Table Of ContentEDITED BY
Rui L. Reis
Julio San Román
BIODEGRADABLE SYSTEMS
in TISSUE ENGINEERING
and REGENERATIVE MEDICINE
CRC PR ESS
Boca Raton London New York Washington, D.C.
Copyright © 2005 CRC Press, LLC
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International Standard Book Number 0-8493-1936-6
Library of Congress Card Number 2004051969
Printed in the United States of America 1 2 3 4 5 6 7 8 9 0
Printed on acid-free paper
Library of Congress Cataloging-in-Publication Data
Biodegradable systems in tissue engineering and regenerative medicine / editors, Rui L.
Reis, Julio San Román.
p. cm.
Includes bibliographical references and index.
ISBN 0-8493-1936-6 (alk. paper)
1. Tissue engineering. 2. Polymers in medicine. 3. Biodegradable plastics. I. Reis,
Rui L. II. San Román, Julio. III. Title.
R857.T55B556 2004
610'.28—dc22
2004051969
1936_C000.fm Page 4 Monday, October 18, 2004 10:36 AM
Copyright © 2005 CRC Press, LLC
Preface
The development of materials for any replacement application should be based on the thorough
understanding of the structure to be substituted. This is true in many fields, but particularly relevant
in substitution and regeneration medicine. The demands on the material properties largely depend
on the site of application and the function it has to restore. Ideally, a replacement material should
mimic the living tissue from a mechanical, chemical, biological, and functional point of view. This
agreement is, however, much easier to write down than to implement in clinical practice.
In the last few years, research in this field has been clearly evolving from the concept of
substitution/replacement to the concept of regeneration. The use of prostheses, implants, and other
nonliving materials to replace damaged or deteriorated tissues is expected to be replaced by the use
of tissue-engineered viable constructs that will regenerate the injured tissues. This evolution, which
is expected to lead to dramatic changes in health care in the upcoming years, will create an all-new
range of therapeutic methodologies. That will only be possible due to the contributions of several
different research fields, but it will not be possible at all without the use of a range of novel
biodegradable polymeric systems. These systems will mainly be used in tissue engineering scaffold-
ing and as carriers for the controlled release of a wide variety of bioactive agents (in many cases
associating those two features in the same system). Nano-biotechnology, smart biomaterials, and
stimulus-responsive materials, among others, will become increasingly more important as a result
of the introduction of novel biodegradable polymeric systems into clinical applications.
Tissue engineering (TE) has emerged in the last decade of the 20th century as an alternative
approach to circumvent the existent limitations in the current therapies for organ failure or replace-
ment, which are mainly related to the difficulty of obtaining tissues or organs for transplantation.
Conventional material technology has resulted in clear improvements in the field of regenerative/sub-
stitution medicine. However, despite the good results with the current methodologies, due to their
severity, most of these injuries are still unrecoverable, creating a major health care problem world-
wide. Consequently, there is a need for the development of advanced functional materials that are
needed to improve the quality of life of thousands of patients suffering from tissue loss or tissue
malfunctions. Only improved therapies may result in a decreased morbidity and mortality of patients
with reduction of the overall costs of health care systems
.
This is particularly relevant if one takes
into account the increasing aging of the population in the more developed countries, together with
the increasing life expectancy, which has led to a tremendous growth of age-related problems.
Internationally, the combination of materials technology (namely using biodegradable poly-
mers) and biotechnology is seen as the sector in which most major breakthroughs can be expected
for medical devices in the coming future. Substantial gains are expected to be obtained both from
a medical and economic standpoint as a result of this emerging technology. One of the main
difficulties related to performing research in this area is the multidisciplinary approach of the teams.
A strong group working on tissue engineering and regeneration must combine the expertise of
materials scientists, polymer chemists, engineers, chemists, biologists, biochemists, etc. The prob-
lem is not only to join the correct team, but also to make team members understand all the
requirements needed from the polymer and biotechnology side, thus generating synergies in their
daily activities.
However, one should always keep in mind that the most important materials that are used in
the development of adequate biomaterials for tissue engineering, replacement, and regeneration are
based on polymers and their composites reinforced with bioactive ceramics. We decided to answer
positively to the request from CRC Press to write a book titled
Biodegradable Systems in Tissue
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Copyright © 2005 CRC Press, LLC
Engineering and Regenerative Medicine when we realized that there was a clear need for a textbook
that would address in an integrated way many topics relevant to the field of the development and
uses of biodegradable materials in biomedical applications, from the materials design to its pro-
cessing, testing, and resulting applications. In fact, biodegradable polymer-based systems are
playing and will continue to play a key role in tissue engineering, replacement, and regeneration
in the near future. This increasingly more biologically driven materials science is believed to be
one of the more appealing and well-funded research areas in the first decades of the 21st century.
