

226  Electrospun Materials and Their Allied Applications instrumental parameters such as electric field, salt addition, concentration, and feeding rate. For in-vitro drug release studies, the prepared nanofibrous mats were dipped in 20 mL buffer solution and release profile confirmed that all the drug was released within 48 h. Polymeric drug delivery system is also of great interest to deliver biomolecules and nucleic acids. A “smart” polymeric drug delivery system has been fabricated using carbon nanofibers for encapsulation of DNA. Prior to DNA encapsulation, it was inserted into cells by centrifuging it along with the cells. In this way the genes encoded by the inserted DNA were able to express effectively and cell viability was not altered [35]. Another drug loaded, pH-responsive polymer system was developed to target the diseased cells through ligand and cell receptor binding. This polymeric construct enters the endosomes of the cells through endocytosis. After entering the endosome, due to low pH the drug separates from the polymer backbone, disturbs the endosomal membrane and finally releases the drug into the cells cytoplasm [36, 37]. This drug delivery system can also be used to deliver vaccines of specific cell types, antisense oligonucleotides to target specific organelles of cells and silencing RNA [38]. Electrospun nanofibers offer their benefits for use in cosmetic cares including skin cleaning and skin treatments. Revolution Fibres has developed a nanofiber dressings for cosmetics use. actiVLayr™ skin delivery system is a marine collagen based fiber patch which is water soluble and it can be incorporated with a wide variety of fruit and plant extracts which are clinically verified to improve moisture retention, skin elasticity and diminish the presence of sun spots and wrinkles from the skin. Skin Repair dressings and actiVLayr® Anti-aging patches are some of potential products which are manufactured using electrospun nanofibers as a delivery platform. actiVLayr® is capable to target several skin benefits or appearances depending on the type of extract (kiwi, seaweed, blackcurrant, grapes, etc.) used [12]. The nanofibrous scaffold developed via electrospinning could be effectively used by surgeons for cosmetic surgery. Poly (vinyl butyral) (PVB) microcapsules prepared via electrospinning were used to encapsulate honey. The microencapsulation of honey gave an antibacterial properties to the polymer construct. The resultant microbicidal nanofibers are useful in cosmetic cleaning care as pads and wipes [13]. Currently, a broad range of products are achievable using electrospun nanofibers in cosmetics industry such as elasticity face masks and skin moisturizers, anti-­inflammatory patches, patches for skin brightness (full face or under-eye), acne treatment, skin burn treatment with antimicrobial additives or extracts, nappy liners

Electrospun Materials in Industrial Applications  227 that reduce skin irritation and delivery of essential oils, plant extracts, and enzymes onto skin [12].

8.3.2 Defense and Security Military, law enforcement, firefighter and medical personnel need higher protection when they are dealing with biological and chemical threats such as chemicals like mustard gas, nerve agents, biological toxins (viruses, bacterial spores), and blood agents (like cyanides) in various environments including war, industrial, and agricultural. Nanostructures because of their large surface area, small size, and light weight are capable to detect biological and chemical warfare agents with efficient selectivity and sensitivity. Polymer electrospun nanofibers are regarded as an excellent material for destructive breakdown of harmful toxins [39, 40]. Nanofibers used for warfare agents have such high sensitivity that they are able to detect biological and chemical toxins even in parts per billion concentration [41]. Around the world, governments are investing to reinforce the protection levels given to the soldiers in the battlefield. Currently different methods are studied to modify nanofiber surfaces to improve their ability to capture and decontaminate warfare agents. One of these methods includes surface modification of nanofibers using chemicals and reactive groups such as cyclodextrins, oximes, and chloramines that are capable to detoxify warfare agents [42, 43]. Preliminary testing on the nanofibers functionalized with chemical warfare simulants like dimethyl methyl phosphonate and paraoxon indicate evidence of decontamination. Moreover, nanofibers embedded with metal nanoparticles such as Ti, MgO, Ag, Ni, etc., have also shown capabilities in decomposition of warfare agents [38].

8.3.3 Textile Industry Electrospun nanofibers due to their large surface area, lightweight, great filtration efficiency, high porosity, etc., have found their application in textile industries in production of functional fabric materials and protective clothing [15]. Electrospun nanofibrous membranes having highly porous nature, high surface area, and minimum pore size can neutralize the chemical agents without impedance of water vapor and air permeability to the clothing. Preliminary studies have shown that the electrospun nanofibers are extremely effective to trap aerosol particles in comparison with the conventional textiles [16]. A lightweight protective clothing consisting of

228  Electrospun Materials and Their Allied Applications electrospun poly (ethylenimine) nanofibers was prepared by Smith et al. [14] in order to capture and neutralize warfare agents. This fabric have potential applications in the development of protective breathing apparatuses, because it contains poly (ethylenimine) which offers numerous amine sites for the selective attack and decomposition of nerve gases and mustard gases. A bilayer protective mask was manufactured by combining a layer of electrospun nanofibers with cellulose and wool based moist fabric [44]. By means of co-axial electro-spinning a submicrosized fiber with a polyurethane core and a nonwoven fabric was prepared. The prepared fabric showed high filtration efficiency and mechanical strength which was useful in aviation clothing and exposure suits. Nonwoven wiping clothing which is soft, antistatic, and hygroscopic in nature was prepared via melt-­ electrospinning of polyethylene glycol (PEG) and polybutylene terephthalate (PBT). The resultant PEG and PBT membranes were pressed using high temperature of 140°C temperature in order to prepare a nonwoven structure with superb wiping properties. An air-permeable and water-resistant laminated fabric was prepared by spreading hot-melt polyester in the form of dots on the surface area of the electrospun fabric. The prepared fabric showed effective air permeability and moisture permeability [14]. Recent protective clothing gives full barrier protection such as protective over garments and hazardous materials (HAZMAT) suits which are permeable and adsorptive like those used by the US military. The limitations associated with these suits are moisture and weight retention which obviously prevent the user to wear them for long periods [45].

8.3.4 Catalyst A catalyst specifically binds to its relevant substrate and its activity relies on its active surface area. Catalytic activity of a catalyst can be improved through coating of that catalyst on Nanofibrous materials to enhance the active surface area [46]. Catalyst entrapment into the nanofibrous membranes using electrospinning process was first reported by Reneker et al. [14]. They revealed the fabrication process by using nylon solution as a fiber-producing material, formic acid and aluminum as a solvent and a catalyst and entrapped them into a fibrous-immobilized form via electrospinning process. Electrospun nanofibers have large surface area and significantly higher capacity for catalyst loading and hence are considered as a potential solid support material for conventional catalysts and enzymes. Additionally, nanofibrous catalysts possess other benefits such as they offer

Electrospun Materials in Industrial Applications  229 less resistance to the flow of gases and liquids and easily adaptive to any geometry. The catalyst recovery potential of electrospun nanofibrous catalysts is higher than that of nanoparticle catalysts due to the fact that they can be reused and recycled easily. Enzyme-linked electrospun nanofibers also have prospective applications in the development of biosensors. Enzymes due to their high specificity offer a great potential for efficient biosensors applications [47–49]. In another study, Birkan et al. [14] revealed a method to develop carbon nanofibers having catalyst nanoparticles. A solution of titanium oxide (TiO2), niobium (Nb) nanofibers, and poly (acrylonitrile) was used as a photocatalyst to electrospun the template polymer and nanofiber containing Nb alkoxide and alkyl titanate. The resultant titania fiber showed good handling property and high photocatalytic activity. The electrospun nanofibers containing oxide precursor can be calcinated to prepare a nanofibers based Pt/TiO2 catalyst having hardness greater than 0.5 MPa. The fibrous catalyst prepared by this method also display excellent handling property and rigidity.

8.3.5 Energy Harvest The energy demand has been increasing with time throughout the world due to higher consumption rate. Electrospun nanofibers have received much interest in lithium cells, capacitors, fuel cells, transistors, solar cells applications, etc. Moreover, electrospun nanofibers with electro-optical and electric properties showed potential applications in manufacturing optoelectronic and nanoscale electronic devices [32]. Shrinivsan Madhavi and Seeram Ramakrishna reported a novel anode system based on TiNb2O7 nanofibrous material for application in fuel cell [50]. Electrospun nanofibers are used in fabrication of electrolyte and electrode material for excellent construction of high performance Li-ion batteries. Kim et al. [51] synthesized electrospun nanofibers based Cu/Sn/C composite using dual nozzle electrospinning method and carbonization. These prepared composite nanofibers were tested against capacity of Na and Li-ions. The ionic mobility was increased/decreased depending on the nature of conductive polymeric fibers and in this way it also affected storage capacity. Polymeric conductive membranes are also used in photovoltaic devices, electromagnetic interference shielding, sensors, production of nanoscale electronic devices, etc. [17]. Nanofibrous materials generally have higher potential toward storage and energy conversion as compared to other materials. Electrospun nanofibers have been employed as a catalyst in the fuel cells owing to their high durability and good catalytic efficiency.

230  Electrospun Materials and Their Allied Applications Electrospun nanofibers have also found application in dye-sensitized solar cells. Electrospinning can also be used to prepare different types of electric materials with efficient energy scavenging ability. During manufacturing of super capacitors, carbon nanofibers are used where they offer great capacitive behavior. Nanofibrous mats fabricated from different polymers were used in lithium ion batteries as battery separator [29].

8.3.6 Filtration For more than a decade, electrospun nanofibers have been used for filtration applications and some companies such as Donaldson, DuPont and Amsoil have developed filters based on electrospun nanofibers for their use in different applications including apparel, automobile and defense. In many engineering fields fiber filtration is necessary and according to an estimation the future filtration market in 2020 would reach around 700 billion US dollars [16]. Electrospun fibers were specifically produced for their application in air filtration by assessing fiber diameter and determining filtration performance of fibers [52]. Media fiber filters have advantage of small air repellent and high filtration performance [53, 54]. Recent studies by Podgorki et al. [55] revealed that fibrous filters prepared from electrospun nanofibers are important economic tools to improve filtration capacity of the penetrated aerosol particles. Fibrous filters are mostly applied in the areas where higher air purification is required such as in healthcare facilities, hospitals, research labs, government, and military agencies, electronic component manufacturing companies, pharmaceutical and food and biotechnology companies. High efficiency particulate air (HEPA) filters are considered as high efficiency air filtering media with minimum efficacy of 99.97% for particles removal and fibers diameter is greater than 0.3 µm. Nylon 6 nanofilter are prepared from the fibers having 10.75 g/m2 basic weight and 80–200 nm diameter and their filtration efficiency is calculated as 0.3 µm. These nanofilter are considered superior in filtration efficiency to the commercialized HEPA filter [56]. Heating, ventilating and air conditioning (HVAC) air filters are categorized as antimicrobial air filters. HVAC air filters are used for air purification in the areas which are most susceptible for fungal, bacterial, and mold attacks such as dark, ambient temperature and damp conditions. In some cases these microorganisms stick to the accumulated dust on the filter and use this dust as food and reproduce. Hence the condition became worse and it resulted in production of bad odor and air quality was also deteriorated. The most common microorganisms that attack HVAC filters

Electrospun Materials in Industrial Applications  231 are from Cladosporium, Staphylococcus, Klebsiella, Aspergillus, and Serratia species. In recent studies, researchers tried to functionalize the filtering media by adding some antimicrobial agents to their surface for long-term antimicrobial activity [57, 58]. Water in oil emulsion separation has gained more attention in recent years but in some applications water drop with less than 100 µm size is very difficult to dispersed and separate. Coalescence filters are introduced for effective separation of this type of secondary dispersions [59]. Performance of coalescence filter depends on drop sizes in the feed, flow rate of feed, properties of filter material and depth of filter bed. Coalescence fibrous filters are economical and provide high filtration efficiency. Performance and pressure drop of coalescence filters can be significantly improved by adding polystyrene nanofibers in it [60]. An optimum quantity of nanofibers is incorporated in the coalescence filter media to attain the desired perfection in coalescence efficacy [61]. Development of active and stable enzymes for successful industrial applications is still a challenging issue. Highly specific catalysts such as enzymes can be reused and recycled by coating and stabilizing on surface of electrospun nanofibers. In this way, the surface area of nanofibers can be increased by decreasing the diameter of the fibers. Moreover, electrospinning process can be applied to generate a desired surface area depending upon the fibers diameter. Fibrous membranes prepared from porous fibers enhance the specific surface area. The nanofibrous media are considered superior over mesoporous media due to its intra-fiber porosity and reduced thickness. In another study Jian et al. [62] revealed the covalent attachment of enzymes with the polystyrene nanofibers. Affinity membranes used for highly selective separations can also be prepared by the surface functionalization of electrospun nanofibers [63– 65]. These functionalized membranes are specifically used in protein purifications. Ion exchange resins commonly used for preparation of these membranes includes granular structure or a gel structure with acrylic or styrene as a structural material. Gel type materials are superior to granular resinous materials due to their low ion-exchange capacity and large pore volume but the granular materials have improved mechanical strength as compared to gel like materials. Fibrous materials due to their contact efficiency and ease of preparation was used to prepare ion-exchange filtering media to improve ion-exchange functionality [66]. Polymeric nanofibers due to their porosity, high surface area and capillary motion, when used for ion exchanger preparation showed greater swelling behavior than other media [67].

232  Electrospun Materials and Their Allied Applications

8.3.7 Sensor Applications A biosensor is a device or system used for the detection of specific analytes comprises a physicochemical detecting component and a biological recognition system. Using electrospinning technique efficient and functionally improved biosensors have been manufactured by incorporating a biomimetic or biological sensing element. Electrospun nanofibers because of their high surface area have also become attractive for sensor applications. The larger surface area of nanofibers is one of the most desired property for conductometric sensors because larger surface area tend to absorb more gas analytes which significantly alter the sensor’s conductivity [68, 69]. Electrospun light-emitting nanofibers are offering a great potential for optical sensing applications such as optical sensors, miniaturized light devices, and detectors. Fluorescent electrospun fibers are fabricated by embedding emissive materials like bio-chromophores, dyes, and quantum dots in optically inactive polymer matrices or by directly exploiting light-emitting conjugated polymers. In photonics, electrospun nanofibers are successfully used to develop detectors, novel micro-scale light sources, optical sensors, and lasers [38]. The sensing and detection of heavy metals especially of cations is particularly important for their huge effect on health and environment. These ions have strong ability to quench the emission/production of conjugated polymeric compounds, offering an effective tool for optical sensing or detection [68, 70, 71]. For this purpose, electrospun fiber mats doped with specific fluorescent compounds like 1,4-dihydroxyanthraquinone and pyrene are exposed to metal ions. Recently a very selective optical sensor was developed by F. J. Orriach-Fernández et al. [69] for detection of Hg2+ in water. This system was based on spirocyclic phenylthiosemicarbazide Rhodamine 6G derivative (FC1) doped electrospun fiber mats, which showed fluorescence if Hg2+ ions are present in the water. In optical sensing, detection of explosive compounds is considered an important issue. In optical sensing of explosive compounds, detection is basically done without contact with the explosive. In this case, the system is extremely sensitive to friction, shock and impact and it uses the quenching emission mechanism of fluorescent conjugated compounds, induced by the presence of explosive molecule [72]. Optical sensors are also used to detect gases or volatiles related to intoxications, infections and metabolic disorders. Moreover, it has been reported that compounds with biological significance such as bacteria, hemoglobin, metabolites, proteases, and ions can be successfully measured using

Electrospun Materials in Industrial Applications  233 specific sensors. Being a main parameter, pH is also considered as a biological marker in certain processes such as infection and wound healing and tumor metabolism. Electrospun nanofibers can give rise to dressings to monitor wound healing [73]. Diagnostics, health care, and biomedicine signify areas of application of biosensors. Biosensors performances such as sensitivity can be improved by incorporating nanomaterials in it, which is of great importance for diagnostic analyses. From a clinical viewpoint, nanosensors are involved in many clinical applications such as detection of urinary tract bacterial infections, glucose detection in diabetic patients, cancer diagnosis, and in detection of HIV and AIDS. In biomedicine the common analytes tested are urea, glucose, pesticides, lactate, cholesterol, and DNA [74] and the nanobiosensors developed for these specific compounds generally involve the binding of enzyme and nanomaterials. Several nanosensors have been developed for glucose detection. Most of them are based on enzyme-free sensing systems while some are manufactured using electrospinning technology. Recently, amperometric glucose biosensors were fabricated which were based on glucose oxidase (GOD), a compound having importance in clinical diagnostics, fermentation, and food production [75]. DNA-based biosensors are known as bioaffinity nanobiosensors and are considered as important sensing systems. At present, many kinds of DNA-based recognition systems are known such as aptamers, nucleotide sequence hybridization systems, aptazymes, ribozymes, DNAzymes, and peptide nucleic acids. These systems are categorized depending on the specific nucleotide structure involved. Immunosensors are used to detect the presence of antigen–antibody complexes by converting into electrical signals with the help of an appropriate transducer. As compared to enzyme sensors, immunosensors confer extremely high sensitivity due to slightly different affinity constants of each antibody. Immunosensors are particularly employed in disease diagnosis and in procedure of immunoassays such as ELISA (Enzyme-Linked Immunosorbent Assay) were they mainly detect presence of specific antigens or antibodies in body fluids (especially serum) [49]. The accumulation of heavy metals in the environment or even in the human body can cause extremely toxic effects and now researchers are putting their significant efforts to develop sensitive and reliable systems for their detection. Chemical sensors are appeared as a promising detection system or method which use optically active nanofibers prepared by the electrospinning technique [76]. Colorimetric sensors on fibrous materials, patterned paper or plastic material were prepared as a user-friendly and

234  Electrospun Materials and Their Allied Applications less expensive system for medical diagnosis, control of food quality, and environmental monitoring. These sensors are linked with both electrochemical and colorimetric detection systems. Electrospun nanofibers offer their promising importance in the development of colorimetric sensors for example the sensors used for colorimetric sensing of heavy metal ions [77].

8.3.8 Food In the context of application, electrospinning is less explored in the field of food science as compared to other fields discussed above. Electrospinning was found as a potential application in the nano and micro-encapsulation of enzymes and food bioactive compounds. Moreover, this technique can also be used in the applications of active or functional food packaging. Beside these, a promising but less explored application of electrospun nanofibers is their use as filtration membranes in beverage and food processing [78]. Electrospinning have an effective role in encapsulation and delivery of food bioactive compounds. This process is actually entrapping an active food ingredient including vitamins, antioxidants, fatty acids, etc. or living cells like probiotics, etc., within a walled material such as protein, carbohydrate and lipids. This encapsulation process not only helps to improve the bioavailability, stability, and sustained release of these biomolecule but it also assists in suppressing the unwanted taste and odor of the biomolecule [79]. Various techniques for nano and micro-encapsulation of food bioactive compounds exist for example, freeze drying, spray drying, emulsification, nanoprecipitation, coacervation, etc., but each technique have their own merits and demerits [78]. Beside from encapsulation of food, food scientists are also interested in biological preservation of food material, which maintained the stability and viability of the bacteriocins and probiotic bacteria throughout the food storage process. Some studies have focused on the possible application of electrospinning process for entrapment of bacteriocins and alive probiotic cells. For example, the sustainability of Bifidobacterium strains was significantly higher after encapsulating it into polyvinyl alcohol (PVA) electrospun nanofibers [80]. Enzymes as a natural catalysts have found many industrial applications owing to their high efficiency and specificity. However, their temperature sensitivity, high cost, inactivation possibility by various agents, and pH limitations have limit its application for commercial purposes. The idea of immobilized enzymes was generated to overcome these limitations. In the enzyme immobilization process, the enzymes are kept on a physical solid

Electrospun Materials in Industrial Applications  235 support or encapsulated within solid mediums, in this way the catalytic activities of enzymes are preserved. Immobilized enzymes are extensively used in the food industry and in food packaging of bioactive compounds to ensure the food safety and quality standards. However, for enzyme immobilization the usage of electrospinning process is not commercialized yet and mostly reported work on produced fibers is carried out by employing lab scale electrospinning unit. For glucose oxidase immobilization numerous work have been reported. Glucose oxidase is employed in glucose based biosensors and have significant importance in clinical and analytical laboratories [81] and fermentation and food industries [48]. Association between manufacturers and researchers which are dealing with production of industrial level nanofibers and electrospinning machines like eSpin, Elmarco, Asian Nanostructures Technology Company, and Electrospunra can lead to possible applications of these electrospinning process in the food sector [78]. Apart from improving the shelf life of the product, edible coatings on the food materials also functions as a barrier material. A common procedure used for coating of food materials is spray coating. However, electrospraying technique helps in achieving uniform coating on large areas of food substrates with controlled film thickness and deposition rate. Starch films with 40 mm diameter can be efficiently produced using electrospraying system that are also utilized as edible coatings [82]. The food packaging applications serve as preservation or protection of food materials and reduce food wastage. It is particularly important to prevent the entry of bacteria in to the food which otherwise will ultimately leads to food spoilage and disposal. Meat products packaging is predominantly important to provide a barrier from the external environment and a clear wrapping offers visual inspection [83]. Another study reported functionalized food coatings by electrospinning of poly (H-caprolactone) with vitamin E (Į-tocopherol) which is a plant-based phenolic antioxidant. In this approach electrospinning allows the production of high surface area materials and thus offering an increased antioxidant activity. Moreover, this quality packaging also avoid oxidative degradation reactions of proteins, fats, and pigments, which otherwise influence its appearance and lead to customer rejection and larger waste. Figure 8.4 shows a schematic representation of the concept of the anti-oxidant packaging of food materials [83]. Food packaging also offer certain additional functionalities for food protection for example Lagaron et al. [84] work contributed in the development of in-built temperature control packaging and the work by Krepker et al. [85] revealed food packaging with antimicrobial activity.

236  Electrospun Materials and Their Allied Applications Conventional low permeability barrier film for oxygen

Protected volume for meat or other produce

High surface area electrospun coating containing antioxidant

Figure 8.4  Schematic representation of the concept of the anti-oxidant packaging of food materials. Reproduced with permission from Ref. [83]. Copyright ©2017 Elsevier.

8.4 Current and Future Developments In the last decades, a tremendous progress has been observed in the industrial applications of electrospun materials due to the efforts of various companies and research groups. But still, many electrospinning techniques are restraints to lab scale production due to some limitations that need to be addressed for electrospun nanofibers to be employed for industrial level applications. For this purpose, more theoretical modeling and experimental studies are necessary to attain controlled morphology and size of electrospun fibers. At the present stage, fabrication of electrospun nanofibers which are less than 30 nm in diameter, is still considered a difficult phenomenon. Furthermore, to improve the capabilities of electrospun nano­ fibers, a lot of efforts are required to develop new methods that can be used in combination with electrospinning. For example, the layer-by-layer (LbL) technique in combination with electrospinning has been extensively used for production of a variety of material-coated nanofibers which are used in many applications [86]. Moreover, it is extremely important to upgrade the laboratory-scale production of electrospun nanofibers for commercialization of electrospun products and nanofibers. It is expected that with the passage of time in coming years, with further research and progress on electrospinning technology, electrospun nanofibers will be more broadly employed for various industrial applications and electrospinning will be the most important technological field of the century.

Electrospun Materials in Industrial Applications  237

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9 Antimicrobial Electrospun Materials Samson Afewerki1,2*, Guillermo U. Ruiz-Esparza1,2 and Anderson O. Lobo3† Division of Engineering in Medicine, Department of Medicine, Harvard Medical School, Brigham and Women’s Hospital, Cambridge, MA, USA 2 Harvard-MIT Division of Health Science and Technology, Massachusetts Institute of Technology, MIT, Cambridge, MA, USA 3 LIMAV—Interdisciplinary Laboratory for Advanced Materials, Department of Materials Engineering, UFPI—Federal University of Piauí, Teresina, PI, Brazil 1

Abstract

The fast-growing public health awareness and concern of the devastating problems with bacterial infections and the mounting resistance of bacteria to conventional antibiotic treatments have made this theme the top concern. At the same time the problem will not be solved through solely inventions of antimicrobial materials preventing the prevalence of bacteria resistance. Nevertheless, the fabrication and design of these materials are highly important to find its translational applications in our daily life. In this context, electrospun materials with their inimitable advantages and facile production make them a suitable candidate for various applications. The electrospinning technology represents a versatile and facile approach for the construction of ultrathin electrospun fibers from various materials. Then, it allows the fabrication of electrospun fibers with various and controlled dimensions such as nanosized fibers which have gained significant attention due to their valuable properties such as high surface area, large porosity, and lightweight. Through the combined electrospinning and antimicrobial material employment, a very powerful, robust, and vital strategy for engineered material can be generated. These materials can be employed in many areas such as healthcare (e.g., tissue repair, drug delivery, and wound healing), environmental application (e.g., filters and membranes), energy applications (solar and fuels cells), and in protecting clothing for medical and chemical workers.

*Corresponding author: [email protected] † Corresponding author: [email protected]. Inamuddin, Rajender Boddula, Mohd Imran Ahamed and Abdullah M. Asiri (eds.) Electrospun Materials and Their Allied Applications, (243–264) © 2020 Scrivener Publishing LLC

243

244  Electrospun Materials and Their Allied Applications Keywords:  Electrospun material, antimicrobial, biomaterial, antibiotic resistance, electrospinning, nanofibers, biomaterials

9.1 Introduction The grand challenges with infections and the prevalence of antibiotic resistance microbes has promoted the topic as imperative subject worldwide due to its significant burden on the public health and global economy [1, 2]. Hereto, the primary focus both in the academia and industry have been devoted to the development of innovate and sustainable solution to this big problem by employing antibiotic-free materials and agents [3, 4]. From this perspective, the employment of electrospun material with induced antimicrobial properties [5] have recently gained increased attention due to their favorable properties, low cost and facile production [6]. There are several strategies for promoting antimicrobial property of electrospun materials [7], for instance, through surface modification [8], integration with nanomaterials [9, 10], addition of antibiotics [11], or addition of antimicrobial agent and materials (Figure 9.1) [12]. Despite, the wide study of this topic, there are still horizons to explore and the desire of invention for more potent solutions. Therefore, in this chapter we will select and discuss some important antimicrobial electrospun materials and their chemistry and applications [13]. Initially, the fundamental and overview of electrospinning technology will be discussed and subsequently some antimicrobial materials will be highlighted. Last, conclusions and some future directions will be discussed.

9.1.1 Electrospinning Technology Electrospinning technology has emerged as a versatile and vital method for the production of ultrathin electrospun fibers from various materials

Surface modification Addition of antibiotics Addition of antimicrobial agents/materials Integrate with nanomaterials

Colonized Electrospun fiber

Engineering antimicrobial property

Antimicrobial Electrospun fiber

Figure 9.1  Strategies for engineering antimicrobial properties onto electrospun fibers.

Antimicrobial Electrospun Materials  245 (e.g., polymers, composites, and ceramics) in a facile, efficient, low cost, and with relatively high production rate [14]. The principles of electrospinning technology is depicted in Figure 9.2, where strong electric field is applied to a liquid of droplet fluid [15]. The basic traditional setup consists of a pump injecting the solution, high voltage power supply, and a collector (Figure 9.2a). Here the potential is applied between the nozzle (in this case the needle) and the collector, and this electrical field promotes the formation of Taylor cone (a jet of charged particles). Moreover, the electrostatic repulsion endorses motion and the formation of fine fibers that are placed onto the collector (Figure 9.2b) [16]. These allows the preparation of electrospun fibers with various and controlled dimensions such as nanosized fibers [17]. However, the technology is highly influenced from parameters such as applied voltage, solvent employed, concentration, properties of the solution, viscosity, surface tension, conductivity, solvent volatility, temperature and humidity, flow rate, and distance between the collector and nozzle tip [18]. Within this framework, electrospun nanofibers have gained much attention due to their beneficial properties such as high surface-to-volume ratio, large porosity, lightweight, tunable morphology, and small dimensions [19, 20]. Therefore they have shown a wide range of potential applications, such as, in healthcare; tissue repair [21], drug delivery [22], and wound healing purposes [23, 24] in environmental aspects; [25], as filters and membrane, e.g., for water and air purification [26], in energy aspects; solar cells and fuel cells [27], defense material; chemical and biological protection sensor and cloths [28], as catalysts and in batteries (Figure 9.3) [29]. A plethora of various materials have been employed for the engineering of electrospun fibers such as proteins (e.g., collagen and gelatin), hyaluronic acid [18], chitin and polyvinyl alcohol (PVA)-based, etc. [29], and more specifically materials with inherent antimicrobial properties [29], such as chitosan [30], silk fibroin [31], cellulose [32], and poly(ethylene oxide) (PEO) [33]. (a)

Collector (b) Syringe

Solution

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Applied voltage Solvent Concentration Solution property Viscosity Surface tension Conductivity Solvent volatility Distance (Nozzle and collector) Temperature Humidity Flow rate

Figure 9.2  (a) The basic setup for electrospinning technology and (b) the influential parameters on the generated electrospun materials.

246  Electrospun Materials and Their Allied Applications Healthcare

Tissue engineering Wound healing Drug delivery

Defense material Sensor Chemical and biological protection

Catalysts

Environmental Filters Membrane

Energy

Solar cells Fuels cells Batteries

Figure 9.3  The illustration for the application of electrospun nanofibers.

9.1.2 Antimicrobial Materials To date, the consciousness of the vast growing problem with antibiotic resistant pathogenic microbes has been profound to the society [34]. Therefore, there is an increasing need for the development of antimicrobial materials, which would provide alternatives to the employment of antibiotics [35]. De facto, these materials are important in many different application areas such as in biomedical applications (e.g., medical devices and implants) [36], in protective clothing and textiles [37], food [38], animal feed [39], and packaging [40, 41]. Over the years, a wide range of materials with antimicrobial properties have been developed such as natural based; chitosan [42, 43], and polyphenols [44, 45], carbon nanostructures [46], antimicrobial peptides (AMPs) [47], and various nanoparticles; from elements such as cerium [48], selenium [49], silver [50], and copper [51].

9.1.3 Antimicrobial Electrospun Materials As vide supra highlighted the urge and huge necessity for the development of materials with antimicrobial properties entail the advancement within the field. In this context, electrospun nanofibers could function as an important candidate in this quest [7]. Here, Lobo, Afewerki, and coauthors devised electrospun nanofibers as a potential scaffold for orthopedic applications by combining the three different polymers polycaprolactone (PCL), polyethylene glycol (PEG), and gelatin methacryloyl (GelMA) and then further crosslinking the fiber blend [52]. The material displayed ultrathin fibers prior to crosslinking (~0.24 μm) and a small increase in diameter post UV-crosslinking (of the light sensitive GelMA in the polymer blend) (~0.66 μm) (Figure 9.4a–d). The biomaterial

Antimicrobial Electrospun Materials  247 (a) a.1

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Figure 9.4  Electrospun nanofibers composed of (a) polycaprolactone (PCL), (b) PCL:polyethylene glycol (PEG), (c) PCL:PEG:gelatin methacryloyl (GelMA), (d) crosslinked PCL:PEG:GelMA. The antibacterial study of the nanofibers for 24 h against (e) Staphylococcus aureus (S. aureus), (f) Pseudomonas aeruginosa (P. aeruginosa), (g) Methicillin resistant Staphylococcus aureus (MRSA). Reproduced with permission from Ref. [53]. Copyright 2018, De Paula (CC BY) license.

demonstrated improved mechanical, hydrophilicity, and biological performance when compared to nanofiber made of only PCL. The nanofiber blend was further evaluated for its antibacterial property against Staphylococcus aureus (S.  aureus), Pseudomonas aeruginosa (P. aeruginosa), and Methicillin resistant Staphylococcus aureus (MRSA) [53]. Interestingly, the crosslinked nanofiber demonstrated the best antibacterial efficacy of all the various nanofiber blends tested with a bacteria reduction of >90% (Figure 9.4e–g). Very recently, the same group further expanded their strategy by designing ultrathin core–shell fiber, where the core consisted of PCL and the shell of PEG and gelatin loaded with

248  Electrospun Materials and Their Allied Applications an osteogenic growth peptide [54]. This core–shell strategy did not only provide a controlled and sustained release of the peptide, nevertheless it also demonstrated good biological performance (osteogenic) and most importantly bacteria reduction against P. aeruginosa. Furthermore, Si et al. presented a daylight-driven, rechargeable and antibacterial electrospun nanofibrous material comprised of poly(vinyl alcohol-co-ethylene) (PVA-co-PE) [55]. Interestingly, the antibacterial property of the nanofiber is created through the generation of reactive oxygen species (ROS) that is driven by daylight. This was possible due to the incorporation of daylight-active molecules with the ability to generate ROS (Figure 9.5a–d). Fascinatingly, the strategy promotes the antibacterial activity to function under dark condition and still be able to release the ROS (Figure 9.5e and f). The antibacterial performance was demonstrated (a)

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Figure 9.5  (a) The structure of the daylight active molecules. (b) The morphology of the fibers loaded with the active molecules. (c) Image of the nanofiber samples. (d) Scheme demonstrating the mechanism of action for the antibacterial activity. (e) Diagram demonstrating the excitation of the molecules. (f) The plausible mechanism of the photoactivation. Reproduced with permission from Ref. [55]. Copyright 2018 American Association for the Advancement of Science (CC BY-NC) license.

Antimicrobial Electrospun Materials  249 against the Gram-negative Escherichia coli (E. coli) and the Gram-positive Listeria innocua (L. innocua) and impressively it showed excellent bactericidal performance (>99.9999%). The practicability of the technology was further verified by applying the material as a surface shielding layer on protective equipment [55]. Moreover, Wang et al. envisioned fabricating a three-dimensional (3-D) nanofiber scaffold providing both resistance toward bacterial colonization and simultaneously promoting tissue-cell adhesion and proliferation [56]. These properties were induced by incorporating microgels containing peptides, which were prepared by hierarchical assembly of the anionic microgels and the cationic AMP. Based on the results from the study, the authors suggested that the antimicrobial agent would only be released upon demand, otherwise it would remain within the fibers in case any bacteria appear at a later stage. Furthermore, Li et al. employed recombinant silkworm-based AMP that was mixed with poly(L-lactic acid) (PLLA) and then further electrospun [57]. The activity was studied against a wide range of bacteria (Seiiatio maicesceis (S. ­ maicesceis), Bacillus bombysepticus (B. bombysepticus), E. coli and S. aureus) and the AMP showed a dose dependent performance. The SEM images demonstrated the destruction and deformation of the cell surface and wall. Therefore, it was concluded that the mechanism of action was through electrostatic attraction between the cationic AMP and negative charged cell membrane. This was confirmed through monitoring of the Zeta (ζ)-potential of the cells, which showed a rise of ζ-potential when AMPs were added. Similar mechanism of action for AMPs have previously been proposed [58]. Moreover, the most abundant and sustainable natural polymer on earth cellulose and its nanoform (nanocellulose) have gained great attention due to their unique properties such as biocompatibility, biodegradability, renewable, cost-effective, mechanical resilience, and hydrophilicity [59, 60]. It can be extracted from various sources such as forest, tunicate, algae, and bacteria and have been widely engineered inducing antibacterial properties [61]. Very recently, electrospun made from cellulose acetate blended with the antibacterial agent silver-sulfadiazine as a potential wound dressing was demonstrated [32]. Different strategy was presented by Wahab et al., where they first generated the cellulose acetate and then further coated with silver nitrate (AgNO3) inducing the antimicrobial activity [62, 63]. Various metal nanoparticles (copper nanoparticles (CuNPs), iron nanoparticles (FeNPs) and zinc nanoparticles (ZnNPs)) as the antimicrobial agent have been integrated with carboxymethyl cellulose (CMC) and then further electrospinning [64]. The electrospun material demonstrated antibacterial activity against S. aureus and P. aeruginosa

250  Electrospun Materials and Their Allied Applications and was proposed as a potential bandage material. In this context, polyvinylpyrrolidone (PVA) based nanofibers have also successfully being incorporated with silver-, copper-, and zinc metals in order to encourage antimicrobial property [65]. Additionally, several other reports have been disclosed employing cellulose based materials solely [66–69] or merged with other materials [70–76]. Another type of interesting saccharide-based compounds for the delivery of various antimicrobial agents is the cyclic oligosaccharides cyclodextrins (CDs) with their unique chemical structure having a hydrophilic outer surface and a lipophilic central cavity [77–79]. A polylactic acid (PLA) and triclosan(TR)-CD inclusion complexation (IC) based electrospun nanofibers have been prepared though electrospinning approach (Figure 9.6) [80]. Interestingly, the employment of the a-CD did not provide any complexation with the TR, probably due to the smaller dimensions, while the β- and γ-CD provided successfully. The nanofibers with the TR–CD–IC demonstrated better antibacterial efficiency against S. aureus and E. coli compared to the nanofibers loaded with only the TR. In this context it would be interesting to perceive the release profile from the two nanofibers. However, the authors concluded that the increased solubility of the TR emanate from the CD–IC was the underlying mechanism for the improved antibacterial performance, which resulted in a more efficient release [80]. Additionally, PCL-based electrospun fibers integrated with zinc oxide (ZnO) have been designed for periodontal application [81]. Its performance was demonstrated on an in vivo rat periodontal defect model; however, the antibacterial performance was not evaluated in vivo. Nevertheless the in vitro antibacterial study against Porphyromonas gingivalis (P. gingivalis) presented significant activity compared to fibers in the absence of ZnO. (a)

0.57 nm

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Figure 9.6  (a) The structures and dimensions of the various cyclodextrin (CD) types. (b) The scheme for the production of the triclosan(Tr)–CD–inclusion complex (IC). (c) The illustration of the strategy for the fabrication of the polylactic acid (PLA)based Tr–CD–IC electrospun nanofibers. Reproduced with permission from Ref. [80]. Copyright 2013 American Chemical Society.

