Responsive Materials and Methods

Mohammed Yaseen and Jian R. Lu 1.1 Introduction 3 1.2 Temperature-Responsive Polymers 5 1.2.1 Thermoresponsive Polymers Based on LCST 5 1.2.2 Biopolym...

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Responsive Materials and Methods

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Advance Materials Series The Advance Materials Series is intended to provide recent advancements of the fascinating field of advanced materials science and technology, particularly in the area of structure, synthesis and processing, characterization, advanced-state properties, and applications. The volumes will cover theoretical and experimental approaches of molecular device materials, biomimetic materials, hybrid-type composite materials, functionalized polymers, superamolecular systems, information- and energy-transfer materials, biobased and biodegradable or environmental friendly materials. Each volume will be devoted to one broad subject and the multidisciplinary aspects will be drawn out in full. Series Editor: Dr. Ashutosh Tiwari Biosensors and Bioelectronics Centre Linköping University SE-581 83 Linköping Sweden E-mail: [email protected] Managing Editors: Swapneel Despande and Sudheesh K. Shukla

Publishers at Scrivener Martin Scrivener ([email protected]) Phillip Carmical ([email protected])

Responsive Materials and Methods State-of-the-Art StimuliResponsive Materials and Their Applications

Edited by

Ashutosh Tiwari and Hisatoshi Kobayashi

Copyright © 2014 by Scrivener Publishing LLC. All rights reserved. Co-published by John Wiley & Sons, Inc. Hoboken, New Jersey, and Scrivener Publishing LLC, Salem, Massachusetts. Published simultaneously in Canada. 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, scanning, or otherwise, except as permitted under Section 107 or 108 of the 1976 United States Copyright Act, without either the prior written permission of the Publisher, or authorization through payment of the appropriate per-copy fee to the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, (978) 750-8400, fax (978) 750-4470, or on the web at www.copyright.com. Requests to the Publisher for permission should be addressed to the Permissions Department, John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, (201) 748-6011, fax (201) 748-6008, or online at http://www.wiley.com/go/permission. Limit of Liability/Disclaimer of Warranty: While the publisher and author have used their best efforts in preparing this book, they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and specifically disclaim any implied warranties of merchantability or fitness for a particular purpose. No warranty may be created or extended by sales representatives or written sales materials. The advice and strategies contained herein may not be suitable for your situation. You should consult with a professional where appropriate. Neither the publisher nor author shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages. For general information on our other products and services or for technical support, please contact our Customer Care Department within the United States at (800) 762-2974, outside the United States at (317) 572-3993 or fax (317) 572-4002. Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic formats. For more information about Wiley products, visit our web site at www.wiley.com. For more information about Scrivener products please visit www.scrivenerpublishing.com. Cover design by Russell Richardson Library of Congress Cataloging-in-Publication Data: ISBN 978-1-118-68622-5

Printed in the United States of America 10 9 8 7 6 5 4 3 2 1

Contents Preface PART 1 1

2

xiii Stimuli-Responsive Polymeric Materials

Smart Thermoresponsive Biomaterials Mohammed Yaseen and Jian R. Lu 1.1 Introduction 1.2 Temperature-Responsive Polymers 1.2.1 Thermoresponsive Polymers Based on LCST 1.2.2 Biopolymers and Artificial Polypeptides 1.2.3 Temperature Sensitivity of Polymers 1.3 Development of Thermoresponsive Surfaces 1.3.1 Surface Modifications Using Energetic Oxidation 1.3.2 Surface Grafting of Polymers 1.3.3 Graft Polymerization 1.4 Surface Characterization 1.5 Cell Culture and Tissue Engineering Applications 1.6 Chromatography 1.7 Conclusion References Light-Triggered Azobenzenes: From Molecular Architecture to Functional Materials Jaume Garcia-Amorós and Dolores Velasco 2.1 Why Light-Triggered Materials? 2.2 Azobenzene-Based Light-Activatable Materials

1 3 3 5 5 8 8 10 10 13 14 15 16 20 22 22

27 28 29

v

vi Contents 2.3

Photoswitchable Azobenzene-Based Materials 2.3.1 Photochromic Switches Based on Azobenzene-Doped Liquid Crystals 2.3.2 Photochromic Oscillators Based on Fast Thermal Isomerizing Azo Dyes 2.3.3 Fast Isomerizing Azobenzenes and Their Potential Use for Biological Applications 2.3.4 Photoelectronic Switches Based on Azo Dyes 2.4 Photodeformable Azobenzene-Based Materials: Artificial Muscle-like Actuation 2.5 Conclusion and Perspectives Acknowledgements References 3

