Table Of ContentBiomedical Applications
of Hydrogels Handbook
Editor-in-Chief
Raphael M. Ottenbrite
Editors
Kinam Park
Teruo Okano
Biomedical Applications
of Hydrogels Handbook
Editor-in-Chief
Raphael M. Ottenbrite
Professor Emeritus
Virginia Commonwealth University
Richmond, VA, USA
[email protected]
Editors
Kinam Park Teruo Okano
Biomedical Engineering and Pharmaceutics Institute of Biomedical Engineering
Purdue University Tokyo Women’s Medical University
West Lafayette, IN, USA Shinjuku-ku, Tokyo, Japan
[email protected] [email protected]
Associate Editors
Rolando Barbucci Arthur J. Coury
Interuniversity Research Centre for Advanced Vice President
Medical Systems Biomaterials Research
University of Siena Genzyme Corporation
Siena, Italy Cambridge, MA, USA
[email protected] [email protected]
Advisory Board Chair
Haruma Kawaguchi Nicholas A. Peppas
Graduate School of Science and Technology Department of Chemical Engineering
Keio University The University of Texas at Austin
Yokohama, Japan Austin, TX, USA
[email protected] [email protected]
ISBN 978-1-4419-5918-8 e-ISBN 978-1-4419-5919-5
DOI 10.1007/978-1-4419-5919-5
Springer New York Dordrecht Heidelberg London
Library of Congress Control Number: 2010929391
© Springer Science+Business Media, LLC 2010
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Advisory Board
Nicholas A. Peppas, Chair
Department of Chemical Engineering
The University of Texas at Austin
Austin, TX, USA
Allan Hoffman
University of Washington Engineered Biomaterials
University of Washington
Seattle, WA, USA
Emo Chiellini
Chemistry & Industrial Chemistry
University of Pisa
Pisa, Italy
Fu-Zhai Cui
Director of Biomaterials
Tsinghua University
Beijing, China
Karel Dusek
Institute of Macromolecular Chemistry
Academy of Sciences of the Czech Republic
Prague, CHEK
Jindrich Kopecek
Department of Bioengineering and of Pharmaceutics
and Pharmceutical Chemistry, University of Utah
Salt Lake City, Utah, USA
Claudio Migliaresi
Department of Materials Engineering
University of Trento
Trento - Italy
Yoshihito Osada
Division of Biological Sciences
Hokkaido University
Sapporo, Japan
Buddy D. Ratner
Director, University of Washington Engineered Biomaterials
University of Washington
Seattle, WA USA
v
vi Advisory Board
Nathan Ravi
Department of Ophthalmology
Washington University
Etienne Schacht
Polymer Material
Ghent University
Ghent, Belgium
Tianwei Tan
College of Life Science and Technology
Bejing 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
vii
viii Preface
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 1
Hossein Omidian and Kinam Park
Crosslinked Polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Hydrogels Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
Expansion of a Hydrogels Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Swelling Forces in Hydrogels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
Swelling Mechanism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Water in Hydrogels. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Hydrogels Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Hydrogels Characterization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Hydrogels Applications. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Part I Stimuli-Sensitive Hydrogels 17
Stimuli-Responsive Hydrogels and Their Application
to Functional Materials 19
Ryo Yoshida and Teruo Okano
Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
Stimuli-Responsive Gels as Functional Materials . . . . . . . . . . . . . . . . . . . . 19
Function of Mechanical Motion . . . . . . . . . . . . . . . . . . . . . . . . . 20
Function of Information Transmission and Transformation . . . . . . . . . . . 20
Function of Mass Transport . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
Cell-Sheet Engineering Using an Intelligent Surface . . . . . . . . . . . . . . . . . . 24
Cell-Sheet Engineering. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
Intelligent Surfaces. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
Design of Network Structure for Functional Gels . . . . . . . . . . . . . . . . . . . . 29