Antimicrobial Electrospun Materials  251 In addition, Faria et al. devised electrospun based on a combination of poly(lactide-co-glycolide) (PLGA) and chitosan, and then further chemically functionalized with graphene oxide and AgNPs (GO–Ag) to inherent antimicrobial activity [82]. The chemical modification was performed by first activating the GO–Ag with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and N-hydroxysulfosuccinimide (NHS) coupling reaction. Subsequently, the coupling between the NHS activated GO–Ag (GO– Ag–NHS) and the free amines on the PLGA-chitosan fibers finalized the reaction (Figure 9.7). Compared to the unmodified fibers the conjugated showed >98% bacterial inactivation against E. coli and P. aeruginosa. The strategy behind combining the GO and AgNPs was to obtain synergistic antimicrobial effect [82]. The approach of combining GO-Ag within electrospun prepared from polylactic acid (PLA) have also been disclosed by Liu et al. [83]. The addition of the GO–Ag did not only provide bactericidal property, however, it also improved the mechanical property (solely PLA: tensile strength ≈ 8.70 MPa and elastic modulus ≈ 0.76 MPa, and PLA–GO (1%)–Ag (7%): tensile strength ≈ 1211.05 MPa and elastic modulus ≈ 5.46 MPa) thermal properties (solely PLA: Tm = 359.6°C and PLA–GO (1%)–Ag (7%): Tm = 366.0°C) and wettability/contact angle (CA) (solely PLA: CA ≈ 131.57° and PLA–GO (1%)–Ag (7%): CA ≈ 102.34°). Renege on chitosan based electrospun, the polysaccharide [30, 84] have further been merged with other components such as PEO and AgNO3 [33], PEO, and Lauric arginate [85] combined with honey, PVA, and the natural extracts Allium sativum and Cleome droserifolia [86], with PVA and Bidens pilosa (a cosmopolitan weed) [87], or chemically modified [88]. Moreover, various other natural based extracts such as Moringa (leaf extracts) [89], and Lanasol (a)

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Figure 9.7  (a) The chemical process for the modification generating GO–Ag functionalized PLGA–chitosan electrospun and (b) the scanning electron microscopy (SEM) images [82]. Copyright 2015 American Chemical Society.

2 µm

252  Electrospun Materials and Their Allied Applications (red sea algae extract) [90], limonene [91], mustard (isothiocyanate) [92], or essential oil [93] have been integrated with the electrospun materials in order to provide antimicrobial property. Very recently, Park et al. fabricated quaternary ammonium-functionalized amphiphilic co-polymers consisting of a hydrophobic part (poly(methyl methacrylate) (PMMA)) and a hydrophilic fragment (poly(N,N-dimethylamino)-ethyl methacrylate (PDMAEMA)), respectively. This block co-polymer was merged with poly(vinylidene fluoride) (PVDF) and GO, and then further fabricated into electrospun blend. Afterward, hydrophilicity was introduced by further coating with PVA providing superhydrophilic and antibacterial nanofiber [94]. The antibacterial study through agar diffusion and dynamic contact tests confirmed the antibacterial activity of the nanofiber blend. Moreover, the antibacterial efficiency was enhanced by increasing the length of the alkyl moieties on the di-block polymer due to the improved interaction with the cytoplasmic membrane of the cells [95]. A superhydrophilic antibacterial nanofiber based on inorganic silica N-halamine [96] have also been disclosed by Liu et al. [97]. The material was prepared by combining electrospinning technology and sol–gel approach. The silica N-halaminebased nanofiber was chlorinated in order to obtain long term, facile, and efficient antibacterial property. The nanofiber was suggested as a profound candidate for water disinfection due to the high chlorine content and highly effective antibacterial property. Nanofibrous antibacterial membrane with 100% (with AgNO3) or 92% (with poly(catechol)) proficiency in reducing bacteria made from PVA, PVDF and from enzymatic prepared poly(catechol) or AgNO3 have also been designed for water ultrafiltration applications [98]. In fact, polydopamine based electrospun fibers have very recently been demonstrated displaying many favorable advantages such as excellent antimicrobial properties, good biocompatibility, optimum wettability, enhanced mechanical property, and improved thermal stability [99]. Very recently, Wang et al. presented a multifunctional electrospun nanofiber, which besides being bactericidal, performed efficiently as air-­ filtration device, and with high photocatalytic activity as a scavenger for dye [100]. The nanofiber was made of a mixture of PVA and the polysaccharide konjac glucomannan, and with the antimicrobial ZnO incorporated. The generated electrospun fibers was further processed by a thermal crosslinking step at 140°C, where esterification occurred between the PVA and the polysaccharide by using citric acid as the crosslinking agent. Furthermore, in 2017, Yang and coauthors fabricated an electrospun fiber against ­multidrug-resistant (MDR) bacteria as a dressing for wound-­ healing application [101]. The MDR agent comprised of gold nanoparticles

Antimicrobial Electrospun Materials  253 (AuNPs) coated with the compound 6-aminopenicillanic acid (6-APA) and the fibers were made from PCL and gelatin mixture. The characterization of the Au–6-APA–NPs exhibited size at ~3 nm with negatively charged particles (ζ-potential = −26.3 ± 0.6). The nanoparticles demonstrated high stability and could be stored without any changes for almost 7 months. The antibacterial activity was tested against clinically isolated MDR strains and the Au–6-APA–NPs demonstrated high efficiency, and even outperformed the antibiotic ampicillin (which was ineffective against the isolated MDR E. coli). The practicality of the fibers was further demonstrated in infected skin wound healing application. The in vivo model was a dorsal wound model of rat which was exposed to various MDR bacteria. The study showed that the local bacterial levels decreased after 7- and 14-days of treatment. Furthermore, it also demonstrated faster wound healing ability where the wound treated with this fiber decreased to a larger extent compared to the fibers in the absence of the MDR agent [101]. Additionally, PLLA-co-PCL nanofibers loaded with AgNPs have shown to function as a good scaffold for wound healing [102]. Some of the challenging limitations in the design of nanofibers with antimicrobial agents is the tailoring of the delivery system, providing controlled, sustained (thus avoiding systemic toxicity), prolonged and site specific delivery with sufficient encapsulation efficiency [103]. For instance, a cephalexin (antiseptic drug) loaded into alginate based halloysite nanotube electrospun fiber was demonstrated to provide sustained release [104]. Initially, the halloysite nanotube displayed 95% drug release already after 24 h; however, by introducing a crosslinking step the drug released could be prolonged to 76% and 89% after 8 h and 7 days, respectively. Different strategy was presented by Hassiba et al., where they designed a double layered nanocomposite electrospun fibers as wound dressing [105]. The upper layer of the fibers comprised of PVA and chitosan loaded with AgNPs, and the lower of PEO or PVP containing chlorohexidine (antibacterial agent). The underlying mechanism behind the strategy was that the upper layer would function as a protecting deposit against environmental germ invasions and the lower interacting with the injured site and promote the healing and at the same time protects from any conceivable wound infections. Elasticity is an important feature for the design of stretchable electrospun material for applications such as textiles, wearable electronic, and tissue engineering applications [106]. Very recently, Kang et al. devised an engineered trachea made from 3D-printed thermoplastic polyurethane enwrapped with PLA electrospun and loaded with ionic liquid ­functionalized-GO to provide antimicrobial property. Nevertheless, the

254  Electrospun Materials and Their Allied Applications elasticity originate from the 3D-printed thermoplastic and not from the electrospun fibers [107]. However, electrospun materials fabricated from polyurethane and PLGA loaded with the antibiotic tetracycline hydrochloride have been demonstrated as an elastic nanofiber [108].

9.1.4 Conclusions and Future Directions As have been highlighted in this chapter, electrospun material with inherent antimicrobial property could function as an important candidate in many fields (e.g., environment, biotechnology, food, packaging, medicine, and cosmetics) and for countless of applications. Prominently its facile fabrication and production makes it an interesting technology for industrial and large-scale production [109]. Moreover, since the technology is highly influenced from several experimental factors it is very important investigating those factors, in particularly, when designing an optimal, solid, scalable, and reproducible protocol. Despite all the advancement within the topic and the development of a wide range of various electrospun materials with antimicrobial properties made from various materials, there is still limitations and avenues to explore [110]. Exempli gratia, several challenges need to be further addressed in the antimicrobial strategy, such as the controlled and sustained release of the antimicrobial agents from the nanofibers. Moreover, to date the demonstrations and examples of scalable and translational antimicrobial electrospun technologies are still limited. Despite the several commercially available industry-scale electrospinning apparatuses that are available, the application is still limited and there are still economic challenges that need to be encountered. For instance, electrospun materials in biomedical application is still limited due to the issues with biological safety and efficacy challenges [111]. Moreover, the combined effort for the invention of novel chemistries allowing the facile tailoring of electrospun materials making them robust with anti­ microbial activity, and simultaneously the development of highly potent, long-­lasting, and broad antimicrobial agents and materials are some features that will boost the field further. Additional future direction is the advancement of the electrospinning technology which hopefully will bring new methods for the production of various electrospun fiber types [112, 113]. For instance, the existing different methods available such as mono-­ axial [114], co-axial [115], and tri-axial [116] allow the tailoring of various nanofibers. Nevertheless, the invention of new sophisticated approaches could broaden the assortment and fabrication of nanofibers from the electrospinning technology.

Antimicrobial Electrospun Materials  255

Acknowledgments Professor Lobo acknowledges the financial support from the Brazilian National Council for Scientific and Technological Development (CNPq, grant #404683/2018-5). Dr. Afewerki gratefully acknowledges the financial support from the Sweden–America Foundation (The Family Mix Entrepreneur Foundation) and Olle Engkvist Byggmästare Foundation.

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262  Electrospun Materials and Their Allied Applications (vinyl alcohol) Coating Layer on Graphene Oxide/Poly (vinylidene fluoride) Electrospun Nanofibers for Superhydrophilic and Antibacterial Properties. Sci. Rep., 9, 1, 383, 2019. 95. Gupta, A., Landis, R.F., Li, C.-H., Schnurr, M., Das, R., Lee, Y.-W., Yazdani, M., Liu, Y., Kozlova, A., Rotello, V.M., Engineered Polymer Nanoparticles with Unprecedented Antimicrobial Efficacy and Therapeutic Indices against Multidrug-Resistant Bacteria and Biofilms. J. Am. Chem. Soc., 140, 38, 12137–12143, 2018. 96. Hui, F. and Debiemme-Chouvy, C., Antimicrobial N-Halamine Polymers and Coatings: A Review of Their Synthesis, Characterization, and Applications. Biomacromolecules, 14, 3, 585–601, 2013. 97. Liu, C., Shan, H., Chen, X., Si, Y., Yin, X., Yu, J., Ding, B., Novel InorganicBased N-Halamine Nanofibrous Membranes As Highly Effective Antibacterial Agent for Water Disinfection. ACS Appl. Mater. Interfaces, 10, 51, 44209–44215, 2018. 98. Coelho, D., Sampaio, A., Silva, C.J., Felgueiras, H.P., Amorim, M.T.P., Zille,  A., Antibacterial electrospun poly (vinyl alcohol)/enzymatic synthesized poly (catechol) nanofibrous midlayer membrane for ultrafiltration. ACS Appl. Mater. Interfaces, 9, 38, 33107–33118, 2017. 99. Leung, C.M., Dhand, C., Dwivedi, N., Xiao, A., Ong, S.T., Chalasani, M.L.S., Sriram, H., Balakrishnan, Y., Dolatshahi-Pirouz, A., Orive, G., Combating Microbial Contamination with Robust Polymeric Nanofibers: Elemental Effect on the Mussel-Inspired Cross-Linking of Electrospun Gelatin. ACS Appl. Bio Mater., 2, 2, 807–823, 2018. 100. Lv, D., Wang, R., Tang, G., Mou, Z., Lei, J., Han, J., De Smedt, S., Xiong, R., Huang, C., Ecofriendly Electrospun Membranes Loaded with Visible-LightResponding Nanoparticles for Multifunctional Usages: Highly Efficient Air Filtration, Dye Scavenging, and Bactericidal Activity. ACS Appl. Mater. Interfaces, 11, 13, 12880–12889, 2019. 101. Yang, X., Yang, J., Wang, L., Ran, B., Jia, Y., Zhang, L., Yang, G., Shao, H., Jiang, X., Pharmaceutical intermediate-modified gold nanoparticles: against multidrug-resistant bacteria and wound-healing application via an electrospun scaffold. ACS Nano, 11, 6, 5737–5745, 2017. 102. Jin, G., Prabhakaran, M.P., Nadappuram, B.P., Singh, G., Kai, D., Ramakrishna, S., Electrospun Poly(L-Lactic Acid)-co-Poly(-Caprolactone) Nanofibres Containing Silver Nanoparticles for Skin-Tissue Engineering. J. Biomater. Sci. Polym. Ed., 23, 18, 2337–2352, 2012. 103. Ulubayram, K., Calamak, S., Shahbazi, R., Eroglu, I., Nanofibers based antibacterial drug design, delivery and applications. Curr. Pharm. Des., 21, 15, 1930–1943, 2015. 104. De Silva, R.T., Dissanayake, R.K., Mantilaka, M.P.G., Wijesinghe, W.S.L., Kaleel, S.S., Premachandra, T.N., Weerasinghe, L., Amaratunga, G.A., De  Silva, K.N., Drug-loaded halloysite nanotube-reinforced electrospun

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10 Application of Electrospun Materials in Gene Delivery GSN Koteswara Rao1, Mallesh Kurakula2 and Khushwant S. Yadav3* Department of Pharmaceutics, K L College of Pharmacy, Koneru Lakshmaiah Education Foundation, Guntur, Andhra Pradesh, India 2 Department of Biomedical Engineering, The University of Memphis, Memphis, Tennessee, USA 3 Shobhaben Pratapbhai Patel School of Pharmacy and Technology Management, SVKM’s NMIMS (Deemed to be University), V.L Mehta Road, Vile Parle (W), Mumbai, India 1

Abstract

Gene therapy has emerged as a promising strategy for treatment of many acquired or inherited diseases providing ample benefits over conventional therapies. Even the cost factor and stability are attractive with gene therapy than majority of the protein formulations. It is a successful combination of gene delivery technologies with the electrospinning methods to enhance the potential of gene therapy in several biomedical and pharmaceutical applications like cancer treatment, stem cell treatment, chronic genetic disorders, and tissue engineering. Electrospun nanofibrous scaffolds area is the leading research field in gene therapy with their advantageous characteristics utilizing the available categories of polymers. In this chapter, detailed information about gene therapy, comparison of viral with non-viral vectors, electrospinning methods, materials useful for nanofibrous scaffolds fabrication, characterization of those scaffolds, applications of scaffolds in gene delivery, their significant role, marketed products, present challenges, and future scope will be provided. Keywords:  Gene therapy, electrospinning technology, biodegradable, scaffolds, biomedical, pharmaceuticals

*Corresponding author: [email protected]; [email protected] Inamuddin, Rajender Boddula, Mohd Imran Ahamed and Abdullah M. Asiri (eds.) Electrospun  Materials and Their Allied Applications, (265–306) © 2020 Scrivener Publishing LLC

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266  Electrospun Materials and Their Allied Applications

10.1 Introduction Gene therapy has been emerged as a promising treatment with significant advantages over other therapies for the treatment of enormous acquired or inherited diseases, e.g., cancers and even for the areas like tissue ­regeneration/repair, wound management, etc. [1–3]. The research for improvements in gene therapy for application in biomedical field has been growing day by day. The advancements in the technology, manufacturing methods, and widespread knowledge of suitability of vectors are driving the gene therapy toward new successes every time. Nanofiber scaffolds are presented as the most successful carriers for the gene delivery. Viral vectors are bypassed due to their safety limitations like immunogenicity, infectious nature, expensiveness, and low loading efficiency [4]. Hence, as an alternative, nonviral vectors (e.g., liposomes, chitosan, calcium phosphate, polymeric systems, dendrimers) gained the importance due to their advantages like less toxicity, lower immunogenicity, lower transduction efficiency, shorter expression duration, more loading capacity, broad choice of selection of materials/production methods, etc. [5–7]. Tissue engineering is a revolutionary treatment strategy for the repair of injured tissues and for the enhancement of biological functions. Tissue engineering involves the application of cells or polymeric materials (as scaffolds) as carriers for drugs, proteins, genes or growth factors for building the new tissue or repairing the damaged tissue [8–10]. In addition to tissue engineering, several other areas like wound management, dentistry, bone regeneration, skin regeneration are also depending on the use of nanofibers due to their advantages. Electrospinning is the well-known and established technique for the production of 3D nanofibrous scaffolds for the purpose of tissue engineering and other applications [11–13]. Several models and advancements in the manufacturing instrument has gained grip on the modulation of size, shape, texture, porosity, and other ­physicochemical/mechanical parameters of the system [14, 15]. In this chapter, a detailed discussion about the importance of gene therapy, types of vectors, electrospinning methods, applications of electrospun materials for delivery of gene, DNA, RNA, drug, and other therapeutics in different fields, challenges and future scope is provided.

10.2 Gene Therapy In biomedical field, gene therapy has its own importance due to its versatile nature in handling multiple diseases and disorders with good success rate.

Electrospun Materials in Gene Delivery  267 The availability of several research strategies and systems for gene delivery is able to treat many acquired or inherited diseases, e.g., cancers and many chronic and genetic disorders [1–3]. Gene therapy has also gained its importance in the treatment strategies for stem cell therapy, and tissue engineering. As a treatment strategy for diseases, there will be a delivery of drug or growth factor or protein that shows its physiological or pharmacological action and minimizes/ cures the disease condition. Keeping drug delivery aside, there are several disease conditions/health obligations which necessitate tissue engineering or fulfilling the shortage, where the direct administration of the deficient moiety, e.g., proteins or cells or growth factors, is a unique treatment strategy. But such a direct administration may lead to toxicity due to burst availability and faces limitations like difficulty in production followed by purification, stability issues, lack of continuous supply, toxicity, low halflife of administering natural growth factors/proteins, high cost for the processing of pure growth factors/proteins [16, 17]. To overcome some of these limitations, an alternative strategy includes the encapsulation of such moieties in suitable carrier systems which give control over the release rate, better stability on comparing with handling of pure moiety and efficiency in treatment. However, this strategy of using carrier systems also suffers from certain limitations like stability problems of the growth factors/ proteins, i.e., denaturation during production and/or encapsulation of carrier systems with those moieties, difficulty to protect the bioactivity during preservation, cost factor and lack of providing permanent solution to the problem [18, 19]. As a remedy for all these problems, instead of planning to administer the direct growth factor/protein, it is wise to deliver the source gene to produce the required growth factor/protein, as a factory for generating the deficient molecule, as and when required by the body for a particular physiological function answering the shortage permanently [16]. Hence, gene delivery can be defined as the administration of genes through vectors at the target site to transfect the host cells enabling them to produce the required therapeutic proteins [7]. Genetic information modulation at target cells through the delivery of gene from external resources could serve several purposes to treat the disease conditions or tissue engineering or stem cell therapy. The expected outcomes of gene therapy may include [20]: ➢➢ Elicitation of required signals like apoptosis in cancer cells ➢➢ Secretion of required growth regulating factors like autocrine or paracrine factors

268  Electrospun Materials and Their Allied Applications ➢➢ Differentiation of target cells ➢➢ Production of cellular therapeutics like proteins Any of these strategies may work for the treatment of a particular disease under study. Gene delivery can be done in different ways like [16] (i) (ii) (iii) (iv) (v)

Direct delivery of gene Direct delivery of gene vector Scaffold based gene delivery Scaffold based gene vector delivery Gene manipulated stem cell delivery

Direct delivery of gene involves the supply of genetic material like DNA or RNA directly into the host cell by following specific methods like electroporation or microinjection. For better handling of the gene delivery, it can be loaded into a vector as viral vector or nonviral vector and then the vector is supplied to the host cell by certain physical or chemical methods. Chemical methods include the use of cationic lipids or cationic polymers or naked DNA. An advanced level of gene delivery is the use of nano­fiber scaffolds to load and administer the genetic material to the host cell. Scaffolds are specially developed nanofiber network by electrospinning method or such suitable technique. Further, the gene vector may be developed and encapsulated in the scaffolds for still better control over the delivery of gene to the host cell. Gene manipulated or genetically modified stem cells can be a better therapeutic tool for gene based treatment [16].

10.3 Cellular Uptake of Nonviral Gene Delivery After administration of gene loaded nonviral vectors at target site, the uptake of them by the target host cell involves a complex process and is influenced by several parameters related to both host cell and carrier system. The uptake pathways are classified as endocytosis and non-endocytosis pathways [16]. Endocytic pathway is the most efficient natural cellular uptake pathway followed by the nonviral gene delivery. Despite of poor availability of internalized genes in target cells like DNA or siRNA and expose to lysosomal harsh microenvironment, the endocytosis pathway is still the natural occurring pathway. Endocytosis pathway is further comprised of four mechanisms, namely, (i) phagocytosis, (ii) clathrin-mediated-endocytosis, (iii) caveolae-mediated endocytosis, and (iv) micropinocytosis [16].

Electrospun Materials in Gene Delivery  269 Non-endocytic pathways are unnaturally happening processes where special provisions are made for better uptake of nonviral vectors into the cytosol of host cells. The techniques that come under non-endocytosis pathway include (i) microinjection (use of rapid injection), (ii) permeabilization (use of pore-forming agents in the formulation), (iii) electroporation (use of electrical field). As the non-endocytic techniques are invasive, they cannot be preferred in vivo for gene delivery [16].

10.4 Vectors Gene delivery is a treatment strategy for certain diseases where gene manipulation is required or where the gene acts as a source factory to produce the required proteins or growth factors. The strategies may include ➢➢ Delivery of the deficient or required growth factor or protein directly ➢➢ Delivery of the required gene directly to produce the respective growth factor or protein ➢➢ Delivery of the required gene through a carrier like viral vector or nonviral vector Additional concern should be there for the site of action. If the gene delivery does not happen properly, then it may result in gene manipulations at the off-target areas which are of either no use or toxic in nature. The researchers identified the several possibilities to deliver the gene to the target area, i.e., nucleus of a target cell and many classified the gene delivery options as viral vectors and nonviral vectors. Vectors are the carriers used for the delivery of gene to the target location. They are of two types: viral and nonviral. A detailed flowchart on classification of gene delivery methods is shown in Figure 10.1.

10.4.1 Viral Vectors These are well-known vectors where non-virulent recombinant viruses are used as carriers for loading the genes [1, 4, 7]. These viral vectors show higher transfection efficiency. However, they have the risk of toxicity/ adverse effects, potentially infectious, carcinogenic, expensive, and a lot of care has to be taken while attenuating their virulence character. These also suffer from less encapsulation efficiency, lack of flexibility in formulation

270  Electrospun Materials and Their Allied Applications Retrovirus Viral vectors

Adenovirus

Gene delivery vectors

Baculovirus Direct (Gene gun) Electroporation (Voltage) Physical methos

Sonoporation (Ultrasound) Hydroporation (Hydrodynamic) Magnetofection (Magnetism)

Nonviral vectors

Cationic lipds Chemical methods

Cationic polymers Naked DNA

Figure 10.1  Classification of gene delivery methods [16].

and production, lack of control over the release rate of gene, and stability issues. Examples of viral vectors include retrovirus, adenovirus, and baculovirus [21].

10.4.2 Nonviral Vectors A nonviral vector is an attractive alternative of viral vectors [5, 6, 8, 22, 23]. These include polymeric carriers either natural or synthetic source. These nonviral vectors offer several advantages like low toxicity (manageable or tailorable toxicity), low antigenicity (immunogenicity), flexibility in formulation/production, excess loading capacity (large surface area), ability to hold the genes of big size too, enhanced stability, control over the gene delivery. However, nonviral vectors do have drawbacks like low gene transfection efficiency and the chance of burst release on failure of the carrier system. Examples of nonviral vectors include cationic polymers,

Electrospun Materials in Gene Delivery  271 cationic lipids, and naked DNA. Some specific examples of polymers that are used to develop the nonviral vectors are chitosan, calcium phosphate, polycaprolactone (PCL), poly(lactide-co-glycolide) (PLGA), poly(ethylene glycol) (PEG), polycations (poly-L-lysine) (PLL) and polyethyleneimine (PEI), and several block copolymers [24–26]. Systems like liposomes, nanoparticles, and polyplexes are also used. These polymers do have the properties of biocompatibility and biodegradability that make them suitable for the gene delivery purpose [1]. Polyethylenimine (PEI) is one of the famous cationic polymers that load the long DNA chains into submicron particles [7, 27–29]. PEI is regarded as a potent nonviral transfection agent, showing high transfection activity in vitro and of course moderate activity in vivo. To enhance the transfection efficiency of nonviral vectors, different strategies are proposed by the researchers: 1) Development of polymer composites (copolymerization) and modification of polymers ratio [30] 2) Encapsulation of nonviral vectors on scaffolds 3) Applying biomechanical techniques like sonoporation, electroporation, magnetoreception, and hydroboration [31].

10.4.3 Delivery of Genes through Vectors A vector is used to deliver the gene into the nucleus of the host cell. The vectors carrying genes are administered directly into the extracellular matrix of affected area by IV or IM route, where the vector introduces the new genetic material in the place of missed gene or damaged gene to further continue the expected process. A direct administration of genes through vectors as liquid formulation may also lead to systemic toxicity due to the uncontrolled distribution of the vectors in off-target regions followed by gene expressions [32]. In particular, it will be of more risk when the vector is viral vector which has high transfection efficiencies. Even it leads to short duration of action due to burst release which demands more frequent administration of the dose [33]. Hence, the proper delivery of gene through vectors at extracellular environments of target cells became the challenging task for researchers and could achieve it by developing the novel carrier systems following several upgraded manufacturing techniques. Genes are loaded into vectors (termed as genetically modified carriers) and further these vectors are loaded onto carriers/nanofibers/scaffolds. For example, the best

272  Electrospun Materials and Their Allied Applications Advantages of viral vectors

Disadvantages of viral vectors

Advantages of nonviral vectors

Disadvantages of nonviral vectors

High transfection efficiency

High immunogenicity

Low immunogenicity

Low transfection efficiency

High transgene expression

High production cost

Low toxicity, better safety

Possible burst release

Low packaging capacity

More flexibility in production

Low cellular uptake

Lack of control over gene release

Better encapsulation

Risk of toxicity

Better stability

Better control over release

Figure 10.2  Advantages and disadvantages of viral and nonviral vectors for gene delivery.

among the identified systems include electrospun generated nanofiber scaffolds of polycaprolactone which has gained a lot of interest and success in delivering the genes in tissue engineering, cancer treatment, and stem cell therapies. Even several other treatments are also reported using the scaffold-based gene delivery [34]. Rather than viral vectors, encapsulating the nonviral vectors onto scaffolds is easier in terms of stability, intactness, and flexibility. By doing such encapsulation onto scaffolds, the transfection efficiency of nonviral vectors has been increased [30]. Thus, gene delivery is a promising alternative to conventional protein therapy and solve the associated problems of protein therapy like shorter half-life, less biological activity, toxicity, production cost, and stability. Nonviral vectors may be used for gene delivery through physical means or chemical means. Physical means include the application of some specific forces like voltage (electroporation), ultrasound (sonoporation), hydrodynamic force (hydroboration), gene gun (direct delivery)

Electrospun Materials in Gene Delivery  273 magnetism (magnetoreception). Chemical means include the application of cationic polymers and cationic lipids based on their properties [16]. Viral vectors show higher transfection efficiency. However, they have the risk of toxicity/adverse effects, potentially infectious, carcinogenic, expensive, and a lot of care has to be taken while attenuating their virulence character. These also suffer from less encapsulation efficiency, lack of flexibility in formulation and production, lack of control over the release rate of gene and stability issues [16]. Nonviral vectors offer several advantages like low toxicity (manageable or tailorable toxicity), low antigenicity (immuno­genicity), flexibility in formulation/production, excess loading capacity (large surface area), ability to hold the genes of big size too, enhanced stability, control over the gene delivery. However, nonviral vectors do have drawbacks like low gene transfection efficiency and chance of burst release on failure of the carrier system [16]. These polymers do have the properties of biocompatibility and biodegradability that make them suitable for the gene delivery purpose. Advantages and disadvantages of viral and nonviral vectors are shown in Figure 10.2. The combination of gene delivery approach with polymeric scaffolds is an excellent strategy which has proved in giving promising advantages over conventional gene delivery at the target site.

10.5 Nanofibers/Scaffolds Scaffolds are nanofiber mesh or mat or web-like structures made of natural or synthetic polymers. Scaffolds produced by electrospinning method are quite interesting for application in several therapies in particular at tissue engineering field. These scaffolds offer high surface area, remarkable porous architecture, similar morphological features as tissue matrix. In addition to their success as close proximity with the extracellular matrix of host tissues, the electrospun nanofiber scaffolds are driven still forward as carriers for drugs and biologicals. They have been a part of many treatment strategies and a lot of successful results are reported in the literature [16]. As further progress, encapsulation of genes into the electrospun nanofiber scaffolds becomes a promising platform for better transfection of gene into the target cells. They provide both localized and sustained release of the genetic material in the host target cells. It allows long term gene expression at physiological need and prevents the toxic effects at off-­target regions. Scaffolds also provide protection against harsh environments with less immunogenicity. This concept is the best alternative for viral vector-based gene delivery which is suffering from several drawbacks.

274  Electrospun Materials and Their Allied Applications Hence, researchers focused more on the area of scaffold-based gene delivery. The advantage of modulation of system and process parameters to obtain desired characteristics for the scaffold and availability of different versions of electrospinning techniques and also the suitability of good number of polymers for the design of scaffolds with incorporation of genes either during the process or attachment after the process is making the area more promising. The electrospun scaffold-based gene delivery allows better transfection of the gene into the host target cells and produces sustained synthesis of growth factors or proteins as a treatment strategy [16]. There can be different ways of electrospun scaffold loading with genetic material. In one strategy, the genetic material may be encapsulated by mixing with the polymeric solution and allowing it for the spinning process such that the final nanofibers loaded with genetic material will be produced. This method has the advantage of obtaining uniformly distributed biomaterial as a matrix system, however, suffers from the drawback of damage to the genetic material due to treatment of organic solvent or temperature or electric field. Hence, care must be taken while selecting the process. The assay of genetic material needs to be done in order to estimate the final content of the gene in product. In another strategy, nanofiber scaffolds can be prepared first and then they can be merged with genetic material by physical adsorption or chemical crosslinking. This method has the advantage of getting protection for genetic material from adverse environment of organic solvent/temperature/electric field exposure. Another strategy like linking agent can be used to provide better immobilization of the genetic material. Gene delivery through scaffolds [12, 35], hydrogels [36], and micro­ particles or nanoparticles [37] is reported for several treatment strategies. Incorporation of gene vectors with scaffolds can be of two ways, either into or onto them [16]. Incorporating gene vectors into the scaffold interiors can be done by • Encapsulating in the nanospheres • Direct mixing • Encapsulating by core–shell structures Incorporating gene vectors onto scaffold exterior can be done by • Physical attraction • Covalent immobilization It was reported that the polymeric solution of polycaprolactone (PCL) polymer with either polyethyleneimine (PEI) or PEI-polyethylene glycol (PEG)

Electrospun Materials in Gene Delivery  275 was spun to produce nanofiber scaffolds. Later the plasmid DNA was adsorbed on the scaffolds through electrostatic interaction between the positively charged PEI and negatively charged DNA, same way with PEIPEG. This sort of new approach has several benefits like protection from harsh environments like solvent/temperature/electric field, immobilization of genetic material can be modulated based on the content of cationic polymer PEI or PEI-PEG and also the immobilization of any DNA can be done on the plain carriers prior to treatment which solves any sort of stability issues during storage conditions [38]. Porous scaffolds offer benefits like similarity to natural extracellular matrix, porous and interconnected pores give access for nutrients and waste exchange, support natural cell growth, less adherence avoids inconvenience to tissue growth, appropriately functionalized for tissue growth and cell migration. All these characteristics encouraged researchers to develop electrospun scaffolds for delivery of genes, drugs, and biomolecules [16].

10.6 Electrospinning Nanofibers can be generated by following several processes like template synthesis, phase separation, self-assembly, and electrospinning. Electrospinning produces nanofibers in small and large scale as well as in nano and micro size in a fast and cheap level. Hence, lot of efforts are kept on electrospinning method by many researchers to completely establish the process in such a way the modulation of the nanofibers is possible to meet the desired expectations for a particular application [39]. Variations in the handling of polymeric mixtures through electrospinning process include solution spinning, wet spinning, dry spinning, melt spinning, and gel spinning. Nanofibers produced from electrospinning process possess exceptional physical properties than their bulk-size fibers (e.g., mechanical, thermal, electrical, optical, and magnetic properties). As the title indicates, the principle involved in electrospinning is, the spinning of polymeric solution or melt under high electric field (high DC voltage supply) at elevated temperatures. Almost all available natural and synthetic polymers can be used to produce electrospun nanofibers by making use of an appropriate solvent system [39]. The major difference of electrospinning with conventional spinning is that the former one works on the principle that the applied electrostatic field interacts with the polymer electrical charges to generate shearing forces, that means only electrostatic forces are involved, whereas in the latter conventional spinning several forces like shearing, rheological,

276  Electrospun Materials and Their Allied Applications gravitational, inertial and aerodynamic forces act on the fibers through the spindles present in the set up [39].

10.6.1 Steps Involved in the Electrospinning Process 1. The setup is comprised of a pump, spinneret (a syringe with needle/capillary tube), high DC voltage supplier, two electrodes, screen/collector. Schematic representation of experimental setup of electrospinning is shown in Figure 10.3 [39, 40]. 2. Polymeric solution (viscoelastic solution) or the melt of the polymer (from which the electrospun nanofibers are to be prepared) of certain concentration is filled into the syringe (of varying capacity 1–10 ml syringe fitted to a needle/ capillary of gauge 20 or 22). 3. The capillary tip of the syringe is connected to an electrode which is connected with positive charge of the high voltage DC supply. 4. Another electrode of negative charge from DC supply is connected to the collector/screen (e.g., the collector is kept at a distance of around 15 cm from spinneret). 5. High voltage electric field (up to 30 kV, e.g., in between 7 to 30 kV based on polymer nature) is applied as per requirement. 6. With the pump, the polymeric solution is pumped slowly (e.g., at a rate around 1–3 ml/min) against the collector.

Syringe Pump

Spinneret

Electrospun nanofiber collector

Taylor cone

High DC supply

Figure 10.3  Experimental setup of the electrospinning process [39].

Electrospun Materials in Gene Delivery  277 7. Due to surface tension, the solution is held on the tip of the capillary. 8. Due to the applied electric field, mutual charge repulsion results in the induction of longitudinal stresses. 9. The charged ions in the solution move toward the collector having opposite charge. 10. When the applied electrostatic forces get equilibrated with the surface tension of the polymeric solution, then the pendant drop of the polymeric solution at the tip of the capillary will take the hemispherical shape, commonly called as a Taylor cone [41]. 11. Once the applied electrostatic field crosses the surface tension value, then the Taylor cone gets elongated taking the form as a linear jet and travels as a straight path called as jet length (around 1–2 cm). 12. After that, the linear jet experiences the bending instability (after stress relaxation) resulting in whipping or spiral motion (linear path gets changed as looping path). 13. This bending instability stretches (thousands of times than its original size) the jet very long and thin, thus resulting in plastic deformation (large extent of plastic deformation) finally resulting in the formation of ultrafine fibers to a level of nanoscale. 14. Then the solvent gets completely evaporated and the nanofibers will be deposited on rotating collector/metallic screen as nonwoven nanofiber scaffold mats or webs (rotation of the collector defines the scaffold mat-like structure). Different shaped nanofibers can be obtained by electrospinning process which depends on the system and processing parameters. Examples of different shapes include round, bead, linear, branched, flat ribbon, ribbon with other shapes, and split fibers. As an example, the more the polymer concentration, the more will be the fiber diameter. Even the size may vary from nano to micro-level, mainly basing on the polymer concentration [39, 42]. Scanning electron microscope (SEM) images of linear and branched electrospun nanofibers are shown in Figure 10.4. Nanofibers are the nanostructured fibers made from natural or synthetic polymers and are in the size range of 3–2000 nm. They provide tailorable fiber diameter, high surface area to volume ratio, manageable morphologies (porosity, density, hollowness), and easy functionalization with biological molecules. Nanofibers, in addition to its presence in other sectors, have also shown

278  Electrospun Materials and Their Allied Applications

(a)

(b)

Figure 10.4  SEM images representing the structure of electrospun nanofibers, (a) linear and (b) branched [39].

versatile application in biomedical and pharmaceutical fields as carrier systems for several drugs and biologicals. Nanofibers forming a mesh-like arrangement with specific features are called a scaffold. These nanofiber scaffolds are in research very actively for the last two decades due to their promising characteristics in drug delivery, gene delivery, and DNA/RNA delivery [23]. Electrospinning technique is used for the production of nanofiber scaffolds for biomedical and pharmaceutical applications [23]. It is well described in the literature as unique, versatile, promising, highly productive, simple technique for the fabrication of polymers, composites, inorganic materials, and small molecules to produce nanofibers as scaffolds. This technique mainly depends on the electrostatic repulsion, between the charges on opposite surfaces, that draws the nanofibers constantly from the charged viscoelastic fluid [43]. The technique is tailorable to produce solid, porous, hollow or core-sheath nanostructures with the surface properties able to be functionalized with the biomaterials either during or after the electrospinning process [44]. The processing parameters can be controlled to obtain varied nanofiber diameter and porosity. Parameters that can be modulated for electrospinning technique include [23, 39, 40, 45–49]: (i) Polymer–solvent system parameters a. polymer concentration b. the molecular weight of polymer c. nature of solvent d. polymer solution properties (viscosity, conductivity, dielectric constant, surface tension, cross-linking)

Electrospun Materials in Gene Delivery  279 (ii) Processing parameters a. electric potential b. flow rate c. feeding rate d. temperature, humidity e. air velocity f. distance between the capillary and collector g. collector rotation speed h. type of needle/spinneret like using coaxial or triaxial needles for hollow, core–shell or multi-sheathed structures) (iii) Controlled post-processing parameters a. heating rate b. heating temperature Electrospinning is a direct method used for the fabrication of nonwoven mat/mesh of polymeric nanofibers, termed as scaffolds, compared to conventional methods which include extrusion molding, melt spinning, and wet spinning [50–52].

