Biomedical Applications of Hydrogels Handbook

Editor-in-Chief Raphael M. Ottenbrite Editors Kinam Park Teruo Okano

Biomedical Applications of Hydrogels Handbook

ISBN 978-1-4419-5918-8 e-ISBN 978-1-4419-5919-5DOI 10.1007/978-1-4419-5919-5Springer New York Dordrecht Heidelberg London

Library of Congress Control Number: 2010929391

© Springer Science+Business Media, LLC 2010All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Springer Science+Business Media, LLC, 233 Spring Street, New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden.The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights.

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Springer is part of Springer Science+Business Media (www.springer.com)

Editor-in-ChiefRaphael M. OttenbriteProfessor EmeritusVirginia Commonwealth UniversityRichmond, VA, USAottenbrite@vcu.org

EditorsKinam Park Biomedical Engineering and Pharmaceutics Purdue UniversityWest Lafayette, IN, USAkpark@purdue.edu

Teruo OkanoInstitute of Biomedical EngineeringTokyo Women’s Medical UniversityShinjuku-ku, Tokyo, Japantokano@abmes.twmu.ac.jp

Associate EditorsRolando BarbucciInteruniversity Research Centre for Advanced Medical Systems University of SienaSiena, Italybarbucci@unisi.it

Haruma KawaguchiGraduate School of Science and TechnologyKeio UniversityYokohama, Japanharuma@applc.keio.ac.jp

Arthur J. CouryVice President Biomaterials ResearchGenzyme CorporationCambridge, MA, USAart.coury@genzyme.com

Advisory Board ChairNicholas A. PeppasDepartment of Chemical EngineeringThe University of Texas at AustinAustin, TX, USA peppas@che.utexas.edu

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Advisory Board

Nicholas A. Peppas, ChairDepartment of Chemical EngineeringThe University of Texas at AustinAustin, TX, USA

Allan HoffmanUniversity of Washington Engineered BiomaterialsUniversity of WashingtonSeattle, WA, USA

Emo ChielliniChemistry & Industrial Chemistry University of PisaPisa, Italy

Fu-Zhai CuiDirector of BiomaterialsTsinghua UniversityBeijing, China

Karel DusekInstitute of Macromolecular ChemistryAcademy of Sciences of the Czech RepublicPrague, CHEK

Jindrich Kopecek Department of Bioengineering and of Pharmaceuticsand Pharmceutical Chemistry, University of Utah Salt Lake City, Utah, USA

Claudio MigliaresiDepartment of Materials EngineeringUniversity of TrentoTrento - Italy

Yoshihito OsadaDivision of Biological SciencesHokkaido UniversitySapporo, Japan

Buddy D. RatnerDirector, University of Washington Engineered Biomaterials University of WashingtonSeattle, WA USA

vi Advisory Board

Nathan RaviDepartment of OphthalmologyWashington University

Etienne SchachtPolymer MaterialGhent University Ghent, Belgium

Tianwei TanCollege of Life Science and TechnologyBejing University of Chemical Technology

Preface

Substances that absorb significant quantities of water are called gels or hydrogels. Naturally occurring materials with these properties play a very important role in all forms of life. In this Handbook, the biomedical applications of hydrogels are addressed by experts in the field from around the world. The phenomenal properties of hydrogels continue to stimulate scientists to seek new insights into the development of novel biomaterials and bioapplications.

Composed of three-dimensional polymer networks, hydrogels can absorb large quantities of water. Consequently, they are soft, pliable, wet materials with a wide range of potential biomedical applications. Hydrogels are currently widely used in bioapplications and play a crucial role in modern strategies to remedy malfunctions in and injuries to living systems.

The high water content of hydrogels renders them compatible with most living tissue and their viscoelastic nature minimizes damage to the surrounding tissue when implanted in the host. In addition, their mechanical properties parallel those of soft tissue, which makes them particularly appealing to tissue engineers. These novel, bioactive materials are capable of interacting with the host tissues, assisting and improving the healing process, and mimicking functional and morphological characteristics of organ tissue.

Biomaterials play a crucial role in modern strategies of tissue replacement and restoration because they provide the biophysical and biochemical surroundings that are able to direct cellular behavior and functions. The concept of designing hydrogels as temporary or permanent devices for regeneration and restoration of tissues is being vigorously pursued in many laboratories, that often involve international cooperative endeavors. Both natural and synthetic hydrogels are used for repairing and regenerating a wide variety of tissues and organs. The ability to engineer composite hydrogels has generated new opportunities in addressing challenges in tissue engineering as well as in tissue function restoration.