4

Functionalization with Interpenetrating Smart Polymer Networks by Gamma Irradiation for Loading and Delivery of Drugs Franklin Muñoz-Muñoz and Emilio Bucio Abbreviations 3.1 Introduction 3.2 General Concepts 3.2.1 Graft Copolymers and Ionizing Radiation 3.2.2 Methods of Radiation for Preparing Grafts 3.3 Radiation Synthesis and Modification of Polymers (Approaches) 3.3.1 Thermosensitive Networks 3.3.2 pH-Sensitive Networks 3.3.3 IPNs 3.3.4 Graft Copolymers Acknowledgements References Biomedical Devices Based on Smart Polymers Angel Contreras-García and Emilio Bucio 4.1 Introduction 4.2 Stimuli Responsive Polymers 4.3 Sensitive Hydrogels 4.4 Responsive Materials for Drug Delivery Systems

31 31 37 39 43 47 53 54 54

59 60 61 63 63 65 74 75 76 77 80 88 88 105 106 107 108 109

Contents 4.5 Intelligent Polymers for Tissue Engineering 4.6 Types of Medical Devices Acknowledgements References 5

6

Stimuli-Responsive Polymers as Adjuvants and Carriers for Antigen Delivery Akhilesh Kumar Shakya and Kutty Selva Nandakumar Abbreviations 5.1 Introduction 5.2 Responsive Polymers as Antigen Carriers 5.2.1 Charge Responsive Carrier 5.2.2 Oxidation Responsive Carrier 5.2.3 pH-Responsive Carrier 5.2.4 Temperature-Responsive Carrier 5.3 Factors Affecting Adjuvant Potential of Stimuli-Responsive Polymeric Adjuvant Acknowledgements References Cyclodextrins as Advanced Materials for Pharmaceutical Applications Vesna D. Nikolic, Ljubisa B. Nikolic, Ivan M. Savic, and Ivana M. Savic 6.1 Inclusion Complexes 6.2 Preparation of Inclusion Complexes 6.3 Historical Development of Cyclodextrins 6.4 Equilibrium 6.5 Confirmation of Formed Inclusion Complexes 6.6 Application of Cyclodextrins in the Pharmacy 6.7 Cyclodextrins as a Drug Delivery System 6.8 Cyclodextrin as Solubilizers 6.9 Pharmaceutical Formulation Containing Cyclodextrin 6.10 Conclusion References

vii 112 113 117 117

123 124 124 129 129 129 130 131 135 136 136

141

142 143 145 149 152 153 154 157 158 160 161

viii

Contents

PART 2 7

8

Smart Nano-Engineered Materials

Advances in Smart Wearable Systems Rajesh Kumar Saini, Jaya Bajpai, and A. K. Bajpai 7.1 Introduction 7.2 Classification of Smart Polymers 7.2.1 Shape-Memory Polymers 7.2.2 Conducting Polymers 7.2.3 Stimuli-Responsive Hydogels 7.2.4 Nanomaterials 7.3 Applications 7.3.1 Smart Fabrics 7.3.2 Smart Skin 7.3.3 Biosensors 7.4 Current Features of Wearable Systems 7.5 Conclusions 7.6 Challenges and Future Prospects References Functionalization of Smart Nanomaterials Sharda Sundaram Sanjay and Avinash C. Pandey 8.1 Introduction 8.1.1 Importance of Functionalization 8.1.2 Advantages of Surface Functionalization 8.2 Functionalizing Agents 8.2.1 Mode/Ways to Surface Functionalization 8.2.2 Strategy for the Conjugation 8.2.3 Classification of Surface Functionalization of Nanomaterials 8.2.4 Methodology 8.2.5 Conditions Favorable for Biofunctionalization 8.3 Carbon Nanomaterials 8.3.1 Functionalization of Carbon Nanotubes 8.4 Silica Nanoparticles 8.5 Confirmation of Functionalization 8.5.1 Confirmation through Infrared Spectral Analysis 8.5.2 Confirmation through Optical/ Colorimetric Assay

167 169 170 172 173 175 177 179 181 182 185 189 192 194 194 195 201 202 203 204 205 206 206 207 210 213 217 218 224 225 225 227

Contents Confirmation through Contact Angle Measurement 8.5.4 Confirmation with the Help of Metathesis Reactions Acknowledgements References

ix

8.5.3

9

Role of Smart Nanostructured Materials in Cancers Rizwan Wahab, Farheen Khan, Javed Musarrat, and Abdulaziz A.Al-Khedhairy 9.1 Introduction 9.1.1 What is cancer? 9.1.2 Types of Cancers 9.1.3 Importance of Nanostructures 9.2 Experimental 9.2.1 Nanomaterials Synthesis 9.2.2 Characterizations of Synthesized Nanomaterials 9.2.3 Biological Characterizations for the Identification of Cancers 9.3 Results Related to Use of Smart Nanostructured Materials to Control Cancers Cells 9.4 Summary and Future Direction Acknowledgement References