10.6.2 Types of Electrospinning Electrospinning techniques can be broadly divided into five categories [23]: 1. 2. 3. 4. 5.

Blend electrospinning Coaxial electrospinning Emulsion electrospinning Melt electrospinning Gas jet electrospinning

Blend electrospinning is a basic method in which the polymer is dissolved in a solvent and the drug/biomolecules are mixed uniformly to obtain matrix type nanofibers loaded with drug/biomolecules. The presence of solvent may denature or degrade the drug/biomolecule, hence need to be cautious while selecting this particular method. And also, these nanofibers may cause burst release [53, 54]. Coaxial electrospinning is an advanced version of conventional blend electrospinning where two nozzles

280  Electrospun Materials and Their Allied Applications with two different solutions are handled producing core–shell morphology in the nanofibers. With this structure improved protection of the drug/ biomolecule loaded within the core is possible. The cargo can also help for sustained release due to our shell layer of release controlling polymer [52, 53, 55, 56]. In emulsion electrospinning, two immiscible solvents are spun simultaneously to generate core–shell nanofibers. Initially, a w/o emulsion of drug/biomolecule will be formed with the help of a surfactant and then mixed with polymer matrix solution. This method also provides cargo loading of drug/biomolecule at the core and hence protection and sustained release [55, 57–59]. Schematic representation of coaxial and emulsion electrospinning are shown in Figure 10.5. Melt electrospinning has the added advantage of skipping the use of a solvent which may sometimes be hazardous to the formulation due to residual content or may cause damage to the drug/biomolecule. In this process polymer melt is used in the place of solution and maintained with multiple heating zones, hence the thermolabile polymers are not suitable

(a)

(b)

Figure 10.5  Schematic representation of (a) coaxial electrospinning, (b) emulsion electrospinning [20].

Blend electrospinning

Electrospinning Electrospinning methods methods

Coaxial electrospinning Melt electrospinning Gas jet electrospinning Rotating disk electrospinning Needleless electrospinning Nearfield electrospinning Rotating disk and translating spinneret Rotating electrode electrospinning

Figure 10.6  Different methods of electrospinning [23, 39, 64].

Electrospun Materials in Gene Delivery  281 to handle in this method. Cooling is the phenomenon involved rather than solvent evaporation mechanism for the final stage fabrication of nanofibers. The drawback here is that the formed fibers will have broader diameter than that obtained from other methods [60, 61]. Gas jet electrospinning is an improvement of melt electrospinning technique where there will be an additional set up of the gas jet device due to the application of hot gas through a jacket surrounding the coaxial jet, which solves the problem of obtaining thick nanofibers in melt electrospinning [62, 63]. Several modifications for the fabrication process have been reported in order to develop continuous long aligned fibers with ordered architecture making the electrospun nanofibers useful for vast applications. The modified methods include [39, 64]: • • • •

Rotating disk electrospinning, Needleless electrospinning, Near-field electrospinning, and Electrospinning with a rotating disk and translating spinneret

Different methods of electrospinning technique are presented in Figure 10.6.

10.7 Characterization Characterization of any developed system is important to understand its properties and performance. Nanofibers developed by electrospinning technique also required several characterization procedures to understand its behavior, quality, loading efficiency, and performance. Based on the specific properties to be studied, the selection of analytical methods will be done. Structural characterization can be done by using different analytical methods like scanning electron microscope (SEM), X-ray diffraction (XRD), transmission electron microscope (TEM), scanning probe microscope (SPM), scanning tunneling microscope (STM), atomic force microscope (AFM), laser-based optical spectroscopy, electron spectroscopy, ionic spectroscopy, Raman spectroscopy, Fourier-transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA), X-ray photoelectron spectroscopy (XPS), UV-visible spectroscopy, and vibrating sample magnetometer (VSM) [65, 66]. Several features that can be studied from above methods include morphology, size, surface characteristics, chemical composition, elemental features, fiber alignment, texture, dimensional analysis, crystallinity, porosity, thermal stability, water holding capacity, compatibility,

282  Electrospun Materials and Their Allied Applications

(a)

(b)

Figure 10.7  SEM image of electrospun nanofibers: (a) aligned fibers, (b) random fibers [66, 67].

etc. [65, 66]. SEM images of aligned and random nanofibers are shown in Figure 10.7 [66, 67]. Even several in vitro and in vivo studies like cell culture experiments, assays, fluorescence analysis, histopathological studies, etc., will be conducted to determine the cytotoxicity, cell viability, cell attachment, content of loaded drug or gene or therapeutic agent, release kinetics, interaction studies, transfection efficiency, gene expression, structural integrity, cell proliferation/cell growth, new tissue formation, etc. [16, 65].

10.8 Applications of Electrospun Materials Electrospun nanofibers loaded with biomolecules (growth factors, proteins, genetic materials) can be called as bioactive nanofibers which provide physical support for the host cells as well as allow localized and sustained release of the encapsulated biomolecule with functionalized characteristics.

10.8.1 Electrospun Materials in Gene Delivery The ever increasing interest of electrospun materials in gene delivery is due to the promising results reported by researchers in different treatment strategies. Several applications of electrospun nanomaterials in gene delivery are briefly discussed below.

10.8.1.1 Tissue Engineering Tissue engineering is an emerging field where the damaged or diseased tissues are repaired or replaced. Tissue regeneration and establishment of

Electrospun Materials in Gene Delivery  283 new blood vessels to develop the natural phenomenon of nutrient supply is a challenging task that can be achieved by tissue engineering. Angiogenesis is an important issue in the formation of new tissue and new blood vessels necessary for the oxygen and nutrients supply [68, 69]. Angiogenic growth factors promote such vasculature. Direct delivery of those angiogenic factors can provide scope for better therapy, however, it has multiple limitations like burst release leading to toxicity, lower shelf life, lack of preservation, denaturation during encapsulation, costly production and purification process [18, 19]. Hence, to overcome these problems, the encapsulation of angiogenic growth factors can be replaced with the delivery of genes which can encode those angiogenic factors at the host cells making them as a factory for the production of physiologically required amounts of essential angiogenic growth factors as and when needed [16]. Various genes that encode proteins and growth factors are most frequently encapsulated with electrospun polymeric scaffolds for efficient therapy [20, 70, 71]. A synthetic cationic polymer highly used as a nonviral vector for gene delivery is Polyethylenimine (PEI). Despite its efficiency both in vivo and in vitro, it suffers from cytotoxicity and may significantly be restricted from its use [72]. As a remedy, PEI has been modified with inclusion of PEG which enhanced the biocompatibility of PEI without losing its gene transfection efficiency [73, 74]. the principle involved might be the cloaking layer of PEG avoiding the direct interaction of PEI with intracellular components. The utilization of electrospun scaffolds for gene delivery has given promising solution for elevation of desired gene expression to produce growth factors, cytokines, proteins for desired cellular functions which further accelerate functional tissue formation [17, 75–77]. In order to have localized effect, there should be localized delivery of genes. Hence to achieve that goal, researchers have incorporated the gene in tissue engineering scaffolds and then administered locally at target site [78]. PEI– DNA complexes were prepared and then incorporated into the electro­spun scaffolds for effective delivery of the genetic materials at the target environment [79, 80]. With such approach, the prolonged release of the localized plasmid was demonstrated up to 3 months for tissue regeneration in a most effective manner [81]. Electrospun nanofiber scaffolds gained importance as tissue engineering scaffolds for new tissue formation due to the native similarity with extracellular matrix supporting the cell adhesion, proliferation, and differentiation [82–84]. As per Zhang et al., the electrostatic interaction allows the adsorption of PEI thereby loading the scaffolds with plasmid DNA. Upon administration at the target site, this PEI-DNA complex gets released into the target

284  Electrospun Materials and Their Allied Applications cells during cell culture. The researchers also reported that the complex size is 145 nm for PEI–DNA and 200 nm for PEI–PEG–DNA with uniform distribution. Cell culture studies also revealed that the scaffolds showed 65% transfection efficiency in human embryonic kidney 293 cell line and around 40% in primary mesenchymal stem cells. Sustained release of the PEI-DNA or PEI-PEG-DNA complexes from scaffolds was observed for 72 h. In vivo studies were also conducted in mouse and found better transfection efficiency than other strategies tried. This indicates that the electrospun material based gene delivery with modulation of the fabrication will provide promising results and better therapeutic effects [38]. Sakai et al. developed electrospun nanofibers of poly(L-lactic acid) (PLLA) with the incorporation of PEI and pDNA using a layer-by-layer technique for Luciferase gene delivery. African green monkey fibroblast cells (COS-7) were used as the target cells and found two-fold enhanced gene delivery efficiency on comparing with flat films. The gene expression was found to be retained for 5 days post-seeding [85]. Saraf et al. studied the PEI and Hyaluronic acid (HA) based nanofibers loaded with a nonviral vector-based enhanced green fluorescent protein (EGFP) genetic material for testing its efficiency in rat fibroblasts and observed an extended pDNA release for about 60 days with transgene expression [79].

10.8.1.2 Regenerative Medicine Scaffolds with their three-dimensional nanofibril structures act as excellent biological media to support cell proliferation and differentiation in regenerative medicine. For improved properties, the nanocomposite scaffolds can be developed to best suit the tissue engineering requirements [86].

10.8.1.3 Vascular Grafts Several attempts were made by the researchers to make the gene delivery efficient by using electrospun scaffolds. The best example is the strategies followed for effective delivery of DNA for vascular grafts. Coaxial electrospinning technique is followed to load the PEI–DNA complex in the core and covering of PEI–hyaluronic acid (PEI–HA) in the sheath [11, 12]. In another strategy, adsorption of PEI–DNA polyplexes or DNA alone to the nonwoven fibers was tried [18]. As another strategy, surface immobilization of PEI and plasmid DNA was done to the scaffolds using a layer-bylayer approach [19]. To overcome the denaturation of DNA on exposure to solvent or processing conditions, initially the PEI-PEG composite is added to the PCL solution and electrospinning was done to obtain the nanofiber

Electrospun Materials in Gene Delivery  285 scaffolds. Then the formed scaffolds are incubated in aqueous solution containing plasmid DNA [1].

10.8.1.4 Bone Regeneration Jiang et al. developed nanofiber scaffolds by using PCL in acetonitrile as polymer solution mixed with a pCMVb–GFP plasmid for electrospinning following other favorable conditions. The operating conditions followed include electric field of 25 kV, flow rate of 20 μl/min, aluminum foil as collector maintained at a distance of 25 cm from syringe needle and syringe capacity of 10 ml with plastic needle of gauge 20. The obtained scaffolds were characterized for morphology using SEM, cytotoxicity and biocompatibility by doing assay, DNA release by fluorescence test, exogenous transfection efficiency by cell culturing, and transgene quantification by electrophoresis. The results showed that the pore size is around 530 ± 265 nm, absence of cytotoxicity, good biocompatibility, initial burst release of DNA followed by sustained release for a duration of 7 days, 70% transfection efficiency with good transgene production. They concluded that scaffolds based DNA delivery can be quite useful in bone regeneration and arthroplasty. Manipulation of physical treatment conditions like sonication and lowering of pH level can effectively enhance the transfection efficiency of PCL-plasmid DNA scaffolds [1]. Ramalingam et al. developed electrospun scaffolds of poly(lacticco-glycolic acid) (PLGA) with nanolayers of chitosan and alginate following layer-by-layer technique. This scaffold has been encapsulated with pDNA–dendrimer complex through functionalization of scaffolds by alginate (anionic) and chitosan (cationic) polyelectrolyte materials coating. The developed scaffold was found to support the adhesion and growth of human mesenchymal stem cells and favored cell differentiation toward osteogenic lineage. The polyelectrolyte coating also conferred sustained release and protected the pDNA from degradation, too [8]. Tissue engineering utilizes cells, scaffolds, biologicals for developing a new tissue or for regeneration of damaged or repaired tissue [1, 2]. Electrospinning technique produces 2D and 3D fiber matrices suitable for the tissue ­engineering/repair purpose [11–13]. Electrospun scaffolds are capable of delivering biochemical signals that help for cell differentiation and proliferation resulting in tissue regeneration through the supply of proteins, growth factors or genes [87, 88]. However, protein delivery has several limitations. Hence, gene delivery was recognized as an alternative strategy and gained importance as DNA is less expensive than protein and also more stable [10, 89]. Qiao et al. prepared

286  Electrospun Materials and Their Allied Applications bioactive core–shell scaffolds of PEI–pBMP2 (bone morphogenetic ­protein-2 plasmid)-PLGA ((poly D,L-lactic-co-glycolic acid) by following coaxial electrospinning technique. They tested the controlled delivery of gene to hPDLSCs (human periodontal ligament stem cells). PEI–pBMP2 acts as core and PLGA as shell to control the release rate of gene. They have conducted characterization studies, mechanical properties determination, and gene release behavior studies. The results revealed that there is a burst release for first few days followed by controlled release for a duration of next 28 days. The scaffold has also shown high transfection efficiency. The gene expression was also shown for prolonged period of 28 days [7]. Luu et al. have developed nanostructured scaffold prepared by electrospinning using PLGA and PLA–PEG copolymers for the controlled release of DNA. The nonviral vector plasmid DNA was used for delivery the b-Gal and GFP into the mouse osteoblastic cells. The results indicated that there was a burst release for the initial 30 min followed by sustained release up to 20 days with maximum release occurring approximately at 2 h. It was also found that the gene expression was observed for 48 h post-seeding [6]. Gelatin grafts were constructed by Zou et al. to create fibrous scaffolds with variations in hydroxyapatite (HA) contents, crystal size, and mechanical properties following in situ mineralization. Plasmid DNA (pDNA) was incorporated at different levels during the mineralization process on the basis of HA gradients. Obvious gradients in cell density, collagen deposition, osteoblastic differentiation, pDNA release, and the expression of target proteins were found as results, with a temporally and spatially controlled delivery of growth factors from the scaffolds. These 3D scaffolds provided efficient regeneration of tissues including spatial distributions of the cell proliferation, differentiation, and matrix secretion [90].

10.8.1.5 Diabetic Ulcer Treatment Kim et al. developed a nanofibrous matrix fabricated for the controlled release of DNA as a response to matrix metalloproteinase (MMPs) in diabetic ulcers. Linear PEI (LPEI) was chemically conjugated with the surface-exposed amine functional groups on the scaffold matrix using MMP cleavable peptide linkage. Then DNA was incorporated on to the matrix electrostatically at different ratios. The release profiles of DNA and immobilized LPEI were determined with respect to the MMP-responsiveness of the matrix. The gene expression was also found to be more appreciable than naked DNA studies. Finally, the authors concluded that the animal experiments revealed the superiority of LPEI immobilized gene delivery from electrospun nanofibers than the naked DNA matrix without LPEI

Electrospun Materials in Gene Delivery  287 in terms of gene transfection efficiencies and control over the release rate [91, 92]. Kim et al. have studied in vitro and in vivo epidermal growth factor gene therapy by developing electrospun nanofiber scaffold with matrix metalloproteinase (MMP) responsiveness over the release of plasmid human epidermal growth factor (phEGF). The testing is done in diabetic ulcers. For MMP responsiveness, LPEI was immobilized on scaffold using MMP-cleavable linker for electrostatic incorporation of phEGF. The results showed that there was significant [93]. Since, growth factors (GFs) are intended to transmit signals motivating or inhibiting cellular proliferation, differentiation, and ECM secretion, the administration strategies for growth factors became interesting for researchers. However, bolus administration of GFs was found to be ineffective since they rapidly diffuse out of target site and readily get enzymatically digested or deactivated. Hence, Yang et al. developed electrospun core–sheath nanofiber scaffolds loaded with basic fibroblast growth factor (bFGF) for better expression and skin regeneration using diabetic rats as animal models. They found 10-fold increase in gene expression from the scaffolds comparing with plain pDNA/Poly(ethylene glycol)-poly(DLlactide) blends. Dense and mature capillary vessels were regenerated in 2 weeks after treating the target area with bFGF-loaded nanofibers [94].

10.8.1.6 Cancer Treatment Achille et al. developed PCL scaffolds for loading the DNA encoding against the Cdk2i responsible for breast cancer proliferation. The DNA release was sustained for over 21 days and found the suppression of proliferation and enhanced death rate of breast cancer cells using a breast cancer cell line, MCF-7 [95].

10.8.1.7 Blood Vessel Regeneration Blood vessel formation is a challenging task in tissue engineering. Chen et  al. assessed the suitability of electrospun fibers for loading multiple pDNA for localized gene delivery for efficient development of new mature blood vessels. A reverse microemulsion technique was followed to encapsulate the pDNA in calcium phosphate nanoparticles which were further loaded onto electrospun nanofibers. This has shown the sustained release of pDNA for 4 weeks which provided cell proliferation, gene transfection, and extracellular matrix regeneration and increased regeneration of blood vessels. Fibers with encapsulated nanoparticles of plasmids encoding for vascular endothelial growth factor (pVEGF) and also basic fibroblast growth

288  Electrospun Materials and Their Allied Applications factors (pbFGF) showed significant high density of developed mature blood vessels than those having individual plasmid [96]. He et al. developed scaffolds incorporated with polyplexes of plasmids VEGF and bFGF and tested for the regeneration of mature blood vessels. The results showed sustained release for 4 weeks and have shown potentiality of scaffolds to regenerate functional tissues in human umbilical vein endothelial cells [19].

10.8.1.8 Wound Management Kobsa et al. developed PCL and PLLA based scaffolds for the loading of plasmid encoding keratinocyte growth factor (KGF) and tested in mice for treatment of full-thickness wounds. The results showed improvement in the rate of wound re-epithelialization, a proliferation of keratinocyte and granulation response [97].

10.8.1.9 Carrier for Genetic Material Loaded Nanoparticles As naked DNA administration has shown low transfection efficiency, nanoparticles of DNA were tried for better delivery and high transfection efficiency. But, unfortunately, these nanoparticulate systems are facing strong immunological reactions. Hence, as the best remedy, for preserving the advantages of nanoparticles and reducing the side effects, the novel approach of encapsulating these DNA loaded nanoparticles on to the electrospun nanofiber scaffolds has been reported well in the literature [98]. Nie and Wang have fabricated PLGA–Hydroxylapatite (HAp) composite scaffolds and loaded with chitosan nanoparticles of DNA (encoding bone morphogenetic protein-2 (BMP-2)) in both the ways of during electrospinning and post spinning. The studies revealed that there is high transfection, high cell viability, promising cell adhesion, with a sustained release of DNA for 45–55 days [98, 99].

10.8.1.10 Myocardial Infarction Treatment Che et al. studied the nanofiber mediated gene delivery in the treatment of myocardial infarction. PCL–PEI nanofiber scaffolds were immobilized with VEGF nanoparticles which were complexed with crosslinked PEI. Nanoparticles loaded with Luciferase, red fluorescence protein (RFP), and therapeutic gene VEGF were studied in H9C2 myoblasts and found promising transfection efficiency confirming the application electrospun nanofiber scaffolds as an excellent delivery mechanism for genes [100].

Electrospun Materials in Gene Delivery  289

10.8.1.11 Stem Cell-Based Therapy For bone tissue regeneration, a central gene Runt-related transcription factor 2 (RUNX2) is found to be responsible for osteoblast phenotype induction. Hence, Monteiro et al. developed liposomes of pDNA loaded RUNX2 from human bone marrow-derived mesenchymal stem cells (hBMSCs) was encapsulated on PCL electrospun nanofiber scaffolds. These scaffolds immobilized with RUNX2 loaded liposomes have shown long term gene expression of eGFP and RUNX2 by cultured hBMSCs. Osteogenic differentiation was also observed [101].

10.8.1.12 Gene Silencing RNA interference (RNAi) is known to interrupt gene expression. RNAi contains double-stranded small interfering RNA (siRNA) molecules of 21–22 nucleotides length that cause sequence-specific enzymatic cleavage in target mRNA by complementary base pairing. This permits specific suppression of gene expression for investigating the cellular gene functions and is useful as a therapeutic drug. Due to the susceptibility nature (serum degradation, renal clearance, and poor cellular uptake), the therapeutic potential of siRNA is restricted. Nanoparticles are the suitable carriers for siRNA to enhance the pharmacokinetics, cellular delivery, and intracellular transferring of siRNA. Chitosan nanoparticles loaded with siRNA are a promising system to produce increased efficiency of gene silencing [102]. Cao et al. presented a PCL scaffold-mediated approach for the controlled release of siRNA. They achieved controlled release of intact siRNA for 28 days under physiological conditions. Cell culture studies were done using HEK 293 cells and found the controlled release of siRNA from fibrous scaffolds for a period of 30 days providing silencing efficiency of 61–81% in comparison with conventional siRNA transfection. This work demonstrated the potential application of nanofibrous scaffold-mediated siRNA controlled delivery for long-term gene-­ ­ silencing [103]. Rujitanaroj et al. investigated the release of siRNA and siRNA/transfection reagent (TKO) complex from the electrospun scaffolds of PCL and ethyl ethylene phosphate (EEL). It was found that there was a sustained release of bioactive naked siRNA and siRNA/TKO complexes for about 28 days [104]. The controlled differentiation of neural stem/progenitor cells (NPCs) toward functional neurons of the central nervous system (CNS) is a suitable

290  Electrospun Materials and Their Allied Applications treatment strategy for patients with chronic neurodegenerative diseases or acute trauma. Low et al. explored the feasibility of directing neuronal differentiation by synergistic integration of scaffold-mediated knockdown of RE-1 silencing transcription factor (REST) and topographical cues of 3D nanofibrous in mouse NPCs. Polydopamine (PD) coated PCL electrospun nanofibers were successfully functionalized with REST siRNAs. The studies revealed that there was a sustained knockdown of REST in NPCs up to 5 days in vitro and the silencing efficiency was found to be significantly higher than the effect produced through siRNA adsorbed onto non-PD coated sample controls. The silencing of REST along with nanofiber topographical cues significantly enhanced neuronal commitment in NPC to a level of 57.5% [105].

10.8.1.13 Controlled Release of Gene Lee et al. have utilized adeno-associated virus (AAV) as a vector for DNA encoding the green fluorescent protein (GFP) and encapsulated within electrospun scaffolds made up of PCL and elastin-like polypeptides (ELP). The sustained release of AAV from the electrospun nanofiber scaffolds has shown substantial cellular transduction with a high percentage of GFPexpressing cells around >80% [106].

10.8.1.14 DNA Delivery Yunfei et al. developed a controlled dual delivery system of electrospun scaffolds using PEI–carboxymethyl chitosan with pDNA–angiogenin nanoparticles, PLGA, cellulose nanocrystals, and curcumin. The evaluation tests revealed that the release rate of curcumin was up to 6 days while that of angiogenin was up to 20 days. Biocompatibility was also evaluated and found positive results suitable for biomedical use. As a part of in vivo studies, infected burn wounds were transplanted with the prepared nanofibers and biopsy samples were tested for histology, immunohistochemistry, real-time quantitative PCR, Western blotting, and immunofluorescence. The in vivo studies results indicated that the prepared composite nanofibers have simulated the skin regeneration of burn areas in addition to treating the local infection [107]. Ceylan et al. developed and evaluated electrospun nanofiber scaffolds for PCL–pDNA for use in post-cancer treatment [40]. The authors investigated the release of DNA from PCL nanofibers and found that the DNA has shown drastic improvement in green fluorescent protein with

Electrospun Materials in Gene Delivery  291 cytomegalovirus promoter (PCMVb–GFP) that was earlier amplified with E-coli. The average diameter of the scaffolds was found to around 100 nm based on SEM analysis. L-929 cell lines were used for cytotoxicity studies which exhibited cell viability values of 80% up to 7 days. DNA release and gene expression were studied with positive results up to 7 days. Initially, it has shown a burst release of 1.8 ng/ml for about 15 min followed by sustained release for the remaining duration at around 0.575 ng/ml the researchers of this investigation concluded that the novel approach of using scaffolds could be an ideal one for the biomedical application in cancer treatment, tissue engineering, DNA-, gene-, and drugdelivery [40]. Hayenga et al. have developed and evaluated the chitosan-PEO based nanofibers loaded with PEI linked DNA for tissue regeneration. The charge neutralization process was used for the development of cationic PEI and DNA complex which is further incorporated over the nanofibers of chitosan–PEO. These scaffoldings have shown high surface area, good porosity, flexibility which can be of use for tissue regeneration and cell interaction in several treatment strategies. This system can be potentially used for the localized delivery of DNA [108]. Peckys et al. have developed the carbon nanofiber for the immobilization of double-stranded DNA along with coating of the fiber with a gold film following self-assembled monolayer process and analyzed for the release of DNA from the modified nanofibers. In vivo studies were done with Chinese hamster lung epithelial cells and found the DNA release and expression in cells are up to the mark [109]. Castro-Smirnov et al. have developed and analyzed the sepiolite nanofibers as nanocarriers for DNA transfection and found as a good option for the delivery of DNA to the target cells. The DNA from these nanofibers could spontaneously get internalized into the mammalian cells by following different pathways [110].

10.8.2 Electrospun Materials in Drug Delivery In addition to the promising results of electrospun nanofibers as gene delivery carriers, they are also well established in the delivery of other therapeutic agents and for functionalization. Electrospun nanofibers are well reported for their use in tissue regeneration, wound management, dentistry and for the delivery of different categories of drugs like anticancer drugs, antibacterial drugs, nonsteroidal anti-inflammatory drugs, cardiovascular agents, gastrointestinal drugs, antihistamine drugs, contraceptive drugs, and palliative drugs as

292  Electrospun Materials and Their Allied Applications treatment strategy for several diseases [23]. Some of the reported works are outlined here.

10.8.2.1 Antibiotics and Various Antibacterial Agents Ignatova et al. reviewed and listed various antibiotics, such as tetracycline hydrochloride, levofloxacin, ciprofloxacin, and moxifloxacin, and antibacterial agents such as 8-hydroxyquinoline derivatives, benzalkonium chloride, itraconazole, and fusidic acid which were encapsulated in nanofibers for wound-dressing [111]. In most cases, PCL, PLA, and PLGA were used as the carrier polymers. For modulating the biodegradability, characteristics, several other synthetic or natural polymers were added, thus regulating the release behavior. Ceylan et al. developed PCL nanofibers loaded with antibacterial agent, gentamicin at different ratios and studied its effect against different bacteria. The results of studies shown that this gentamicin loaded nanofiber has shown promising antibacterial release and prohibition of bacteria at different inhibition zones [112].

10.8.2.2 Anticancer Drugs For postoperative chemotherapy, several anticancer drugs were tried and got successful results by administering as electrospun nanofibers. Anticancer drugs like doxorubicin, cisplatin, paclitaxel, platinum complexes, and dichloroacetate were among them used for postoperative local chemotherapy. For example, Xu et al. reported the application PEG–PLA electrospun nanofibers loaded with doxorubicin which has shown promising results [113]. Xie et al. reported fabrication of cisplatin-loaded PLA/ PLGA (30/70) nanofibers for long-term sustained release of cisplatin to treat C6 glioma in vitro. Results showed drug encapsulation efficiency of >90% and sustained release for more than 75 days. There was no initial burst release [114]. Aggarwal et al. studied the synthesis and analysis of cisplatin drug-loaded PCL–chitosan nanofibers for the treatment of cancer [115]. They analyzed the prepared nanofibers for local chemotherapy of cervical cancers in mice. The results showed that electrospun nanofibers provided drug-release up to one month.

10.8.2.3 Cancer Diagnosis Chen Z et al. summarized the application of electrospun nanofibers for cancer diagnosis and Therapy [116]. Chen S et al. [117] discussed the major roles of electrospun nanofibers in various sectors like

Electrospun Materials in Gene Delivery  293 ➢➢ ➢➢ ➢➢ ➢➢ ➢➢ ➢➢ ➢➢ ➢➢

cancer research, targeted chemotherapy, localized treatments, combinatorial therapy, cancer cell capture and detection, the behavior of cancer cells, a 3D cancer model with nanofibers, and cancer metastasis.

10.8.2.4 Wound Management Electrospun polymeric nanofiber membranes are proven as very good materials for application in wound management, due to their excellent properties, like high porous structure and well-connected pores which supports permeation of oxygen and moisture. These structures also eliminate infections from external sources and for discharging fluids from the wound. They also help for maintaining optimum wet microenvironment which is required for better wound healing. Electrospun fibers also provide ways for incorporation of drugs for a specific treatment [118].

10.8.2.5 Tissue Engineering The nanofiber scaffolds are three-dimensional frameworks obtained from electrospinning technique and mimic the architecture of tissue at nanoscale, hence these are highly useful in tissue engineering. As they are made up of biodegradable material, it slowly degrades with time and gets automatically replaced by the newly grown tissue. The polymer brings used for fabrication of scaffolds must be biocompatible and biodegradable with no immunogenic reactions. Biomaterials used for fabrication of scaffolds must provide the mechanical and biological properties that match the properties of extracellular matrix for better seeding at the target site [119–122].

10.8.2.6 Bone Tissue Engineering Electrospun materials embedded with several biomaterials like HA with β-tricalcium phosphate (β-TCP) [123], hydroxyapatite–PLLA–human cord blood-derived stem cells [124], mesenchymal stem cells (MSC)– cultured polycaprolactone (PCL) [125], PLLA–collagen [126], silk fibroin [127] were used for bone tissue regeneration.

294  Electrospun Materials and Their Allied Applications

10.8.2.7 Dental Growth Electrospun nanofibrous scaffolds were reported as excellent materials for dental tissue regeneration using dental pulp stem cells (DPSCs). DPSCs are the well-known cell source for the formation of dentine pulp complex [128].

10.8.2.8 Therapeutic Delivery Systems Electrospun nanofibers have gained significant attention for delivery of therapeutics due to their unique characteristics [44]. Several routes of administration are possible with electrospun nanofibers, covering oral, parenteral, transdermal, sublingual, buccal, rectal, vaginal, ocular, nasal, and inhalation [129].

10.8.3 Electrospun Materials in Miscellaneous Applications Electrospun nanofibers are well-known in biomedical and pharmaceutical fields. In addition, the unique properties of electrospun nanofibers make them widely used in several other fields like [40] ➢➢ Filtration and separation of micron-, submicron-, and nanosize organic, inorganic, and biological particles ➢➢ HF antenna fabrication ➢➢ Fabrics/protective clothing ➢➢ Transistors ➢➢ Solar and hydrogen energy ➢➢ Cosmetics ➢➢ Water treatment ➢➢ Environment ➢➢ Energy generation ➢➢ Storage Some of the synthetic biodegradable polymers that are used in the fabrication of electrospun nanofibers include polycaprolactone (PCL), poly(lactic acid) (PLA), poly(glycolic acid) (PGA), polylactic-co-glycolide (PLGA) copolymers, and a blend of them [130]. Some of the natural polymers used in electrospinning for biomedical applications include chitosan, collagen, gelatin, silk, wheat protein, and hyaluronic acid [120].

Electrospun Materials in Gene Delivery  295 Composites or blends of polymers are also used for the preparation of scaffolds as a strategy for improvement of the properties that suit desirable characteristics for a particular treatment.

• • • • • • • • • • • •

• • • • • • •

Delivery of Genes DNA RNA Peptides Antibodies Growth factors Drugs º Anticancer º Antimicrobial º Antiviral º NSAIDs º Cardiovascular º Gastrointestinal º Antihistamine º Contraceptive º Palliative

Biodegradable & Biocompatible Encapsulation efficiency Improved bioavailability Controlled release rate Ability to encapsulate wide variety of therapeutics Stability Permeation Porosity Modulation of properties 3D network structure Prolonged stay and treatment Bio-responsiveness

Characteristics Characteristics

Encapsul Encapsul ated ated agents agents

ELECTROSPUN ELECTROSPUN NANOFIBERS NANOFIBERS

Routesof of Routes administr adminis ation tration

Areas Areasof of application application

• • • • • • • • • • • •

Tissue engineering/regeneration Bone/skin regeneration/wound healing Stem cell treatment Blood vessels growth Dentistry Controlled release of biomolecules/drugs Gene expression/silencing Cancer diagnosis & treatment Other diseases treatment Cosmetics Sensors/catalysts/clothing Filters/water treatment/Storage

Figure 10.8  An overview of electrospun nanofibers.

• • • • • • • • • • •

Oral Parenteral Transdermal Sublingual Buccal Rectal Vaginal Ocular Nasal VInhalation VImplantation

296  Electrospun Materials and Their Allied Applications

10.9 Future Scope and Challenges Undoubtedly, electrospun nanofiber scaffolds can be mentioned as excellent carrier systems for biomedical, pharmaceutical and several other fields because of its unique properties. There is a wide scope for its successful marketing in all those fields. The vast research happened in this area and the findings till date are giving a lot of scopes to answer the deadly disease conditions where tissue engineering, bone regeneration, cancer treatment, etc. If the regulatory concerns are encouraging for the commercialization of these electrospun products, then the future will have more avenues for its entry as therapeutic system. In another way, still lot of research has to be done to explore the best for gene delivery using viral and nonviral vectors with no or very fewer side effects. The feasibility of tailoring the properties of these nanofibers is making them quite attractive for researchers to meet the desired characteristics and it needs exploration of the best available biomaterials. Translational research of these electrospun based drug delivery and gene delivery systems is the present challenge for researchers. Protection of gene/drug while processing or encapsulating, control over the release kinetics, biodegradation mechanisms of the polymeric fibers, biocompatibility without immunogenic reactions are the forefront challenges in developing a stable electrospun nanofiber-based delivery system. At industry perspective, scale-up of the method is another challenge. Toxicity fear of nanomaterials is another challenging point. Positive factors that could favor the translation research include the advantages of composites, modulation in electrospinning techniques, strategies of gene/drug encapsulation, tunability of scaffold properties, existence of good number of biomaterials and promising characteristics of the scaffolds. An overview of the electrospun nanofibers is presented in Figure 10.8.

10.10 Conclusion Electrospinning is the most promising technology that is used to produce fibers of nanoscale showing the properties similar to the extracellular matrix and hence found wide application in tissue engineering/repair. Biocompatibility and biodegradability are the primary properties that should be satisfied by the polymers to be used in this strategy. Electrospun materials found wide application in biomedical and pharmaceutical fields covering tissue engineering/repairing, wound dressings, implants delivery

Electrospun Materials in Gene Delivery  297 of drugs, genes, DNA/RNA, growth factors, and peptides. These products are able to provide localized and targeted therapy. They have also found place in other fields like filtration, catalysts, sensors, and so on. Wellestablished characterization methods are available to fully study the performance of developed electrospun systems. If the regulatory concerns, scale-up issues, stability factors are answered well, then there will be a faster scope for the commercialization of electrospun nanofibers for various applications.