Topological Gels, Double Network Structure Gels, Nanocomposite Gels. . . . 29
Graft Gels. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
Microfabrication of Gels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
Self-Oscillating Gels as Novel Biomimetic Materials . . . . . . . . . . . . . . . . . . 31
Design of Self-Oscillating Gels . . . . . . . . . . . . . . . . . . . . . . . . . 32
Self-Oscillating Behaviors of the Gels . . . . . . . . . . . . . . . . . . . . . . . . . . 33
Self-Oscillation of the Miniature Bulk Gels . . . . . . . . . . . . . . . . . . . 33
Control of Oscillation Period and Amplitude . . . . . . . . . . . . . . . . . . 34
On–Off Regulation of Self-Beating Motion . . . . . . . . . . . . . . . . . . . 34
Peristaltic Motion of Gels with Propagation of Chemical Wave. . . . . . . . . 34
ix
x Contents
Design of Biomimetic Micro-/Nanoactuator Using Self-Oscillating
Polymer and Gels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
Self-Walking Gels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
Microfabrication of the Gels by Lithography . . . . . . . . . . . . . . . . . . 37
Control of Chemical Wave Propagation in Self-Oscillating Gels Array . . . . . 37
Self-Oscillating Polymer Chains as “Nanooscillator” . . . . . . . . . . . . . . 38
Self-Flocculating/Dispersing Oscillation of Microgels . . . . . . . . . . . . . 38
Fabrication of Microgel Beads Monolayer. . . . . . . . . . . . . . . . . . . . 40
Self-Oscillation Under Physiological Conditions . . . . . . . . . . . . . . . . 41
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
Feedback Control Systems Using Environmentally
and Enzymatically Sensitive Hydrogels 45
Irma Y. Sanchez and Nicholas A. Peppas
Hydrogels as Basic Functional Elements of a Control System. . . . . . . . . . . . . . 45
Hydrogels in Sensors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
Optical Transduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
Mechanical Transduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
Electric Transduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
Limitation of Enzyme Secondary Substrate . . . . . . . . . . . . . . . . . . . 48
Preservation of Enzyme Activity. . . . . . . . . . . . . . . . . . . . . . . . . 50
Hydrogels as Actuators. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
Magnetically Controlled Systems . . . . . . . . . . . . . . . . . . . . . . . . 51
Ultrasonically Controlled Systems . . . . . . . . . . . . . . . . . . . . . . . . 51
Electronically Controlled Systems . . . . . . . . . . . . . . . . . . . . . . . . 51
Photo-Controlled Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
Thermally Controlled Systems . . . . . . . . . . . . . . . . . . . . . . . . . . 53
Chemically Controlled Systems . . . . . . . . . . . . . . . . . . . . . . . . . 53
Protein-Responsive and Controlled Systems. . . . . . . . . . . . . . . . . . . 54
Self-Regulated Hydrogel-Based Systems . . . . . . . . . . . . . . . . . . . . . . . . 55
pH Feedback Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
Temperature Feedback Systems . . . . . . . . . . . . . . . . . . . . . . . . . 57
Protein Concentration Feedback Systems . . . . . . . . . . . . . . . . . . . . 57
Enzyme Cofactor Feedback System . . . . . . . . . . . . . . . . . . . . . . . 57
Glucose Concentration Feedback Systems. . . . . . . . . . . . . . . . . . . . 58
Hydrogel-Based Feedforward and Cascade Systems. . . . . . . . . . . . . . . . . . . 60
Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
Biomolecule-Responsive Hydrogels 65
Takashi Miyata
Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
Glucose-Responsive Hydrogels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
Glucose-Responsive Hydrogels Using Glucose Oxidase. . . . . . . . . . . . . 66
Glucose-Responsive Hydrogels Using Phenylboronic Acid . . . . . . . . . . . 67
Glucose-Responsive Hydrogels Using Lectin . . . . . . . . . . . . . . . . . . 69
Protein-Responsive Hydrogels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
Enzyme-Responsive Hydrogels . . . . . . . . . . . . . . . . . . . . . . . . . 72
Antigen-Responsive Hydrogels. . . . . . . . . . . . . . . . . . . . . . . . . . 74