Most hydrogels have biological traits, such as high tissue-like water content and permeability for influx of nutrients and excretion of metabolites. Cells encapsulated in a 3-D hydrogels environment are surrounded by a gels matrix that does not promote attachment or potential phenotype differentiation, thus making hydrogels especially suitable for engineered scaffolds. These hydrophilic composite structures are being designed to mimic the transport and mechanical properties of natural soft tissue. Hydrogels can homogeneously incorporate and suspend cells as well as growth factors and other bioactive reagents while allowing rapid diffusion of hydrophilic nutrients and metabolites to the incorporated cells or surrounding tissue.

One of the essentials for an effective tissue scaffold is that it degrades in a controlled manner so that when the bioreplacement is complete and functional in vivo none of the scaffolding materials remain. Biodegradable hydrogels are derived from fibrin, hyaluronic acid, collagen, chitosan, and poly(lactic acid) components to create hybrid hydrogels that are biocompatible and can provide appropriate signals to regulate cell behavior. Degradation of hydrogels leads to a loss in mechanical strength and finally disintegration. Therefore, the degradation rate of the gels needs to be carefully controlled to match the rate of new tissue formation.

There are a number of hydrogels that behave as smart materials and offer natural adaptations, such as sensing devices, actuating and regulating functions, and feedback control systems. These stimuli-responsive polymer gels react to changes in their surroundings, such

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as surrounding composition, temperature, and pH. They are of interest as intelligent, or smart, biomimetic materials that can function as biosensors, processors, and activators of an electrical response. The applications of electroconductive hydrogels as biorecognition membranes for implantable biosensors, as electro-stimulated drug-eluting devices and as a low interfacial impedance layer on neuronal prostheses present new horizons for biodetection devices. Both biomolecular recognition and responsive functions that perceive a biomolecule target and induce structural changes can be introduced into the hydrogels network.

Hydrogels-based drug delivery systems with integrated smart systems and biomolecular imaging capability open many opportunities for effective therapeutic delivery and monitoring as well as molecular imaging probes in noninvasive procedures for early detection and treatment of disease. This multifunctionality makes it possible to self-regulate and control hydrogels-based devices to maintain physiological variables for applications such as drug delivery and cell cultures.

Hydrogels implants for drug delivery can be preformed or injected. The preformed hydro-gels are processed with the active reagent in vitro prior to in vivo implantation. Injectable hydrogels are implanted as a liquid that gels in situ with the reagent incorporated and sus-pended in the gels precursor prior to gelation, enabling homogenous and facile implantation. In situ gelling of stimuli-sensitive block copolymer hydrogels has many advantages, such as simple drug formulation, site-specificity, sustained drug release behavior, less systemic toxicity, and the ability to deliver both hydrophilic and hydrophobic drugs. For example, PEG-based amphiphilic copolymers are extensively used for biomedical applications due to their unique self-assembly and biocompatibility properties. The PEG-based amphiphilic copoly-mers exhibit unique changes in micellar architecture and aggregation number in response to changes near physiological temperature and/or pH. Therefore, in situ gelling systems made with PEG-based amphiphilic copolymers are being investigated worldwide.

These topics as well as several other biomedical applications of hydrogels are covered in the ensuing chapters by the most highly qualified experts in the field. I wish to thank them and the many others who have contributed to this publication.

Richmond, VA Raphael M. Ottenbrite

Contents

Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii

List of Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xvii

Introduction to Hydrogels 1Hossein Omidian and Kinam Park

Crosslinked Polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1Hydrogels Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2Expansion of a Hydrogels Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . 3Swelling Forces in Hydrogels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4Swelling Mechanism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6Water in Hydrogels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6Hydrogels Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8Hydrogels Characterization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8Hydrogels Applications. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

Part I Stimuli-Sensitive Hydrogels 17

Stimuli-Responsive Hydrogels and Their Application to Functional Materials 19Ryo Yoshida and Teruo Okano

Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19Stimuli-Responsive Gels as Functional Materials . . . . . . . . . . . . . . . . . . . . 19

Function of Mechanical Motion . . . . . . . . . . . . . . . . . . . . . . . . . 20Function of Information Transmission and Transformation . . . . . . . . . . . 20Function of Mass Transport . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