10 Quantum Cutter and Sensitizer-Based Advanced Materials for their Application in Displays, Fluorescent Lamps and Solar Cells Raghvendra Singh Yadav, Jaromir Havlica, and Avinash Chandra Pandey 10.1 Introduction 10.2 Quantum Cutter and Sensitizer-Based Advanced Materials 10.2.1 Visible Quantum Cutting 10.2.2 Near-Infra Red Quantum Cutting 10.3 Conclusion Acknowledgement References

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238 238 239 244 246 246 247 251 258 265 266 266

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274 275 277 284 297 297 298

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Contents

11 Nanofibers of Conducting Polymer Nanocomposites Subhash B. Kondawar and Shikha P. Agrawal 11.1 Conducting Polymers 11.2 Nanostructure Conducting Polymers 11.2.1 Conducting Polymer Nanocomposites 11.2.2 Nanofibers of Conducting Polymer Nanocomposites 11.2.3 Electrospinning 11.2.4 Theoretical Modeling of Electrospun Nanofibers 11.2.5 Electrospun Nanofibers of Conducting Polymer Nanocomposites 11.3 Electrical Conductive Properties of Nanofibers of Conducting Polymer Nanocomposites 11.4 Applications of Nanofibers of Conducting Polymers Nanocomposites 11.4.1 Supercapacitors 11.4.2 Rechargeable Batteries 11.4.3 Sensors 11.5 Concluding Remarks References

341 341 343 344 347 348

PART 3

357

Smart Biosystems Engineering

12 Stimuli-Responsive Redox Biopolymers Sudheesh K. Shukla and Ashutosh Tiwari 12.1 Introduction 12.2 Method of Synthesis, Characterization and Mechanism 12.3 Stimuli-Responsive Redox and Electrical Conductive Behavior 12.4 Biosensor Applications 12.5 Conclusion References

303 304 311 315 319 326 328 333 337

359 359 363 367 372 373 374

Contents 13 Commodity Thermoplastics with Bespoken Properties using Metallocene Catalyst Systems Nikhil Prakash 13.1 Introduction 13.2 Metallocene Catalyst Systems 13.2.1 Evolution of the Metallocenes 13.2.2 Categories of Metallocene Catalysts 13.2.3 Cocatalysts 13.3 Metallocene Thermoplastics 13.3.1 Polyethylene: Manufacture, Structure and Properties 13.3.2 Polypropylene: Manufacture, Structure and Properties 13.3.3 Polystyrene 13.4 Conclusions and Future Prospects References

PART 4

Theory and Modeling

14 Elastic Constants, Structural Parameters and Elastic Perspectives of Thorium Mono-Chalcogenides in Temperature Sensitive Region Krishna Murti Raju Nomenclature 14.1 Introduction 14.1.1 Primer of the Field 14.1.2 Overview 14.2 Formulation 14.3 Evaluation 14.4 Results and Discussions 14.4.1 Higher Order Elastic Constants 14.4.2 Pressure Derivatives 14.5 Conclusions Acknowledgment References Index

xi

377 378 379 381 382 383 385 385 387 391 393 393

397

399 400 400 401 402 404 410 414 415 419 424 424 424 429

Preface The development of tuned materials by environmental requirements is the recent arena of materials research. It is a newly emerging, supra-disciplinary field with great commercial potential. Stimuli-responsive materials answer by a considerable change in their properties to small changes in their environment. They are becoming increasingly more prevalent as scientists learn about the chemistry and triggers that induce conformational changes in material structures and devise ways to take advantage of and control them. New responsive materials are being chemically formulated that sense specific environmental changes and adjust in a predictable manner, making them useful tools. Stimuli-responsive materials are in widespread demand among researchers because they can be customized via chemistry to trigger induced conformational changes in structures or be taken advantage of in the form of structural or molecular regime via minute external environmental changes. Their effectors are both i) physical, i.e., temperature, electric or magnetic fields, mechanical stress; and ii) chemical, i.e., pH, ionic factors, chemical agents, biological agents. Thermoresponsive polymers represent an important class of “smart” materials as they are capable of responding dramatically to small temperature changes. The chapter on “Smart Thermoresponsive Biomaterials” describes a range of thermoresponsive polymers and the criteria that influence their thermoresponsive character for surface modifications and applications, in particular for cell culture and chromatography. In the chapter “Light-Triggered Azobenzenes: From Molecular Architecture to Functional Materials,” the principle of light-triggered materials is covered, for example, azobenzene-based materials, their photochromic switching and oscillation ability, and potential biological and artificial muscle-like actuation applications. The chapter entitled “Functionalization with Interpenetrating Smart Polymer Networks by Gamma Irradiation for Loading and Delivery of Drugs,” discusses the γ-irradiation xiii