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302  Electrospun Materials and Their Allied Applications 72. Neu, M., Fischer, D., Kissel, T., Recent advances in rational gene transfer vector design based on poly(ethylene imine) and its derivatives. J. Gene Med., 7, 992–1009, 2005. 73. Petersen, H., Fechner, P.M., Fischer, D., Kissel, T., Synthesis, characterization, and biocompatibility of polyethylenimine-graft-poly(ethyleneglycol) block copolymers. Macromolecules, 35, 6867–74, 2002. 74. Zhang, X., Pan, S.R., Hu, H.M., Wu, G.F., Feng, M., Zhang, W., Luo, X., Poly(ethylene glycol)-block-polyethylenimine copolymers as carriers for gene delivery: Effects of PEG molecular weight and PEGylation degree. J. Biomed. Mater. Res. A, 84, 795–804, 2008. 75. Pannier, A.K., Wieland, J.A., Shea, L.D., Surface polyethylene glycol enhances substrate-mediated gene delivery by nonspecifically immobilized complexes. Acta Biomater., 4, 26–39, 2008. 76. Mao, Z., Shi, H., Guo, R., Ma, L., Gao, C., Han, C., Shen, J., Enhanced angiogenesis of porous collagen scaffolds by incorporation of TMC/DNA complexes encoding vascular endothelial growth factor. Acta Biomater., 5, 2983–94, 2009. 77. Sahoo, S., Ang, L.T., Goh, J.C., Toh, S.L., Growth factor delivery through electrospun nanofibers in scaffolds for tissue engineering applications. J. Biomed. Mater. Res. A, 93, 1539–50, 2010. 78. Houchin-Ray, T., Whittlesey, K.J., Shea, L.D., Spatially patterned gene delivery for localized neuron survival and neurite extension. Mol. Ther., 15, 705– 12, 2007. 79. Lim, S.H., Liao, I.C., Leong, K.W., Nonviral gene delivery from nonwoven fibrous scaffolds fabricated by interfacial complexation of polyelectrolytes. Mol. Ther., 13, 1163–72, 2006. 80. Saraf, A., Baggett, L.S., Raphael, R.M., Kasper, F.K., Mikos, A.G., Regulated non-viral gene delivery from coaxial electrospun fiber mesh scaffolds. J. Control. Release, 143, 95–103, 2010. 81. Jang, J.H., Rives, C.B., Shea, L.D., Plasmid delivery in vivo from porous tissue-engineering scaffolds: Transgene expression and cellular transfection. Mol. Ther., 12, 475–83, 2005. 82. Zong, X., Ran, S., Kim, K.S., Fang, D., Hsiao, B.S., Chu, B., Structure and morphology changes during in vitro degradation of electrospun poly(glycolide-co-lactide) nanofiber membrane. Biomacromolecules, 4, 416–23, 2003. 83. Newton, D., Mahajan, R., Ayres, C., Bowman, J.R., Bowlin, G.L., Simpson, D.G., Regulation of material properties in electrospun scaffolds: Role of cross-linking and fiber tertiary structure. Acta Biomater., 5, 518–29, 2009. 84. Teo, W.E., He, W., Ramakrishna, S., Electrospun scaffold tailored for tissuespecific extracellular matrix. Biotechnol. J., 1, 918–29, 2006. 85. Sakai, S., Yamada, Y., Yamaguchi, T., Ciach, T., Kawakami, K., Surface immobilization of poly(ethyleneimine) and plasmid DNA on electrospun

Electrospun Materials in Gene Delivery  303 poly(L-lactic acid) fibrous mats using a layer-by-layer approach for gene delivery. J. Biomed. Mater. Res. A, 88, 281–7, 2009. 86. Wahid, F., Khan, T. et al., Nanocomposite scaffolds for tissue engineering; properties, preparation and applications, in: Applications of Nanocomposite Materials in Drug Delivery, pp. 701–35, Woodhead Publishing, Cambridge, 2018. 87. Ji, W., Sun, Y., Yang, F., Beucken, J.J.J.P., Fan, M., Chen, Z., Jansen, J.A., Bioactive electrospun scaffolds delivering growth factors and genes for tissue engineering applications. Pharm. Res., 28, 1259–72, 2011. 88. Yang, Y., Xia, T., Chen, F., Wei, W., Liu, C., He, S., Li, X., Electrospun fibers with plasmid bFGF polyplex loadings promote skin wound healing in diabetic rats. Mol. Pharmaceutics, 9, 48–58, 2012. 89. Heyde, M., Partridge, K.A., Oreffo, R.O., Howdle, S.M., Shakesheff, K.M., Garnett, M.C., Gene therapy used for tissue engineering applications. J. Pharm. Pharmacol., 59, 329–50, 2007. 90. Zou, B., Liu, Y., Luo, X., Chen, F., Guo, X., Li, X., Electrospun fibrous scaffolds with continuous gradations in mineral contents and biological cues for manipulating cellular behaviors. Acta Biomater., 8, 1576–85, 2012. 91. Kim, H. and Yoo, H., MMPs-responsive release of DNA from electrospun nanofibrous matrix for local gene therapy: In vitro and in vivo evaluation. J. Control. Release, 45, 264–71, 2010. 92. Kim, H. and Yoo, H., Matrix metalloproteinase-inspired suicidal treatments of diabetic ulcers with siRNA-decorated nanofibrous meshes. Gene Ther., 20, 378–385, 2013. 93. Kim, H. and Yoo, H., In vitro and in vivo epidermal growth factor gene therapy for diabetic ulcers with electrospun fibrous meshes. Acta Biomater., 9, 7371–80, 2013. 94. Yang, Y., Xia, T., Wei, Z., Wei, L., Weng, J., Zhang, C., Li, X., Promotion of skin regeneration in diabetic rats by electrospun core–sheath fibers loaded with basic fibroblast growth factor. Biomaterials, 32, 4243–54, 2011. 95. Achille, C., Sundaresh, S., Chu, B., Hadjiargyrou, M., Cdk2 silencing via a DNA/PCL electrospun scaffold suppresses proliferation and increases death of breast cancer cells. PLoS One, 7, e52356, 2012. 96. Chen, F., Wan, H., Xia, T., Guo, X., Wang, H., Liu, Y., Li, X., Promoted regeneration of mature blood vessels by electrospun fibers with loaded multiple pDNA–calcium phosphate nanoparticles. Eur. J. Pharm. Biopharm., 85, 699– 710, 2013. 97. Kobsa, S., Kristofik, N., Sawyer, A., Bothwell, A., Kyriakides, T., Saltzman, W., An electrospun scaffold integrating nucleic acid delivery for treatment of full-thickness wounds. Biomaterials, 34, 3891–901, 2013. 98. Nie, H. and Wang, C., Fabrication and characterization of PLGA/HAp composite scaffolds for delivery of BMP-2 plasmid DNA. J. Control. Release, 120, 111–21, 2007.

304  Electrospun Materials and Their Allied Applications 99. Nie, H., Ho, M., Wang, C., Wang, C., Fu, Y., BMP-2 plasmid loaded PLGA/ HAp composite scaffolds for treatment of bone defects in nude mice. Biomaterials, 30, 892–901, 2009. 100. Che, H.L., Muthiah, M., Ahn, Y., Son, S., Kim, W.J., Seonwoo, H., Chung, J.H., Cho, C.S., Park, I.K., Biodegradable particulate delivery of vascular endothelial growth factor plasmid from polycaprolactone/polyethylenimine electrospun nanofibers for the treatment of myocardial infarction. J. Nanosci. Nanotechnol., 11, 7073–77, 2011. 101. Monteiro, N., Ribeiro, D., Martins, A., Faria, S., Fonseca, N., Moreira, J., Reis, R.L., Neves, N.M., Instructive nanofibrous scaffold comprising runt-related transcription factor 2 gene delivery for bone tissue engineering. ACS Nano, 8, 8082–94, 2014. 102. Chen, M., Gao, S., Dong, M., Song, J., Yang, C., Howard, K.A., Jorgen., K., Flemming., B., Chitosan/siRNA nanoparticles encapsulated in PLGA nanofibers for siRNA delivery. ACS Nano, 6, 4835–44, 2012. 103. Cao, H., Jiang, X., Chai, C., Chew, S., RNA interference by nanofiber-based siRNA delivery system. J. Control. Release, 144, 203–12, 2010. 104. Rujitanaroj, P., Wang, Y., Wang, J., Chew, S., Nanofiber-mediated controlled release of siRNA complexes for long term gene-silencing applications. Biomaterials, 32, 5915–23, 2011. 105. Low, W., Rujitanaroj, P., Lee, D., Messersmith, P., Stanton, L., Goh, E., Chew, S.Y., Nanofibrous scaffold-mediated REST knockdown to enhance neuronal differentiation of stem cells. Biomaterials, 34, 3581–90, 2013. 106. Lee, S., Kim, J., Chu, H., Kim, G., Won, J., Jang, J., Electrospun nanofibrous scaffolds for controlled release of adeno-associated viral vectors. Acta Biomater., 7, 3868–76, 2011. 107. Yunfei, M., Rui, G., Yi, Z., Wei, X., Biao, C., Yuanming, Z., Controlled dual delivery of angiogenin and curcumin by electrospun nanofibers for skin regeneration. Tissue Eng. Part A, 23, 597–608, 2017. 108. Hayenga, J., Copper, A., Bhattari, N., Zhang, M., Incorporation of DNA particles into chitosan nanofibers for tissue regeneration. J. Undergrad. Res. Bioeng., 10, 26–30, 2010. 109. Peckys, D.B., Melechko, A.V., Simpson, M.L., McKnight, T.E., Immobilization and release strategies for DNA delivery using carbon nanofiber arrays and self-assembled monolayers. Nanotechnology, 20, 10, 2009. 110. Castro-Smirnov, F.A., Ayache, J., Bertrand, J.R., Dardillac, E., LeCam, E., Pietrement, O., Aranda, P., Ruiz-Hitzky, E., Lopez, B.S., Cellular uptake pathways of sepiolite nanofibers and DNA transfection improvement. Sci. Rep., 7, 5586, 2017. 111. Ignatova, M., Rashkov, I., Manolova, N., Drug-loaded electrospun materials in wound-dressing applications and in local cancer treatment. Expert Opin. Drug Deliv., 10, 469–83, 2013.

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11 Application of Electrospun Materials in Bioinspired Systems Anca Filimon1*, Adina Maria Dobos1, Oana Dumbrava2 and Adriana Popa3 “Petru Poni” Institute of Macromolecular Chemistry, Iasi, Romania Biology Faculty, “Alexandru Ioan Cuza” University of Iasi, Iasi, Romania 3 “Coriolan Drăgulescu” Institute of Chemistry, Timisoara, Romania 1

2

Abstract

Development of a new generation of electrospun polymeric materials with tailored properties for bioinspired systems represents an important goal of the scientific research community. Scaffolds, cells, growth factors, and their interrelation in microenvironment are also the major concerns in the bioinspired systems engineering. The natural polymers, as cellulose/derivative cellulose and chitosan promise to become a such generation of nanofibrous scaffolds with attractive properties associated with biomedical applications. Therefore, the electrospinning is a promising and versatile strategic way addressed to fabricate fibrous polymeric scaffolds for bioinspired systems. In this context, taking into account the high possibility of these new fibrous materials using in the medical field, this chapter briefly presents information related to the natural polymers and how they can be processed in order to obtain special properties required by target applications. The role of the classical and modern methods in the development of new electrospun materials is studied in correlation with processes underlying their origin but also with the way in which they can be functionalized or adapted to become suitable in bioinspired applications. Keywords:  Cellulose, chitosan, electrospun nanofibrous scaffolds, bioinspired systems, biomedical applications

*Corresponding author: [email protected] Inamuddin, Rajender Boddula, Mohd Imran Ahamed and Abdullah M. Asiri (eds.) Electrospun Materials and Their Allied Applications, (307–350) © 2020 Scrivener Publishing LLC

307

308  Electrospun Materials and Their Allied Applications

11.1 Introduction In recent years, there was an increase in the need for the development of materials/systems designed to accomplish multi-performance and multifunction in a bioinspired integrated system [1]. In this respect, the evolution of medical therapy, in order to treat diseases that compromise the normal functions of the human body, or even for the aesthetic, is achieved when the present needs and challenges are met. The fundamental concept underlying the sustainable medical treatment, by the development of a new “construct,” relies on a professional designing and an understanding of the origin and physicochemical properties of the polymeric materials. Additionally, once designed, it must be stable and with high potential for use in obtaining of the valuable products, that is, biocompatible and biodegradable materials. The natural polymers meet some of these criteria, namely exhibit a better biocompatibility, biodegradability, lower immunogenicity than synthetic polymers, tunable mechanical strength, and can provide high efficiency of drug loading [2]. Additionally, the natural polymers provide an excellent matrix for cell adhesion and infiltration. For example, c­ ollagen/gelatin (a kind of denatured collagen) represents one of the main components of the Natural Extracellular Matrix (ECM) and is frequently used as electrospun nanofibrous scaffolds for cell growth, migration, and tissue engineering therapies. Besides the protein-based nanofibrous scaffolds, polysaccharides, such as cellulose, chitosan, dextran, and alginate are also used for the fabrication of electrospun nanofibrous scaffolds and implicitly of biomaterials with various biomedical applications, e.g., regenerative medicine, delivery systems and controlled release of drugs, cosmetics, antibacterial activity, wound dressing, etc. [3–11]. In addition, the use of the natural polymers with the aim of generating nanofibers with well-controlled features and performance for application in bioinspired systems often requires remarkable and combinational qualities. Therefore, it was pursued to obtain and promote the special architectures and functional integration of a natural polymeric material into biological scaffolds that mimic verywell the ECM [12]. Currently, with the increasing of knowledge about concepts such as nanoparticles, nanostructures and scaffolds preparation, the most successful process for preparation has become the electrospinning (see Figure 11.1). This method is preferred because the nanofibers produced possess a large surface area, which helps cell growth and generates a multitude of inter- and/or intra pores [13].

Electrospun Materials in Bioinspired Systems  309 Heart Valves/ Blood Vessels Neural Tissue

Biosensors/ Diagnostics

BIOINPIRED SYSTEMS

Natural nanofibers scaffold

Bone

Cosmetics

Skin/ Wound Dressing Antibacterial Membranes

Muscle Fibers ELECTROSPINNING DEVICE

Pharmaceutical Industy

Cartilage

Figure 11.1  Development of the bioinspired systems by processing of natural polymers solutions using electrospinning, an alternative and innovative technology.

The ability to reconstruct the artificially functional tissues or organs, construction of the biocompatible prostheses, blood vessels and valves, and also cosmetics (e.g., face masks), as well as drug delivery applications [3–11] (Figure 11.1), using fiber-based materials, has been recognized as an advanced technology that allows the control of the nanoscale morphologies and adjusts the bio-chemical properties of nanofibrous biomaterials. The final goal of the new nanofibrous scaffold designed, is the achievement of an ideal structure that can replace the natural ECM so that the host cells repopulate and resynthesize a new natural matrix. Taking into account the high possibility of these new fibrous materials using in the medical field, this chapter briefly presents information related to most commonly natural polymers, e.g., cellulose and chitosan and their significant impact on bioinspired systems.

11.2 Composite Materials Based on Cellulosic Nanofibers Recently, a new area of research has been focused on obtaining of composite materials based on cellulosic macro- and nanofibers that have been used as a reinforced for increasing the properties as stiffness, strength, and thermal stability. Such materials can find applicability in various domains, especially in the biomedical field as result of low density, nonabrasive, low cost, biocompatibility, and biodegradable properties [14–16].

310  Electrospun Materials and Their Allied Applications

11.2.1 Processing of Cellulose-Based Materials Typically, the cellulose electrospinning is influenced by some factors as solvents, solution concentrations, distance between the electrode and collector and applied voltage [17]. Thus, are cases where, when the electrospinning conditions are not suitable, the fibers obtained present some disadvantages. For example, the volatile solvents make the electrospinning process difficult because the needle tip may be blocked as a result of their rapid evaporation. In this context, although the cellulose acetate is soluble in a wide range of solvents as chloroform, N,N-dimethylformamide (DMF), 2-methoxyethanol (2Me), however the electrospinning of the cellulose acetate solution obtained in acetone (Ac) leads to some beads as is shown in Figure 11.2. These inconveniences are usually eliminated by using a binary system containing solvents with high volatility differences in different mixing ratios such as DMF/Ac or acetone/dimethylacetamide (Ac/DMAc) [18]. Although the characteristics of the cellulosic fibers namely diameter or length can be tailored in function of the above-mentioned factors, for the development of the composites with enhanced mechanical features and environmental performance increasing of their hydrophobicity is absolutely necessary. Thus, a series of physical and chemical processes as silylation, mercerization, and other surface chemical modifications are adopted. Most of these composite materials based on cellulose fibers find their applicability in the biomedical field as biosensors components, in drug release, wound dressing or tissue engineering.

11.2.2 Structure–Property–Biological Activity Relationship 11.2.2.1 Biosensors Based on Cellulosic Fibers Baharifar and collaborators have presented in their work the possibility of cellulose acetate fibers and corresponding nanocomposite to be used (a)

(b)

2µm

2µm

Figure 11.2  SEM images of CA electrospun fiber containing beads obtained in Ac (a) and of smooth CA electrospun fibers obtained in mixture of Ac/DMAc (b).

Electrospun Materials in Bioinspired Systems  311 in obtaining of the advanced sensing systems namely optical/colorimetric, and electrochemical sensors and biosensors [19]. For the quantitative evaluation of the desired material are used biosensors and the changes of some UV-VIS spectra are analyzed. The most important aspects of the colorimetric method, technique most often used in quantifying the material concentration, consist in detection of the chromatic substrate of VIS spectra and determination of Λmax or linear region. In this case the cellulose acetate is utilized as membranes for the enzymes, antibodies, and aptamers attachment, its efficiency being raised by using the crosslinking agents or treatment with solution of sodium periodate, ethylenediamine, and glutaraldehyde respectively. These methods of membranes activating will facilitate the immobilization of cholesterol oxidase according to studies from literature [20]. Colorimetric uranyl detection sensors were processed by doping the CA nanofibers with 2-(5-Bromo-2-pyridylazo)-5-(diethylamino) phenol [Br-PADAP] [21]. The use of Br-PADAP as chromogenic and chelating agent suggests the presence of uranyl through a transition from yellow to purple. The naked eye cannot identify the color variations near 50 ppm, which represent the limit of uranyl detection; therefore the approach of this technique is most suitable for quantitative determination of uranyl [22]. In Table 11.1 are presented cellulose fiber based biosensors, activation techniques of cellulose fibers for an increased efficiency and applicability domain. Another type of cellulose nanofiber-based optical sensors was created using anionic fluorescent dendrimer (AFD) which through the fluorescence resonance energy transfer (FRET) process allows the detection of the small concentrations of metalloprotein—protein containing metal ions [23]. In this sense, the CA was firstly deacetylated to cellulose for obtaining a porous structure and to intensifying the molecular interactions, and AFD was then encapsulated in the obtained cellulose nanowires. The detection capacity of the proteins was studied by analyzing the extinguishing behavior of cytochrome, hemoglobin, and bovine serum albumin as a function of concentration. This behavior was a consequence of the energy/electron transfer between the iron-containing proteins and fluorescent core. The fluorescence images of the anionic fluorescent dendrimer encapsulated in the electrospun CA nanofibers show an obvious fluorescence emissions and uniform dispersion of fluorophores in cellulose before the quenching process which highlights the biosensor’s performance. Also, Ren and coworkers have realized an amperometric biosensor based on CA fibers and glutaraldehyde—used as a cross-linking agent— for immobilization of glucose oxidase [25], while Gilmartin et al. have

312  Electrospun Materials and Their Allied Applications Table 11.1  Biosensors based on cellulose fibers, activation techniques of cellulosic fibers and biomedical applications. Analysis method

Immobilized molecules

Optical/ colorimetric biosensors

Electrochemical biosensors

Analyte

Application

Cholesterol oxidase

Cholesterol

Cholesterol biosensors [20]

CA/Fluorescent dendrimers

Protein

Optical biosensors for detection of protein [23]

Uricase

Uric acid

Amperometric sensor for uric acid [24]

Glucose oxidase/ gold nanorods

Glucose

Glucose biosensors [25]

Laccase

Methyldopa

Biosensor for detection of pharmaceutical samples [26]

Alcohol dehydrogenase

Ethanol

Ethanol sensors [27]

processed biosensor for detection of uric acid using cobalt phthalocyanine electrodes coated with CA fibers and immobilized with uricase [24].

11.2.2.2 Delivery Systems and Controlled Release of Drugs Although the cellulose have been used for a long time in obtaining of the pharmaceutical tablets, due to the excellent compaction properties, however many of the researches were focused on the development of new cellulose fiber based systems as delivery carriers for new drugs. Due to the low cost, ease of operation, large surface area, possibility of loading with a high amount of drug as well as of the multiple therapeutic effects, the obtaining of the cellulose nanowires used in controlled drug delivery systems continues to be a challenge for the scientists. Usually, the amount of drug that reaches at the target site of the organism is much smaller than the amount of drug ingested. For this reason, in order to avoid the body exposing to an excess of medications these fibrous systems are approached because of the inherent nanoscale morphological characteristics. Drug-loaded structures ensure the recovery through the cellular differentiation and proliferation

Electrospun Materials in Bioinspired Systems  313 and mimic the native topography, being used both as ingestible tablets and as implants for the controlled release of antibiotics or anti-cancer drugs [6, 28–30]. The literature data have shown that the rate of drug delivery is highly dependent on the amount of drug incorporated, its distribution in nanowires, but also on the diameter of the fibers [31]. Verreck and coworkers have studied the release rate of the drugs loaded into nanofiber membranes of hydroxylpropylmethyl cellulose (HPMC) which have been folded and turned into a gelatin capsule and also of the same membranes in clean condition [31]. They found that the drug release from nanofibers filled in gelatin capsule take place in more than 20 h and from clean nanofiber membranes only after 4 h. The drug release from ethyl cellulose (EC) nanowire obtained through a modified coaxial electrospun method was evaluated by Li and collaborators [32]. They have realized new type of core–shell nanofibers using poly(vinyl pyrrolidone) (PVP) and EC as matrices and two syringe pumps for driving the shell and core fluids independently. The core–shell structure was then loaded with quercetin. The in vitro release has shown that the EC fibers doped with quercetin have a sustained release due to the low water solubility of quercetin and insolubility of EC. On the other hand, the sample of core–shell type with 1.0%, 2.0%, 3.0% (w/v) sheath drug content have indicated an initial release of 31.7%, 47.2%, and 56.8%, when are situated in the dissolution medium for 5 min. These proportions are slightly higher than the drug content from the fibers shells, so it is assumed that this release is mainly from the outer structure of the fiber. Thus, the researchers concluded that PVP, which forms the fiber shell, released very quickly the drug loaded in the solution, while EC—which constitute the core fiber— ensured the sustained release. In the context of the same research directions Hu and collaborators [33] have obtained by electrospinning process, fibers from poly(N-isopropylacrylamide) (PNIPAAm), EC, and their blend in different mixing ratio and they loaded with ketoprofen (KET). They have studied the thermoresponsive drug delivery of the systems and data obtained were discussed in function on fibers different surface wettability. According to some studies [34] the drug delivery occurs faster from a hydrophilic carrier than from a hydrophobic one. In Hu’s studies was found that at 25°C temperature PNIPAAm-containing fibers have a hydrophilic behavior, while EC materials are hydrophobic. Thus, the PNIPAAm/ EC fibers doped with KET present a drug release rate between the two extremes. At a temperature of 37°C the PNIPAAm-containing fibers have presented a drug release rate of 40% from the loaded drug, in the first 5 h of the dissolution, while a slow release can be observed for samples with higher content of EC. In the case of ethyl cellulose, the differences between

314  Electrospun Materials and Their Allied Applications the drug release rates at the two temperatures are not very consistent, which suggests that the ethyl cellulose is not thermos-responsive but can be used for sustained drug release. Generally, the above mentioned properties make fibers suitable for delivery of the pharmaceutical excipients, both by rapid dissolution and controlled release, tissue recovery and wound healing. In this context, in the literature, various classes of drugs that can be loaded into cellulose fibers and used in different therapies have been mentioned (Table 11.2) [5]. Anti-inflammatory drugs—are used to reduce inflammation and swelling and have an analgesic and fever-reducing effect. These drugs were embedded in cellulosic fibers because many of them are poorly soluble in water and their effect is expected to occur in the shortest time possible [35]. Table 11.2  Celluloses used in obtaining of the controlled drug delivery systems, the chemical structure, and active substance contained, respectively. Cellulose derivative

Chemical structure

Ethyl cellulose

Loaded drug Ketoprofen

OR

RO O

O OR

n

R=H or CH2CH3

Cellulose acetate

Ketoprofen

O O

O O

HO

O

O

O

O

O O

O O

Hydroxypropyl methyl cellulose

or CH2CH(OH)CH3

O OR

n

RO

OR RO

OO

O R

OR

* or

O

* OR

Tenofovir disoproxil fumarate

O OR

RO

Diphenhydramine

R=H or CH3

OR

RO O

Cellulose acetate phthalate

n

O OH

Electrospun Materials in Bioinspired Systems  315 Um-I-Zahra and coworkers [36] have obtained nanofibers from cellulose acetate (CA), EC and PVP, they loaded them with Ketoprofen (KETO) and have analyzed in vitro their drug release profiles. The release of ketoprofen in saline solution with a pH of 7.4 at 25°C occurs much faster from PVP nanofibers, followed by that from CA and EC. Thus, they have concluded that the hydrophilic nanofibers have a higher drug loading and a much faster release capacity than the hydrophobic ones, and that the hydrophilic polymers are more suitable for obtaining controlled drug delivery systems. Anti-bacterial drugs—are represented by compounds such as antibiotics, antiviral, antifungals, or antiparasitic acting against bacteria, viruses, fungi, or parasites [37, 38]. One of the studies aimed at incorporating amoxicillin (AMOX) into CA/PVP composite fibers was performed by Castillo-Ortega and collaborators [39]. They have demonstrated that tensile strength of the CA/ PVP–amoxycillin/CA fiber forming the fibrous composite membrane was not affected by the AMOX presence. Moreover the release profile of the antibiotic appears to be managed by a diffusion mechanism and the new obtained system is suitable for dental or cutaneous infections treatment. Also, to prevent infection with human immunodeficiency virus (HIV) cellulose acetate phthalate fibers containing tenofovir disoproxil fumarate were developed [40]. It was found that the CAP fibers that are stable in vaginal fluid (with pH lower than 4.5) dissolves immediately with the human semen addition (pH between 7.4 and 8.4) releasing the encapsulated drug. Depending on pH, the antiviral drugs released as well as the dissolved cellulose acetate phthalate, exhibit intrinsic antimicrobial activity neutralizing the HIV virus. From the literature data it was found that the cellulose fibers most often used as drug delivery systems are those from CA. Cellulose acetate antagonizes adenosine receptors, prevents insomnia, and increases attention. They are often used in the treatment of bronchopulmonary dysplasia in infants, of hypotension but also to relieve headaches [41–43]. In the treatment of the individuals suffering of malnutrition, drugs obtained from cellulose acetate fibers containing riboflavin (RFN) were used in order to combat the protein depletion and infections that they cause. For a faster dissolution and a faster effect of the drug, systems that contain poly(vinyl alcohol) (PVA) were also created. The researchers found that new PVA/CA and PVA/RFN composites present almost the same dissolution time and that, for a faster drug delivery, in 60 s, the percentage of CA should be 100% and RFN up to 40% [41].

316  Electrospun Materials and Their Allied Applications

11.2.2.3 Wound Dressing Another remarkable applicability in the biomedical field of the cellulose derivatives (mainly of bacterial cellulose, (BC)) is the wounds treatment. Wound healing is a complex process that involves several stages. After the skin and blood vessels, implicitly have been damaged, in the affected place platelets gather causing hemostasis. These, through the chemo­tactic centers activate the fibrin and fibroplasts favoring the attachment of the macrophages—one of the three phagocytic cells of the immune system. The tissue inflammation occurs as soon as the bleeding stops and the attached macrophages will start to remove the dead cells, the new tissue begin to recover and the respective area to vascularize. So, the new tissue begins to grow, the epithelial cells covering the wound as can be observed from Figures 11.3 and 11.4 [6, 44, 45]. The main dressing role is to absorb the fluid secreted by the wound as well as to remove the wound after epithelialization. The existing dressings fix by the wound causing pain when they are removed, so that in the last period, emphasis has been placed on obtaining of new bandages that will not be fixed by the wound and their removal will not cause additional welding. In the literature has been presented the possibility of bacterial cellulose fibers (BC) to be used in obtaining and marketing of wound treatment [46–48]. Cellulose dressings as opposed to synthetic ones represent a very favorable environment for cell growth and proliferation (see Figure 11.4).

Provides scaffold for cell growth Forms barrier against infection Encourages natural blood clotting

Minimizes scarring Strengthens new tissue

Provides protein for healling Absords fluids from inflammation Blocks nerve endings to reduce pain

Figure 11.3  Schematic representation of the desired characteristics for wound healing. Reproduced with permission from Ref. [6]. Copyright 2018 PubMed Central.

Electrospun Materials in Bioinspired Systems  317

(a)

(b)

Figure 11.4  (a) Cellulose fiber dressings. (b) For better visualization, (a) of figure was enlarged. Reproduced with permission from Ref. [48]. Copyright 2016 Elsevier.

Julia Pajorova in her work has synthesized medical dressings by incorporating the fibrin and dermal fibroblasts into carboxymethyl cellulose (CMC) fibers [4]. The role of fibrin is to facilitate colonization with dermal fibroblasts of the material. It has been found that fibrin which fills the voids of CMC fibers is a better support for cell growth than fibrin deposited on cellulose fibers. Thus, through this study, the researchers intended to develop a new type of dressing that delivers to the dermal tissue dermal fibroblasts that promotes rapid healing of deep wounds. Also, Barnea and collaborators [49] have showed that silver-impregnated carboxymethyl cellulose (CMC) dressings could be used for heal wounds and ulcers, while Upton and coworkers [50] have demonstrated that although are efficient, dressings from CMC require a replacement as often possible which cause a discomfort for the patient. Another cellulose derivative often used for wounds treatment is cellulose acetate (CA). In this sense some researchers obtained electrospun cellulose acetate nanofibers and have loaded with vitamin A acid and Vitamin E that have a transdermal and dermal therapeutic effect [51–53].

11.2.2.4 Tissue Engineering Recently, in advanced medicine, emphasis has been placed on obtaining biomaterials (matrices/scaffolds) with functions and anatomical structure that mimic very well some human organs. The development of the cellulose nanowires and new biomaterials, respectively, is the appropriate way to obtain a structure that favors the growth, migration, and differentiation of the cells needed to restore damaged tissues or organs. Most suitable for this type of application are nanofiber-based biomaterials (cellulose fibers) that, unlike the one containing large diameter fibers, mimic the native

318  Electrospun Materials and Their Allied Applications structure much better. In this context, in literature, have been mentioned studies regarding the potential applications of celluloses fibers in the engineering of bone, neural, cartilaginous, hepatic, and vascular tissues [54].

11.2.2.4.1 Bone Tissue

Due to the possibility to be adapted by structural modeling, celluloses can be used in the biomimetrice constructions applied to the bone environment [55]. Generally, the hydrogels have low resistance to the physical stress manifested on the bones, and from this reason, cellulose was used as reinforcement. As in literature was mentioned the most widely used method to create cellulose-based nanocomposites with role of bone tissue replacement is electrospinning [56]. The bone tissue has an extremely porous structure and, thus the cellulose fibers obtained must be subjected to special treatments that give them the desired porosity. In this sense, for example, Rodríguez and coworkers, which have realized nanofibrous cellulose acetate (CA) scaffolds by electrospinning have used a computer-­ assisted technique to create pores with diameter between 50 and 300 μm, without affecting the surrounding area of fibers as is shown in Figure 11.5. Also, to make easier the osteoblast fixation and these porous fibrous, structures to be used as bone tissue, they were subsequently mineralized [57]. The literature data show that, fibrous polymeric structures based on cellulose acetate and hydroxyapatite present a good biocompatibility, porosity and values of compression module of 6–330 MPa, and compressive strength of 0.1–12 MPa which means that they can mimic bone tissue very well [58]. Another study performed in order to create new fibrous cellulose structures that can replace the bone tissue was performed by Chahal and collaborators. They have obtained the HEC/PVA nanofibers by electrospunn and they covered with apatite by immersing in a simulated body fluid for different periods of time. The researcher’s studies (Scanning electron (a)

(b)

Figure 11.5  Electrospun cellulose acetate fiber subjected to computer-assisted technique for pore creation. Reproduced with permission from Ref. [57]. Copyright 2014 Elsevier.

Electrospun Materials in Bioinspired Systems  319 microscope (SEM), Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC)) have demonstrated that these apatite coated nanofibrous cellulose scaffolds could be proper for bone tissues [59]. Researches in this direction are numerous which proves that the bone implants becomes a basic concern of the scientists who have tried to replace the metal and ceramic implants with those obtained from cellulose derivatives.

11.2.2.4.2 Cartilage Tissue

The information obtained from the literature has shown that, due to the high water retention capacity and high resistance, the bacterial nanocellulose (BNC) fibers were used for auricular cartilage reconstruction. With a content of 17% bacterial nanocellulose is proper for obtaining resorbable biomaterials with mechanical strength and host tissue response which can mimic very well the auricular cartilage (see Figure 11.6) [60, 61]. Naseri and collaborators [62] were realized a study concerning the obtaining of the cellulose biomaterials with properties that allow them to be used as cartilages. Authors have obtained porous scaffolds with pore diameters of 75–200 μm, using freeze-dried cellulose nanofibers that they stabilized with a gelatin and chitosan matrix. The values obtained for the compression module of 10–60 kPa, calculated in phosphate buffer saline, at 37°C, along with properties as high porosity, great absorption of the buffer solution, cytocompatibility with the chondrocytes make these

(a)

(b)

Figure 11.6  (a) Human ear scaffolds based on cellulose; (b) 3D scaffolds printed with nanofibrillated cellulose. Both scaffolds were seeded with human cells. Reproduced with permission from Ref. [61]. Copyright 2019 PubMed Central.

320  Electrospun Materials and Their Allied Applications materials favorable for cell attachment and extracellular matrix (ECM) production. Martínez and coworkers have obtained scaffolds based on bacterial nanocellulose (BNC) and alginate and they proved that this support is non-toxic and useful in growth and proliferation of human nasoseptal chondrocytes [63]. In order to obtain articular cartilage, the scaffolds based on bacterial nanocellulose fibers were laser perforated and cultured with chondrocytes [64].

11.2.2.4.3 Liver Tissues

In order to solve the liver problems was followed the obtaining of a 3D culture of liver cells instead of the 2D one. Thus, 3D scaffolds were obtained based on cellulose nanofibers and was demonstrated that the new biomaterials favors the good development and functioning of the human liver cells of HepaRG type which were taken from a liver tumor of a patient infected with hepatitis C virus. Concretely, the HepaRG cells have generated a 3D multicellular spheroidal structures with apicobasal polarity and functional structures similar to bile canaliculi [65]. Also for the removal of the metabolic problems, the creation of 3D scaffolds in adipose tissue engineering was proposed to obtain. In this case the bacterial cellulose nanofibers were cross-linked using alginate, the porous structure being obtained through freeze dried process. The new scaffolds were seeded with C3H10T1/2 mesenchymal cells, which were incubated in an adiopogenic medium, and the data obtained have shown a high content of cells with markers of adipogenic cell differentiation. Thus, was demonstrated that these fibrous cellulose scaffolds can be used not only in adipose tissue engineering but also for tumor removal or reconstruction treatments in the case of trauma [66].

11.2.2.4.4 Neural Applications

Physical properties such as resistance and durability, as well as the chemical features related to the chemical structure of the cellulose/cellulose derivatives that allow them an easy processability, also make these polymers suitable for 3D nerve cell proliferation and differentiation [67]. Innala and collaborators have specified in their work that the chemical modification of the cellulose nanofibers by protein coating increases the integrin-based attachment and promotes cell-scaffolds interactions. In this sense they created bacterial cellulose nanowires which were coated with Gluconacetobacter xylinus (G. xylinus) and have shown that the fibrous network has good mechanical properties, with a water content of 99% and possibility to be modeled in 3D structures by cultivation in different forms. On the other hand, in order to increase the adhesion of nerve cells to the fibrous cellulose

Electrospun Materials in Bioinspired Systems  321 scaffold, the researchers resorted to the modification of the nanowire surface and its positive charge by treatment with trimethyl ammonium beta-hydroxypropyl (TMAHP) and collagen type I coating. The scientists have shown through SEM technique and the 3-(4,5-dimethyl­thiazol-2-yl)5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) (MTS) assay that the nerve cells used (SH-SY5Y neuroblastoma cells) attach, grow and differentiate on the formed cellulose scaffolds. Finally, they have tested functional action potentials and have demonstrated the existence of mature neurons suggesting that this 3D model based on BNC scaffolds can be used to investigate neurodegenerative diseases and to find new treatments more efficient. Usually, the nerve tissue engineering is facing with some problems of electrical stimulation and, for this reason, it is intended to obtain the 3-D nano biomaterials electroactive and flexible. Thus, in order to eliminate this inconvenience, new fibrous cellulose scaffolds, coated with poly (3,4-ethylenedioxythiophene) (PEDOT) and multi-walled carbon nanotubes, as conductive materials, were created. These materials present properties as porosity, biocompatibility, mechanical features, and electrical conductivity which accelerate the cell growth and differentiation, thus helping the repair of tissue damaged by stroke [68].

11.2.2.4.5 Blood Vessels

Lately, in vascular surgery, was a need for new polymeric biomaterials that could be used as grafts for very thin blood vessels, instead of grafting vessels already existing and constituted from expanded polytetrafluoroethylene (ePTFE) and poly(ethylene terephthalate) (PET) as result of their thrombosis problems [69]. Data from literature show that the bacterial cellulose as a result of high purity, non-toxicity and tensile strength has a great potential to be used in obtaining of ultrafine fibrous network, respectively artificial blood vessels [70]. The researchers have demonstrated that the bacterial cellulose tubes which were obtained using cylinder glass molds are capable of serving as artificial blood vessels for replacement of atherosclerotic coronaries [71]. Also, the studies have shown that they can be used with maximum efficiency as implant material for carotid artery maintenance. Schumann and collaborators have implanted the new obtained material into a carotid artery defect of a mouse, for one year, and have found that an ingrowth of the active fibroblasts occurs and the homogeneity and intimate attachment correspond to the recipient blood vessel [72]. In addition, they have replaced the carotid artery of a pig, and, after three month, the grafts were removed and macro and microscopically studied.