It will also create the need for the education of new scientists and engineers who are also “hybrids”
and who can perform multidisciplinary research, combining materials and biotechnology.
One of the major features of the book is that it tries to address a range of relevant topics in an
integrated and “looking forward” perspective. There are other books that cover similar topics, but
they are in many cases collections of chapters by many different authors. This book presents the
unique advantage of joining the view of only two of the most active groups in the field. They have
collaborated for a long time and share many common visions, being very complementary (engi-
neering + materials science + biology, and polymer chemistry + materials development/character-
ization). This, in our view, led to a book that is not just a collection of chapters, but instead a strong
effort of integration. Therefore, we believe it will be a good research and education tool for final-
year undergraduate and graduate students and faculty members around the world. The invited
contributors were also carefully selected in order to add some complementary information to the
book. They are well-known experts in their fields of research and were specifically chosen to cover
a particular topic.
The book has the following main features:
•
It provides an extensive and comprehensive description of biodegradable polymers used
in medicine, their design, development, and processing. A wide range of biodegradable
polymeric systems from both synthetic and natural origin is dealt with.
•
Several chapters on the processing and applications of biodegradable systems, from
injectable systems and injectable scaffolds to partially degradable polymeric and com-
posite materials for orthopedics and dentistry, are included. The book also incorporates
chapters on several methods for processing and testing biodegradable polymers and
composites, including bioactive composites. Great attention is also given to the manu-
facturing of scaffolds, including overviews on solid free-forming techniques, fiber bond-
ing, and methodologies based on particle aggregation, as well as on the processing of
fibers, self-curing materials, and hydrogels that can be used to seed different types of
cells. Finally, chapters on the characterization of the enzymatic degradation of natural-
origin degradable systems and on the mechanical characterization of novel biomaterials
are also included.
•
A second less extensive section deals with the field of designing bonelike apatite coatings
on biodegradable polymers by means of biomimetic coating technologies. The incorpo-
ration of proteins and other bioactive agents in such types of coatings is also addressed
in one chapter.
•
A detailed description of different applications of biodegradable polymers in the con-
trolled release of bioactive agents is included. This includes a discussion on the possible
release mechanisms that can be used and the ways to better use them in biomedical
applications. However, the main focus is placed on the use of biodegradable controlled-
release systems to deliver bioactive agents (such as regenerating factors) of use in the
field of tissue engineering as well as on the chemical modification of such types of
systems. Finally, a very detailed chapter on the uses of enzyme immobilization methods
in biomedical applications is included.
•
A discussion of the biological performance of biodegradable systems and the special
requirements that should be taken into account when evaluating their biocompatibility is
1936_C000.fm Page 6 Monday, October 18, 2004 10:36 AM
Copyright © 2005 CRC Press, LLC
also included. The cytotoxicity screening of materials and the problems related to testing
biodegradable polymers are reviewed. Additional chapters deal with the very relevant
topic of protein and cell interactions with degrading implantable systems, as well as with
the mediation of the cytokine network upon implantation of such systems. Great attention
is also given to the immune response to implanted natural-origin degradable systems and
to several methodologies to tailor the cell adhesion and proliferation on the surface of
biodegradable polymers, including the use of surface modification methodologies.
•
The book concludes with a more applied part in which the reader is provided with a
description on the use of biodegradable polymers in tissue engineering of a wide range
of tissues: bone, articular cartilage, liver, skin, nerves, etc. It also includes a chapter on
the design and use of biodegradable hydrogels in drug delivery and tissue engineering.
Finally, we must say that, as most of the readers would know, nobody can organize, write, and
prepare this type of book for publication without the help of hard-working people and support from
several institutions. We would like to acknowledge the contributions of the invited authors who
accepted the invitation to write chapters for this book.
All the supporting institutions — namely the University of Minho and the Department of
Polymer Engineering and CSIC, Institute for Science and Technology of Polymers — that have
supported us, and our students, in so many ways also deserve a word of appreciation.
As main editor of this book, I am especially grateful to all of my postdoc fellows, Ph.D. students,
and staff colleagues who work daily on the 3B’s Research Group — Biomaterials, Biodegradables,
and Biomimetics, which I (RLR) have the pleasure of directing. The outcome of this book is and
will be mainly the result of their hard work, devotion, and commitment and of their own ambitions
and aspirations. The book took more than a year to prepare, but is mainly the result of several main
research lines that took many years to implement. All coauthors have put a great number of hours
into this enterprise and realized that this was an important achievement for all of us. I cannot
mention herein all their names, but you will see their names in the different chapters.