xiv

Preface

assisted graft copolymerization containing interpenetrating polymer networks and other architectures, mainly focusing on the performance of materials modified with stimuli-responsive components capable of high loading therapeutic substances and their control release properties. The recently investigated applications of smart or intelligent polymeric materials for tissue engineering, regenerative medicine, implants, stents, and medical devices are overviewed in “Biomedical Devices Based on Smart Polymers.” The chapter “Stimuli Responsive Polymers as Adjuvants and Carriers for Antigen Delivery,” illustrates the promising advantages of responsive materials in immunology as carriers for an antigen and adjuvant for enhancing immunogenicity of an antigen. “Cyclodextrins and Advanced Materials for Pharmaceutical Applications” highlights the combination of cyclodextrins and pharmaceutical excipients or carriers such as nanoparticles, liposomes, etc., and fosters the progress of the advanced dosage forms with the improved physicochemical and biopharmaceutical properties. “Recent Advances in Smart Wearable Systems,” presents an overview of the smart nanoengineering that yields state-of-the-art wearable systems and sensor technologies, and underlying challenges are overviewed. The high surface functionalities available in such materials provide an opportunity to modify their outer surfaces and achieve multivalent effects. The chapter on “Functionalization of Smart Nanomaterials” describes the surface nanoengineering aimed at coupling advanced features for a range of optoelectronic applications. A thrust towards the development of novel nanoparticles has paved the way for sucessful cancer diagnosis and treatment. The chapter “Role of Smart Nanostructured Materials in Cancers,” summarizes different types of nanoparticles currently available for cancer therapy. Smart nanomaterials including visible quantum cutting and near-infrared quantum cutting phosphors such as fluoride phosphors, oxide phosphors, phosphate phosphors and silicate phosphors, and their potential application for PDPs and Hg-free fluorescent lamps, are the focus of “Quantum Cutter and SensitizerBased Advanced Materials for Their Application in Displays, Fluorescent Lamps and Solar Cells.” The chapter on “Nanofibers of Conducting Polymer Nanocomposites” focuses on the preparative strategies of nanofibers of conducting polymers and nanocomposites and their electrical conductive properties and applications. The biocompatible smart polymeric architect has significantly increased attention in biodevice and system managements.

Preface xv “Stimuli-Responsive Redox Biopolymers” investigates arabicco-polyaniline as pH-responsive redox copolymers and their properties for biosensor applications. The development of the metallocene catalysts, from their discovery to their present state-ofthe-art, is portrayed in “Commodity Thermoplastics with Bespoke Properties Using Metallocene Catalyst Systems,” with an emphasis on weighing up discrete catalysts for stereo-specific polymerization and technologically important processes. The study of elastic properties provides information about the magnitude of the forces and nature of bonding between the atoms. The impact of solids on the world of science and technology has been enormous, covering such diverse applications as solar energy, image processing, energy storage, computer and telecommunication technology, thermoelectric energy conversion, and new materials for numerous applications. The chapter “Elastic Constants, Structural Parameters and Elastic Perspectives of Thorium Monochalcogenides in Temperature Sensitive Region” predicts the anharmonic elastic properties of thorium chalcogenides having NaCl-type structure under high temperature using Born-Mayer repulsive potentials and the long- and short-range interaction approach. This book is written for a large readership including university students and researchers from diverse backgrounds such as chemistry, materials science, physics, pharmacy, medical science, and biomedical engineering. It can be used not only as a textbook for both undergraduate and graduate students, but also as a review and reference book for researchers in the materials science, bioengineering, medical, pharmaceutical, biotechnology, and nanotechnology fields. We hope the chapters of this book will provide valuable insight in the important area of responsive materials and cuttingedge technologies. Editors Ashutosh Tiwari Linköping, Sweden Hisatoshi Kobayashi Tsukuba, Japan August 15, 2013

PART 1 STIMULI-RESPONSIVE POLYMERIC MATERIALS

1 Smart Thermoresponsive Biomaterials Mohammed Yaseen* and Jian R. Lu Biological Physics Group, School of Physics and Astronomy, University of Manchester, Manchester, United Kingdom