Cell-Sheet Engineering Using an Intelligent Surface . . . . . . . . . . . . . . . . . . 24Cell-Sheet Engineering . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24Intelligent Surfaces . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

Design of Network Structure for Functional Gels . . . . . . . . . . . . . . . . . . . . 29Topological Gels, Double Network Structure Gels, Nanocomposite Gels . . . . 29Graft Gels. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30Microfabrication of Gels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30

Self-Oscillating Gels as Novel Biomimetic Materials . . . . . . . . . . . . . . . . . . 31Design of Self-Oscillating Gels . . . . . . . . . . . . . . . . . . . . . . . . . 32

Self-Oscillating Behaviors of the Gels . . . . . . . . . . . . . . . . . . . . . . . . . . 33Self-Oscillation of the Miniature Bulk Gels . . . . . . . . . . . . . . . . . . . 33Control of Oscillation Period and Amplitude . . . . . . . . . . . . . . . . . . 34On–Off Regulation of Self-Beating Motion . . . . . . . . . . . . . . . . . . . 34Peristaltic Motion of Gels with Propagation of Chemical Wave . . . . . . . . . 34

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Design of Biomimetic Micro-/Nanoactuator Using Self-Oscillating Polymer and Gels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34

Self-Walking Gels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34Microfabrication of the Gels by Lithography . . . . . . . . . . . . . . . . . . 37Control of Chemical Wave Propagation in Self-Oscillating Gels Array . . . . . 37Self-Oscillating Polymer Chains as “Nanooscillator” . . . . . . . . . . . . . . 38Self-Flocculating/Dispersing Oscillation of Microgels . . . . . . . . . . . . . 38Fabrication of Microgel Beads Monolayer . . . . . . . . . . . . . . . . . . . . 40Self-Oscillation Under Physiological Conditions . . . . . . . . . . . . . . . . 41

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

Feedback Control Systems Using Environmentally and Enzymatically Sensitive Hydrogels 45Irma Y. Sanchez and Nicholas A. Peppas

Hydrogels as Basic Functional Elements of a Control System. . . . . . . . . . . . . . 45Hydrogels in Sensors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47

Optical Transduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47Mechanical Transduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48Electric Transduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48Limitation of Enzyme Secondary Substrate . . . . . . . . . . . . . . . . . . . 48Preservation of Enzyme Activity . . . . . . . . . . . . . . . . . . . . . . . . . 50

Hydrogels as Actuators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50Magnetically Controlled Systems . . . . . . . . . . . . . . . . . . . . . . . . 51Ultrasonically Controlled Systems . . . . . . . . . . . . . . . . . . . . . . . . 51Electronically Controlled Systems . . . . . . . . . . . . . . . . . . . . . . . . 51Photo-Controlled Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51Thermally Controlled Systems . . . . . . . . . . . . . . . . . . . . . . . . . . 53Chemically Controlled Systems . . . . . . . . . . . . . . . . . . . . . . . . . 53Protein-Responsive and Controlled Systems . . . . . . . . . . . . . . . . . . . 54

Self-Regulated Hydrogel-Based Systems . . . . . . . . . . . . . . . . . . . . . . . . 55pH Feedback Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55Temperature Feedback Systems . . . . . . . . . . . . . . . . . . . . . . . . . 57Protein Concentration Feedback Systems . . . . . . . . . . . . . . . . . . . . 57Enzyme Cofactor Feedback System . . . . . . . . . . . . . . . . . . . . . . . 57Glucose Concentration Feedback Systems . . . . . . . . . . . . . . . . . . . . 58

Hydrogel-Based Feedforward and Cascade Systems . . . . . . . . . . . . . . . . . . . 60Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63

Biomolecule-Responsive Hydrogels 65Takashi Miyata

Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65Glucose-Responsive Hydrogels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66

Glucose-Responsive Hydrogels Using Glucose Oxidase. . . . . . . . . . . . . 66Glucose-Responsive Hydrogels Using Phenylboronic Acid . . . . . . . . . . . 67Glucose-Responsive Hydrogels Using Lectin . . . . . . . . . . . . . . . . . . 69

Protein-Responsive Hydrogels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72Enzyme-Responsive Hydrogels . . . . . . . . . . . . . . . . . . . . . . . . . 72Antigen-Responsive Hydrogels. . . . . . . . . . . . . . . . . . . . . . . . . . 74