322  Electrospun Materials and Their Allied Applications The results have shown that the bacterial cellulose tubes do not cause any inflammation and a complete endothelialization occurs.

11.2.2.4.6 Urethral Reconstruction

As shown in the literature, fibrous, porous 3D structures of bacterial cellulose have also been used for reconstruction of the urethra [3, 73]. For urethral regeneration it is necessary to take into account that this 3D scaffold must provide certain environmental needs of the different cell types and also to ensure the function of diffusion barrier and structural integrity. The researchers have approached several techniques to create such biomaterials, namely the 3D scaffolds were seeded with rabbit lingual keratinocytes, or were the basis for the deposition of a microporous silk fibroin network. For the latter case, the two layers were inoculated with keratinocytes and smooth muscle cells from the lingual tissue of the dog. It was found that the new stratified structure combines the advantages characteristic for both compounds, and that the presence of fibroin leads to the obtaining of pores with diameters between 210.2±117.8 μm, which allow the incorporation of cells, their growth and proliferation. Electron microscopy analyzes have shown that the muscle cells were uniform distributed in the scaffold pores and fixed on silk fibroin, while the lingual keratinocytes were grouped on the cellulose nanofilaments. Thus, the properties as biocompatibility and long-term mechanical strength (suture-retention strength of 1.37±0.14 N) supported the idea of using these scaffolds based on bacterial cellulose and silk fibroin for implantation. It is assumed that these new types of biomaterials could also be used to replace the esophagus or intestine.

11.3 Chitosan Nanofibrous Scaffolds 11.3.1 Overview on Obtained Chitosan From Bio-Waste Source Chitosan is a natural compound present in some living organisms [74]. The main source of commercial chitosan (CS) is the chitin, the second most abundant biopolymer found in nature after cellulose (a plant fiber). This product is synthesized by different species, such as the green algae, fungi, cuticles of insects and arachnids, and in the exoskeleton of crustaceans (shrimp, prawn, crab, and lobster). Generally, the crustacean shells consist of protein (20–40%), calcium and magnesium carbonate (20–50%), chitin (15–40%), and other minor constituents [75]. Although the shrimp head

Electrospun Materials in Bioinspired Systems  323 and other leather materials are considered bio-waste, they can be transformed into useful products such as CS. Chitosan is synthetized by partial acetylation reaction of chitin (Figure  11.7) carry out by the chemical or enzymatic hydrolysis. This compound is a modified carbohydrate polymer composed of β-(1,4)linked glucosamine units (2-amino-2-deoxy-β-D-glucopyranose) and of N-acetylglucosamine units (2-acetamino-2-deoxy-β-D-glucopyranose). The difference between chitosan and chitin consists in the presence of amino (–NH2) groups from the chitosan structure (see Figure 11.7). Depending on the source of origin, various isolation techniques are addressed [76, 77], the vast majority being based on the protein extraction and inorganic matter removal, and others consisting in bleaching by Shrimp waste

washing drying grinding

Deproteination

Shellfish

1M NaOH, 1:10 (w/v) for 24 hr

CH3

Demineralization

O

O HO

1M HC1, 1:10 (w/y) for 24hr at room temp

NH

Deacetylation CHITIN

HO O

O

NH O OH

CH3

60% NaOH solution boild for 2 hours

n

CHITIN

Decolourisation Enzymatic extraction

O

OH

Deacetylation

Fungi

O HO

OH O NH2

HO O

NH2 O OH

CHITOSAN

Figure 11.7  Schematic illustration of processes performed for extraction of the chitosan from bio-waste.

n

324  Electrospun Materials and Their Allied Applications solvent extraction or remaining pigments oxidation [77]. As alternative, the ­enzymatic/microbiological treatment have been tested with success [78] but besides long time-consuming, usually leaves 1–7% of residual protein [79]. Generally, the chitosan isolation assumes the crustacean shells processing following three main steps, namely deproteinization, demineralization (decalcification)/decolorization, and deacetylation (Figure 11.7). 1. Deproteinization: Initially, dried shrimp wastes are treated with NaOH dilute solution at ambient temperature (28 ±2°C) for 24 h to remove the protein. The separation of alkali insoluble fraction is achieved by centrifugation and repeated washing with distilled water till the pH dropped to neutral. 2. Demineralization: Deproteinized shells are usually treated with HCl dilute solutions at room temperature for 24 h to remove minerals. Subsequently, separated acid-insoluble fraction is washed with distilled water until it is absolutely free of acid, then it is kept for drying at 40°C to produce chitin, which presents a slightly pinkish coloration. Before preparing chitosan, the decolorization process it must be done. The HCl concentration and treatment time depend on the source of chitin, however, the high temperatures must be avoided to prevent polymer degradation. Literature indicates that the degradation can be prevented using the ethylenediamine­ tetraacetic acid (EDTA) [80] or ionic liquid extraction [81, 82]. Decolorization the obtained chitin is soaked in potassium permanganate aqueous solutions for 30 min, followed by oxalic acid aqueous solution for 30 min to 2 h. 3. Deacetylation: The decolorized chitin is subjected to deacetylation process to convert into chitosan. This reaction is realized by hydrolysis of the acetamide groups with concentrated NaOH or KOH solutions (40–60%) at temperatures exceeding 100°C. The alkali fraction found in chitosan is separated by centrifugation and excess alkali are drained off and further washed with distilled water till pH reaches to neutral. The resulting chitosan is dried at 40°C and stored at room temperature. The acetylation degree of chitosan, which is given by the number of acetylglucosamine units along the polymer main chain, is highly dependent on the deacetylation conditions. Chitosan is a biodegradable polymer possessing positive ions which have the ability to chemically bind with negatively charged of lipids, cholesterol, metal ions, proteins, and macromolecules [83]. In this respect, due to these versatility and physicochemical properties [76], including its solid-state structure, conformation in solution, the ability to organize in different forms (hydrogels [84], membranes [85], nanofibers [86, 87], micro/nanoparticles [88, 89], scaffolds [90], and sponges [91]), make chitosan to become an interesting polymer for research. Consequently, in

Electrospun Materials in Bioinspired Systems  325 cluster of chitosan nanofibers

exoskeleton of crustacean

ordered structure

Figure 11.8  Schematic presentation of the chitosan nanofibers obtained from exoskeleton of crustaceans with hierarchical structure consisting of nanofibers.

the solid state the rigid crystallites form, due to the regularly arranged hydroxyl and amino groups at the equatorial positions in the β-(1,4)linked D-glucosamine repeating units, while in solution, depending on the chitosan concentration, the hydrogen bonding leads to the nanofibers formation [92, 93] (see Figure 11.8). Such characteristics of the chitosan prefigure the possibility of processing with successful by electrospinning of this material. Because of they have specific properties, e.g., high specific surface area and porosity, the nanofibers are ideal candidates with high potential for application in areas, as wound treatment, drug carriers, tissue regeneration, dental materials, cosmetics and prostheses [94–96].

11.3.2 Specific Applications of Chitosan Nanofibers in Bio Inspired Systems Different polymeric materials processed in the form of tubes, wires, rods, spheres, and fibers have been used in the design of the supramolecular structures with various applications in technological field. For example, in the medical field, it is well-known that almost all tissues and organs, i.e., skin, cartilage, and bone, etc., show a kind of similarity to nanosize fibrous structures. Thus, the electrospun materials usage, in particular of chitosan, in bio-inspired systems led to an extension of the potential applications.

11.3.2.1 Wound Dressing Wound treatment is the most representative bio-applications of the chitin and chitosan. These natural polymers are found in different forms of

326  Electrospun Materials and Their Allied Applications pharmacological products as hydrogels, membranes, fibers, and sponges which are used for wound healing and were extensively studied [95]. As results of their good features, such as porosity, permeation, and high surface area, chitin/chitosan based nanofibers have been widely used. These characteristics favored the hemostasis, cell respiration, moisture retention, skin regeneration, and removal of exudates [97]. Chitosan possess countless biological properties, like the biocompatibility, environmentally friendly, non-toxicity, hemostatic, antioxidative, antifungal, and antibacterial actions; the last ones are very important in the wound healing process [98–100]. The species of target microorganisms, environmental conditions, molecular weight, degree of deacetylation and the type of derivative are the main factors which have an effect on the antimicrobial properties of chitosan. Thus, owing to capacity to stimulate hemostasis and accelerate the wound healing rate, the chitosan is widely used in wound dressing development [7, 101]. It was observed that chitosan generates repulsive interactions between positively charged groups, making difficult its electrospinnability due to its ionic polyelectrolytes in acid solution [102, 103]. In order to overcome the electrospinnability difficulties of the chitosan can be used additives (­natural/synthetic polymers) that facilitate the fiber forming [104, 105]. In a study carried out by Chen et al. [106], nanofibers with a high wound healing efficiency in vivo were obtained by electrospinning, using chitosan, collagen, and polyethylene oxide. Chitosan and polyethylene oxide electrospun nanofibers cause the membranes destruction when interacting with negatively charged bacterial cell wall, leading to an expulsion of intracellular components [107]. An increase in the efficiency of wound healing in vivo, a re-epithelialization and tissue restoration, as well as collagen deposition, were noted in the case of the composite nanofiber scaffolds obtained from chitosan and polyethylene oxide [106]. Furthermore, the in vitro testing of the fibrous scaffolds from chitosan and polyethylene oxide, attests their non-toxicity and compatibility with adipose tissue stem cells [108]. In the work of Prasad and collaborators [109], the chitosan and polycaprolactone were used in order to produce the blended electrospun fibrous mat. In this way it was obtained a good adhesion and multiplication of the human keratinocytes in vitro. In a study carried out by Majd et al. [110], was reported a notable decrease in the length of the epidermis/­dermis area in case of streptozotocine-induced diabetic rats, using dressings obtained from chitosan/polyvinyl alcohol electrospun nanofibers. Another application of nanofibrous scaffolds based on chitosan could be as drug carriers, in order to accelerate the wound healing process with the help of the delivered antibacterial, anti-inflammatory, and

Electrospun Materials in Bioinspired Systems  327 antioxidant agents [8, 111–113]. Chitosan fibers have excellent porosity and drug-­carrying ability. In order to produce dressings they can be electrospun along with the natural/synthetic polymers, namely polyvinyl alcohol (PVA), silk fibroin (SF), poly(L-alanine) (PLLA) [114, 115]. For example, the antimicrobial assays revealed that chitosan and silk fibroin nanofibers with different ratios exhibited effective biocidal action against Escherichia coli; as the concentration of chitosan increased, the antibacterial activity of the fabricated nanofibers increased [116]. Instead, chitosan/ sericin composite nanofibers exhibited a good antimicrobial activity against both Gram-positive bacteria (Bacillus subtilis) and Gram-negative bacteria (Escherichia coli) [117]. Due to the higher surface area and small pore size of thinner fibers, nanofibers produced from cyanoethyl chitosan possess an effective antimicrobial activity against several Gram-negative and Gram-positive bacteria [118]. Moreover, in case of the iminochitosan electrospun in trifluoroacetic acid a similar activity was observed. Thus, fibers with barbed structures and a large surface area, presented efficiency against of microorganisms range [119]. An example of porous antimicrobial mats for wound dressing is the electrospun fiber films which contain silver nanorods. They have the property to inhibit the growth of Escherichia coli [120]. Initially, CS nanofibers with silver nanoparticles (AgNP) were established as composites in wound dressing. Taking into account the tuning surface tension, the diameter of the fiber decreases with the increase in the silver composition [121]. However, there are proposed for wound dressing glutaraldehyde crosslinked mats obtained from dispersions of chitosan-capped AgNP in PVA, collagen–chitosan, silk fibroin, PVA, polyacrylonitrile (PAN), and polyurethane (PU). Miao and coworkers [122] have obtained fibrous scaffolds with antimicrobial activity, based on cellulose modified with lysostaphin, a cell lytic enzyme, for wound healing. They used different methods to associate the lysostaphin to several types of fiber mats [cellulose fiber mats, cellulose/CS fiber mats, cellulose/poly (methyl methacrylate) fiber mats] according to the composition of the electrospun material. Following the results of the antimicrobial tests, a total inhibition of the Staphylococcus aureus culture was noticed. Moreover, the fiber mats are considered a potential candidate for wound dressing due to the low cytotoxicity to keratinocytes cell line [122]. In literature [6, 123] were fabricated the composite nanofibrous mats by mixing PVA with various aqueous salts of chitosan (namely, CS dissolved with hydroxybenzotriazole, thiamine pyrophosphate, and ethylenediamine­ tetraacetic acid individually). The cytotoxicity tests revealed that the

328  Electrospun Materials and Their Allied Applications nano­fibers mats (CS/EDTA/PVA), obtained by mixing of CS with ethylenediaminetetraacetic acid (EDTA) and PVA, are not toxic to human fibroblast cells. Five different wound dressings, namely, gauze (negative control), 30/70 CS/hydroxybenzotriazole (HOBt)/PVA, 30/70 CS/­thiamine pyrophosphate (TPP)/PVA, 30/70 CS/EDTA/PVA nanofiber mats, and commercial antibacterial gauze dressing (positive control), were tested on two wounds placed in near the neck of rats (Figure 11.9). The wound sizes dwindled gradually and reached 2% of the original wound area after 10 days of treatment with different kinds of dressings. Following the treatment with nanofiber mats it was observed that the wounds were dry and smaller than those treated with gauze. According to the high antibacterial activity of the CS/EDTA/PVA nanofiber mats, at 4 days after the operation, this nanofiber mat dressing exhibited a remarkable activity, and in the first week, the 30/70 CS/EDTA/PVA nanofiber mats presented significant wound healing activity [6, 123]. Following the results, it was noticed a high antibacterial activity (against Staphylococcus aureus and Escherichia coli) and wound healing activity in vivo exhibited by the CS/EDTA/PVA nanofibrous mats. Also, the chitosan can be co-electrospun with nanoparticles. For example, it was reported a higher healing properties of a bilayer membrane constituted from chitosan fibers and adipose-derived human extracellular membrane containing nano-titania (TiO2) particles, which was tested

Gauze

30/70 30/70 Commercial 30/70 CS-HOBt/PVA CS-TPP/PVA CS-EDTA/PVA dressing

Day 1

Day 4

Day 7

Day 10

Figure 11.9  The evolution of wound healing at 1, 4, 7, and 10 days after treatment with different wound dressings. Reformulated in accordance with Ref. [6, 123].

Electrospun Materials in Bioinspired Systems  329 on rats [123]. Likewise, electrospun chitosan/poly(ethylene-oxide) (PEO) fibere with nano-silver particles inhibit the growth of two microorganisms implicated in wound infections, Staphylococcus aureus and Escherichia coli [124]. Moreover, it was noticed that electrospun CS/arginine fibers and CS/PVA fibers which contain mafenide acetate presented faster wound healing and antibacterial properties [125]. The last one stopped the growth of Staphylococcus aureus and Pseudomonas aeruginosa [126].

11.3.2.2 Drug Delivery One of the main interests in the medical field is delivering drugs in a feasible physiological manner. The ability of a provided drug to be digested or absorbed by the targeted site is enhanced by its smaller size and a suitable coating material. Using the electrospun nanofibers banks in order to deliver drug to a targeted site is based on the idea that an increase in the surface area of the carrier and the drug itself increases the drug dissolution rate. It had been highlighted, in many reports, that the electrospun nanofibers, as drug delivery system, exhibited numerous advantages [127]. Owing to their various properties the electrospun nanofibers were utilized as drug carriers. These include: (1) large surface area; (2) the easiness to modulate the drug release behavior due to content and structure of the nanofibers; (3) bio-availability of a drug by creating different dosage forms; (4) higher efficiency of drug encapsulation than other nanotechnologies [128]. Until now, different types of therapeutic agents, including anticancer agents, proteins, antibiotics, ribonucleic acid (RNA), deoxyribonucleic acid (DNA) and growth factors have been loaded on nanofibers and used as drug carriers, tissue engineering scaffolds, and wound healing materials [129]. As result of the drug diffusion difficulties, after its release from the nanofibers and polymer damage, it was necessary to consider some factors, like the nanofiber composition, polymers features, modalities of surface modification, as well as the nature of the drug, in order to control the drug release behaviors [128]. The main reason for which the electrospinning technique is widely used in drug delivery and tissue engineering is represented by the diversity offered by this method. Different methods were used in order to prepare the electrospun nanofiber scaffolds, which can act as a nano-cargo carriers and to obtain a controlled and sustained release of a drug at the target site. These include the drug embedding into the nanofibers or drug deposition on their surface [130]. Furthermore, the electrospinning technique exhibited advantages like enhanced therapeutic efficacy, reduced toxicity, and versatility of nanofiber as a carrier. For these

330  Electrospun Materials and Their Allied Applications reasons, the role of nanofiber as a drug delivery system has been extensively studied by many research groups around the world [131]. As a result of tests applied on randomly oriented and aligned poly (­lactic-co-glycolic acid) (PLGA)/CS nanofibers as drug release system, it was noticed that the releases of fenbufen were influenced by the morphology and chitosan concentration from the nanofibers. An increased amount of chitosan led an easier release of the drugs and a higher hydrophilicity of the nanofibers. Furthermore, it was observed that drug release was faster in the case of the aligned PLGA/CS nanofibrous scaffold and that, this type of nanofibrous mats exhibited smaller pore size and higher density. In conclusion, the chitosan concentration, density, and pore size of the nanofibers are the main factors that influence the speed of the drug release [132]. It has been reported [133] that fibrous chitosan scaffolds can be used as delivery media for different kinds of therapeutic agents. Growth factors for bone regeneration can be delivered with the aid of electrospun polycaprolactone (PCL)/CS fibers. Furthermore, a possible mechanism to deliver drugs was noticed in the case of the cellular activities of sheep mesenchymal cells which were stimulated by chitosan fibrous mats impregnated with heparin-bound fibroblast growth factor-2 (FGF-2). Microorganisms such as Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus were inhibited by gentamicin immobilized on liposome and released from chitosan fibers. Scaffolds that can release doxorubicin can be produced by nano graphene-oxide, carbon-based drug carriers, which have also been electrospun along with chitosan/polyethylene oxide (CS/ PEO). The key factor that influences the use of chitosan nanofibers in targeted drug delivery is the amino group which allows cross-linking and ligand attachment [133].

11.3.2.3 Tissue Engineering Tissue engineering is described as an interdisciplinary domain that employs the concepts of engineering and life sciences in order to develop biological substitutes that reestablish preserve or enhance the tissue function. A significant feature of the tissue engineering is represented by the design of polymeric scaffolds which exhibit similar characteristics as native extracellular matrix (ECM) in order to modulate cellular behavior [128]. Two types of extracellular macromolecules, namely proteoglycans and fibrous proteins, are the main components of the natural extracellular matrix (ECM) [92].

Electrospun Materials in Bioinspired Systems  331 The aim of various studies was to identify alternative scaffold materials which possess physicochemical and biological features as those of ECM. The complex, seamless, and three-dimensional (3D) nanofiber scaffolds, which support different kinds of cells to grow into artificial tissues are enable to be produced through the electrospinning technique [92]. Literature reported that nanofibers could serve as scaffolding materials for cell culture and tissue engineering because of their ability to mimic the structure and function of the natural ECM [92]. Due to the fact that the structure of chitin/chitosan nanofibers is very similar to glycosaminoglycans from the ECM, they have been widely applied in tissue engineering. These nanofibers exhibited similar morphological properties to fibrous collagen structures, a major natural ECM component. It was reported that chitin and chitosan nanofibers own a remarkable potential in tissue engineering [92, 128]. In various studied [92, 134, 135] it was shown that the morphology and function of cells grown on ECM are influenced by the size of the material. Thus, Noh et al. [134], who studied the cytocompatibility of chitin nanofibers, noticed that in contrast to chitin microfibers, the chitin nanofibers promote the cell attachment and spreading of normal human keratinocytes and fibroblasts. The cell attachment, growth, and proliferation are provided by favorable parameters, such as the high surface area, 3D features and high surface area to volume ratios of the chitin nanofibers. As a result of the cell studies conducted on fibrous mats prepared from chitin/­polyglycolic acid and chitin/silk fibroin (SF), it was found that normal human epidermal fibroblasts and normal human epidermal keratinocytes had the highest spreading rates on fibrous mats prepared from chitin/SF [92]. Feng et al. [136, 137] showed that the bioactivity and mechanical stability of primary hepatocytes in vitro were improved by achievement of galactosylated chitosan (GC) nanofibers with surface-galactose ligands. GC nanofibrous scaffolds can be used as ECM for hepatocytes owning to their slow degradation and suitable mechanical properties. GC-based nanofibrous scaffolds could be useful for tissue engineering of liver regeneration and bioartificial liver-assist devices due to the fact that Hepatocytes cultured on this type of nanofibers presents excellent bioactivity with the ability to maintain the liver functions through albumin secretions, urea synthesis and cytochrome P-450 enzyme. In a study conducted by Tchemtchoua et al. [138], it was shown that a developed 3D chitosan dressing, by stimulating migration, invasion, and proliferation of the relevant cutaneous resident cells, would shorten the healing time of skin wounds. Furthermore, it was noticed that cell adhesion

332  Electrospun Materials and Their Allied Applications and proliferation in vitro are improved due to the nanofibrillar structure. Moreover, in case of their implantation in mice, mesenchymal cells and blood vessels colonized the nanofibrillar scaffold. Also, CS/PVA-blended nanofibers, designated as dermal substitutes, were described and compared with 2D films of CS/PVA blend, using mouse 3T3 fibroblasts [139]. As a result of their in vitro assessment, authors noticed that the cells adhered and proliferated on the surface of CS/PVA nanofibers. In case of the deep wounds created on rats it was observed a 98.6% wound closure at two weeks post-surgery after the implantation of CS/PVA nanofibers along with topical administration of the growth factor R-Spondin 1. The results demonstrated that the topical administration of the growth factor and CS/PVA nanofibers increase the activity of catalase and superoxide dismutase of the healing tissue. Moreover, chitin and CS nanofibers would be suitable for skin tissue engineering, according to the results obtained by Lin et al. [140], who assessed the potential of pectin/ CS/PVA nanofibrous scaffolds. In contrast to CS scaffolds, on CS/pectin scaffolds, L929 fibroblasts slower proliferated, but cells deposited similar levels of extracellular type I collagen on both materials. In the study carried out by Stafiej et al. [10], it was reported the feasibility of the electrospun PCL/polyglycerol sebacate (PGS) and PCL/CS nanofiber mats as potential biomaterials for the ophthalmological applications. These materials were used in order to replace the human amniotic membrane and to enhance wound healing in defects of the human cornea, acting as scaffolds for human corneal epithelial cells.

11.3.2.3.1 Vascular Tissue Engineering

An alternative approach regarding treat the cardiovascular diseases is represents by the vascular tissue engineering. Artificial grafts, allografts, autologous tissues and xenografts were extensively used to treat cardiovascular diseases in a traditional way. These types of material exhibit some disadvantages, their activity leads to thrombogenicity and infection. In vascular tissue engineering, biodegradable scaffolds are used with the autologous cells in order to produce a vascular construction that is similar to a native vessel. Scaffold materials should exhibit several characteristics such as biodegradability, biocompatibility, to favor the cell attachment and multiplication and non-immunogenicity. Nanostructured scaffolds materials, such as polyglycolide (PGA), poly(lactic acid) (PLA), PCL, collagen, silk, and CS nanofibers, produced through electrospinning were evaluated and widely used in the creation of blood vessels [128]. In this context, the vascular tissue engineering represents one of the several field in which chitosan based nanofibers were employed. For example,

Electrospun Materials in Bioinspired Systems  333 a 3D gradient heparinized CS/PCL nanofibrous scaffold with vascular endothelial growth factor (VEGF–Hep–gCS/PCL) and uniform CS/PCL nanofibrous scaffold with VEGF (VEGF–Hep–uCS/PCL) were obtained with the aim of preventing thrombosis [141]. Researches on endothelial cell growth were evaluated by seeding the human umbilical vein endothelial cells (HUVEC) on nanofibrous scaffolds. The results have shown that, HUVEC rapidly formed a confluent monocellular layer on the lumen surfaces in the gradient CS/PCL within 72 h; with other words, HUVEC expressed abundant F-actin (Alexa Fluor 488 phalloidin) after 72 h. These indicate the development of actin filaments around each cell periphery and in the networks (see Figure 11.10a and c). It was noticed that seeding the human umbilical vein endothelial cells expressed more Von Willebrand factor (vWF) on the surface of gradient scaffold in contrast to the uniform scaffolds (see Figure 11.10b and d). The gradient CS/PCL induced rapid endothelialization and enhanced the proliferation of HUVEC. In contrast

(b) vWF VEGF-Hep-uCS/PCL

(a) F-actin VEGF-Hep-uCS/PCL

100µm

(c) F-actin VEGF-Hep-gCS/PCL

100µm

(d) vWF VEGF-Hep-gCS/PCL

100µm

100µm

Figure 11.10  Morphological characterization of the human umbilical vein endothelial cells (HUVECs) cultured for 72 h on the VEGF–Hep–uCS/PCL (a, b) and VEGF–Hep– gCS/PCL (c, d) scaffolds. The cells were stained with Alexa Fluor 488 phalloidin (F-actin (a, c)) and anti-vWF antibody (vWF (b, d)). Reproduced with permission from Ref. [141]. Copyright 2012 Elsevier.

334  Electrospun Materials and Their Allied Applications to the CS/PCL uniform scaffold, it was observed that the release of VEGF from CS/PCL gradient scaffold were continuous [141]. Consequently, the use of heparinized CS/PCL scaffolds it could lead to the creation of the small diameter blood vessel grafts and rapid induction of re-endothelialization.

11.3.2.3.2 Neural Tissue Engineering

The nervous system is constituted of the central nervous system (CNS) and the peripheral nervous system (PNS). Problems, as the immunological rejection or disease transfer, may occur during non-neuronal treatments. In order to avoid these problems and to facilitate the regeneration of the nervous structures, it is necessary to create environmentally friendly, biocompatible materials that have a high porosity and mechanical resistance. Thus, the fibrous structures created by the electrospun technique can be used, due to the characteristics similar to the native extracellular matrices, in nervous tissue engineering, giving a new perspective on neuronal regeneration [128]. Lately, chitosan based nanofibers have been fabricated with the aim of advancing the scaffolds in regenerative medicine and neural tissue engineering. In the study carried out by Cooper et al. [142], randomly oriented and aligned CS/PCL fibrous scaffolds have been produced and evaluated their usage in neural regeneration. In order to evaluate the potential usage of the CS/PCL nanofibers in nerve regeneration it was neuron cells used, like PC-12. After cultured for 7 days, it was observed that used neuron cells adhered well on randomly oriented CS/PCL nanofibers but also those aligned (see Figure 11.11). As appeared in Figure 11.11B, (b), the neuron cells exhibited a parallel development along the nanofibers direction on (B) (a)

(C) 3 Random Aligned

Normalized Fold Expression

(A) (a)

2

(b)

(b)

1 0

β-tubulin

NF-200

Figure 11.11 (A)  SEM images of randomly (a) and aligned (b) oriented chitosan/PCL nanofibers. (B) Fluorescent images of PC-12 cells cultured on randomly (a) and aligned nanofibers (b). (C) β-tubulin and NF-200 gene expressions of PC-12 cells on nanofibers. Reformulated in accordance with Ref. [142].

Electrospun Materials in Bioinspired Systems  335 aligned CS/PCL nanofibers, in contrast to randomly oriented CS/PCL nanofibers. Moreover, in this study were evaluated gene expressions of β-tubulin and neurofilament-200 (NF-200) of neuron cells on nanofibers. The results suggest that the cells differentiated well on aligned and randomly oriented nanofibers due to the fact that neuron cells used (PC-12) expressed approximately the same NF-200 gene content on both types of nanofibers (Figure 11.11C). Instead, it was noticed that the neurite extended more on the aligned nanofibers because neuron cells expressed almost three times the β-tubulin gene on the aligned nanofibers in contrast to the randomly oriented nanofibers. Technologies of self-assembly and deacetylation represent other methods that have been used in order to produce chitosan nanofibers. With the aim of investigating the potentials to support the cell attachment, the neurite coverage and survival chitosan nanofibers blended with poly-Dlysine (PDL) (the diameter of 4 nm and 12 nm, respectively) were used for mouse cortical neuron cultures [143]. As a result, the neurons situated on CS nanofibers scaffolds with diameter of 4 nm exhibited extensive neurite extension and arborization on the third day compared to day 1. Instead, on the 12 nm nanofibers surface no such further neurite elaboration was observed. The results suggested significantly improved long-term cell viability due to the fact that after 7 days’ culture, CS/PDL nanofibers with a diameter of 4 nm demonstrated a neuron viability of 37.9% compared to only 13.5 % for PDL nanofibers.

11.3.2.3.3 Chitosan in Oral Medicine

Cellulose, collagen, and chitosan, which are part of the natural polymers, exhibit high potential for oral applications as electrospun materials. However, this potential has been less explored. Tissue scaffolds based on chitin, chitosan, alginate, and numerous other natural polymers have been intensively studied because their application in periodontal bone regeneration. Furthermore, it is known that chitosan could be effective in bone regeneration process because it possess mitogenic properties, helping to osteoblastic cells differentiation [11, 144]. Tissue engineering which utilizes mediators, such as biomaterials, cells, and other biochemical factors and nanofibers, improve the healing process of periodontal tissues (ligament and surrounding bone). In a study by Sundaram et al. [11] have synthesized and characterized a bilayered construct and also the functionality of this structure to differentiate human dental follicle stem cells (hDFCs) into osteoblastic and fibroblastic cell types was studied. Authors have developed a the bilayered construct, consisting

336  Electrospun Materials and Their Allied Applications of poly(caprolactone) PCL multiscale electrospun membrane (electrospun fibrous layer, top layer), in order to mimic and regenerate the periodontal ligament (PDL), and chitosan/2 wt% CaSO4 scaffold (layer with osteoconductive material, bottom layer), with the purpose to mimic and regenerate alveolar bone, according to Figure 11.12. The CS/2 wt% CaSO4 scaffold in osteogenic medium favored osteoblastic differentiation of hDFCs and alkaline phosphatase activity, which is one of the early markers of the osteoblastic differentiation, significantly on the seventh day. As a result of this study, it was reported that the attachment, infiltration, proliferation, and differentiation of stem cells into osteoblast and fibroblast were enhanced by using the bilayered construct.

11.3.2.4 Antibacterial Activity It is known that chitosan possess antibacterial activity, owing to ability to inhibit the growth of microorganisms. Chitosan is involved in several emerging applications such as food science, agriculture, wound dressing, pharmaceuticals, and textiles due to this property coupled with nontoxicity, biodegradability, and biocompatibility. Several characteristics, including PCL multiscale electronspun membranes for PDL regeneration bilayered construct

CH/CaSO4 scaffold for alveolar bone regeneration

PCL nano electrospun fiber PCL micro electruspon fiber CaSO4 Chitosan scaffold

Figure 11.12  Bilayered construct consisting of a PCL multiscale (micro/nano) membrane and chitosan/2 wt% CaSO4 scaffold for healing of periodontal tissues. Reformulated in accordance with Ref. [11].

Electrospun Materials in Bioinspired Systems  337 presence of amino groups from the dissolved chitosan nanofibers, molecular conformation, release of small chitosan oligomers, and formed chitosan layer around the bacterial cell, may provide the antibacterial activity of chitosan nanofiber [128, 145]. Antibacterial nanofibers can be developed without the use of any biocides due to the inherent antibacterial ability of chitosan, but there are several issues in fabrication process of nanofibers by electrospinning on account of its polycationic nature in solutions. In order to overcome these difficulties and to produce stronger antibacterial nanofibers, chitosan has been blended with various other polymers, such as PLA, PCL, polyethylene terephthalate (PET), PEO, PVA, and nylon [145]. Additionally, to improve the biocidal activity in the composite nanofibers, chitosan or its derivatives, has frequently been used in combination with nanoparticle of silver (AgNP). It was noticed a synergistic effect between chitosan and AgNP in antibacterial activity [145]. In literature [126, 146–151], the nanofibers consisting of natural/­ synthetic polymers and antibacterial substances, were the most studied antibacterial nanofibers. In this respect, the electrospinning was the technique used with the purpose to produce the CS/PVA/AgNP blended nanofibers [146]. It was observed that nanofibers which contain silver nanoparticles inhibit the growth of bacteria. Moreover, it was shown that CS/PEO/AgNP composite nanofibers exhibit a higher antibacterial activity in contrast to those without Ag nanoparticles [147]. Ag/CS/PEO nanofibers containing 1.1 and 2.2 (wt%) nanoparticles, respectively inhibited all bacteria within 10 and 6 h. Therefore, in contrast to the CS/PEO nanofibers, the nanofibers containing Ag nanoparticles exhibited a better antibacterial activity. Lately, CS/PCL nanofibrous membranes were designed with the aim to be used for antibacterial water filtration [148]. Thereby, by electrospinning were obtained CS/PCL fibers (25, 50, and 75 (wt%) chitosan content) with diameters ranging from 200 to 400 nm. A higher filtration efficiency was observed in case of the CS/PCL fibrous membranes, comparatively with the PCL fibrous membranes. In the last years, the wound dressings with the antimicrobial agent delivery ability has received significant attention to improve different aspects of wound healing process, which include the accelerating of wound healing with better quality scar tissue and even preventing infections. It was reported that levofloxacin, a drug that has been embedded in the chitosan/ polycaprolactone fibrous scaffolds of core/shell type, obtained through the coaxial electrospun method, was released in the course of more than seven days [149]. Similar behaviors were recorded for ciprofloxacin hydrochloride and moxifloxacin hydrochloride, which were embedded, separately in

338  Electrospun Materials and Their Allied Applications chitosan/polyethylene oxide fibrous matrices. Also, has been demonstrated that the fibrous structures, presenting in vitro cytocompatibility with porcine endothelial cells, can prevent the development of Staphylococcus aureus and Escherichia coli [149]. In a study carried out by Abbaspour et al. [126], was evaluated the antimicrobial activity of mafenide acetate loaded CS/PVA nanofibers against Staphylococcus aureus and Pseudomonas aeruginosa. The antibacterial assays revealed that chitosan/PVA nanofibrous films could act as an inhibitor against growth of both microorganisms, due to the antibacterial properties of chitosan. The antibacterial effect observed was stronger and faster as the amount of drug in film formulation increased. It was reported that both drug-free and drug-loaded nanofibrous chitosan/PVA membranes could be used as wound dressings in order to avoid the secondary bacterial infections. Films containing mafenide acetate exhibited a greater antibacterial effect on the studied microorganisms in contrast to the drug-free films. Literature indicated that imipenem-incorporated chitosan/poly(L-­ lactide) composite nanofibers possessed bactericidal action against Escherichia coli and provided a good development and multiplication of the mouse fibroblast cells. Thus, in their study, Jiang et al. [150], have evaluated release behavior of tetracycline hydrochloride loaded chitosan/poly(lactic acid) (Tet–CS/PLA) antimicrobial nanofibrous. The results have indicated that Tet–CS/PLA nanofibrous membranes loaded with different concentrations of tetracycline hydrochloride exhibited an effective and sustainable inhabitance on the growth of Staphylococcus aureus and increasing the concentrations of tetracycline hydrochloride increases the percentage of cumulative release, resulting in increases the antibacterial activity against the Gram positive bacteria. Instead, Alavarse et al. [9], investigated the potential to be used as wound dressing of electrospun CS/PVA and CS/ PVA/Tetracycline hydrochloride (THC) mats and also their morphological, thermal, mechanical, drug release, antibacterial, and cytotoxicity properties. The release of tetracycline hydrochloride occurs suddenly during the first 2 h which means an effective antibacterial activity on the Gramnegative Escherichia coli, as well as on the Gram-positive Staphylococci epidermidis and Staphylococcus aureus. Additionally, Sadri and Arab Sorkhi [151] have developed nanofibers based on CS, PEO, and antibiotic drug, i.e., cefazolin, for the efficient and controlled release of cefazolin. In order to obtain fibrous biomaterials that can be used in the wounds treatment, in this work a relationship between the bactericidal properties and antibiotic used has been established (Figure 11.13). As a result of the antibacterial assays (see Figure 11.13), it was noticed that chitosan/PEO/1wt% cefazolin nanofibers possessed antibacterial

Electrospun Materials in Bioinspired Systems  339 (a)

(b)

10 mm 12 mm

Figure 11.13  The inhibitory effect of chitosan/PEO/1wt% cefazolin nanofibers against Staphylococcus aureus (a) and Escherichia coli (b) bacteria. Reproduced with permission from Ref. [151]. Copyright 2017 Iranian Society of Nanomedicine.

effect against Escherichia coli and Staphylococcus aureus bacteria. Cefazolin destroyed both type of bacteria, but exhibited a higher inhibitory effect on the growth of Gram-positive bacteria compared to the Gram-negative bacteria.