Abstract Thermoresponsive materials represent an important class of advanced materials that have evolved over the past few decades. These materials are also designated as “smart” materials as they are capable of responding dramatically to small temperature changes. In this chapter we will present a select range of polymers that exhibit thermoresponsive behavior, with a particular focus on polyacrylamide-based polymers. We also review the criteria that influence their thermoresponsive character. Inherently, many materials are not thermoresponsive, thus approaches for surface modification of such materials resulting in unique thinly-coated thermoresponsive surface layers or films are also shown. Finally, select biological applications of thermoresponsive biomaterials are presented, in particular for cell culture and chromatography applications. Keywords: Temperature responsive, functional polymers, nanofilms, cell culture, chromatography

1.1

Introduction

Synthetic polymers that can respond to external stimuli in a controlled manner are increasingly of interest to science and industry. Such polymers have been designed to mimic natural biopolymers, such as proteins, polysaccharides and nucleic acids in living organisms within which responses to stimuli are common processes. Such “smart” or “intelligent” stimuli-responsive polymers are capable of undergoing relatively large and abrupt changes in response to *Corresponding author: [email protected] Ashutosh Tiwari and Hisatoshi Kobayashi (eds.) Responsive Materials and Methods, (3–26) 2014 © Scrivener Publishing LLC

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small external environmental changes. The exemplar stimuli are often classified as either physical (temperature, electric or magnetic fields, and mechanical stress) or chemical effectors (pH, ionic factors, chemical agents, biological agents), resulting in changes of the interactions between polymer chains or between chains and solvents at the molecular level (Figure 1.1). Such changes in the physiochemical properties of the polymers can subsequently affect their interactions with other systems, for example, adherent cells. These stimuli-responsive polymer systems are attractive to biorelated applications such as cell expansion, tissue engineering, controlled drug delivery, non-viral gene transfection, enzymatic activity control, biotechnology and chromatography for biomolecular separation and purification [1, 2]. Significant scientific research towards the understanding and development of dynamically responsive materials has resulted in a number of excellent reviews by other authors on the general topic of thermoresponsive polymer materials and related areas. The references in this chapter are hence primarily provided as starting points for further reading [3–7]. In this chapter we will describe the development of a select range of temperature-responsive polymers that exhibit thermoresponsive behavior. In particular we will review the use of polyacrylamide-based polymers and also the criteria that influence their temperature-responsive character. Inherently, many materials are not thermoresponsive, thus approaches for surface (a) In bulk solution Stimulus

Responsive polymer (b) At surface

Water

Stimulus

Increasing temperature Soluble hydrated polymer

Insoluble dehydrated polymer

Decreasing temperature

Figure 1.1 A schematic representation of stimuli-responsive polymer change for (a) free polymer in aqueous bulk environment, and (b) surface immobilized polymer. The temperature-dependent soluble (hydrated below the LCST) to insoluble (dehydrated above the LCST) change of polymer in aqueous media is shown.

Smart Thermoresponsive Biomaterials 5 modification of such materials need to be taken to produce unique thinly-coated thermoresponsive surface layers or films. Finally, we will present cell culture and chromatographic purification as select biological applications of thermoresponsive biomaterials.

1.2 1.2.1

Temperature-Responsive Polymers Thermoresponsive Polymers Based on LCST

The change of temperature is a relatively easy and widely used stimulus for causing responsive behavior of polymers. A common phenomenon is the change in solubility when the temperature is shifted across the critical solution temperature at which the phase of a polymer solution or composite changes discontinuously. In general, solutions that appear as monophasic (isotropic state) below a specific temperature and turn biphasic above it, exhibit a lower critical solution temperature (LCST). LCST is hence the critical temperature beyond which immiscibility or insolubility occurs. Acquisition and control of LCST within the physiological temperature range is essential for applications such as cell culture and drug delivery. LCST is dependent on factors such as the ratios of monomers, their hydrophobic and hydrophilic nature, polydispersity, branching and the degree of polymerization [5]. Thus the LCST of polymers in water can be altered by incorporating hydrophilic or hydrophobic moieties. For example, the copolymerization of N-isopropylacrylamide (NIPAAm) with hydrophilic monomers results in the increase of the LCST [7, 8]. In contrast, the LCST decreases when copolymerized with hydrophobic monomers, but this process may also affect the temperature sensitivity of NIPAAmbased copolymers. The copolymerization of ionizable groups such as acrylic acid (AAc) or N,N’-dimethylacrylamide (DMAAm) with NIPAAm can result in the discontinuous alternation or even disappearance of LCST at the pKa of the ionizable group [9]. For polymers such as poly(N-isopropylacrylamide) (PNIPAAm), an important characteristic is its intermolecular interaction with water molecules. Depending on its physical states, e.g., macromolecular solution, micellar aggregation or gel, changes in temperature across LCST have a huge impact on hydrogen bonding and hydrophobic interactions resulting in big differences in their amphiphilic properties. The extent of hydrophobic interaction can be manipulated by tuning the balance of monomer ratios