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Other Biomolecule-Responsive Hydrogels. . . . . . . . . . . . . . . . . . . . . . . . 77Molecularly Imprinted Hydrogels . . . . . . . . . . . . . . . . . . . . . . . . 77Other Biomolecule-Responsive Hydrogels. . . . . . . . . . . . . . . . . . . . 80

Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84

Stimuli-Responsive PEGylated Nanogels for Smart Nanomedicine 87Motoi Oishi and Yukio Nagasaki

Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87Synthesis and Characterization of Stimuli-Responsive PEGylated Nanogels . . . . . . 88Tumor-Specific Smart 19F MRI Nanoprobes Based on pH-Responsive PEGylated Nanogels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90pH-Responsive PEGylated Nanogels for Intracellular Drug Delivery Systems . . . . . 94Smart Apoptosis Nanoprobe Based on the PEGylated Nanogels Containing GNPs for Monitoring the Cancer Response to Therapy . . . . . . . . . . . . . . . . . . . 98Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104

Stimuli-Sensitive Microhydrogels 107Haruma Kawaguchi

Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107Stimuli-Sensitive Microgels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107

Preparation of Microhydrogels . . . . . . . . . . . . . . . . . . . . . . . . . . 107Stimuli Responsiveness of Microhydrogels . . . . . . . . . . . . . . . . . . . 109Preparation of Inorganic Nanoparticles/Polymer Composite Microgels . . . . 112Polymer Composite Microgel Functions . . . . . . . . . . . . . . . . . . . . . 114Metal Oxide Nanoparticles/Thermosensitive Polymer Composite Microgels . . 114Miscellaneous Nanoparticles/Thermosensitive Composite Microgels . . . . . . 116

Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117

Part II Hydrogels For Drug Delivery 121

In-Situ Gelling Stimuli-Sensitive PEG-Based Amphiphilic Copolymer Hydrogels 123Doo Sung Lee and Chaoliang He

Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123Thermogelling PEG–PNIPAM Block Copolymers. . . . . . . . . . . . . . . . . . . . 124Pluronic-Based In-Situ Forming Hydrogels . . . . . . . . . . . . . . . . . . . . . . . 126Thermogelling PEG/PLGA Amphiphilic Block Copolymers . . . . . . . . . . . . . . 127Thermogelling Star-Shaped and Graft PEG/PLGA Amphiphilic Copolymers. . . . . . 131Thermogelling PEG–PCL Amphiphilic Copolymers . . . . . . . . . . . . . . . . . . 132Thermogelling PEG-Based Amphiphilic Multiblock Copolymers. . . . . . . . . . . . 134pH- and Thermo-Sensitive PEG–Polyester Amphiphilic Copolymer Hydrogels . . . . 134PEG-Based Amphiphilic Copolymers Modified by Anionic Weak Polyelectrolytes . . 135PEG-Based Amphiphilic Copolymers Modified by Cationic Weak Polyelectrolytes . . 138

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Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142

Biodegradable Hydrogels for Controlled Drug Release 147Luis García, María Rosa Aguilar, and Julio San Román

Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147The Nature of Biodegradable Hydrogels . . . . . . . . . . . . . . . . . . . . . . . . . 148Physical Hydrogels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149Hydrophobic Interactions Hydrogels . . . . . . . . . . . . . . . . . . . . . . . . . . . 150Ionic Interaction Hydrogels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152Hydrogen Bonded Hydrogels. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153Chemically Bonded Hydrogels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154

Thermo-Responsive Biodegradable Hydrogels from Stereocomplexed Poly(lactide)s 157Tomoko Fujiwara, Tetsuji Yamaoka, and Yoshiharu Kimura

Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157Micelles and Hydrogels with Various Block, Graft, and Armed PLA Copolymers . . . 158Stereocomplexation of Enantiomeric PLAs, and the Hydrogels Applications . . . . . . 159Hydrogels Study on Enantiomeric PLA–PEG Linear Block Copolymers . . . . . . . . 162

Motivation of the Study on Stereocomplexed Micellar Hydrogels . . . . . . . 162Copolymer Synthesis and Gels Formation . . . . . . . . . . . . . . . . . . . . 163Hydrogels from Micellar Solutions of ABA Triblock Copolymers . . . . . . . 163Hydrogels from BAB Triblock Copolymers . . . . . . . . . . . . . . . . . . . 167Hydrogels from AB Diblock Copolymers . . . . . . . . . . . . . . . . . . . . 168Hydrogels Properties and Applications . . . . . . . . . . . . . . . . . . . . . 173

Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173

Hydrogels-Based Drug Delivery System with Molecular Imaging 179Keun Sang Oh and Soon Hong Yuk

Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179Hydrogels Polymers for Imaging Probes . . . . . . . . . . . . . . . . . . . . . . . . . 180Poly(Ethylene Glycol) (PEG) and Its Copolymers . . . . . . . . . . . . . . . . . . . . 183Poly(N-isopropylacrylamide) (PNIPAM). . . . . . . . . . . . . . . . . . . . . . . . . 183Molecular Probes for Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184Gold Nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184Magnetic Nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184Fluorescence Dyes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185Microbubbles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187Quantum Dots . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187Molecular Probe/Polymer Composite Systems. . . . . . . . . . . . . . . . . . . . . . 187Iron Oxide Nanoparticles/Polymer Composite Systems . . . . . . . . . . . . . . . . . 189

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Quantum Dot/Polymer Composite Systems . . . . . . . . . . . . . . . . . . . . . . . 190Microbubble/Polymer Composite Systems. . . . . . . . . . . . . . . . . . . . . . . . 191Drug Delivery System with Molecular Imaging Capability . . . . . . . . . . . . . . . 191Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193

Part III Hydrogels for Tissue Engineering 201

Hydrogels for Tissue Engineering Applications 203Rong Jin and Pieter J. Dijkstra

Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203Hydrogels Designs for Tissue Engineering. . . . . . . . . . . . . . . . . . . . . . . . 204Crosslinking Methods to Form Hydrogels . . . . . . . . . . . . . . . . . . . . . . . . 206

Chemical Crosslinking by Radical Polymerization . . . . . . . . . . . . . . . 206Crosslinking Functional Groups . . . . . . . . . . . . . . . . . . . . . . . . . 207Crosslinking by Enzymatic Reactions . . . . . . . . . . . . . . . . . . . . . . 210Crosslinking by Stereocomplexation . . . . . . . . . . . . . . . . . . . . . . . 211Hydrogels by Thermo-Gelation . . . . . . . . . . . . . . . . . . . . . . . . . 212Crosslinking by Self Assembly. . . . . . . . . . . . . . . . . . . . . . . . . . 212Crosslinking by Inclusion Complexation. . . . . . . . . . . . . . . . . . . . . 213Combining Physical and Chemical Crosslinking. . . . . . . . . . . . . . . . . 214

Naturally Derived Hydrogels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215Protein-Based Polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215Polysaccharides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216

Synthetic Hydrogels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217Hydrogels Based on PEG–PLA and PEG–PGA Copolymers . . . . . . . . . . 217Fumaric Acid-Based Hydrogels . . . . . . . . . . . . . . . . . . . . . . . . . 217Hybrid Hydrogels. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217

Tissue Engineering Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219Bone Graft Substitutes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219Cartilage Regeneration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220

Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221

Composite Hydrogels for Scaffold Design, Tissue Engineering, and Prostheses 227V. Guarino, A. Gloria, R. De Santis, and L. Ambrosio

Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227Basic Concepts and Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228Scaffolds for Tissue Regeneration . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242

Hydrogels for Cartilage Tissue Engineering 247Pierre Weiss, Ahmed Fatimi, Jerome Guicheux, and Claire Vinatier

Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247Characterization of Hydrogels . . . . . . . . . . . . . . . . . . . . . . . . . . 248Theory of Viscoelastic Behavior . . . . . . . . . . . . . . . . . . . . . . . . . 248

xiv Contents

Cartilage Morphology, Properties and Diseases . . . . . . . . . . . . . . . . . 250Composition of Articular Cartilage . . . . . . . . . . . . . . . . . . . . . . . 250Chondrocyte . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250Histological Organization of Articular Cartilage. . . . . . . . . . . . . . . . . 251Extracellular Matrix (ECM) . . . . . . . . . . . . . . . . . . . . . . . . . . . 253Pathology of Articular Cartilage . . . . . . . . . . . . . . . . . . . . . . . . . 253Cartilage Repair . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254

Cartilage Regeneration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255Tissue Engineering (TE) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255Hydrogels Polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257In Situ Crosslinkable Hydrogels . . . . . . . . . . . . . . . . . . . . . . . . . 261Polymer Associations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 262Physical and Mechanical Behavior . . . . . . . . . . . . . . . . . . . . . . . . 262

Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264

Gelatin-Based Hydrogels for Controlled Cell Assembly 269Xiaohong Wang, Yongnian Yan, and Renji Zhang

Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269Gelatin-Based Hydrogels for the Controlled Hepatocyte Assembly . . . . . . . . . . . 274Establishing a Multicellular Model by 3D Cell Assembly for Metabolic Syndrome . . 278Cryopreservation of 3D Constructs Based on Controlled Cell Assembly . . . . . . . . 280Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283

Double Network Hydrogels as Tough, Durable Tissue Substitutes 285Takayuki Murosaki and Jian Ping Gong

Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285Robust Gels with High Elasticity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286

DN Gels from Synthetic Polymers . . . . . . . . . . . . . . . . . . . . . . . . 286Necking Phenomenon of DN Gels . . . . . . . . . . . . . . . . . . . . . . . . 288Local Damage Zone Model for the Toughening Mechanism of DN Gels . . . . 290Robust Gels from Bacterial Cellulose . . . . . . . . . . . . . . . . . . . . . . 290

Sliding Friction of Gels. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292Frictional Behavior of Gels. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292

Dependence on Load . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292Sample Area Dependence . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293Substrate Effect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294

Extremely Low Friction Gels. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295Template Effect on Gels Surface Structure and Its Friction . . . . . . . . . . . 295

Robust Hydrogels with Low Friction as Candidates for Artificial Cartilage . . . . . . . 296Wear Properties of Robust DN Gels . . . . . . . . . . . . . . . . . . . . . . . . . . . 298Biocompatibility of Robust DN Hydrogels. . . . . . . . . . . . . . . . . . . . . . . . 298

Evaluation of Robust Gels . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 300 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301

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Hydrogels Contact Lenses 303Jiri Michalek, Radka Hobzova, Martin Pradny, and Miroslava Duskova

Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303Contact Lens Terminology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306Materials Used for Hydrogels Contact Lenses . . . . . . . . . . . . . . . . . . . . . . 307

HEMA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307Other Glycol Methacrylates . . . . . . . . . . . . . . . . . . . . . . . . . . . 307Dihydroxy Methacrylates. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 308Methacrylic Acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 308Acrylamides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309

1-Vinyl-2-Pyrrolidone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 310FDA Contact Classification. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 310Selected Types of Hydrogels Contact Lens Materials . . . . . . . . . . . . . . . . . . 311Silicone Hydrogels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312Current Trends in Silicone-Hydrogels Lenses . . . . . . . . . . . . . . . . . . . . . . 313Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 314

Part IV Hydrogels With Unique Properties 317

Electroconductive Hydrogels 319Ann M. Wilson, Gusphyl Justin, and Anthony Guiseppi-Elie

Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 319Inherently Conductive Electroactive Polymers . . . . . . . . . . . . . . . . . . . . . . 320Hydrogels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 323Electroconductive Hydrogels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325Synthesis of Electroconductive Hydrogels . . . . . . . . . . . . . . . . . . . . . . . . 326Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333

Self-assembled Nanogel Engineering 339Nobuyuki Morimoto and Kazunari Akiyoshi

Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 339Self-Assembled Polysaccharide Nanogels . . . . . . . . . . . . . . . . . . . . . . . . 339

Stimuli-Responsive Self-Assembled Nanogels. . . . . . . . . . . . . . . . . . 341Thermoresponsive Nanogels . . . . . . . . . . . . . . . . . . . . . . . . . . . 342Dual Stimuli (Heat-Redox)-Responsive Nanogels . . . . . . . . . . . . . . . . 343Photoresponsive Nanogels . . . . . . . . . . . . . . . . . . . . . . . . . . . . 344

Biomedical Applications of Polysaccharide Nanogels . . . . . . . . . . . . . . . . . . 345Design and Function of Nanogel-Based Hydrogels Materials . . . . . . . . . . . . . . 346

Hybrid Gels Crosslinked by Polymerizable Nanogels . . . . . . . . . . . . . . 346Rapid Shrinking Hydrogels Using Nanogel Crosslinker . . . . . . . . . . . . . 347Biodegradable Nanogel-Crosslinked Hydrogels and Application in Regenerative Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . 347

Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 348 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 348

xvi Contents

Engineered High Swelling Hydrogels 351Hossein Omidian and Kinam Park

Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 351Engineered Hydrogels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 352Purity of HSHs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 358Hydrogels Characterization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 360Hydrogels Stability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 364Engineered HSH Polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 365Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 369 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 369