This book is dedicated to my wife Olga, my 3-year-old boy Bernardo, and to all my scientific
kids (my students!) who made everything, including this book, possible. It is now time for us to
move to other challenges. As Marie Curie once said, “One never notices what has been done: one
can only see what remains to be done.”
We hope the readers will enjoy the book as much as we enjoyed preparing it.
Rui L. Reis
Julio San Román
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Copyright © 2005 CRC Press, LLC
Editors
Rui L. Reis
is 36 years old and was born in Porto, Portugal, where he still
lives. At the present, he is an associate professor in the Department of
Polymer Engineering at the University of Minho in the northern part of
Portugal, where he is director of the 3B’s Research Group — Biomaterials,
Biodegradables, and Biomimetics
.
This is a research unit of
Excellence
,
directly funded by the Portuguese Foundation for Science and Technology
(FCT). Previously, he has been a lecturer at the Department of Metallurgical
and Materials Science and Engineering, University of Porto. He was director
of the undergraduate program in Materials Science and Engineering, and at
the present, he is also director of graduate studies (M.Sc. and Ph.D.) in Materials Science and
Engineering at the University of Minho. He was one of the primary individuals responsible for the
creation and preparation of the new program in biomedical engineering that was started at the
University of Minho in 2002. Furthermore, he is the Socrates/Erasmus (European student/staff
mobility scheme) coordinator for Materials Science and Engineering at the University of Minho.
He is also the director of R&D of the Cork Industries Holding of the AMORIM Group, one of the
main economic groups with worldwide operations based in Portugal, where he directs a team fully
devoted to the development of new cork-based products.
Dr. Rui L. Reis’ education background includes (1) a degree in Metallurgical Engineering,
University of Porto, (2) a master’s degree by research in Materials Science and Engineering/Bio-
materials, obtained in a joint program of the six major technical universities in Portugal, and (3) a
Ph.D. in Polymer Engineering/Biomaterials, University of Minho, Portugal, a degree that was pre-
pared in cooperation with Brunel University, London, United Kingdom. Rui L. Reis has been involved
in biomaterials research since 1990. He has worked several periods abroad, in different universities
and companies. His main area of research is the development of biomaterials from natural-origin
polymers (starch, casein, soy, chitin, chitosan, algae, silk fibroin, etc.) that in most cases his group
originally proposed for a range of biomedical applications, including bone replacement and fixation,
drug delivery carriers, partially degradable bone cements, and tissue engineering scaffolding.
Lately the research of his group has been mainly focused on tissue engineering and drug delivery
applications. He has been responsible for several cooperation programs, with universities and
companies in the United Kingdom, the Netherlands, Spain, France, Finland, Germany, Italy, Turkey,
Singapore, the United States, Canada, and Japan. Previously, he was responsible at the University
of Minho for the European Union (EU) projects “ISOBONE — A Tissue Engineering Living Bone
Equivalent,”
BRITE-EURAM III, which developed new tissue engineering strategies using starch-
based scaffolds, and “ALGISORB — Algae Origin Bone Stimulators Enriched with Growth Factor,”
CRAFT,
which developed new biomaterials fully from marine origin. At the present moment, he
is the co-coordinator of a major EU research project, funded under FP6, the STREP “HIPPO-
CRATES — A Hybrid Approach for Bone and Cartilage Tissue Engineering Using Natural-Origin
Scaffolds, Progenitor Cells, and Growth Factors,”
that has a 3M-Euro budget. Furthermore, he
coordinates the only European Network of Excellence (NoE) on Tissue Engineering, “EXPERTIS-
SUES — Novel Therapeutic Strategies for Tissue Engineering of Bone and Cartilage Using Second-
Generation Biomimetic Scaffolds,” which was approved on the first call of FP6. This highly funded
NoE (budget of around 8M Euros) is composed of 20 partners, several being industrial, from 13
countries, and is expected to lead the way in all tissue engineering research in Europe. He is also
responsible for several other projects funded by Portuguese, European, and American biomaterials
1936_C000.fm Page 9 Monday, October 18, 2004 10:36 AM
Copyright © 2005 CRC Press, LLC
and polymeric industries and for a range of bilateral concerted actions. At present he is the principal
investigator (PI) on grants totaling around 12M Euros.