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and common examples are often seen from different diblock poly(ethylene oxide)–poly(propylene oxide) (PEOm-co-PPOn) and their triblock copolymers (PEOm-co-PPOn-co-PEOm), where changes in the ratio of m to n can lead to very different physiochemical properties including thermoresponsive behavior. Homopolymers: A number of other polymers can also display thermoresponsive behavior across their LCST with examples given in Figure 1.2. With some adjustments, the range of their thermoresponsive switches can be made useful for cell thermoresponsive detachment upon confluence. For example, poly(vinyl methyl ether) (PVME) has the LCST of around 36°C and is usually synthesized via solution polymerization (Figure 1.2ii) [10]. Another exemplar thermoresponsive polymer is poly(N-vinyl caprolactam) which can be easily prepared by free radical polymerization of N-vinyl caprolactam in solution, and has LCST of 32–34°C (Figure 2iii) [11]. Poly (N-substituted acrylamide) polymers are by far the most popular and well-researched thermoresponsive polymers. PNIPAAm is the most well known of the thermo responsive polymers having a sharp phase transition in water (LCST) within the physiological range of about 32°C (Figure 1.2i). These polymers are also prevalent because of the fact that poly(N-substituted acrylamide) polymers are easy to prepare by radical polymerization [12, 13]. Other poly (N-substituted acrylamide) polymers shown in Figure 1.2 include poly(N, N’-diethylacrylamide) (PDEAAm) with LCST in the range of 25–35°C [14], poly(2-carboxyisopropylacrylamide) (PCIPAAm) composed of a isopropylacrylamide group and carboxyl group, thus having the advantage of temperature response and additional functionality in its pendant groups [15]. Interestingly, the polymer poly(N-(L)-(1-hydroxymethyl) propylmethacrylamide) (P(L-HMPMAAm)) (Figure 1.2iv) has optical activity associated with it and shows a different thermosensitive phase transition from that of optically inactive P(DL-HMPMAAm) [16]. The polymer poly(N-acryloyl-N’-propylpiperazine) with the LCST of 37°C is both temperature and pH responsive [17]. However, the Poly(N-acryloyl-N’-propylpiperazine) homopolymers based on methylpiperazine and ethylpiperazine were found not to exhibit LCST due to their weak hydrophobicity [18]. Copolymers: The co-polymerization of different N-substituted acrylamide monomers can provide further copolymer functionality and LCST tuning potential arising from the hydrophilic-hydrophobic balance of monomer units. The copolymer PNIPAAm-co-PCIPAAm has similar sensitivity and LCST to the homopolymer PNIPAAm

Smart Thermoresponsive Biomaterials 7 (i)

(ii)

CH2

(iii)

CH C

CH

CH2

CH

CH2

n

n

n

N

O CH2

O

O

C N H CH

(iv)

(v)

CH3 CH2

(vi) CH

CH2

CH

C

O

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n

O

C

N

N H H2 C

OH

CH2

C

CH

CH2 n

n

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N H CH2 CH

H2 C

CH3

CH3

CH3

CH2

CH3 (vii)

C CH2

O

OH

CH n

O

C

R =

N

CH2

OR

CH2

CH3

CH3 CH2

N

CH3

R

Figure 1.2 Chemical structures of polymers showing LCST; (i) poly(Nisopropylacrylamide) (PNIPAAm); (ii) poly(vinyl methyl ether) (PVME); (iii) poly(N-vinyl caprolactam); (iv) poly(N-(L)-(1-hydroxymethyl) propylmethacrylamide (P(L-HMPMAAm)); (v) poly(N, N’-diethylacrylamide) (PDEAAm); (vi) poly(2-carboxyisopropylacrylamide) (PCIPAAm); (vii) poly(N-acryloyl-N’-alkylpiperazine).

[15, 19]. It has structural similarity to PNIPAAm-co-poly(acrylic acid), but the two have very different temperature-responsive behavior. Triblock copolymers such as PEOm-co-PPOn-co-PEOm also exhibit temperature-responsive micellization and gelation

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arising from their amphiphilic balance [20, 21]. The replacement of the PPO block with other hydrophobic groups such as the poly(1,2butylene oxide) (PBO) results in a shift of the thermoresponsive LST behavior [22]. Likewise, its substitution by poly(L-lactic acid) (PLLA) and (DL-lactic acid-co-glycolic acid) (PLGA) can also result in the shift of the thermoresponsive performance with the added benefit of biodegradable ester group incorporation [23, 24].