11.4 Conclusions Unlike other polymeric materials, the cellulose and chitosan possess many useful characteristics, as biocompatibility, antibacterial activity, multifunctionality, and by molecularly design enhances their performance, becoming biologically inert and nontoxic compounds with adjustable morphological characteristics. Based on the above-mentioned properties, these polymers can be processed by electrospinning to create new fibrous materials that can be used in numerous bioinspired systems for example, in the development of blood-contact devices, cell- and tissue-contact devices, nerve generation, carriers in drug delivery, and wound-dressing. The ability of the nanofibers scaffolds to accept and modulate the growth of the different cells, including endothelial, nerve, and chromaffin cells, and to reconstruct the artificially functional tissues/organs, or construction of the biocompatible prostheses has shown a bright future of these new materials in the field of tissue engineering/regenerative medicine.

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12 Smart Electrospun Materials Gaurav Sharma1, Shivani Rastogi1 and Balasubramanian Kandasubramanian2* Nanomaterials Characterization Lab, Center for Converging Technologies University of Rajasthan, JLN Marg, Jaipur, Rajasthan, India 2 Nano Surface Texturing Lab, Department of Metallurgical and Materials Engineering, Defence Institute of Advanced Technology (DU), Girinagar, Pune, India

1

Abstract

Thriving technological advancements in various distinct disciplines demand for the continuous expansion of innovation and implementation to step toward civilization enlightenment. This progressive scientific scheme looks for smart technological materials. Electrospun materials have been extensively adopted in various fields for regular applications due to their exceptional properties, but currently researchers have initiated their exercise in smart materials by incorporating various functionalities. These smart materials are advantageous over conventional because of their ability to merge divergent specialties and dispensing numerous novel materials with ameliorated properties and enormous future scope. Electrospinning is a voltage-driven procedure of drawing ultrathin fibers having a diameter in submicrometer (99% efficacy [4].

Electrospun Technology  443 Electrospun fibers has also displayed their readiness in electro & magnetic domains where incorporations of charge-favored fillers ameliorated electromagnetic (microwave) absorption, manifested shielding, electronic, and dielectric properties [6, 9, 15]. Additionally, transistors fabrication from electrospun fibers was reported to be utilized as photodetectors in presence of near-infrared radiations and facilitating temperature sensing [16, 17]. Other applications tailor properties for its absorption utilization in chillers, heat exchangers, and solar (since it facilitated swift diffusion path to hydrogen in water splitting reaction) applications [8, 18]. Researchers, among various patterns of electrospun non-woven fibers, have delved into development of membranes. Fibrous membranes contrive enumerate pores evincing exaggerated surface area availability for electrochemical or catalysts reaction, mass transferring (diffusion), and preferential interphase barrier for selective molecules [19, 20]. Additionally, it is being utilized to captivate the deleterious and environmental unfriendly molecules, e.g., CO2 where reactions at membrane-gas boundary could facilitate efficacy amelioration in its removal. This effective adsorption exhibited 40% inclination when build adsorbs humidity by 5% thus, instituting mass conductive passage which further exaggerated with high flow rate of gas [21]. Thus, time rate of molecules (to be diffused or filtered) interaction on membrane, geometry and dimensions of intentionally tailored pores, dimensions of fiber build-up, superficial roughness, mechanical strength, molecule-adhere effectiveness, fabricated thickness, permeability, etc., are the utmost pre-requisites being considered to build productive membranes [19, 22, 23]. To enkindle properties for expeditious work efficiency, varied range of materials and reinforcements, devoted to signified applications, have been proposed through various scientific contributions. For instance, PVDF excels in hydrophobic property which confronts bio-molecular (proteins) fouling with an adverse impact on productive performance of membrane. Researchers proposed reinforcement of hydrophilic unit of persulfonic acid and graphene oxide in PTFE which had encouraged water interaction concurrently tuning pore geometry (elongation, irregularity, smoothness) had manifested anti-fouling characteristics by effectively barricading protein diffusion up to ~93.9% [24]. Moreover, graphene oxide had also been investigated as blockade for gases (e.g., oxygen, nitrogen, etc.) and radioactive radon while the later had showed aversion in diffusion to Tg or Tm ii) water engenders swelling transformation when H2O molecules seeps in between chains thus, causing plasticization iii) Light entails molecules morphological change (e.g., cis–trans in azobenzene) for non-thermal transfiguration. While indirect i.e. photothermal shape mutation sources chains excitation as incorporated particles like, carbon black, graphene, gold nanoparticles, or organic dyes favors

Electrospun Technology  445 thermal energy increment through surface plasmon resonance or conjunction of Beer’s Lambert’s law and hyperthermia iv) magnetic stimulus, by directional orientation or rearrangement of dipoles in external magnetic field v) electrical which comprises conductive reinforcements stimulating in voltage, current or electric field to enkindle heat in specific pattern for complicated folding or movement vi) some other stimuli are composed of solvent and pH (functioning analogous to water except for sensitivity change toward specific functional group) [28, 37–40]. Thus, electrospinning of membranes integrate the synergy from three domains of smart materials (comprising stimuli-responsive and shape memory which establishes adjacent environmental communication and response), electrospinning (imparts fidelity, robustness, microscopic intricate engineering for colossal surface area, and geometric independence of pores tunability), and membranes (which paves the way to design a channel for selective transference). Therefore, electrospun smart membranes administer changeable permeability, defense by barricading the unwanted by fiber density adjustment, efficient nutrient infiltration (for biomedical), material and weight optimization which are pre-requisite when targeting wearable textiles to combat extreme conditions in military, etc., to name few [36, 41, 42]. As a result, this book chapter delineates state-of-art literature for advanced smart researches on electrospun membranes. These built entities (without smart materials) have vast dedicated literature which marks the momentousness of electrospun membranes though representing a static permeation unit. Similarly, smart in-built feature of membranes through electrospinning of smart materials has restricted literature availability depicting widened scope to delve in. Furthermore, necessity also arises to keep in rhythm with everyday innovation for ever-increasing dexterity, thereupon, mingling nature-inspired smartness with artificial manufacturing of smart membranes has also been described in this chapter.

16.2 Some General Smart Applications of Electrospun Membranes Membrane technology has acclaimed its applicability as a cross-­disciplinary research interest to accomplish sophisticated and convoluted future mankind demands for bio and engineering. Selective permeability of fluids or chemicals by tailored interconnected porosity in fibers renders mammoth surface area to membranes for filtration and sustained transference of biological fluids (nutrients, enzymes, etc.) in medical for, e.g., drug delivery. Efficacy in membrane surface area and density (surface) can

446  Electrospun Materials and Their Allied Applications further be augmented to ~40 m2/g and 4 mm) could tune oleophobicity under water to ~>150° exaggerating self-cleaning and anti-fouling potential for saline/oil containing wastewater treatment [46]. Alternatively, with 30% ammonium tetrathiomolybdate (ATTMo)–PAN and 30% tetraethylorthosilicate (TEOS)–PAN membranes hydrophilic, roughness, and viscosity amelioration attributed to enhanced entanglement of chains was observed. These admixed membranes with wrinkles and branches facilitated colossal average surface area for photocatalytic degradation rate up to 90% with ATTMo and 80% with TEOS PAN composite membrane. Additionally, impediment of viruses on un-flat surface had consequently affected virus expulsion from water achieving maximum ~99% with TEOS addition thus, witnessing modification in selectivity with reinforcement [47]. Omnipresence of pollutants has ventured into breathable air wagering the human life in danger as also depicted in 2018 WHO reports which acquainted the declination of qualitative virtue of air impacting >80% people having exposure below minimal standard of breathing for health-conscious life. Pre-requisite of every filtration mechanism is surplus proportion of porosity for mammoth surface

Electrospun Technology  447 area facilitating particles entrapment [48]. Morphological arrangement or additive has substantial influence on filtration efficiency of, e.g., PAN electrospun fiber membranes. Low precursor PAN concentration rendered beaded structure (200 nm while connection 55 nm) were engineered with high concentration (Figure 16.1) (bead-free) or silver nanoparticles were incorporated. These formulations modulate surface tension to steer viscosity, fiber packing density roughness and thereby, filtration efficiency. Bilayer designing or silver-PAN membranes furnished 2.93 µm pores (>96% porosity) with efficiency > 88% reaching to 100% while silver allowed anti-bacterial property abolishing 108 CFU/ml bacteria in 6 h therefore exceeding functioning of some commercial air filtration membranes [49, 50]. Albeit tailoring of materials for morphological stability, their mechanical performance aid in long-term steady operation of membranes for diverse applications. Fiber or infiltrate interaction determine strength for incoming diversities, e.g., non-bonding of polyimide fibers was subdued by epoxy infiltration which had enhanced adherence thereby, demonstrating proportional increment (approximately four times) in tensile stress (3.6 MPa, 9.2 MPa, 12.9 MPa) with epoxy concentration (0 wt%, 0.5 wt%, 2.5 wt%), respectively, for 99.9% efficient removal of particulate matter (diameter Mg2+) ascribable to influence in electrostatic interaction [62]. These properties were employed for distinguished applications in security (breathable barrier clothings toward chemicals, etc.), medial (drug delivery, wound healing), fuel cells, tissue engineering, and as 5

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450  Electrospun Materials and Their Allied Applications other filtrates for purification [20, 41, 56, 63, 64]. However, for filtration related applications, polysulfone membranes assisted with thermal post treatment had favored higher selectivity in obstructing unwanted agents (membrane filtration rate = 147 kg/m2 h) [63]. In addition, with sulfonation propensity for proton conveyance, polyetheretherketone had been modified and impregnated on polydopamine modified PVDF membrane for its operation in proton exchange fuel cells. These hydrophobic (124.9°)-turned-hydrophilic (complete absorption due to polydopamine) PVDF composite membranes experienced 32.3% water uptake, high proton conductivity (around 0.02 S/cm at 20°C to 0.06 S/cm at 80°C) and principally, large methanol blockage (3.8 × 10−7 cm2/s at 20°C while increasing to 23.5 × 10−7 cm2/s at 70°C) for effective performance in fuel cells [57]. Membranes from PLGA mixture with silica nanoparticles, gelatin, dexamethasone, doxycycline hyclate had amalgamated osetoegenic property and anti-bacterial property from two separate agents while encouraging cell proliferation and sustainability in drug release (21 days) complimenting the osteogenic profile in natural bones [56]. Moreover, drug-modified PVA and L-lysine membranes were reported to exhibit an immense benefit for would healing applications. With mechanical property conforming skin, electrospun blend had >50% porous structure which contributed to natural degradation in presence of body fluids, swelling-eliminating generated wound waste from site promoting cleaning and protection from infection, ~>1400 ml/m2/day water vapor transferral for healing, ~55°–64° water contact angle rendering efficacy for cell growth environment, and also conferring defense against bacteria germination (ranging~20% to 96.6% for different surface modification and bacteria) [65]. This empowerment against bacterial growth serves as a pre-eminent protection measure for hygienic wound healing in biomedical domain. Substituting with quaternary ammonium salt in PVA evinced direct proportional relation of modification fraction on thermal stability and anti-bacterial ability (efficiency >99%), latter of which is an innate possession of chitosan [66]. Alternatively, when electrospinned PVA was mixed with chromogenic agent, ninhydrin, results proffered discernible detection of l-tyrosine after reaction by generating purple hue and thus, unveiled the potency for acids (from bio production) and amino molecules identification [67]. Further­ more, Lin et al. had devised a sensor by electrospinning PTFE which was later sandwiched between two carbon sheets for electrical performance attributable to its innate characteristics in electric and sensing. Besides, it displayed air permeation and enough mechanical support (3.8 MPa of tensile strength and 220% strain prior to break) which directionalized its functioning toward wearable sensing electric. Device was tested at elbow

Electrospun Technology  451 joint and fabricated nanogenerator devices outputs 56.35 mW electric power while targeting self-powered devices for real time observation of bodily motion and internal fluidic motion respiration, blood flow, etc. [68]. Other electric devices are batteries (Li–S) where nanofibrous structure (electrolyte) membrane has ensured its utility by precautiously separating anode from cathode with robust selectivity (enhanced with low surface energy as in composite PMIA separator membrane) toward ­ passingthrough molecules like polysulfides. These were achieved by fluorination (of admixed composite PMIA membranes) which aid in pore dimension reduction (.5576 µm (without) → 0.4145 µm) and overall, it rendered thermal protection during short-circuits [69]. Electrospinned membrane products had also transcended its utility in food industry for sensing, as precursor material (cellulose acetate) could be formulated with sensitive indicator (fluorescein isothiocyanate (FITC)-biogenic amine detection and protoporphyrin IX (PIX)) for respective food response indicative of spoilage or freshness of edibles especially seafood. PIX addition with FITC in cellulose acetate (FITC:PIX = 5:1) reciprocate to intensity of spoilage with perceivable color change under UV light when in contact with ammonia or biogenic amines (Red fluorescence indicative of fresh traversing to yellow for little spoilt but edible while inconsumable seafood displayed green fluorescence). Credibility for practicality was confirmed by food inspection standard, total volatile basic nitrogen (TVBN) test which showed equivalent indication with smart membrane, i.e., 0.25 mg/g → completely spoiled ← green (Figure 16.4) [55]. Modification in surface treatment of cellulose acetate membranes with grafted silica nanoparticles and subsequently chemical vapor deposited fluorinated silane (surface energy declination) had rendered superhydrophobicity (150° or 155° which was >138° for silica-modified membranes). This engendered characteristic following cassie–baxter roughness model advocated its utilization in desalination owing to omniphobicity with operative efficiency maintained for >8 h thus, claiming supremacy over available commercialized PVDF and PTFE membranes. These membranes were also customized to tune wetting interaction other liquids (except water) possessing lower surface tension (e.g., decane, methanol (10%), and castor oil) with 13.6 kg/m2 h permeability flux (decane) proposing it an constructive membrane for desalination compared to PTFE and PVDF [70, 71]. With reference to abovesaid literatures, doping stimulates the chemistry and bonding of the material engendering an apt performance for varied applications from similar precursors. Following this, Ponnamma et al. had reported electrospun membrane technology owing to its flexibility and

452  Electrospun Materials and Their Allied Applications UV O

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Figure 16.4  Combination of two fluorophores renders different color fluoroscence (irrespective of their single fluoresce ability) indicative of freshness of seafood for edibility in food inspection [55].

weight effectiveness in smart textiles. Authors concocted laminate-type composite membranes of PVDF–hexafluoropropylene formulated with cellulose nanocrystals and iron-doped zinc oxide inducing innate ferroelectricity as well as crystallinity, a pre-requsite for piezo behavior. Either of which unveiled directional piezoelectric behavior (considerable output voltage) by virtue of electric filed-aided alignment of reinforcement domains. Researchers further testified mechanical deformation generated voltage production by movements sourced from finger tapping, ultrasonic waves (20 kHz produced 2 V), elbow 90° bend and cloth folding (1.1 V) thus, expediting for membrane-based textiles for energy harvesting and their storage [72]. Electrospinned membrane has substantial biomedical cogency which led its widespread research for various biological sub-domains aimed to augment fluid interaction and cell proliferation sites for speedy functioning of regenerative medicines. Various modifications in fabrication aid during engineering of requisite membranes, e.g., thermal treatment (50°C in succession with ethanol immersion of calcium phosphate incorporated

Electrospun Technology  453 PLGA electrospun membranes) facilitated diameter curtailment while incrementing stability (Tg), bioactivity, mechanical modulus (~162 MPa for 5% PLGA), and resultant porosity for osteogenic differentiation in bone regeneration [73]. Similarly, for wound healing biomedical engineering, selective transport of fluids steers the nutrient availability. Wu et al. asymmetrically attune the water–membrane interaction by piloting hydrolysis of cellulose triacetate, governed by replacement of acetyl with hydroxyl group (reduction extent—2.92 to 1.96). Modification ensued double-­layered janus membrane with water-loving (73.3°) on one side and 131.1° on other by electospinning differentially hydrolyzed (lower degree replacement—hydrophilic and vice-versa) cellulose triacetate solution embodying silver for targeted antibacterial property induction (Figure  16.5) [74]. Bacteria-resistant activity could also be emphasized with biopolymer chitosan deposited on PCL membrane. However, surface wettability performance (hydrophilicity) was instigated by treatment with plasma in presence of oxygen [41]. This influenced pore dimension which dwindled to 1.79 µm posterior to treatment than 3 µm promoting selectivity for blockage of fibroblasts (>8 µm) thus, enkindling anti-­adhesiveness for anticipated solution to prevent health adversities after abdominal surgery caused by adhesion [75]. Correspondingly, calcination procedure could favor production of lanthanum zirconate fibers from lanthanum and zirconium-based formulated electrospinning. They were subsequently infused with polypropylene carbonate followed by sandwiching with cellulose membrane by single-sided graphite coating for ameliorating interfacial interaction between prepared composite electrolyte membrane and anode for requisite electrochemical operation (Figure 16.6). Manufactured component displayed capability of 154.2 mA h/g discharge when assembled to work in solid state batteries [76].

(b)

(a) Back

Front

10s

20s

30s

60s

100µm

Figure 16.5  (a) Double-sided electospinning of modified cellulose acetate represented in SEM micrograph. (b) Resultant water preference of differently hydrolyzed electrospinned surfaces of membrane [74].

454  Electrospun Materials and Their Allied Applications PPC solution with LZO fiber

Graphite layer

Cellulose nonwoven PPC solution with LZO fiber

Sandwiched composite membrane electrolyte

PPC electrolyte film

Figure 16.6  Complex production of sandwich electrolyte membrane with electrospinned lanthanum zirconate fibers with polypropylene carbonate infusion, cellulose, and graphite coating [76].

Thus, above-mentioned literatures explicated probability of diverse electrospun membranes for selective target for applications in varied filtration, food, sensing, batteries, fuel cells, and other biomedical domains for promoting healthy growth of cells and nutrient seepage. Albeit propounding noteworthy membranes, these present inadequacy by irresponsiveness toward environment exposed to, i.e., represents staticity and therefore, pore size or intricacy of working are pre-defined, limited, and un-tunable.

16.3 Stimuli Responsive or Shape Memory Electrospun Membranes Invariability in performance of materials while in operation has brought about incongruousness with exceptionally innovative and smart yet convoluted technology. Therefore, stimuli-responsive materials or smart materials emerges as propitious technology being able to react to external exposed conditions which is inspired from nature’s sophisticated organization in creatures like mimosa pudica, sunflower, etc. This active participation toward adjacent environment has been mimicked in fibrous membranes for design efficient modulation during filtration, drug delivery, tissue engineering, catalysis, textiles etc. with water, electrical, thermal, pH, solvent, and other suitable stimuli [20, 28, 41, 77]. Bio-medical apportions manifold utilization of smart membranes in scaffolds, adsorption, drug delivery, and other regenerative medicines owing to its additional freedom toward environmental trigger. Transmuted shapes of smart membranes encouraged by stimulus subsumed recovery immediate to dismissal of external energy, i.e., stimuli-­ responsiveness or memorize presumed pattern until next stimulus ­application, i.e., shape memory by chemical or physically governed interactions. Functionality change, sensing, morphological difference from minuscule divergence in immediate adjacent properties typifies stimuli-­responsive

Electrospun Technology  455 materials which empower mimic of ostentatious nature architecture into arti­ ficial design [20]. Pliability of materials toward temperature as a driving force has acclaimed its utility in wide-range applications with efficient control of properties. Complying with these necessities, poly(N-­isopropylacrylamide) (PNIPAm) displayed thermal energy-responsive swelling and contraction, thus controlling the thickness of fiber for allowance or restricting the filtration process. However, to widen the workable realm of individual cellulose acetate and PNIPAm, surface modification with PNIPAm on cellulose acetate membranes was conducted for hydro-­thermo-responsiveness. Thus, below lower critical solution temperature (LCST), i.e., 75% efficiency for oil– water separation as a function of temperature (water-in-oil or oil-in-water interaction = f (temperature)). This interrelation also had governed water-­ harvesting in deserts where water was accrued at night and utilized during day with core (cellulose acetate)–shell (PNIPAm) engineering of fiber in membranes. Similar superhydrophilic behavior though with higher angle of ~19° at 25°C might be attributed to different arrangement of precursors to build membrane (as compared to above-stated). This delineated ~208% moisture at 20°C (fog, mist, or humidified air) adsorption at < LCST with droplet nucleation in 5 s and growth over time (pertained to extra inclusion of hydrophilic bonds with cellulose acetate) while lowest at >LCST (~20% at 60°C thus, release) (accredited to speedy diffusion) (Figure 16.7) [78, 79]. Similar analogy of thermal-assisted water absorption in UV crosslinked layered PU-PNIPAm membranes was elucidated for actuators with 20 times and performance even in presence of water vapor [80]. This direct thermal energy (stimulus) restricts sensitive and precise targeted application on demand especially in biomedicals. Consequently, near infrared electromagnetic energy (NIR), being transparent to tissues, could be focused specifically to stimulate artificially injected fabrications e.g. membranes for drug release [81]. Photothermal active material, as instance, polypyrrole (hyperthermia and absorbance [81]) had been functionalized (>C=O, from PCL, interaction with –N+H) on

456  Electrospun Materials and Their Allied Applications H H O

H H O

O H

H O H H

O

H H O

H

O

N H HN H H H O

H

O

O O H

H N N H O H H

O H

H O H

H

O

H

O

H

O H H

H N

H N

O

N

O H

H

PNIPAM Cellulose acetate PNIPAM O

O

O H H H O H

H

H

O O H H

H N N H O H H

O

N

10 µm

50 sec

O H H

H

O

20 sec

5 sec

O H H

O

PNIPAM Cellulose acetate PNIPAM H

O H H

H H O

H

O

H

O H H

10 µm

90 sec

Temp < LCST

Temp > LCST

10 µm

70 sec

10 µm

110 sec

10 µm

10 µm

Figure 16.7  Depiction of water droplet nucleation (within 5 s) and growth below LCST by core–shell cellulose acetate–PNIPAm fibers for water arrestation at low temperature with subsequent release at high [79].

drug (paclitaxel)-containing PCL membranes for treatment against tumors. As inherent to photothermal, temperature delineated acclivity from 43°C → 52.4°C → 62°C which had marked enhancement in polypyrrole percent 1% → 2% → 3%, respectively, at 5000 W/m2 in 300 s which sourced selective demise of tumor-infected cells by hyperthermia. Swelling-guided PTX release at low pH (5.5) of 42% had ascended to ~66% (for 104 W/m2) release in 148 h when assisted with NIR-steered temperature rise implying speedy diffusion. Tumor cells decease to ~100% with NIR and drug release while solo functioning relying on thermal energy confined cell liveliness within 33% [82]. Contrary to low pH effective release of 42% drug (for cancer) at 5.5 pH than 25% at 7.4 pH by Tiwari et al. [82], Kim et al. [59] reported neutral pH delivery efficiency of anti-HIV drugs which implies inevitability of target-directed material formulations. Researchers availed low pH (4.5) swelling mechanism (protonation of 1,4-Bis(2-hydroxyethyl)piperazine) in polyurethane to modulate pores size of membranes (~2.2 µm at pH 7  >~1.8 µm at pH 4.5). Later, this swelling mechanism in conjugation with attractive/repulsive interaction between encapsulated drug and PU membrane, which impede or encourage drug release ushered by pH (60% at pH 7 >~28% at 4.5 pH), was proposed as window for HIV treatment through intravaginal transport [59]. An another aspect of pH sensitivity was presented by Liu et al. with poly(acrylamide-co-maleic acid) when pH-driven swell-ability revealed two increments separated by plateau between 4.5 to 8.6 pH (Figure 16.8). Two ascending regions were elucidated by dissociation constants of Poly maleic acid whose value >3.2 and >8.1 at 25°C triggered swelling owing to –COOH group ionization to negative carboxy and carboxylate group respectively to engender repulsion among fibers. However,

Electrospun Technology  457 25

c-P(AM-MA)-5%DEG c-P(AM-MA)-10%DEG

Q (g/g)

20

15

10

5

0

0

2

4

6

8

10

12

14

pH

Figure 16.8  Depicting the proportional swelling effect (Q) relation with pH from acidic to basic as stimulus and with higher crosslinker (diethylene gycol (DEG)) concentration in electrospinning solution [83].

plateau region was accredited to intra-hydrogen bonding forming COO– HOOC in maleic acid after –COOH dissociation (Figure 16.9). Accelerated effect (swelling crosslinker) was witnessed with intensive crosslinking with higher diethylene glycol (functioning as crosslinker). In addition to pH, tailored hydrogel was impactfully sensitive to ionic strength of solution 24 c-P(AM-MA)-5%DEG c-P(AM-MA)-10%DEG

20

Q (g/g)

16 12 8 4 0

0.0

.5

1.0

1.5

2.0

2.5

Ionic strength (mol/dm3)

Figure 16.9  Emphasizing the inverse relation of swelling in membranes with increasing ionic strength as stimulus and crosslinker (DEG) concentration in electrospinning solution [83].

458  Electrospun Materials and Their Allied Applications although delineating inverse relation, i.e., swelling (ionic strength)−1 as Na+ ions for increasing ionic strength had enshrouded negative –COO− charge repulsion which further waned with crosslinker concentration [83]. Validating above-stated ionic strength relation, zein protein–cellulose acetate electrospun membrane obstructed water seepage at 0.6 ionic strength as negative charges were clustered inside positive restricting repulsion and further increment could veil pH influence (responsivity). Protein release behavior displayed ~30% sustained output for membrane when zein = 15%, cellulose acetate = 5.2% and acetic anhydride = 5.5% with degradation ranging to 20% for period of ~7 days, deducing its applicability in wound healing [84]. Inherent to above-mentioned stimuli i.e. thermal, water, pH, and ionic strength lies direct contact of membrane except for infrared radiations whose energy packets supplies considerable trigger to actuate or respond by heat increase [28, 39]. Molecules or atoms with indirect energy conversion, e.g., gold (Au) nanoparticles employ surface plasmon resonance (SPR)—shuttling of electrons with crest and trough of wave, dye molecule administered by hyperthermia and Beer–Lambert’s law while carbon compounds like graphene, CNT, etc., due to unsaturated bond delocalization [38]. Spadaro et al. experimented with He–Ne laser of wavelength = 632 nm consisting of 21 mW/cm2 intensity which instigated indirect heatdriven drug release (40% within 40 h) from PEG–PLGA–SLB–Au–Fe2O3 composite membrane due to Au nanoparticles (PEG = polyethylene glycol, PLGA = poly (L glycolic acid), SLB = Silibinin, Fe2O3 = iron oxide). However, iron oxide, being a magnetic material, imparted magnetic field response releasing 20% drug in 40 h further, witnessing 42°–44°C increase in 60 h [85]. Additionally, magnetization effect on iron oxide through external magnetic field could also aid in on-site delivery and magnitude scaled up with subsequent concentration increment from 2–10% but beyond 30% could foster beaded fiber in membrane with probable deterioration in property [86]. Apart from these common external input, more accessible stimulus has potency to tailor expeditious, cost-effective, and also custom-based impetus. Succeeding the notion, Che et al. customized electrospinning of amidine-containing copolymer membrane to attune reversible wettability corresponding to oil or water by exposing to CO2 or N2. Mechanism followed under water as:



CO2

N2

Amidine  (1) → Amidine  bicarbonate  (2)→ Amidine  (1)

Thus, engineered membrane in water displayed hydrophobicity but when subjected to CO2, due to protonation and amidine, captured water in free

Electrospun Technology  459 volume altering the chemistry to hydrophilic which switched back to hydrophobic in N2. Meanwhile, membrane hydrophobicity portrayed oleophilicity in water (36°) and later super-oleophobicity (150°) with CO2 (Figure 16.10). Membrane proposed a permeable switch with multiple oils, e.g., hexane, heptane, and petroleum ether however, hexane reusable efficacy (30 ppm water retention) exceeded later two (60 ppm and 40 ppm water retainment) after reusable frequency of five cycles and are positively envisaged for oilspills microfluidics, etc. [87]. Specifically, stimuli sensitivity can also be custom tailored with peculiar bond chemistries, e.g., cholesterol esterase an enzyme secreted in wound against infection, are precisely sensitive to ester bonds causing hydrolysis. Captivating the performance of ester-sensitive enzyme Shi et al. electrospun PCL composite membrane and immersed in varied concentration of enzyme for optimization thereby, controlling and channelizing it in drug (esterified metronidazole) release applications for tissue/bone regeneration purpose. Esterified drug-­containing membranes in enzyme solution predicted scaling up of release with concentration from 0% ester bond cleavage (subsequent release) at 0 µg/ml enzyme to approximately 100% (within limits) at 10 µg/ml for unpredicted infection severity (with enhanced enzyme secretion). Employed quantity is in concordance with natural infection-guided release (4.6–11.3 µg/ml). Furthermore, in vitro bacterial testing witnessed decease of ~66% bacteria with10 µg/ml enzyme envisaging as a viable treatment recourse for infection prevention after surgery [88]. Congruent with above-said literature, amine sensitive fluorescent response (1 s) indicative of edibility (freshness) of seafoods was displayed with incorporation of fluorescein isothiocyanate and protoporphyrin IX in electrospinned membranes [55].

Hexane Heptane Petroleum ether

CO2

N2

= Water

= Oil

Amidine containing = composite membrane

Figure 16.10  Portray reversibility of membrane hydro/olephobicity and hydro/ olephilicity in CO2 and N2 as a switch [87].

460  Electrospun Materials and Their Allied Applications Shape memory materials (SMM) are the specific category of stimuli responsive materials associated with shape change and consecutively, retaining the memory of traversed path for recovery. SMM’s transformability by stimulus action and recovery had ushered understanding toward mimicking of involuted nature’s engineering [89]. Temperature-steered structure transmutation circumscribes wide range of materials with each relied on tailored transition temperature from different composition in single or composite materials. Replicating the notion in biomedical, Bao et al. had reported body temperature stimulated poly(D,L lactide) (PDLA) copolymerized trimethylene carbonate (TMC) electrospun fiber membrane at 36.7oC for 0.8 PDLC fraction which linearly ascended to 44.2°C with 0.9 PDLC fraction. Consequently, osteoblasts subsisted on tailored membrane for bone tissue formation and proliferated which was validated by calcium indications (Calcium:Phosphorus = ~2.01:1). Furthermore, thermal-sourced network-guided shape memory in composite proclaimed >8 triggered cycles with >99% shape recovery/fixity (PDLC:TMC = 8:2) in minimum of 6 s [90]. In another research on periosteal membrane for healing of post bone transplant, authors employed triblock polymer with polyethylene glycol end-capped by copolymer of lactide and glycolide which are subsequently mixed with hydroxyapatite to simulate bodily environment and ease cells proliferation. This bone mineral incorporation had curtailed degradation to 30–50% from 35–60% in 12 weeks and mechanical performance magnitudinally elevated to upto 330 MPa. However, slight deterioration (~up to 94.9% from 100%) in shape recovery was witnessed owing to crystallinity reduction of polyethylene glycol thereby, stiffness (hard segments), when tested at transition of 50°C. Moreover, composite membranes empowered 37°C self-wrapping performance from flat programmed state in saline with proposed aid for post-­ surgery healing [91]. Yet another material with wide-range scope for diverse actuation in and beyond biomedicals was characterized by long operational period, natural compatibility and magnitudinally low temperature transitions in PCL. Programmed electrospun PCL membrane had displayed directionalization and relaxation (Figure 16.11) among fibers with respect to applied force within 10°–60°C accounting to ~11% fluctuation in pore size for filtrating passage in textiles, etc. [92]. PCL, being a artificially prepared polymer presented deficiency in cells supportive factors on surface and therefore, gelatin methacrylate addition forming bilayers with poly lactic acid trimethylene carbomamate for improving cell attachment, mechanical functioning and lowering transition toward body temperature [93]. Nevertheless, PCL composite membrane was prepared with epoxy, thermoset—owing to strength, deformation ease, and

Electrospun Technology  461

20 µm

20 µm

Figure 16.11  Depiction of SEM (left) showing temperature-guided relaxation of mobile chains into curl state while (right) illustrating directionalization of fibers through macroscopic force application [92].

wettability ease (18o), first by spin coating epoxy solution over PCL fibrous membrane with uniform lay off employing wetting-ability of precursor. Secondly with core–shell technology with epoxy as cylindrical core to PCL outer cover which were subsequently crosslinked with 100 W 365 nm UV. Both processes rendered uniformity of fabricated fiber in membrane except that rigorous control of feed rate difference between inner and outer flow (greater than inner which aided in epoxy stretchability for fiber formation) while spin rotation rpm for complete penetrability. Moreover, due to intrinsic involvement of epoxy with PCL in core-shell, storage modulus witnessed an elevation to 92 MPa > ~75 MPa for pure PCL along with other mechanical refinement in strength (2.41 MPa) and strain at break however, evidenced decrement in reference with epoxy (530 MPa—epoxy > 300 MPa—spin-coated electrospun composite). Shape memory was scrutinized at 70°C under stress with deduction of >97% recovery with life cycle assessment to 20 programming-recovery cycles. Spin-coated electrospun membranes were also examined for repeated self-healing cycles displaying 10 min efficacy at 80°C while core–shell evinced non-toxicity and >80% viable cells after 4 days of culture for miscellaneous practical employment [94, 95]. Bio- or cell activity enriches with hydrophilicity therefore, PCL, possessing hydrophobic character necessitated surface energy modulation to truncate contact angle and was acquired by co-spinning polyethylene oxide (PEO) with PCL to engineer bilayer hybrid (PCL–PCL/ PEO–PCL–) membrane system. This aid in water facilitation through pores for wet membranes ascertaining actuation in 12 s at 55°C unlike 120  s no activity in control wet PCL membranes. Water catalyzed PEO fiber melting in membranes which, contrastingly, ameliorates shape recovery force by securing its melt fibers on PCL (amplified crosslinking) albeit rendering macroscopic modulus weakening by approximately > 0.2 MPa in magnitude during wet than dry membranes [60]. Additionally, PEO is a non-ionic polymer which in association with ionic polymer, e.g., chitosan

462  Electrospun Materials and Their Allied Applications can quench its ionic interaction when in excess and thereby, its repulsive force whose controlled magnitude competes with voltage-generated charged fiber jet-out for building smooth and small diameter fibers. Furthermore, surfeit PEO addition introduced soft segments augmenting governed shape recovery but chitosan (being brittle) scantiness lessened hard segments for shape fixity and thereby, recovery temperature still averaging to ~90% recovery in ~17.2 s [96]. Contrary to sole temporary programmed structure in above-said research, PEO homogenization with Nafion, ascribed to wide working temperature range (55°–130°), empowered membrane with freedom of two, three, and four temporary structural halts. First, with two temporary halts, temperature programmed from 160°C (high mobility, high strain) → 100°C at 0.1 N force and 100°C → 40°C at 0.2 N owing to decrement in eternal energy and subsequently recovering back (~90%) while transiting from same temperatures. Similar study was manifested for three temporary shapes at 160°C → 120°C → 80°C → 40°C with 74–80% recovery. However, four temporary shapes were orchestrated at temperature traversing from 160°C → 135°C → 110°C → 90°C → 65°C with recovery efficiency varying in-between 67% and 93% thus, corroborating performance tunability freedom intelligent implementation (Figure 16.12) [97]. Moreover, tailoring nafion ink formulation with polyacrylonitrile (PAN) rendered membrane remote accessibility with voltage or alternatively, electricity which meanwhile, attenuated human direct interference or errors. Voltage-derived change was induced by sandwiching with carbonized (1000°C) PAN fibrous membranes, i.e., carbon fibers within nafion polymer, owing to inherited allowance for electron passage. Therefore, dramatic increment in indirect temperature through voltage rendered swift recoverability, i.e., Voltage (8, 14, 16 V) temperature (66°C, 130°C, 165°C, respectively) shape actuation in 5 s with 100% recuperation into parent structure when conductivity was ensured to be 12.3 S/cm [98]. In another research, PAN carbonization was positively channelized to instigate roughness hierarchy from shrinkage exposing attached SiO2 particles (PAN–SiO2 electrospinning) which conclusively had encouraged hydrophilicity (~20.6°) as per Cassie model for surface wettability causing amelioration in protein adsorption (30 mg/g). SiO2 had additionally, advocated mechanical softness by curtailing stiffness (~69 mN) and modulus fortifying it for unnatural conditions. Thus, these membranes had demonstrated astounding shape memory in sufficiently low liquid N2 and high flame environs by enduring bending forces without inducing brittle fracture thus displaying flexibility (bending to 80%, Tm composite = 58.3°C, shape memory—70°C/RT, 6.2 s with 100% recovery, ono-toxic

Co-axial electrospinning, core–shell

Electrospinning, chemical vapor polymerization, core–shell

Co-axial electrospinning, core–shell

Polycaprolactone, epoxy SMP–core

PLA–core, polypyrrole

PEG, Silibinin, Au, Fe2O3, poly (lactic-co-glycolic) acid

Smooth quality fibers, 30% silibinin released in NIR light in 40 h, magnetothermal drug delivery with temperature increase to 44°C in 40 h reporting first 20 h with fast drug release

Heart disease treatment, electroactive membranes, thinner PLA à high conductive membrane, time and temperature impact membrane conductivity, shape memory—15–40 V, 90–2 s, respectively, safe voltage limit LCST, 30°C) → cell attachment, wound healing— cirrhosis, diabetic patient, burnt tissues

(Continued)

[93]

[91]

References

Endothelial cells (human umbilical vein), shape recovery of blood vein mimic tube at 37°C, retention of properties after five cycles, 6 days culture with improved seeding and growth, human organs and tissue engineering