As a result of these projects and other projects, he directed or is directing the work of around
45 (37 at the present moment) postgraduate researchers (postdocs, Ph.D. students, and M.Sc.
students) from Portuguese, Spanish, Dutch, Slovak, Chinese, Bulgarian, Brazilian, Venezuelan, and
Turkish origin, and he has been responsible for setting up two new labs at the University of Minho
to carry out these activities. The researchers have a multidisciplinary background, including mate-
rials science and engineering, polymer engineering, chemical engineering, chemistry, biological
engineering, textile engineering, biochemistry, biology and applied biology, medicine, and dentistry.
In addition, four other members of staff at the University of Minho work in his research group.
As a result of his academic activities, Rui L. Reis has been awarded several prizes. The last
two were the ESAFORM 2001 Scientific Prize for his work on the processing of starch-based
biomaterials and the Jean LeRay Award 2002 by the European Society for Biomaterials for his
outstanding contributions to the biomaterials field as a young scientist. In addition, he is a member
of several editorial boards and acts as referee for a number of scientific journals, and has been
presenting author, member of the scientific committees and organizing committees, referee, chair-
man, discussion leader in Gordon research conferences, and invited lecturer in many conferences
worldwide (Japan, United States, Canada, Australia, Israel, Turkey, Cuba, Singapore, and a large
number of European countries).
He was the director and the main person responsible for organizing the NATO Advanced Study
Institute on Polymer-Based Systems in Tissue Engineering, Replacement, and Regeneration, held
in Algarve, Portugal, October 2001. Furthermore, he was the chair and the main organizer of a
special symposium on “New Challenges on Biodegradable Polymers,” held in Tampa, Florida,
during the annual meeting of the Society for Biomaterials (United States) in 2002. He was also
the chairman of the workshop “Tissue Engineering: The Essential Elements,” held in Reno, NV,
in April 2003 during the Annual Meeting of the Society for Biomaterials (United States). He is
also organizing a symposium for the World Biomaterials Congress to be held in May 2004 in
Sydney, Australia. He was the director and main organizer of the NATO ASI on “Learning from
Nature How to Design New Implantable Biomaterials: From Biomineralization Fundamentals to
Biomimetic Materials and Processing Routes,” held in Algarve, Portugal, in October 2003. He is
editor of several international books and guest editor of several special issues of journals (Journal
of Materials Science: Materials in Medicine, Macromolecular Bioscience, Current Opinion on
Solid State & Materials Science, Materials Science & Engineering Part C: Biomimetic and
Supramolecular Systems).
Dr. Reis has authored more than 100 papers in scientific journals, three books, five journal
special issues, 80 book chapters in books of international circulation and in international encyclo-
pedias, and more than 360 communications in conferences. He has also presented 35 invited lectures
and is a member of 10 international research societies. His research work has been covered by
news and interviews in the most prestigious Portuguese newspapers and radio stations and several
times by national television.
1936_C000.fm Page 10 Monday, October 18, 2004 10:36 AM
Copyright © 2005 CRC Press, LLC
Julio San Román studied chemistry at the University Complutense of
Madrid (1972) and became a Doctor in Polymer Chemistry in 1975. He is
the head of the Department of Macromolecular Chemistry at the Institute
of Science and Technology of Polymers, CSIC of Spain and founded the
Biomaterials Group at that institution in 1990. His scientific activities are
centered in the study and development of polymer systems for biomedical
applications, specifically tissue engineering, polymer drugs, and drug deliv-
ery systems. He has published more than 250 refereed articles in specialized
journals — Polymer Science, Biomaterials, Macromolecules, Biomacromol-
ecules, Journal of Biomedical Materials Research, Journal of Biomaterials Science — and related
journals in the biomedical field.
He has contributed more than 20 chapters to specialized books and is co-editor of two books
on biodegradable polymers for biomedical applications and biomaterials. In addition, he is the
author of several patents on the application of bioactive polymers with antithrombogenic properties
and self-curing bone and dental cements, some of which have been transferred to industry for
development and commercialization. He has been invited to present lectures at more than 50
international meetings in the field of polymer materials, controlled release, biomedical polymers,
and biomaterials. He has participated in several international projects, including EU-funded projects
and the FP6 Network of Excellence on Tissue Engineering — EXPERTISSUES.