1.2.2

Biopolymers and Artificial Polypeptides

Temperature-responsive behavior is common in some biopolymers such as gelatin, agarose and gellan benzyl ester [25–27]. These polypeptides can form helix conformations, leading to physical crosslinking. Gelatin is obtained from collagen by breaking its triple-helix structure into single-stranded molecules. It is a thermally reversible hydrogel and its film stability at 37°C is poor. Thus, it is not ideal for direct use as thermoresponsive cell culture substrate under the normal cell culture conditions. Stable hydrogels of gelatin have, however, been obtained by chemical crosslinking or conjugation with chitosan by tyrosinases [28]. A substrate based on a triblock copolymer, poly (N-isopropylacrylamide)-co-poly[(R)-3hydroxybutyrate]-co-poly (N-isopropylacrylamide) (PNIPAAmco-PHB-co-PNIPAAm), co-coated with gelatin, has been developed for thermoresponsive cell culture. It was found to be superior to the PNIPAAm homopolymer coating in terms of film stability, surface coating and cell growth [29]. Surface deposition of collagen in low density on PNIPAAm was also found to enhance cell adhesion but did not affect cell detachment compared to uncoated PNIPAAm [30]. Biomimetic polypeptides such as elastin-like polypeptides (ELPs), composed of Val-Pro-Gly-Xaa- Gly amino acid repeat units (where Xaa is a guest residue, not proline), have shown thermally reversible phase transition behavior. ELPs are water-soluble below their transition temperature. But above the transition temperature they precipitate, driven by hydrophobic aggregation. For example, a block co-polypeptide composed of ELPs segment and silk-like segment has been reported to undergo sol-gel transition [31, 32].

1.2.3

Temperature Sensitivity of Polymers

For the versatility of applications, temperature-responsive polymers require high sensitivity or fast response over a narrow temperature. The incorporation of phase-separated structures can

Smart Thermoresponsive Biomaterials 9 result in rapid swelling/deswelling within hydrogels, resulting in the change of physical form associated with a large shift in surface area and amphiphilicity [33]. The inclusion of hydrophilic moieties can also increase the deswelling rate of PNIPAAm hydrogel network. For example, the random copolymerization of NIPAAm with acrylic acid (AAc) or methacrylic acid (MAAc) provides the hydrogels with faster deswelling kinetics than PNIPAAm hydrogel by itself [34]. However, for AAc-content above 1.3 wt%, the deswelling rate decreased when more AAc segments were added. An increase in the AAc content divided the long linear NIPAAm segments into short ones, causing the decrease of the driving force for hydrophobic aggregation and the subsequent disappearance of the LCST. In contrast, hydrophilic PEO grafts similarly introduced onto the PNIPAAm backbone were found not to interfere with long PNIPAAm sequences. The copolymerization of PNIPAAm with poly(ethylene glycol) (PEG) onto porous culture membranes was carried out by electron beam irradiation to provide better detachment of the cells. In this case, the NIPAAm monomers and PEG macromonomers (PEG methacrylate, MW = 4000) were dissolved in propanol containing 0.05% distilled water at a total concentration of 60 wt/ wt%. This monomer-containing solution mixture was spread uniformly over the surface of a porous membrane (Cell Culture Insert) and irradiated using an electron beam resulting in the covalently bound polymer. In cell sheet detachment experiments, only 19 min were required to detach the cell sheets from PNIPAAm co-grafted with 0.5wt% of PEG, compared to approximately 35 min incubation at 20°C to completely detach the cell sheets from PNIPAAm coated on the same porous culture membranes. When the porous membranes were used, water molecules could access PNIPAAm molecules grafted on the surfaces from both underneath and peripheral to the attached cell sheets, resulting in more rapid hydration of grafted PNIPAAm molecules and faster detachment of cell sheet than nonporous tissue culture polystyrene (TCPS) dishes [35]. Alternatively, rapid deswelling (faster acceleration of the polymer shrinking rate) was shown by PNIPAAm hydrogels having a comb-type molecular architecture rather than a linear-type structure [36]. However, in the case of surface-immobilized PNIPAAm films, the free mobile linear PNIPAAm showed a more rapid phase transition than PNIPAAm randomly crosslinked onto the surface, due to their different chain mobilities [37].

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1.3

Development of Thermoresponsive Surfaces

Many applications utilize thermoresponsive polymers in solution or in the bulk state, however, temperature-responsive surface or interface has important biomedical applications such as temperaturemodulated membranes, chromatography and cell culture dishes [38–40]. PNIPAAm polymers have been extensively investigated for the development of various temperature-responsive surfaces because of their specific advantages in biomedical applications. An important advantage includes a reversible temperature-dependent phase transition (LCST) in aqueous solution within the physiological range. Thus copolymers based on NIPAAm have been investigated and further developed for chromatography, tissue engineering and cell culture applications through controlled surface modification, but not all surfaces are directly amenable to modification.