Degradation prevention of composite due to HA up to 70% residual mass after 12 weeks, elastic modulus increase up to 330 MPa, shape transformation at 50°C with fixity >99% and up to 94.9% recovery, attains permanent design in 20 s of saline rinse, treatment of injuries in long bones, skeletal tissue engineering

Properties

Table 16.1  Tabulation of stimuli-responsive and shape memory data of electrospun membranes for varied applications. (Continued)

468  Electrospun Materials and Their Allied Applications

PAN/SiO2 membrane carbonization at 850°C for CNF, SiO2 increases fiber roughness and declines conductivity, composite membranes are less stiffer (69 mN), increasingly hydrophilic (20°), high adsorption (30 mg/g) of proteins, shape memory at microscopic level (also in flame and liq. N2) CO2 and N2 responsive, 25 wt% polymer = stable jet, membrane untreated water contact angle = 140° → CO2 treatment → 36° in 5 min → N2 → back to original, with oil droplet surrounded with water = 36° → CO2 → 150° → N2→ back to original behavior, CO2 ameliorates roughness, reusable Shape recovery = 70% at temperature = 66°C, fixity = 80%, two-way shape memory, temperature decrement favor large pore size under stress for filtering, however, entanglements deviate porosity results

Electrospinning,

Electrospinning

Electrospinning

SiO2, carbon nanofiber (CNF)

PMMA, poly(N,Ndimethylaminoethyl methacrylate) (PDMAEMA)

SMPU

Properties

Processing

Materials

(Continued)

[102]

[87]

[99]

References

Table 16.1  Tabulation of stimuli-responsive and shape memory data of electrospun membranes for varied applications. (Continued)

Electrospun Technology  469

590% swelling in thickness at 4°C and contraction to 280% at 40°C-bending, 20 cycles, modulus alters over 15 time in magnitude with temperature 4°–40°C, for smart actuators

Electrospinning

Electrospinning

Electrospinning

PNIPAm, PU, 4-acryloylbenzophenone

Polyacrylamide-maleic acid

Oleic acid-Fe2O3, methyl methacrylate copolymer with 2-(acetoaceetoxy) ethyl methacrylate

Biomedical, lower magnetization of membranes than magnetic particles due to surface effect

Response to acidic and basic pH, deswells at normal pH around 7 to ooze out encapsulated medicine, low concentration of diethylene crosslinker swells at low pH and vice versa

pH stimulus, pore size at pH = 7 > pH = 4.5 due to stimulated swelling while reverse pH relation for membrane thickness, colored PS nanoparticles, and CCR5–siRNA–SLN display stable/higher release at pH = 7 than pH = 4.5, In vitro analysis for anti-HIV drugs

Electrospinning

PU copolymer displaying response to pH

Properties

Processing

Materials

(Continued)

[86]

[83]

[80]

[59]

References

Table 16.1  Tabulation of stimuli-responsive and shape memory data of electrospun membranes for varied applications. (Continued)

470  Electrospun Materials and Their Allied Applications

Membranes displayed ductile-type fracture, temperature shape memory, three-way, four-way, and five-way actuation, second temporary shape recovery = ~93.2%, first temporary shape recovery = ~87.7%, fixity >90%, temperature 160°C → 100°C → 40°C, membranes— light weight, permeable, biomimetic, medicines, actuators, smart-cloth Voltage diameter of fiber owing to large electrostatic −1 force (conductivity) , transition voltage actuation = 14 V (130°C), Recovery time = 5 s, 100% shape back to original owing to temperature distribution Smooth and narrow diameter fibers for 40 min UV after 55°C heat treatment, without UV → membrane melted, pre-curing (prior to electrospinning) crosslinking strength, shape memory at 55°C in 6 s, under thermal stimulus aided by water, Fe nanowire empowers visible light photothermal response, light stimulus recovery in 100 s, i.e., 18-fold slower response than thermal, Fe augments hydrophobicity (137°–147°), filtration application with smart features

Electrospinning

Electrospinning

Electrospinning,

Nafion, polyethylene oxide

Nafion, PAN (electrospinned and post-carbonization)

Ethylene vinyl acetate, Fe nanowire

Properties

Processing

Materials

(Continued)

[100]

[98]

[97]

References

Table 16.1  Tabulation of stimuli-responsive and shape memory data of electrospun membranes for varied applications. (Continued)

Electrospun Technology  471

Processing

Electrospinning, spin-coating

Electrospinning

Materials

Bisphenol A epoxy, PCL (membrane)

Polyethylene oxide, chitosan

PEO concentration viscosity bead-free fiber fiber −1 diameter (elastic modulus) recovery % (shape −1 −1 fixity) (recovery time) , shape fixity and recovery >90%, recovery time < 20 s, five memory cycles, smart structures

Shape memory and self healing property with non-shape memory materials, defect-free composite with higher wetting of membrane (18°) with epoxy, self-healing in 10 min at 80°C, composite → transition temperature = 63.8°C, modulus = 300 MPa, shape recovery at 70°C in 10 s, recovery >97% for 20 cycles, fixity ~95.5%, also favored with silica rubber and PCL composite, drug release, micro-energy harvesting

Properties

[96]

[94]

References

Table 16.1  Tabulation of stimuli-responsive and shape memory data of electrospun membranes for varied applications. (Continued)

472  Electrospun Materials and Their Allied Applications

Electrospun Technology  473 Non-Uniform deformation in hot water driven by 3D printed lines 37°C

0°C

37°C

37°C

0°C

0°C

Figure 16.14  Illustration of 3D printed engendered non-uniform transformation (in-plane and out-of-plane) at temperatures between 0°C and 37°C [103].

which advocate shape change under external trigger. Merging this sophisticated 3D build-up with fine-tune fiber fabrication, Chen et al. dispensed clay–PNIAPm composite photopolymerizable ink over electrospun PNIPAm membrane which imposed constriction near printed pattern and aided in stress generation which administered anisotropic swelling at >LCST. This mechanism invigorated intricate swelling/shrinkage transformation driving buckling (with varied pattern printing) at above and below LCST (0°C to 37°C) as illustrated in Figure 16.14. Furthermore, authors reported material’s endurance for >20 cycles and pronounced curvatures in 120 s as actuation temperature exceeded 25°C while de-swelling in around 60 s when entity had 100 µm thickness [103]. Thus, shape memory biomimicked membranes had facilitated implantation suppleness with temporary shapes being transmute to pre-determined shape after bodily actuation. Biomedical—high predictability for bandages [60].

16.4 Conclusion This book chapter has outlined the essence of electrospinning, a brief depiction of essential components involved, influential parameters which enables attuning final properties, emphasizing tailoring of polymers, hydrogels, and composites with reinforcements that empowers material

474  Electrospun Materials and Their Allied Applications sensing for apposite response. Designed membranes, though inherit tremendous performance but embedding in the shape memory property or stimuli responsiveness is provident for smart textiles which scanning the exposed environment tune the porosity allowing or barricading heat or miscellaneous particles (simultaneously acting as sensor). Another extensively experimented field is filtration of air and water, both cherish life, significantly toward fuel cell for permeation of requisite fluid, and a pre-eminent proportion in biomedical for wound healing, surgeries, and tissue engineering permitting transference of nutrients, medicinal drugs, body fluids, and air (oxygen) nourishing while simulating bodily conditions and fineness architecture. Thus, this book chapter has endeavored to present the recent typesetting trends of membranes with savor of intelligent material sensing capability evidencing a glimpse of scope of untying the obscurity residing for various application domains.

Acknowledgment The authors would like to thank Dr. C.P. Ramanarayanan, Vice Chancellor, Defence Institute of Advanced Technology (DU), Pune for support. Prasansha Rastogi would also like to acknowledge Mr. Prakash Gore for his technical support.

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17 Antimicrobial Electrospun Materials Rushikesh S. Ambekar1,2 and Balasubramanian Kandasubramanian1* Rapid Prototype and Electrospinning Lab, Department of Metallurgical and Materials Engineering, DIAT (DU), Ministry of Defence, Girinagar, Pune, Maharashtra, India 2 NanoEngineering Lab, Department of Metallurgical and Materials Engineering, Indian Institute of Technology Kharagpur, West Bengal, India 1

Abstract

The human body needs to be protected from invaders in the world like microbes as WHO data shows that 17 million people die every year due to infectious diseases, source of these infectious diseases are microbes such as bacteria, fungi, protozoa, and viruses. In the last 20 years, 30 new diseases were discovered by researchers. Bacteria are the most common microbe which attacks the human body; therefore, protection from such life-threatening microorganism is extremely necessary. Anti-microbial drugs were discovered long back but their sustained dose only help in antibacterial effects otherwise burst release of the drug can cause side effects on the human body. To acquire sustained release drug embedded biopolymer system are most commonly practiced in this way drug release can be tuned with the degradation of biopolymers. There are many techniques for fabrication of drug/­polymer system but to achieve higher efficiency rate higher surface area is required, therefore, nanotechnology utilizes for designing such high surface area materials such as nanofibers. Nanofibers can be fabricated via melt spinning, pressurized gyration, phase separation and electrospinning, out of which electrospinning is most popular due to enormous surface area, tunable fiber diameter, highly biocompatible, cost-effectiveness. In the present chapter, we have discussed recent advances in drug embedded biodegradable electrospun nanofibers as well as non-biodegradable electrospun nanofibers for anti-bacterial applications. Keywords:  Polymer nanofibers, electrospinning, anti-bacterial drug, biodegradable polymers, drug delivery

*Corresponding author: [email protected] Inamuddin, Rajender Boddula, Mohd Imran Ahamed and Abdullah M. Asiri (eds.) Electrospun Materials and Their Allied Applications, (483–514) © 2020 Scrivener Publishing LLC

483

484  Electrospun Materials and Their Allied Applications

17.1 Introduction The human body needs protection from life-threatening infections which is caused due to the failing of the immune system while protecting the body from microbial attack [1]. WHO data shows that in the last 20 years, 30 new diseases were discovered. The microbes are species that evolve themselves in such a way that they can habituate in hot as well as cold places [2, 3], also in copious media such as soil, water and air [4–6]. Presently, researchers have developed anti-microbial drugs but day-by-day, microbes itself develop themselves to tackle these drug [7], therefore, the effectiveness of the drug is not observed at low dose whereas, at higher dose side effect of the drug can cause secondary illness [8]. Researchers have fabricated systems where the higher dosage of drug delivery is possible via sustain drug release such as drug embedded polymeric nanocarriers [9, 10]. There are mainly two types of bacteria according to stain test, Gram-positive and gram-negative bacteria, S. pneumoniae is gram-positive bacteria whereas, Escherichia coli, Vibrio cholera are gram-negative bacteria. Bacteria can also be classified on the basis of its shapes such as round (cocci), cylindrical (bacilli), and spiral bacteria (spirilla) [11, 12] (as shown in Figure 17.1). The drug discovery and drug development are one of the most emerging fields in the health sector, specifically for anti-bacterial application drug can be synthetic or natural along with nanoparticles of metal and ceramics are also utilized to achieve for higher bacterial inhibition. researchers have developed copious synthetic drugs such as Doxycycline, Amoxicillin, Metronidazole, and Ciprofloxacin [13, 14], a various natural drug such as clove, curcumin, lavender oil, tea extract, and Cinnamon essential oil [15, 16], nanoparticles such as CuO, ZnO, Ag, WS2 are also utilized for anti-­ bacterial activity [17, 18]. Polymers are one of the finest materials for combination with drug against bacterial activity, drug embedded biodegradable

Classification of Bacteria

Gram stain

Gram-positive bacteria

Gram-negative bacteria

Shape

Spirilla

Bacilli

Figure 17.1  Classification of bacteria on the basis of gram stain and shape.

Cocci

Antimicrobial Electrospun Materials  485 polymers such as Chitosan, Poly(ε-caprolactone), Cellulose acetate, Polylactic Acid, Poly(vinyl alcohol), Poly(lactic-co-glycolic acid) have application in wound dressing, tissue engineering, and drug delivery whereas, drug embedded non-biodegradable polymers like Polyacrylonitrile, Poly(ethylene oxide), Polystyrene, and Nylon 6 have application in catalysis, food packaging and water filtration. The surface area of these carriers plays a prime role in anti-bacterial effectiveness therefore in the context of enormous surface area nanotechnology is a most beneficial option as it also has other properties such as topography and roughness [19], wettability and free energy [20–22], and surface chemistry [23]. These multifunctional properties of nanotechnology have a large spectrum of fields like electronics [24–26], environmental [27–29], food agriculture [30], renewable energy [31], textile [32], and biomedical, out of which in biomedical most emerging applications are tissue engineering [33–35], drug delivery [36], wound dressing [37], bio-adhesive [38], and anti-bacterial platform [39–41]. Copious nanofibers production methodologies are available like melt spinning [42], pressurized gyration [43, 44], phase separation [45], and electrospinning [46], out of them electrospinning is most attractive due to its large specific surface area, oxygen permeability, porosity, tunable fiber diameter, and cost-effectiveness [47, 48]. In this chapter, we have discussed the antibacterial properties of drug incorporated biodegradable and nonbiodegradable polymer nanofibers.

17.2 Drug-Loaded Polymer Nanofibers There are two types of drug loaded polymer nanofibers, biodegradable and non-biodegradable nanofibers as depicted in Figure 17.2.

17.3 Drug-Loaded Biodegradable Polymer Nanofibers Biodegradable polymers contains chitosan, Polycaprolactone, cellulose acetate, Polylactic Acid, poly(vinyl alcohol) and Poly(lactic-co-glycolic acid), these nanofibers haves applications in drug delivery, tissue engineering, wound dressing due to their biocompatibility, and biodegradability. Uygun et al. prepared RF hydrazine plasma modified chitosan nanofibers via electrospinning technique to enhance the NH2 functional groups in chitosan which is confirmed with FTIR and fluorescence analysis. TGA analysis reveals that moisture absorption capability of plasma modified

486  Electrospun Materials and Their Allied Applications Polymer Nanofibers

Biodegradable Polymer Nanofibers

Non-biodegradable Polymer Nanofibers

Chitosan

Polyacrylonitrile

Poly(ε-caprolactone)

Poly(ethylene oxide)

Cellulose acetate

Polystyrene

Poly(lactic acid)

Nylon 6

Poly(vinyl alcohol) Poly(lactic-co-glycolic acid)

Figure 17.2  Classification of polymer nanofibers based on degradability.

chitosan was three times augmented compared to pristine chitosan nanofibers. Anti-bacterial test confirms that plasma modified chitosan nano­ fibers have enhanced bacterial resistance than pristine chitosan nanofibers [49]. Yadav and Balasubramanian proposed eugenol loaded chitosan electrospun nanofibers for wound dressing and tissue engineering function. Cytotoxic test was performed on as-prepared nanofibers and found that it has 45% fibroblast cell line viability as well as in anti-bacterial study, eugenol loaded chitosan nanofibers have 0.9 to 1 cm, 0.4 to 0.6 cm, and 1.2 to 1.5 cm zone of inhibition against K. pneumonia, S. aureus, and B. subtilis, respectively [40]. In addition inhibition mechanism of eugenol against gram-negative bacteria was also mentioned. Monteiro et al. fabricated gentamicin encapsulated liposomes loaded chitosan electrospun nanofibers for wound dressing application. Drug release study shows that gentamicin loaded chitosan nanofibers have burst release compare to gentamicin release from liposome which is immobilized on chitosan nano­ fibers. Anti-bacterial study suggests that zone of inhibition of as-prepared nanofibers have 25, 24, and 16 mm against S. aureus, E. coli, and P. aeruginosa, respectively [50]. L. monocytogenes bacteria responsible for spoilage of meat products, therefore, Lin et al. developed Chrysanthemum essential oil incorporated chitosan nanofibers for beef packaging. The anti-bacterial test shows that bacterial count was reduced in chrysanthemum essential oil incorporated chitosan nanofibers compared to pristine nanofibers. They have also studied temperature-dependent drug release where they found that increase in temperature 4°C (45%), 12°C (58%), and 25°C (64%) in

Antimicrobial Electrospun Materials  487 15 days helps in faster drug release [51]. Honey is well known for its antibacterial, anti-inflammatory and antioxidant properties, Wessam et  al. reported honey loaded chitosan/PVA nanofibers via electrospinning technique. Anti-bacterial study confirms that as-prepared nanofibers have better resistance to E. coli (0.9 CFU/mL bacteria) than S. aureus (3.1 CFU/ mL) for 24 h of incubation time. Similarly, for 48 h of incubation period as-prepared nanofibers show enhanced bacterial resistance toward E. coli (2.9 CFU/mL bacteria) than S. aureus (8.25 CFU/mL) [52]. Cai et al. prepared Fe3O4 nanoparticles embedded chitosan/gelatin nanofibers via electrospinning technique. Mechanical properties such as Young’s modulus, tensile strength, and toughness was increased by 155%, 128%, and 100% with addition of 1 wt% Fe3O4 nanoparticles compared to pristine chitosan/ gelatin nanofibers. Similarly, anti-bacterial study shows that zone of inhibition of 1 wt% Fe3O4 nanoparticles/chitosan/gelatin nanofibers (20 mm) was greater than pristine chitosan/gelatin nanofibers (15  mm) against E.  coli. Similarly, 1 wt% Fe3O4 nanoparticles/chitosan/gelatin nanofibers (19  mm) was greater than pristine chitosan/gelatin nanofibers (13  mm) against S. aureus [53]. Kuntzler et al. proposed Phenolic compound embedded ­chitosan/polyethyleneoxide electrospun nanofibers for Active packaging function. Phenolic compound extracted from Spirulina sp. LEB 18, as-­prepared chitosan/polyethylene oxide nanofibers has 262 ± 32 nm diameter. Anti-bacterial study shows that addition of phenolic compound slightly increases zone of inhibition of CS/PEO nanofibers (6.4 ± 1.1 mm) compared to pristine CS/PEO nanofibers (6.0 ± 0.7 mm) against S. aureus [54]. Annur et al. fabricated plasma-treated Ag nanoparticles loaded ­chitosan/PEO co-electrospun nanofibers for water filtration. SEM test shows that as-prepared chitosan nanofibers have approximately 130 nm diameter and anti-bacterial study confirms that 1.5 min plasma-treated nanofibers (0.78 mm) increase zone of inhibition twice compare to plasma untreated nanofibers (0.36 mm) [55]. Zupančič et al. developed Metronidazole and Ciprofloxacin loaded PCL electrospun nanofibers for drug delivery application. Drug release study shows that the release rate of MNZ was faster than CIP drug in MNZ/CIP/PCL nanofibers. Anti-bacterial study reveal that MNZ/CIP/ PCL nanofibers (4.5 cm) have higher zone of inhibition compared to MNZ/PCL nanofibers (1.8 cm) and CIP/PCL nanofibers (4.2 cm) against A. actinomycetemcomitans similarly, MNZ/CIP/PCL nanofibers (7.2 cm) have higher zone of inhibition compared to MNZ/PCL nanofibers (7 cm) and CIP/PCL nanofibers (4.5 cm) against F. nucleatum [56]. Permyakova et al. reported COOH/anhydride functionalized Gentamicin loaded PCL nanofibers via needleless electrospinning technique for wound healing.

488  Electrospun Materials and Their Allied Applications The anti-bacterial test shows that as-prepared nanofibers have 28, 22, and 16 mm zone of inhibition for E. coli K-19, E. coli K-261, and E. coli K-41, respectively [57]. Fakhri et al. prepared WS2 nanoparticles decorated Neomycin loaded PCL and chitosan nanofibers via electrospinning technique. Bactericidal efficiency of Neomycin/WS2 nanoparticles/PCL nanofibers (20 × 108 CFU) was higher than Neomycin/WS2 nanoparticles/PCL nanofibers (22 × 108 CFU) against E. coli correspondingly Neomycin/ WS2 nanoparticles/PCL nanofibers (5 × 108) was higher than Neomycin/ WS2 nanoparticles/PCL nanofibers (7 × 108) against S. aureus [58]. Curcumin is one of the active ingredients of turmeric which has multiple useful properties such as anti-infective, anti-oxidant, and anti-­ inflammatory, a similar set of properties required during wound healing; therefore, Mohammadi et al. proposed curcumin embedded Gum­ tragacanth/PCL nanofibers for diabetic wound healing. Drug release study reveals that as-prepared nanofibers have 65% release in 20 days. Anti-bacterial study shows that as-prepared nanofibers have 99% resistance against Methicillin-resistant S. aureus and 85.14% resistance against extended-spectrum β lactamase [16]. Ramírez-Agudelo et al. fabricated Doxycycline loaded Poly-caprolactone/gelatin/hydroxyapatite nanofibers as drug delivery carriers. Kinetic study of drug release shows that burst release was observed in first stage whereas, remaining drug release slow down over 55 h. Anti-bacterial study confirms that PCL/gelatin/ hydroxyapatite nanofibers have 25 mm and 27 mm zone of inhibition against P. gingivalis and S. aureus, respectively [18]. Wahab et al. developed Ag nanoparticles loaded cellulose nano­fibers via electrospinning technique. Area of inhibition zone enhanced by heat-­ treatment as-prepared nanofibers such as 2 h heat-treated Ag/­cellulose nanofibers (347.1305 mm2) shows enhanced resistance than 1  h heattreated Ag/cellulose nanofibers (270.345 mm2) against S. aureus, similarly, 2 h heat-treated Ag/cellulose nanofibers (269.9637 mm2) shows enhanced resistance than 1 h heat-treated Ag/cellulose nanofibers (223.76 mm2) against E. coli [59]. Nthunya et al. reported Ag/Fe nanoparticles loaded cellulose acetate/β-cyclodextrin electrospun nanofibers for water treatment. TEM confirms that average diameter of as-prepared nano­fibers was approximately 382.12 ± 30.09 nm. Anti-bacterial test suggests that 0.125 gm/mL Ag loaded β-CD/CA (3.125 gm/mL) nanofibers possess resistance against E. faecalis, P. mirabilis, whereas 0.25 gm/mL Ag loaded β-CD/CA (6.25 gm/mL) nanofibers possess resistance against all the bacteria [60]. Jatoi et al. prepared AgNPs anchored TiO2 nanoparticles loaded cellulose acetate nanofibers via electrospinning technique. TEM study confirms that Ag nanoparticles (5.9 nm) are densely anchored on TiO2

Antimicrobial Electrospun Materials  489 nanoparticles (36.12 nm). Anti-bacterial study reveal that 10 wt% AgNPs/ TiO2/cellulose acetate nanofibers (1.8 mm) have better resistance against S. aureus than 5 wt% AgNPs/TiO2/cellulose acetate nanofibers (1.61 mm), similarly, 10 wt% AgNPs/TiO2/cellulose acetate nanofibers (1.73 mm) have better resistance against E. coli than 5 wt% AgNPs/TiO2/cellulose acetate nanofibers (1.47 mm) [61]. Jia et al. proposed TiO2 and graphene oxide loaded cellulose acetate electrospun nanofibers for biomedical and anti-bacterial textiles. Bacterial inhibition rate of TiO2 and graphene oxide loaded cellulose acetate nanofibers (95%) was greater than pristine cellulose acetate nanofibers (10%) against B. subtilis, similarly, pristine cellulose acetate nanofibers (5%) have lower bacterial inhibition rate than TiO2 and graphene oxide loaded cellulose acetate nanofibers (95%) [62]. Mei et al. fabricated chlorogenic acid and Stereocomplex crystallite loaded poly (lactic acid) electrospun nanofibers for filter and mask application. Tensile strength of composite nanofibers augments from 1 MPa to 7 MPa due to heat treatment at 65°C for 1 h, as well as Young’s modulus also improves from 40 MPa to 260 MPa. The anti-­bacterial test confirms that pristine PLA nanofibers (0%) have poor bacterial inhibition efficiency whereas, composite nanofibers (99.99%) have excellent bacterial inhibition efficiency [63]. Zhang et al. developed graphene oxide (GO) and dopamine methacrylamide (DMA) embedded PLA electrospun nanofibers for biomedical applications. Wettability study shows that pristine PLA nanofibers (138.7°) have higher water contact angle than PLA/GO nanofibers (36.6°) and PLA/GO/DMA nanofibers (37°). Cell viability study confirms that PLA/GO/DMA nanofibers (55%) have lower E.  coli viability than PLA/ GO nanofibers (18%) [64]. Nguyen et al. reported PLA/chitosan nanofibers via coaxial electrospinning technique, in which PLA acts as core and chitosan acts as a shell material. Chitosan is popular for its anti-bacterial property but reduction in concentration of chitosan by increasing core feed rate causes poor bacterial resistance such as PLA/chitosan nano­ fibers (0.16) with core feed rate of 1.0 µL/min have greater optical density than PLA/chitosan nanofibers (0.27) with core feed rate of 4.0 µL/ min [65]. Zhang et al. prepared Ag nanowires loaded poly­vinyl alcohol electrospun nanofibers for copious applications like wound dressing, air purification and water filtration. SEM image shows that Ag nanowire has 86 nm diameter and spun nanofiber has 189 nm diameter. Anti-bacterial study reveals that 100 μL Ag NW/PVA nanofibers (99%) exert better bacteriostasis rate than 25 μL Ag NW/PVA nanofibers (42%) against E. coli similarly in case of S. aureus 50 μL Ag NW/PVA nanofibers (>99%) exert better bacterio-stasis rate than 25 μL Ag NW/PVA nanofibers (85%) [66]. Aytac et  al. proposed allyl isothiocyanate/β-cyclodextrin encapsulated

490  Electrospun Materials and Their Allied Applications polyvinyl alcohol electrospun nanofibers for active food packaging and biomedical applications. Drug release study shows that cumulative release of allyl isothiocyanate becomes faster with enhancement in the temperature from 30°C to 50°C and 75°C. Anti-bacterial study suggest that allyl isothiocyanate/β-cyclodextrin/PVA nanofibers (99.82%) have better growth inhibition rate against S. aureus compared to allyl isothiocyanate/ PVA nanofibers (53.55%), similarly, allyl isothiocyanate/β-­cyclodextrin/ PVA nanofibers (94.41%) have better growth inhibition rate against E. coli compared to allyl isothiocyanate/PVA nanofibers (31.98%) [67]. Shalumon et al. fabricated ZnO nanoparticles loaded Sodium alginate/ PVA electrospun nanofibers for wound dressing. Thermal analysis shows that pristine alginate and PVA have degradation temperature at 250°C and 240°C, respectively, whereas, alginate/PVA nanofibers start degradation at 300°C and this stability of blend at higher temperature confirms the compatibility of blend. Anti-bacterial study shows that alginate/PVA nano­ fibers (0 mm) have lower zone of inhibition than 0.5 wt% ZnO/­alginate/ PVA nanofibers (15 mm) against S. aureus [68]. Zheng et al. developed Amoxicillin and nano-hydroxyapatite loaded poly(lactic-co-glycolic acid) electrospun nanofibers for tissue engineering function. Drug release study confirms that Amoxicillin/nano-hydroxyapatite/PLGA nano­fibers release 30% Amoxicillin in 15 days. Anti-bacterial study shows that as-prepared composite nanofibers with 60 µg/mL concentration (95%) exert better S. aureus inhibition rate that 20 µg/mL concentration (15%) [69]. Qi et al. reported Tetracycline hydrochloride and halloysite embedded PLGA electrospun nanofibers for tissue engineering and drug delivery application. Drug release study shows that Tetracycline hydrochloride embedded PLGA nanofibers (99% in 15 days) have burst release whereas, 2 wt% Tetracycline hydrochloride/halloysite/PLGA nanofibers (65% in 42 days) have sustained release. Bacterial inhibition rate of composite nanofibers with 40 µg/mL concentration (80%) was better than 10 µg/mL concentration (38%) of tetracycline hydrochloride [70]. Among the above discussed biodegradable nanofibers, allyl isothiocyanate/β-cyclodextrin/ PVA nanofibers (99.82%) have highest bacterial growth inhibition rate and chlorogenic acid and stereocomplex crystallite loaded poly(lactic acid) nanofibers have highest bacterial inhibition efficiency and apart from this, gentamicin encapsulated liposomes loaded chitosan electrospun nanofibers have 25 mm zone of inhibition against S. aureus and gentamicin loaded PCL nanofibers have 28 mm zone of inhibition against E. coli K-19. Characteristics of drug loaded biodegradable polymer nanofibers are consolidated in Table 17.1.

Drug

–

Eugenol

Gentamicin

Polymer

Chitosan

Chitosan

Chitosan

Materials

–

–

–

Filler

Wound dressing

dressing

and wound

Tissue engineering

application

Biomedical

Application

Table 17.1  Drug loaded biodegradable polymer nanofibers.

P. aeruginosa

S. aureus, E. coli, and

and B. subtilis

K. pneumonia, S. aureus,

In vitro

In vitro

–

B. subtilis, S. aureus, E. coli, and P. aeruginosa

Condition

Resistance to bacteria

(P. aeruginosa)

G/Ch NFM—16 mm

G/Ch NFM—24 mm (E. coli)

[50]

[40]

[49]

Ref.

(Continued)

G/Ch NFM—25 mm (S. aureus)

Zone of inhibition

(B. subtilis)

Chitosan/Eugenol—1.2 to 1.5 cm

(S. aureus)

Chitosan/Eugenol—0.4 to 0.6 cm

(K. pneumonia)

Chitosan/Eugenol—0.9 to 1 cm

Zone of inhibition

5 cfu/mL

Plasma treated Chitosan—log

Chitosan—log 6.5 cfu/mL

Antibacterial effect against

Results/properties

Antimicrobial Electrospun Materials  491

Chitosan/PVA

Honey

–

Wound dressing

S. aureus and E. coli –

Bacterial population

CFU/mL bacteria in 48 h

[52]

[51]

Ref.

(Continued)

5.5% chitosan/honey/PVA—2.9

CFU/mL bacteria in 24 h

5.5% chitosan/honey/PVA—0.9

E. coli

CFU/mL bacteria in 48 h

5.5% chitosan/honey/PVA—8.25

3.1 CFU/mL bacteria in 24 h

5.5% chitosan/honey/PVA—

S. aureus

Antibacterial activity against

7 days

CHEO/CS—2.5 log cfu/mL after

CS—4 log cfu/mL after 7 days

after 1 days

CHEO/CS—1.25 log cfu/mL

CS—2.25 log cfu/mL after 1 day

In vitro

L. monocytogenes

Results/properties

(CHEO)

Beef packaging

–

Condition

Resistance to bacteria

Initial conc—6.5 log cfu/mL

Chrysanthemum

Chitosan

Application

Filler

essential oil

Drug

Polymer

Materials

Table 17.1  Drug loaded biodegradable polymer nanofibers. (Continued)

492  Electrospun Materials and Their Allied Applications

Phenolic

Chitosan/PEO

oxide)

poly(ethylene

Chitosan/

Fe3O4 nanoparticles

Chitosan/gelatin

(AgNPs)

Ag nanoparticles

compounds

Drug

Polymer

Materials

–

–

–

Filler

Water filtration

Active packaging

Wound dressing

Application

–

S. aureus and E. coli

–

–

E. coli and S. aureus

E. coli

Condition

Resistance to bacteria

Table 17.1  Drug loaded biodegradable polymer nanofibers. (Continued)

treatment)

0.78 mm (1.5 min plasma

2 wt% AgNPs chitosan/PEO—

treatment)

0.36 mm (without plasma

2 wt% AgNPs chitosan/PEO—

Zone of inhibition

± 1.1 mm [55]

[54]

[53]

Ref.

(Continued)

CS/PEO/phenolic compound—6.4

CS/PEO—6.0 ± 0.7 mm

S. aureus

Zone of inhibition

nanofiber—19 mm

1 wt% Fe3O4/CS/GE

CS/GE nanofiber—13 mm

S. aureus

20 mm

1 wt% Fe3O4/CS/GE nanofiber—

CS/GE nanofiber—15 mm

Zone of inhibition against E. coli

Results/properties

Antimicrobial Electrospun Materials  493

(PCL)

Polycaprolactone

Gentamicin

Ciprofloxacin

Metronidazole and

Poly(ε-

caprolactone)

Drug

Polymer

Materials

polymers

plasma

COOH-anhydride

–

Filler

Wound healing

Drug delivery

Application

K-261

E. Coli K-41 and E. Coli

E. Coli K-19, –

(E. coli K-261)

nanaofibers—22 mm

PCL-MA-GMi

(E. coli  K-41)

nanofibers—16 mm

PCL–MA–GMi

(E. coli K-19)

nanofibers—28 mm

PCL–MA–GMi

Zone of inhibition

PCL/MNZ/CIP—7.2 cm

PCL/CIP—4.5 cm

PCL/MNZ—7 cm

F. nucleatum

PCL/MNZ/CIP—4.5 cm

PCL/CIP—4.2 cm

PCL/MNZ—1.8 cm

actinomycetemcomitans

Zone of inhibition against A. actinomycetemcomitans

In vitro

F. nucleatum,

Results/properties

P. gingivalis, and A.

Condition

Resistance to bacteria

Table 17.1  Drug loaded biodegradable polymer nanofibers. (Continued)

(Continued)

[57]

[56]

Ref.

494  Electrospun Materials and Their Allied Applications

hydroxyapatite

gelatin/

caprolactone/

Poly-

caprolactone)

poly(Ɛ-

Gum tragacanth/

Doxycycline

Curcumin

Neomycin

Polycaprolactone

and chitosan

Drug

Polymer

Materials

–

–

2

WS nanoparticles

Filler

Drug delivery

healing

Diabetic wound

–

Application

S. aureus and P. gingivalis

lactamase (ESBL)

extended spectrum β

S. aureus (MRSA) and

In vitro

In vitro

–

S. aureus and E. coli

Methicillin resistant

Condition

Resistance to bacteria

Table 17.1  Drug loaded biodegradable polymer nanofibers. (Continued)

8

8

8

8

P. gingivalis

[18]

[16]

[58]

Ref.

(Continued)

PCL/gelatin/HA—25 mm against

S. aureus

PCL/gelatin/HA—27 mm against

Zone of inhibition

ESBL

PCL/GT/Cur—85.14% against

MRSA

PCL/GT/Cur—99% against

Antibacterial activity

dark (S. aureus)

2

NEO/WS /PCL—5 × 10 CFU in

in dark (E. coli)

2

NEO/WS /PCL—20 × 10 CFU

dark (S. aureus)

2

NEO/WS /CS—7 × 10 CFU in

dark (E. coli)

2

NEO/WS /CS—22 × 10 CFU in

Bactericidal efficiency

Results/properties

Antimicrobial Electrospun Materials  495

(2 h heat treated) 2

bacteria

[60]

[59]

Ref.

(Continued)

(6.25 g/mL)—resist to all the

S. sonnei, and

0.25 g/mL Ag loaded β-CD/CA

E. cloacae

mirabilis, S. boydii,

E. faecalis, P. mirabilis

2

0.125 g/mL Ag loaded β-CD/

Antibacterial test

(2 h heat treated)

Ag/Cellulose—269.9637 mm

(1 h heat treated)

Ag/Cellulose—223.76 mm

E. coli

2

CA (3.125 g/mL)-resist to

–

B. cereus, E. faecalis,

2

Ag/Cellulose—347.1305 mm

(1 h heat treated)

Ag/Cellulose—270.345 mm

S. aureus

Area of inhibition zone

P. aeruginosa, P.

-

S. aureus and E. coli

Results/properties

K. oxytoca,

Water treatment

–

Condition

Resistance to bacteria

Fe NPs

β-cyclodextrin

Cellulose acetate

–

–

Application

E. coli, K. pneumonia,

AgNPs

Cellulose

Filler

(β-CD) and Ag/

Drug

Polymer

Materials

Table 17.1  Drug loaded biodegradable polymer nanofibers. (Continued)

496  Electrospun Materials and Their Allied Applications

Cellulose acetate

AgNPs anchored

Cellulose acetate

2

graphene oxide

TiO nanofiber and

Nanoparticles

2

TiO

Drug

Polymer

Materials

2

2

2

2

2

TiO /GO/CA—95%

CA—5%

B. cereus

2

TiO /GO/CA—95%

CA—10%

textile

Inhibition rate

CA—1.73 mm

10 wt% AgNPs/TiO /

CA—1.47 mm

5 wt% AgNPs/TiO /

E. coli

CA—1.8 mm

10 wt% AgNPs/TiO /

CA—1.61 mm

5 wt% AgNPs/TiO /

S. aureus

Zone of inhibition against

Results/properties

B. subtilis

–

–

E. coli and S. aureus

B. cereus and B. subtilis

Condition

Resistance to bacteria

antibacterial

Biomedical and

–

–

–

Application

Filler

Table 17.1  Drug loaded biodegradable polymer nanofibers. (Continued)

(Continued)

[62]

[61]

Ref.

Antimicrobial Electrospun Materials  497

–

Biomedical and

application

Biomedical

application

–

Poly(lactic acid)

(DMA)

methacrylamide

dopamine

(GO) and

Graphene oxide

packages

crystallite

chitosan

–

Polylactic acid

Filters, masks, and

Stereocomplex

Application

filtration

Chlorogenic acid

Poly(lactic acid)

Filler

(PLA) and

Drug

Polymer

Materials

E. coli

–

–

–

E. coli and S. aureus

E. coli

Condition

Resistance to bacteria

Table 17.1  Drug loaded biodegradable polymer nanofibers. (Continued)

4.0 µL/min)

[65]

[64]

[63]

Ref.