Superabsorbent Hydrogels 375Grigoriy Mun, Ibragim Suleimenov, Kinam Park, and Hossein Omidian

Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 375Hydrogels Swelling. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 376Mechanism of Hydrogels Swelling . . . . . . . . . . . . . . . . . . . . . . . . . . . . 378The Effect of Neutralization and Acidity on the Swelling Capacity of Polycarbonic Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 380Donnan’s Equilibrium and Potential in a Hydrogels Solution System . . . . . . . . . . 380Effect of Concentration Redistribution . . . . . . . . . . . . . . . . . . . . . . . . . . 384Kinetics of Hydrogels Swelling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 390References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 390

Name Index 393

Subject Index 423

List of Contributors

María Rosa Aguilar, Institute of Polymer Science and Technology, CSIC and CIBER-BBN, Juan de la Cierva 3, 28006 – Madrid, Spain

Kazunari Akiyoshi, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-surugadai, Chiyoda-ku, Tokyo 101-0062, Japan

L. Ambrosio, Institute of Composite and Biomedical Materials, National Research Council, P.le Tecchio 80, Naples 80125, Italy

R. De Santis, Institute of Composite and Biomedical Materials, National Research Council, P.le Tecchio 80, Naples 80125, Italy

Pieter J. Dijkstra, Polymer Chemistry and Biomaterials, Faculty of Science and Technology, University of Twente, The Netherlands

Miroslava Duskova, Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic, Heyrovsky sq. 2, 162 06, Prague 6, Czech Republic

Ahmed Fatimi, Laboratoire d’ingénierie Ostéo-articulaire et dentaire, LIOAD Faculté de chirurgie dentaire, Université de Nantes, IFR 26, 1 place A. Ricordeau, F-44042, Nantes, France

Tomoko Fujiwara, Department of Chemistry, University of Memphis, Memphis, TN 38152, USA

Luis García, Institute of Polymer Science and Technology, CSIC and CIBER-BBN, Juan de la Cierva 3, 28006 – Madrid, Spain

A. Gloria, Institute of Composite and Biomedical Materials, National Research Council, P. le Tecchio 80, Naples 80125, Italy

Jian Ping Gong, Faculty of Advanced Life Science, Hokkaido University, Sapporo 060-0810, Japan

V. Guarino, Institute of Composite and Biomedical Materials, National Research Council, P.le Tecchio 80, Naples 80125, Italy

Jerome Guicheux, Inserm, UMR_S 791, Laboratoire d’ingénierie Ostéo-articulaire et den-taire, LIOAD, 1 place A. Ricordeau, F-44042, Nantes, France; Laboratoire d’ingénierie Ostéo-articulaire et dentaire, LIOAD Faculté de chirurgie dentaire, Université de Nantes, IFR 26, 1 place A. Ricordeau, F-44042, Nantes, France

Chaoliang He, Department of Polymer Science and Engineering, Sungkyunkwan University, Suwon, Gyeonggi 440-746, Republic of Korea

Anthony Guiseppi-Elie, ABTECH Scientific, Inc., Biotechnology Research Park, 800 East Leigh Street, 23219, Richmond, VA, USA; Center for Bioelectronics, Biosensors and Biochips (C3B), Clemson University Advanced Materials Center, 100 Technology Drive, 29625, Anderson, SC, USA

Radka Hobzova, Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic, Heyrovsky sq. 2, 162 06, Prague 6, Czech Republic

Rong Jin, Polymer Chemistry and Biomaterials, Faculty of Science and Technology, University of Twente, The Netherlands

Gusphyl Justin, Center for Bioelectronics, Biosensors and Biochips (C3B), Clemson Univer-sity Advanced Materials Center, 100 Technology Drive, 29625, Anderson, SC, USA

Haruma Kawaguchi, Department of Chemistry, Kanagawa University, Yokohama, Japan

xvii

xviii List of Contributors

Yoshiharu Kimura, Department of Polymer Science and Engineering, Kyoto Institute of Technology, Kyoto, Japan

Doo Sung Lee, Department of Polymer Science and Engineering, Sungkyunkwan University, Suwon, Gyeonggi 440-746, Republic of Korea

Jiri Michalek, Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic, Heyrovsky sq. 2, 162 06, Prague 6, Czech Republic