1.3.1

Surface Modifications Using Energetic Oxidation

Surface properties of materials with no functional oxygen or nitrogen groups are often required to be altered prior to monomer or polymer grafting. The modification of surfaces is also required to facilitate cell attachment and growth. Surfaces for cell culture or tissue culture applications, other than polystyrene, include thermoplastic polymers such as polyethylene terephthalate (PET) which are also easy to mold and manufacture. However, they are hydrophobic in nature, so will exhibit a very different surface topology and chemical nature from the extracellular matrix (ECM). Other surfaces that require some form of surface modification to further facilitate cell attachment and growth include polycarbonate and glass. An important route for surface modification of materials includes the use of high-energy irradiation. A number of methods that use high-energy irradiation are available for modifying the surface of polymers. The resulting surface oxidation can make it more hydrophilic by introduction of hydroxyl and carboxyl functional groups. There are a variety of treatments that can be used to do this, such as UV, corona discharge, gamma irradiation, plasma treatments and electron beam irradiation. X-rays and electron beams are more penetrating than heat, light and microwave. Electrons, X-rays and gamma rays ionize the material they strike by stripping electrons from the atoms of the exposed material. This ionized environment is very damaging to bacteria or

Smart Thermoresponsive Biomaterials 11 viruses and can also change the chemical composition and surface structure of a material. Generally, these techniques can all effectively bombard the surface with ions, electrons or photons, resulting in a subtle difference between the chemical groups formed on the surface. The bombarding radiation breaks some of the bonds in the polymer chains as well as the gaseous material surrounding them, to produce readily available free radicals on the culture surface, and these have the ability to quench nearby molecules. For a particular material, each technique can result in different density of surface oxidized groups, such as hydroxyl or carboxyl groups. For the polystyrene surface, research has shown that plasma treatment produces a wide variety of functional groups such as alkylperoxide, aldehyde, and carboxylic, and also up to 15% of hydroxyl groups, as shown in Figure 1.3. The percentage of hydroxyl groups formed by UV was 12%, and 8% by corona, but gamma radiation was found to produce very little of the hydroxyl groups. In summary, by using an energetic source for irradiation the surface of polymers like polystyrene can be oxidized. The resulting interactions with H

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High Energy Irradiation

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Figure 1.3 Schematic drawing showing that the surface of polystyrene is hydrophobic but the oxidized surface has both hydroxyl and carboxyl functional groups making it more hydrophilic and susceptible to polymer attachment.

12

Responsive Materials and Methods

polystyrene lead to carbon-carbon scissions and generation of a variety of oxygen-containing functionalities at the polymer surface. Modification of polymer surfaces can be performed cleanly and rapidly by plasma treatment, also leading to the formation of various active species on the surface of polymers such as polyethylene (PE), polypropylene (PP), and polytetrafluoroethylene (PTFE) [41]. However, this method also results in polymerization, functionalization, etching, roughening and crosslinking. Plasma can be described as a partially ionized gas consisting of free radicals, ions, photons and electrons. It can be created by gases such as oxygen and argon excited by an external energy such as heat or electric discharge. The effectiveness of plasma treatment depends on the chemical monomers or gases used to generate the reactive species. The plasma treatment of polyethylene terephthalate (PET) using air as the gas results in a large increase in hydrophilicity [42]. The treatment of poly(hydroxymethylsiloxane) surfaces by either O2 plasma or 6 keV Ar+ beams also resulted in different adhesion, proliferation and spreading of normal human dermal fibroblast cells. Low cell adhesion and scarce viability was found from O2 plasma treated surfaces, but complete cell confluence, optimal spreading and proliferation were observed in the case of 6 keV Ar+ beams. The observed differences in cell responses were attributed to the relative surface free energy as a result of the two different plasma beams applied [43]. The high energy modification treatments such as gamma radiation and lasers for surface modification can lead to the modification of polymers as well as providing improvement to surface biocompatibility [44]. To achieve a specific gamma radiation effect it is necessary to apply a specific dose to the material. The radiation dose is a measure of the radiation energy deposited in unit mass of the material, measured in Gray (Gy) (1 Gy means 1 joule of radiation energy deposited in each kilogram of material). For example, to sterilize medical devices low doses of the order of 25 kGy are required, but the control of pathogens can be achieved with doses of 1.5 to 3.0 kGy, to allow preservation of the material and to render it biologically inert. The crosslinking of plastics and polymers requires much higher doses of up to 200 kGy, and certain polymers are known to undergo chain scission whilst others predominantly crosslink. The susceptibility of different polymeric materials to radiation crosslinking depends mainly on their chemical structure and some can be crosslinked at low doses, while others containing non-reactive