(Continued)

PLA/chitosan—0.27 (feed rate-

1.0 µL/min

PLA/chitosan—0.16 (feed rate-

Optical density

PLA/GO/DMA—18%

PLA/GO—55%

E. coli viability (live)

(20)—99.99%

SC–PLA/PDLA–CTS

PLA (20)—0%

Bacterial inhibitory efficiency

Results/properties

498  Electrospun Materials and Their Allied Applications

(PVA)

Polyvinyl alcohol

PVA/AITC—31.98% PVA/AITC-CD—94.41%

E. coli

complex (IC)

PVA/AITC-CD—99.82%

application

(CD)-inclusion

PVA/AITC—53.55%

biomedical

Growth inhibition rate

cyclodextrin

–

(AITC)/Β-

S. aureus and E. coli

50 μL Ag NW/PVA—>99%

25 μL Ag NW/PVA—85%

S. aureus

Active food

100 μL Ag NW/PVA—99% S. aureus

25 μL Ag NW/PVA—42%

purification

Bacteriostasis rate

and air

–

S. aureus and E. coli

Results/properties

E. coli

Condition

Resistance to bacteria

water filtration,

Wound dressing,

Application

packaging and

–

–

Filler

isothiocyanate

Allyl

Ag nanowires

Poly(vinyl

alcohol)

Drug

Polymer

Materials

Table 17.1  Drug loaded biodegradable polymer nanofibers. (Continued)

(Continued)

[67]

[66]

Ref.

Antimicrobial Electrospun Materials  499

Zone of inhibition

glycolic acid)

Poly(lactic-co-

glycolic acid)

Poly(lactic-co-

20 µg/mL

40 µg/mL TCH/PLGA—80%

delivery

(TCH)

Bacterial inhibition %

µg/mL

AMX/n-HA/PLGA—95% at 60

AMX/n-HA—10% at 60 µg/mL

10 µg/mL TCH/PLGA—38%

Tissue engineering

science

AMX/n-HA/PLGA—15% at

Bacterial Inhibition

pharmaceutical

In vitro

In vitro

AMX/n-HA—10% at 20 µg/mL

S. aureus

S. aureus

and

Tissue engineering

and drug

Halloysite

hydroxyapatite

Nano-

hydrochloride

Tetracycline

Amoxicillin

5% ZnO/SA/PVA—15 mm

0.5% ZnO/SA/PVA—14 mm

SA/PVA—0 mm

E. coli

5% ZnO/SA/PVA—16 mm

0.5% ZnO/SA/PVA—15 mm

SA/PVA—0 mm

–

S. aureus and E. coli

Results/properties

alcohol)

Wound dressing

Condition

Resistance to bacteria

S. aureus

–

Nano ZnO

Sodium alginate/

Application

poly(vinyl

Filler

Drug

Polymer

Materials

Table 17.1  Drug loaded biodegradable polymer nanofibers. (Continued)

[70]

[69]

[68]

Ref.

500  Electrospun Materials and Their Allied Applications

Antimicrobial Electrospun Materials  501

17.4 Drug-Loaded Non-Biodegradable Polymer Nanofibers Non-biodegradable polymers contain Polyacrylonitrile, Poly(ethylene oxide), Polystyrene, and Nylon-6 nanofibers. These nanofibers have applications in food packaging, catalysis, and water filtration due to their mechanical strength, crystallinity, and structural stability in various solvents. Natural products extracted from the plant are widely known for their use in pharmaceutical science due to their ease of availability, eco-friendly, and biocompatibility these products even have capability to inhibit microbial colonization. In the same context Balasubramanian and Kodam prepared Lavender oil incorporated polyacrylonitrile electrospun nanofibers for biomedical, textile, and water treatment application. In-vitro release study of as-prepared nanofibers, they observed that sustain release (37% in 24 days) of lavender oil from nanofiber film and excellent anti-bacterial property against S. aureus and K. pneumoniae where zone of inhibition was 14–15 mm up to 14 days [41]. Yadav and Balasubramanian fabricated PAN/Syzygium aromaticum electrospun nanofibers for drug delivery application in which Syzygium aromaticum is also called clove oil. Drug release study shows that as-prepared nanofibers have sustained release, in addition cytotoxicity study confirm that it also has 100% cell viability of NIH/3T3 cell lines. The anti-bacterial study shows that PAN/Syzygium aromaticum nanofibers have higher zone of inhibition against gram-­negative bacteria (2.5 cm for 30 days) than gram-positive bacteria (1.8 cm for 30 days) [71]. Yadav and Balasubramanian developed curcumin loaded PAN electrospun nanofibers for water filtration. Drug release study shows early burst release for 5 h and then sustained release of 11–12% at 7.4 pH. Molecular dynamics simulation tool utilize to understand the interaction between curcumin and PAN. Anti-bacterial study shows that as-prepared nanofibers have 0.8 to 1 cm zone of inhibition against S. aureus and B. subtilis [40]. Furthermore Yadav and Balasubramanian also proposed Lavander oil loaded PAN electrospun nanofibers for water filtration. In case of drug release study, control release was observed of 38% lavender oil release in 24 h and as-prepared nanofibers have zone of inhibition 14–15 mm up to 30 days against copious bacteria such as E. coli, S. aureus, B. magaterium, and B. subtilis [40]. Shalaby et al. prepared Ag, CuO, or ZnO nanoparticles embedded PAN electrospun nanofibers for water filtration. Antibacterial study shows that Ag/PAN nanofibers (23 mm) have higher zone of inhibition than ZnO/PAN nanofibers (19 mm) and CuO/PAN nano­ fibers (17 mm) against S. aureus. Moreover Ag/PAN nanofibers (25 mm)

502  Electrospun Materials and Their Allied Applications has higher zone of inhibition than CuO/PAN nanofibers (18 mm) and ZnO/PAN nanofibers (17 mm) against E. coli [72]. Yang et al. fabricated Ampicillin and agar (polysaccharide complex) loaded PAN electrospun nanofibers for drug storage and cell imaging function. Drug release study shows that addition of agar exert significant effect on ampicillin release rate such as Ampicillin/PAN nanofibers (95% in 180 h) have faster drug release than Ampicillin/agar/PAN nanofibers (70% in 180 h), but addition of agar decrease the zone of inhibition against E. coli like Ampicillin/PAN nanofibers (20 mm) have higher bacterial resistance than Ampicillin/agar/ PAN nanofibers (17.5 mm) [73]. Cui et al. developed plasma-treated Beta-cyclodextrin (β-CD) and tea tree oil embedded poly(ethylene oxide) (PEO) electrospun nano­ fibers for food packaging. Anti-bacterial study reveals that 2 min at 600 W ­plasma-treated composite nanofibers (log 3.5 cfu/ml) have higher antibacterial activity than plasma untreated composite nanofibers (log 1 cfu/ml) [74]. Lin et al. reported cinnamon essential oil/β-cyclodextrin (CEO/β-CD) proteoliposomes loaded PEO electrospun nanofibers for food packaging. Bacterial inhibition study was carried out as a function of temperature and found that CEO/β-CD proteoliposomes PEO nanofibers (4 log cfu/g at 4°C) have better antibacterial activity against B. cereus than CEO/β-CD proteoliposomes PEO nanofibers (3 log cfu/g at 37°C) [75]. Furthermore antibacterial efficiency enhanced by Lin et al. by proposing polysaccharide from dandelions (CD) and carboxymethylated derivative (CPD) embedded PEO electrospun nanofibers for food packaging function. SEM study confirms that pristine PEO nanofibers (274 ± 15 nm) have higher fiber diameter than PD/PEO nanofibers (176 ± 21 nm) and CPD/ PEO nanofibers (132 ± 12 nm). Anti-bacterial study shows that CPD/PEO nanofibers (1.9 Log cfu/mL) have improved antibacterial effect than PD/ PEO nanofibers (2.8 Log cfu/mL) and pristine PEO nanofibers (4.8  Log cfu/mL) in 3 days of incubation period [76]. Henke et al. fabricated tetraphenyl­porphyrin loaded polystyrene nanofibers via electrospinning technique. Wettability study shows that pristine polystyrene nanofibers (130 ± 4°) have apparent contact angle higher than surface-modified polystyrene nanofibers (6000m.a.s.l.) Mineral Soils of the Atacama Region. J. Geophys. Res. Biogeosci., 117, 2, G02028, 2012. 4. Thakali, S., Allen, H.E., Di Toro, D.M., Ponizovsky, A.A., Rooney, C.P., Zhao, F.J., McGrath, S.P., Criel, P., Van Eeckhout, H., Janssen, C.R. et al., Terrestrial Biotic Ligand Model. 2. Application to Ni and Cu Toxicities to Plants, Invertebrates, and Microbes in Soil. Environ. Sci. Technol., 40, 22, 7094–7100, 2006. 5. Lapizco-Encinas, B.H., Davalos, R.V., Simmons, B.A., Cummings, E.B., Fintschenko, Y., An Insulator-Based (Electrodeless) Dielectrophoretic Concentrator for Microbes in Water. J. Microbiol. Methods, 62, 3 SPEC. ISS., 317–326, 2005. 6. Adams, R.I., Miletto, M., Taylor, J.W., Bruns, T.D., Dispersal in Microbes: Fungi in Indoor Air Are Dominated by Outdoor Air and Show Dispersal Limitation at Short Distances. ISME J., 7, 7, 1262–1273, 2013. 7. Al-Ani, I., Zimmermann, S., Reichling, J., Wink, M., Pharmacological Synergism of Bee Venom and Melittin with Antibiotics and Plant Secondary Metabolites against Multi-Drug Resistant Microbial Pathogens. Phytomedicine, 22, 2, 245–255, 2015. 8. Green, F.J., Lavelle, K.J., Aronoff, G.R., Vander Zanden, J., Brier, G.L., Management of Amikacin Overdose. Am. J. Kidney Dis., 1, 2, 110–112, 1981. 9. Chou, S.F., Carson, D., Woodrow, K.A., Current Strategies for Sustaining Drug Release from Electrospun Nanofibers. J. Control. Release, 220, 584–591, 2015. 10. Xie, J. and Wang, C.H., Electrospun Micro- and Nanofibers for Sustained Delivery of Paclitaxel to Treat C6 Glioma in Vitro. Pharm. Res., 23, 8, 1817– 1826, 2006. 11. Schleifer, K.H., Classification of Bacteria and Archaea: Past, Present and Future. Syst. Appl. Microbiol., 32, 8, 533–542, 2009. 12. Cerny, G., Studies on the Aminopeptidase Test for the Distinction of GramNegative from Gram-Positive Bacteria. Eur. J. Appl. Microbiol. Biotechnol., 5, 2, 113–122, 1978.

Antimicrobial Electrospun Materials  509 13. Xue, J., Niu, Y., Gong, M., Shi, R., Chen, D., Zhang, L., Lvov, Y., Electrospun Microfiber Membranes Embedded with Drug-Loaded Clay Nanotubes for Sustained Antimicrobial Protection. ACS Nano, 9, 2, 1600–1612, 2015. 14. Sharifi, F., Sooriyarachchi, A.C., Altural, H., Montazami, R., Rylander, M.N., Hashemi, N., Fiber Based Approaches as Medicine Delivery Systems. ACS Biomater. Sci. Eng., 2, 9, 1411–1431, 2016. 15. Suganya, S., Senthil Ram, T., Lakshmi, B.S., Giridev, V.R., Herbal Drug Incorporated Antibacterial Nanofibrous Mat Fabricated by Electrospinning: An Excellent Matrix for Wound Dressings. J. Appl. Polym. Sci., 121, 5, 2893– 2899, 2011. 16. Mohammadi, M.R., Rabbani, S., Bahrami, S.H., Joghataei, M.T., Moayer, F., Antibacterial Performance and in Vivo Diabetic Wound Healing of Curcumin Loaded Gum Tragacanth/poly(ϵ-Caprolactone) Electrospun Nanofibers. Mater. Sci. Eng. C, 69, 1183–1191, 2016. 17. Mahapatra, A., Garg, N., Nayak, B.P., Mishra, B.G., Hota, G., Studies on the Synthesis of Electrospun PAN-Ag Composite Nanofibers for Antibacterial Application. J. Appl. Polym. Sci., 124, 2, 1178–1185, 2012. 18. Ramírez-Agudelo, R., Scheuermann, K., Gala-García, A., Monteiro, A.P.F., Pinzón-García, A.D., Cortés, M.E., Sinisterra, R.D., Hybrid Nanofibers Based on Poly-Caprolactone/gelatin/hydroxyapatite Nanoparticles-Loaded Doxycycline: Effective Anti-Tumoral and Antibacterial Activity. Mater. Sci. Eng. C, 83, 25–34, 2018. 19. Yim, E.K.F., Darling, E.M., Kulangara, K., Guilak, F., Leong, K.W., Nanotopography-Induced Changes in Focal Adhesions, Cytoskeletal Organization, and Mechanical Properties of Human Mesenchymal Stem Cells. Biomaterials, 31, 6, 1299–1306, 2010. 20. Gore, P.M. and Dhanshetty, M., K, B. Bionic Creation of Nano-Engineered Janus Fabric for Selective Oil/organic Solvent Absorption. RSC Adv., 6, 112, 111250–111260, 2016. 21. Gore, P.M. and Kandasubramanian, B., Heterogeneous Wettable Cotton Based Superhydrophobic Janus Biofabric Engineered with PLA/ functionalized-Organoclay Microfibers for Efficient Oil–Water Separation. J. Mater. Chem. A, 6, 17, 7457–7479, 2018. 22. Gore, P.M., Purushothaman, A., Naebe, M., Wang, X., Kandasubramanian, B., Nanotechnology for Oil-Water Separation. In: Advanced Research in Nanosciences for Water Technology, 1st edn. Springer Science+Business Media, New York, NY., 299–339, 2019. 23. Castner, D.G. and Ratner, B.D., Biomedical Surface Science: Foundations to Frontiers. Surface Science, Elsevier., 500, 1-3, 28-60, 2002. 24. Tahalyani, J., Rahangdale, K.K., Aepuru, R., Kandasubramanian, B., Datar, S., Dielectric Investigation of a Conducting Fibrous Nonwoven Porous Mat Fabricated by a One-Step Facile Electrospinning Process. RSC Adv., 6, 43, 36588–36598, 2016.

510  Electrospun Materials and Their Allied Applications 25. Magisetty, R.P., Kumar, P., Gore, P.M., Ganivada, M., Shukla, A., Kandasubramanian, B., Shunmugam, R., Electronic Properties of Poly (1,6-Heptadiynes) Electrospun Fibrous Non-Woven Mat. Mater. Chem. Phys., 223, 343–352, 2019. 26. Prajapati, D.G. and Kandasubramanian, B., Progress in the Development of Intrinsically Conducting Polymer Composites as Biosensors. Macromol. Chem. Phys., 220, 10, 1800561, 2019. 27. Gore, P.M., Khurana, L., Siddique, S., Panicker, A., Kandasubramanian, B., Ion-Imprinted Electrospun Nanofibers of chitosan/1-Butyl-3-Methylimidazolium Tetrafluoroborate for the Dynamic Expulsion of Thorium (IV) Ions from Mimicked Effluents. Environ. Sci. Pollut. Res., 25, 4, 3320–3334, 2018. 28. Simon, S. and Balasubramanian, K., Facile Immobilization of Camphor Soot on Electrospun Hydrophobic Membrane for Oil–Water Separation. Mater. Focus, 7, 2, 295–303, 2018. 29. Bhalara, P.D., Balasubramanian, K., Banerjee, B.S., Spider–Web Textured Electrospun Composite of Graphene for Sorption of HgII) Ions. Mater. Focus, 4, 2, 154–163, 2015. 30. Guo, H., White, J.C., Wang, Z., Xing, B., Nano-Enabled Fertilizers to Control the Release and Use Efficiency of Nutrients. Curr. Opin. Environ. Sci. Health, 6, 77–83, 2018. 31. Prajapati, D.G. and Kandasubramanian, B., Biodegradable Polymeric Solid Framework-Based Organic Phase-Change Materials for Thermal Energy Storage. Ind. Eng. Chem. Res., 58, 25, 10652–10677, 2019. 32. Korde, J.M. and Kandasubramanian, B., Fundamentals and Effects of Biomimicking Stimuli-Responsive Polymers for Engineering Functions. Ind. Eng. Chem. Res., 58, 23, 9709–9757, 2019. 33. Rastogi, P., Njuguna, J., Kandasubramanian, B., Exploration of Elastomeric and Polymeric Liquid Crystals with Photothermal Actuation: A Review. Eur. Polym. J., 121, 109287, 2019. 34. Ambekar, R.S. and Kandasubramanian, B., Progress in the Advancement of Porous Biopolymer Scaffold: Tissue Engineering Application. Ind. Eng. Chem. Res., 58, 16, 6163-6194, 2019. 35. Rastogi, P. and Kandasubramanian, B., Review of Alginate-Based Hydrogel Bioprinting for Application in Tissue Engineering. Biofabrication, 11, 4, 42001, 2019. 36. Ambekar, R.S. and Kandasubramanian, B.A., Polydopamine-Based Platform for Anti-Cancer Drug Delivery. Biomater. Sci., 7, 5, 1776-1793, 2019. 37. Ambekar, R.S. and Kandasubramanian, B., Advancements in Nanofibers for Wound Dressing: A Review. Eur. Polym. J., 117, 304–336, 2019. 38. Korde, J.M. and Kandasubramanian, B., Biocompatible Alkyl Cyanoacrylates and Their Derivatives as Bio-Adhesives. Biomater. Sci., 6, 7, 1691–1711, 2018.

Antimicrobial Electrospun Materials  511 39. Balasubramanian, K., Yadav, R., Prajith, P., Antibacterial Nanofibers of Polyoxymethylene/gold for pro-Hygiene Applications. Int. J. Plast. Technol., 19, 2, 363–367, 2015. 40. Yadav, R. and Balasubramanian, K., Bioabsorbable Engineered Nanobiomaterials for Antibacterial Therapy, in: Engineering of Nanobiomaterials: Applications of Nanobiomaterials, Elsevier 2, 77–117, 2016. 41. Balasubramanian, K. and Kodam, K.M., Encapsulation of Therapeutic Lavender Oil in an Electrolyte Assisted Polyacrylonitrile Nanofibres for Antibacterial Applications. RSC Adv., 4, 97, 54892–54901, 2014. 42. Chung, S., Ingle, N.P., Montero, G.A., Kim, S.H., King, M.W., Bioresorbable Elastomeric Vascular Tissue Engineering Scaffolds via Melt Spinning and Electrospinning. Acta Biomater., 6, 6, 1958–1967, 2010. 43. Altun, E., Aydogdu, M.O., Crabbe-Mann, M., Ahmed, J., Brako, F., Karademir, B., Aksu, B., Sennaroglu, M., Eroglu, M.S., Ren, G. et al., Co-Culture of Keratinocyte-Staphylococcus Aureus on Cu–Ag–Zn/CuO and Cu.Ag–W Nanoparticle Loaded Bacterial Cellulose: PMMA Bandages. Macromol. Mater. Eng., 304, 1, 1800537, 2019. 44. Altun, E., Aydogdu, M.O., Koc, F., Crabbe-Mann, M., Brako, F., KaurMatharu, R., Ozen, G., Kuruca, S.E., Edirisinghe, U., Gunduz, O. et al., Novel Making of Bacterial Cellulose Blended Polymeric Fiber Bandages. Macromol. Mater. Eng., 303, 3, 1700607, 2018. 45. Li, G., Li, P., Zhang, C., Yu, Y., Liu, H., Zhang, S., Jia, X., Yang, X., Xue, Z., Ryu, S., Inhomogeneous Toughening of Carbon Fiber/epoxy Composite Using Electrospun Polysulfone Nanofibrous Membranes by in Situ Phase Separation. Compos. Sci. Technol., 68, 3–4, 987–994, 2008. 46. Yadav, R. and Balasubramanian, K., Metallization of Electrospun PAN Nanofibers via Electroless Gold Plating. RSC Adv., 5, 32, 24990–24996, 2015. 47. Badhe, Y. and Balasubramanian, K., Nanoencapsulated Core and Shell Electrospun Fibers of Resorcinol Formaldehyde. Ind. Eng. Chem. Res., 54, 31, 7614–7622, 2015. 48. Kandasubramanian, B. and Govindaraj, P., Peeling Model for Cell Adhesion on Electrospun Polymer Nanofibres. J. Adhes. Sci. Technol., 28, 2, 171–185, 2014. 49. Uygun, A., Kiristi, M., Oksuz, L., Manolache, S., Ulusoy, S., RF Hydrazine Plasma Modification of Chitosan for Antibacterial Activity and Nanofiber Applications. Carbohydr. Res., 346, 2, 259–265, 2011. 50. Monteiro, N., Martins, M., Martins, A., Fonseca, N.A., Moreira, J.N., Reis, R.L., Neves, N.M., Antibacterial Activity of Chitosan Nanofiber Meshes with Liposomes Immobilized Releasing Gentamicin. Acta Biomater., 18, 196–205, 2015. 51. Lin, L., Mao, X., Sun, Y., Rajivgandhi, G., Cui, H., Antibacterial Properties of Nanofibers Containing Chrysanthemum Essential Oil and Their Application as Beef Packaging. Int. J. Food Microbiol., 292, 21–30, 2019.

512  Electrospun Materials and Their Allied Applications 52. Sarhan, W.A. and Azzazy, H.M.E., High Concentration Honey Chitosan Electrospun Nanofibers: Biocompatibility and Antibacterial Effects. Carbohydr. Polym., 122, 135–143, 2015. 53. Cai, N., Li, C., Han, C., Luo, X., Shen, L., Xue, Y., Yu, F., Tailoring Mechanical and Antibacterial Properties of Chitosan/gelatin Nanofiber Membranes with Fe 3 O 4 Nanoparticles for Potential Wound Dressing Application. Appl. Surf. Sci., 369, 492–500, 2016. 54. Kuntzler, S.G., Costa, J.A.V., Morais, M.G., de. Development of Electrospun Nanofibers Containing chitosan/PEO Blend and Phenolic Compounds with Antibacterial Activity. Int. J. Biol. Macromol., 117, 800–806, 2018. 55. Annur, D., Wang, Z.K., Liao, J., Der; Kuo, C. Plasma-Synthesized Silver Nanoparticles on Electrospun Chitosan Nanofiber Surfaces for Antibacterial Applications. Biomacromolecules, 16, 10, 3248–3255, 2015. 56. Zupančič, Š., Preem, L., Kristl, J., Putrinš, M., Tenson, T., Kocbek, P., Kogermann, K., Impact of PCL Nanofiber Mat Structural Properties on Hydrophilic Drug Release and Antibacterial Activity on Periodontal Pathogens. Eur. J. Pharm. Sci., 122, 347–358, 2018. 57. Permyakova, E.S., Polčak, J., Slukin, P.V., Ignatov, S.G., Gloushankova, N.A., Zajíčková, L., Shtansky, D.V., Manakhov, A., Antibacterial Biocompatible PCL Nanofibers Modified by COOH–Anhydride Plasma Polymers and Gentamicin Immobilization. Mater. Des., 153, 60–70, 2018. 58. Fakhri, A., Gupta, V.K., Rabizadeh, H., Agarwal, S., Sadeghi, N., Tahami, S., Preparation and Characterization of WS2 Decorated and Immobilized on Chitosan and Polycaprolactone as Biodegradable Polymers Nanofibers: Photocatalysis Study and Antibiotic-Conjugated for Antibacterial Evaluation. Int. J. Biol. Macromol., 120, 1789–1793, 2018. 59. Jatoi, A.W., Kim, I.S., Ni, Q.Q.A., Comparative Study on Synthesis of AgNPs on Cellulose Nanofibers by Thermal Treatment and DMF for Antibacterial Activities. Mater. Sci. Eng. C, 98, 1179–1195, 2019. 60. Nthunya, L.N., Masheane, M.L., Malinga, S.P., Nxumalo, E.N., Barnard, T.G., Kao, M., Tetana, Z.N., Mhlanga, S.D., Greener Approach to Prepare Electrospun Antibacterial β-Cyclodextrin/Cellulose Acetate Nanofibers for Removal of Bacteria from Water. ACS Sustain. Chem. Eng., 5, 1, 153–160, 2017. 61. Jatoi, A.W., Kim, I.S., Ni, Q.Q., Cellulose Acetate Nanofibers Embedded with AgNPs Anchored TiO2 Nanoparticles for Long Term Excellent Antibacterial Applications. Carbohydr. Polym., 207, 640–649, 2019. 62. Jia, L., Huang, X., Liang, H., Tao, Q., Enhanced Hydrophilic and Antibacterial Efficiencies by the Synergetic Effect TiO2 Nanofiber and Graphene Oxide in Cellulose Acetate Nanofibers. Int. J. Biol. Macromol., 132, 1039–1043, 2019. 63. Mei, L., Ren, Y., Gu, Y., Li, X., Wang, C., Du, Y., Fan, R., Gao, X., Chen, H., Tong, A. et al., Strengthened and Thermally Resistant Polylactic Acid)Based Composite Nanofibers Prepared via Easy Stereocomplexation with Antibacterial Effects. ACS Appl. Mater. Interfaces, 10, 49, 42992–43002, 2018.

Antimicrobial Electrospun Materials  513 64. Zhang, Q., Tu, Q., Hickey, M.E., Xiao, J., Gao, B., Tian, C., Heng, P., Jiao, Y., Peng, T., Wang, J., Preparation and Study of the Antibacterial Ability of Graphene Oxide–Catechol Hybrid Polylactic Acid Nanofiber Mats. Colloids Surf. B Biointerfaces, 172, 496–505, 2018. 65. Nguyen, T.T.T., Chung, O.H., Park, J.S., Coaxial Electrospun Polylactic Acid)/chitosan Core/shell) Composite Nanofibers and Their Antibacterial Activity. Carbohydr. Polym., 86, 4, 1799–1806, 2011. 66. Zhang, Z., Wu, Y., Wang, Z., Zhang, X., Zhao, Y., Sun, L., Electrospinning of Ag Nanowires/polyvinyl Alcohol Hybrid Nanofibers for Their Antibacterial Properties. Mater. Sci. Eng. C, 78, 706–714, 2017. 67. Aytac, Z., Dogan, S.Y., Tekinay, T., Uyar, T., Release and Antibacterial Activity of Allyl Isothiocyanate/β-Cyclodextrin Complex Encapsulated in Electrospun Nanofibers. Colloids Surf. B Biointerfaces, 120, 125–131, 2014. 68. Shalumon, K.T., Anulekha, K.H., Nair, S.V., Nair, S.V., Chennazhi, K.P., Jayakumar, R., Sodium Alginate/polyvinyl Alcohol)/nano ZnO Composite Nanofibers for Antibacterial Wound Dressings. Int. J. Biol. Macromol., 49, 3, 247–254, 2011. 69. Zheng, F., Wang, S., Wen, S., Shen, M., Zhu, M., Shi, X., Characterization and Antibacterial Activity of Amoxicillin-Loaded Electrospun NanoHydroxyapatite/polylactic-Co-Glycolic Acid) Composite Nanofibers. Biomaterials, 34, 4, 1402–1412, 2013. 70. Qi, R., Guo, R., Zheng, F., Liu, H., Yu, J., Shi, X., Controlled Release and Antibacterial Activity of Antibiotic-Loaded Electrospun Halloysite/­ polylactic-Co-Glycolic Acid) Composite Nanofibers. Colloids Surf. B Biointerfaces, 110, 148–155, 2013. 71. Yadav, R. and Balasubramanian, K., Polyacrylonitrile/Syzygium Aromaticum Hierarchical Hydrophilic Nanocomposite as a Carrier for Antibacterial Drug Delivery Systems. RSC Adv., 5, 5, 3291–3298, 2015. 72. Shalaby, T., Hamad, H., Ibrahim, E., Mahmoud, O., Al-Oufy, A., Electrospun Nanofibers Hybrid Composites Membranes for Highly Efficient Antibacterial Activity. Ecotoxicol. Environ. Saf., 162, 354–364, 2018. 73. Yang, H., Gao, P.F., Wu, W.B., Yang, X.X., Zeng, Q.L., Li, C., Huang, C.Z., Antibacterials Loaded Electrospun Composite Nanofibers: Release Profile and Sustained Antibacterial Efficacy. Polym. Chem., 5, 6, 1965–1975, 2014. 74. Cui, H., Bai, M., Lin, L., Plasma-Treated Polyethylene Oxide) Nanofibers Containing Tea Tree Oil/beta-Cyclodextrin Inclusion Complex for Antibacterial Packaging. Carbohydr. Polym., 179, 360–369, 2018. 75. Lin, L., Dai, Y., Cui, H., Antibacterial Polyethylene Oxide) Electrospun Nanofibers Containing Cinnamon Essential Oil/beta-Cyclodextrin Proteoliposomes. Carbohydr. Polym., 178, 131–140, 2017. 76. Lin, L., Zhu, Y., Li, C., Liu, L., Surendhiran, D., Cui, H., Antibacterial Activity of PEO Nanofibers Incorporating Polysaccharide from Dandelion and Its Derivative. Carbohydr. Polym., 198, 225–232, 2018.

514  Electrospun Materials and Their Allied Applications 77. Henke, P., Kozak, H., Artemenko, A., Kubát, P., Forstová, J., Mosinger, J., Superhydrophilic Polystyrene Nanofiber Materials Generating O2 (1 Δ G): Postprocessing Surface Modifications toward Efficient Antibacterial Effect. ACS Appl. Mater. Interfaces, 6, 15, 13007–13014, 2014. 78. Liu, Z., Yan, J., Miao, Y.-E., Huang, Y., Liu, T., Catalytic and Antibacterial Activities of Green-Synthesized Silver Nanoparticles on Electrospun Polystyrene Nanofiber Membranes Using Tea Polyphenols. Compos. Part B Eng., 79, 217–223, 2015. 79. Shi, Q., Vitchuli, N., Nowak, J., Noar, J., Caldwell, J.M., Breidt, F., Bourham, M., McCord, M., Zhang, X., One-Step Synthesis of Silver Nanoparticle-Filled Nylon 6 Nanofibers and Their Antibacterial Properties. J. Mater. Chem., 21, 28, 10330, 2011. 80. Sedghi, R., Shariati, M., Zarehbin, M.R., Soorki, A.A., High-Performance Visible Light-Driven Ni–ZnO/rGO/nylon-6 & Ni–ZnO/rGO/nylon-6/Ag Nanofiber Webs for Degrading Dye Pollutant and Study Their Antibacterial Properties. J. Alloys Compd., 729, 921–928, 2017.

Index 3D printing, 464, 465 Active layer, 226 Aerogel, 204, 206 Ag nanoparticles, 487 Aligned fibers, 8 Amoxicillin, 490 Amperometric, 233 Antibacterial, 336, 442, 447, 450 Antibiotic, 244 Anticancer, 292 Antimicrobial, 246 Applied tension, 382 Bioinspired, 307, 309 Biopolymers, 135 Biosensors, 310, 311 Blood vessel, 287, 321 Bone regeneration, 285 Bone tissue, 318 Cancer, 106, 287 Carbon, 115, 220, 418 Cartilage tissue, 319 Catalysis, 113 Catalyst entrapment, 228 Cell electrospinning, 30 Cellular uptake, 268 Cellulose, 132 Cellulose ace­tate, 249, 488 Cellulose derivatives, 316, 325, 326 Cellulosic nanofibers, 309, 310 Centrifugal electrospinning, 388

Characterization technique, 76 Chitosan, 251, 323, 335, 486 Ciprofloxacin, 487 Coacervation, 139 Coalescence, 231 Coaxial electrospinning, 389 Conductive nanofibrous scaffolds, 222 Configuration, 56 Core-shell nanofibers, 14, 225, 247 Curcumin, 488 Cyclic oligosaccharides, 250 Cyclodextrin, 250 Degradation, 122 Desorption, 405, 409 Diabetic ulcer treatment, 286 DNA, 233, 290 Doxycycline, 488 Drug delivery, 106, 312–315, 329, 330 Donaldson, 219, 230 Dupont, 219, 230 Dye removal, 167 Electroblowing, 23, 387 Electronics, 218 Electrospinning, 132, 186, 191, 194, 195, 198, 219, 244, 246, 275, 291, 386, 387, 401, 403–406, 410, 411 Electrostatic, 442, 449, 471 Emulsification, 139

515

516  Index Endosomes, 226 Endothelialized, 224 Environment, 63, 121 Enzyme, 229, 234 Eugenol, 486 Extracellular matrix, 221 Extracting agents, 404 Fe3O4, 487 Filtration, 217, 401–03, 442, 445–48, 450, 454–55, 464, 474 Flux, 195, 199, 201, 203, 206 Food packaging, 234 Gas masks, 216 Gene, 266, 289 Gentamicin, 486 Glass, 132 Gold nanoparticles, 253 Gram-negative Escherichia coli (E. coli), 249 Graphene oxide, 489 Heavy metal ion removal, 154 Honey, 487 Humidity, 386 Hybrid, 25 Hydrogen, 120 Hydrophilic, 202 Hydrophilicity, 208 Hydrophobic, 193, 194, 202 Hydrophobicity, 187, 193, 208 Important parameters, 382 In situ electrospinning, 33 Inorganic silica, 252 Jet, 56 Lavender oil, 501 Layer-by-layer (LbL), 236 Lithium metal oxides, 423 Liver tissues, 320

Magnetic electrospinning, 388 Media fiber, 230 Melt electrospinning, 19 Membrane, 204, 205, 206, 207, 208 Membrane transport, 102 Metal oxide, 117, 419 Metronidazole, 487 Microbe, 176 Microbial, 132 Milestone, 88 Miniaturized devices, 218 Mulberry bark, 132 Multidrug-resistant (MDR), 252 Multiple needle electrospinning, 387 Myocardial infarction, 288 Nanoframework, 104 Nanoenscapsulation, 138 Nanofiber, 135,187,189,195, 202, 203, 206, 207, 245, 273, 402, 410, 411, 416 Nanofibrous, 185, 186, 187, 190, 191, 193, 198, 199, 200, 203, 206, 207, 228 Nanogenerator, 451 Nanoprecipitation, 139 Nanosized fibers, 402 Nanospider, 141 Nanotechnology, 132 Near field electrospinning, 22 Needleless electrospinning, 388 Needle-to-collector, 384 Neomycin, 488 Neural applications, 320, 334 Nonviral vectors, 270 Nozzle, 56, 57 Nylon, 6, 507 Oil–water separation, 172 Oily wastewater, 185, 203, 204, 205, 208 Oleophilic, 194 Oleophilicity, 187

Index  517 Optical sensor, 232 Organic linker, 103 Osteogenic growth peptide, 248 Oxidation, 118, 121 Packaging, 131 Paper, 132 Parameters, 62, 63 Periodontal, 224, 250 Photothermal, 444, 455–56, 467, 471 Photovoltaic devices, 229 Physical characterization, 87 Piezoelectric, 452 Poly(ethylene oxide), 502 Polylactic acid, 249, 489 Poly(lactic-co-glycolic acid), 490 Poly(N-isopropylacrylamide) (PNIPAm), 455–56, 465–66, 468, 470, 473 Poly(vinyl alcohol-co-ethylene) (PVA-co-PE), 248 Poly(vinyl alcohol), 489 Polyacrylonitrile, 501 Poly­caprolactone (PCL), 246, 487 Polydopamine, 252 Polymer, 116, 133, 426 Polymer–inorganic, 430 Polystyrene nanofibers, 502 Polyurethane dressing, 222 Porous anionic MOF, 105 Process, 380 Protective clothing, 227 Randomly oriented, 3 Recent advances, 386 Reduction, 119, 122 Regenerative medicine, 284 Setup, 56 Shape memory, 444–45, 454, 460–62, 464–74 Smart electrospun materials, 354, 357, 360, 367, 371

Smart membrane, 445, 451, 454 Sodium alginate, 490 Soft tissue prostheses, 224 Solution concentration, 384 Solution conductivity, 385 Solution eject rate, 382 Surface tension, 385 Solvent effects, 385 Sorption, 187, 190, 193, 208, 401, 404–407, 410 Sorbent, 187, 190, 193, 208, 404, 406 Sorptive mats, 403, 405, 406, 410 Spinneret, 442, 448 Spinning, 62 Staphylococcus aureus (S. aureus), 247 Stem cell-based therapy, 289 Stimuli responsive, 444–45, 454, 460, 464–72, 474 Submicron fibers, 219 Superhydrophilicity, 186, 195, 202, 205 Superhydrophobicity, 186, 193, 194, 195, 198 Superoleophilic, 455 Superoleophilicity, 186, 195, 198, 200, 205 Superoleophobicity, 186, 195, 201, 205 Support, 115 Surface plasmon resonance, 458 Surface tension, 133, 385 Syzygium aromaticum, 501 Taylor cone, 56, 442 Template, 116 Therapeutic delivery, 294 TiO2 nanoparticles, 489 Tissue engineering, 216, 221, 282, 317, 331, 442, 447, 449, 454, 464, 466, 468, 474 Toxic influents, 402

518  Index Transition metal oxides, 424 Types of electrospinning, 279 Ultrafine nanofibers, 224 Urethral reconstruction, 322 Vascular grafts, 284 Vascular tissue engineering, 332 Vectors, 269

Warfare agents, 227 Wastewater, 403–405, 409, 411 WHO, 446 Wood, 132 Wound healing, 326, 327, 328 ZnO nanoparticles, 490