Takashi Miyata, Department of Chemistry and Materials Engineering, Kansai University, Suita, Osaka 564-8680, Japan

Nobuyuki Morimoto, Department of Materials Processing, Graduate School of Engineering, Tohoku University, 6-6-02 Aramaki-aza Aoba, Aoba-ku, Sendai, 980-8579 Japan

Grigoriy Mun, Department of Chemical Physics and Macromolecular Chemistry, Kazakh National University, Almaty, Republic of Kazakhstan

Takayuki Murosaki, Faculty of Advanced Life Science, Hokkaido University, Sapporo 060-0810, Japan

Yukio Nagasaki, Tsukuba Interdisciplinary Materials Science (TIMS), University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki 305-8573, Japan

Keun Sang Oh, Department of Advanced Materials, Hannam University, 461-6 Jeonmin Dong, Yusung Gu, Daejeon, Korea 305-811

Motoi Oishi, Tsukuba Interdisciplinary Materials Science (TIMS), University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki 305-8573, Japan

Teruo Okano, Institute of Advanced Biomedical Engineering and Science, TWIns., Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan

Hossein Omidian, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL, USA

Kinam Park, Departments of Biomedical Engineering and Pharmaceutics, Purdue University, West Lafayette, IN, USA

Kinam Park, Departments of Biomedical Engineering and Pharmaceutics, Purdue University, West Lafayette, IN, USA

Nicholas A. Peppas, Pratt Chair of Engineering, Department of Biomedical Engineering, The University of Texas at Austin, TX 78712, USA

Martin Pradny, Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic, Heyrovsky sq. 2, 162 06, Prague 6, Czech Republic

Julio San Román, Institute of Polymer Science and Technology, CSIC and CIBER-BBN, Juan de la Cierva 3, 28006 – Madrid, Spain

Irma Y. Sanchez, Department of Mechatronics and Automation, Tecnologico de Monterrey, Monterrey, Nuevo León 64849, Mexico

Ibragim Suleimenov, Almaty Institute of Power Engineering and Telecommunications, Almaty, Republic of Kazakhstan

Claire Vinatier, Inserm,UMR_S 791, Laboratoire d’ingénierie Ostéo-articulaire et dentaire, LIOAD, 1 place A. Ricordeau, F-44042, Nantes, France; Laboratoire d’ingénierie Ostéo-articulaire et dentaire, LIOAD Faculté de chirurgie dentaire Université de Nantes IFR 26, 1 place A. Ricordeau, F-44042, Nantes, France; GRAFTYS SA, 415 rue Claude Ledoux, 13854 Aix en Provence, France

Xiaohong Wang, Key Laboratory for Advanced Materials Processing Technology, Ministry of Education & Center of Organ Manufacturing, Department of Mechanical Engineering, Tsinghua University, 100084, Beijing, China; Institute of Life Science and Medicine, Tsin-ghua University, 100084, Beijing, China

Ann M. Wilson, ABTECH Scientific, Inc., Biotechnology Research Park, 800 East Leigh Street, 23219, Richmond, VA, USA

xixList of Contributors

Pierre Weisse, Inserm, UMR_S 791, Laboratoire d’ingénierie Ostéo-articulaire et dentaire, LIOAD, 1 place A. Ricordeau, F-44042, Nantes, France; Laboratoire d’ingénierie Ostéo-articulaire et dentaire, LIOAD Faculté de chirurgie dentaire, Université de Nantes, IFR 26, 1 place A. Ricordeau, F-44042, Nantes, France

Yongnian Yan, Key Laboratory for Advanced Materials Processing Technology, Ministry of Education & Center of Organ Manufacturing, Department of Mechanical Engineering, Tsinghua University, 100084, Beijing, China; Institute of Life Science and Medicine, Tsinghua University, 100084, Beijing, China

Tetsuji Yamaoka, Advanced Medical Engineering Center, National Cardiovascular Center Research Institute, Osaka, Japan

Ryo Yoshida, Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan

Soon Hong Yuk, Department of Advanced Materials, Hannam University, 461-6 Jeonmin Dong, Yusung Gu, Daejeon, Korea 305-811

Renji Zhang, Laboratory for Advanced Materials Processing Technology, Ministry of Educa-tion & Center of Organ Manufacturing, Department of Mechanical Engineering, Tsinghua University, 100084, Beijing, China; Institute of Life Science and Medicine, Tsinghua University, 100084, Beijing, China