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Copyright © 2005 CRC Press, LLC
Contributors
Gustavo A. Abraham
Department of Macromolecular Chemistry
Institute of Polymer Science and Technology
Madrid, Spain
María Rosa Aguilar
Department of Macromolecular Chemistry
Institute of Polymer Science and Technology
Madrid, Spain
Catarina M. Alves
3B’s Research Group — Biomaterials,
Biodegradables, and Biomimetics
Department of Polymer Engineering
University of Minho
Braga, Portugal
Helena S. Azevedo
3B’s Research Group — Biomaterials,
Biodegradables, and Biomimetics
Department of Polymer Engineering
University of Minho
Braga, Portugal
E. T. Baran
3B’s Research Group — Biomaterials,
Biodegradables, and Biomimetics
Department of Polymer Engineering
University of Minho
Guimarães, Portugal
L. F. Boesel
3B’s Research Group — Biomaterials,
Biodegradables, and Biomimetics
Department of Polymer Engineering
University of Minho
Guimarães, Portugal
S. A. Costa
3B’s Research Group — Biomaterials,
Biodegradables, and Biomimetics
Department of Polymer Engineering
University of Minho
Braga, Portugal
O. P. Coutinho
Department of Biology
University of Minho
Braga, Portugal
Y. Murat Elcin
Tissue Engineering and Biomaterials
Laboratory
Faculty of Science and Biotechnology Institute
Ankara University
Ankara, Turkey
Carlos Elvira
Department of Macromolecular Chemistry
Institute of Polymer Science and Technology
Madrid, Spain
Alberto Gallardo
Department of Macromolecular Chemistry
Institute of Polymer Science and Technology
Madrid, Spain
Manuela E. Gomes
3B’s Research Group — Biomaterials,
Biodegradables, and Biomimetics
Department of Polymer Engineering
University of Minho
Braga, Portugal
J. A. Hunt
Clinical Engineering Department
University of Liverpool
Liverpool, United Kingdom
Dietmar W. Hutmacher
Division of Bioengineering
Department of Orthopaedic Surgery
National University of Singapore
Singapore
Yoshito Ikada
Faculty of Medical Engineering
Suzuka University of Medical Science
Suzuka, Japan
1936_C000.fm Page 13 Monday, October 18, 2004 10:36 AM
Copyright © 2005 CRC Press, LLC
H. L. Khor
Division of Bioengineering
National University of Singapore
Singapore
I. B. Leonor
3B’s Research Group — Biomaterials,
Biodegradables, and Biomimetics
Department of Polymer Engineering
University of Minho
Braga, Portugal
Patrícia B. Malafaya
3B’s Research Group — Biomaterials,
Biodegradables, and Biomimetics
Department of Polymer Engineering
University of Minho
Braga, Portugal
J. F. Mano
3B’s Research Group — Biomaterials,
Biodegradables, and Biomimetics
Department of Polymer Engineering
University of Minho
Guimarães, Portugal
A. P. Marques
3B’s Research Group — Biomaterials,
Biodegradables, and Biomimetics
Department of Polymer Engineering
University of Minho
Braga, Portugal
Antonios G. Mikos
Department of Bioengineering
Rice University
Houston, Texas
N. M. Neves
3B’s Research Group — Biomaterials,
Biodegradables, and Biomimetics
Department of Polymer Engineering
University of Minho
Guimarães, Portugal
K. W. Ng
Department of Surgery
National University of Singapore
Singapore
A. L. Oliveira
3B’s Research Group — Biomaterials,
Biodegradables, and Biomimetics
Department of Polymer Engineering
University of Minho
Braga, Portugal
I. Pashkuleva
3B’s Research Group — Biomaterials,
Biodegradables, and Biomimetics
Department of Polymer Engineering
University of Minho
Guimarães, Portugal
Carlos Peniche
Centro de Biomateriales
Universidad de la Habana
Habana, Cuba
Rui L. Reis
3B’s Research Group — Biomaterials,
Biodegradables, and Biomimetics
Department of Polymer Engineering
University of Minho
Braga, Portugal
Julio San Román
Department of Macromolecular Chemistry
Institute of Polymer Science and Technology
Madrid, Spain
A. J. Salgado
3B’s Research Group — Biomaterials,
Biodegradables, and Biomimetics
Department of Polymer Engineering
University of Minho
Braga, Portugal
Gabriela A. Silva
3B’s Research Group — Biomaterials,
Biodegradables, and Biomimetics
Department of Polymer Engineering
University of Minho
Braga, Portugal
R. A. Sousa
3B’s Research Group — Biomaterials,
Biodegradables, and Biomimetics
Department of Polymer Engineering
University of Minho
Guimarães, Portugal
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Copyright © 2005 CRC Press, LLC
