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POLYMERIC

BIOMATERIALS
Second Edition, Revised and Expanded

Severian Dumitriu
University of Sherbrooke
Sherbrooke, Quebec, Canada

Marcel Dekker, Inc. New York • Basel
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Copyright © 2002 Marcel Dekker, Inc.

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Dedicated with affection

In memory of my parents

To my wife, Maria,
and my children, Daniela and Cristina,
who make everything worthwhile

Copyright © 2002 Marcel Dekker, Inc.

Preface

The need for spare parts for the human body has never been greater than at present. More people than ever are living longer, but the
human body, shaped by millions of years of evolution, isn’t keeping up. Spare parts must be available to replace organs and tissues
that are worn out from operating beyond their expiration dates, as well as those damaged by injury, disease, or developmental mishaps.
The biomaterials field has come a long way from its empirical beginnings, with researchers taking whatever materials were available
and attempting to integrate them into the human body, sometimes with disastrous results. Now, the body’s response to foreign materials
is better understood than ever before. Furthermore, the past 15 years have seen great strides in tissue engineering. Spare parts consisting
of living tissues are poised for significant clinical application. Tissue engineering, especially of tissues derived from the patient’s own
cells, offers total acceptance by and integration with the patient’s body, unlike nonliving materials or living tissues from other humans
or species.
The active ingredient in a medicine is only part of the arsenal against disease. The drug must somehow get to the right place at the
right time. That’s where drug delivery comes in. Drug delivery companies work to devise new dosage forms for medications. The main
challenge is to create the technologies for the easier and most convenient systematic delivery systems. For proteins and other macromole-
cules, however, the oral route is by far the hardest to accomplish.
From a practical perspective, medical applications of polymers fall into three broad categories: (1) extracorporeal uses (catheters,
tubing, and fluid lines; dialysis membranes/artificial kidney; ocular devices; wound dressings and artificial skin), (2) permanently im-
planted devices (sensory devices; cardiovascular devices; orthopedic devices; dental devices), and (3) temporary implants (degradable
sutures; implantable drug delivery systems; polymeric scaffolds for cell or tissue transplants; temporary vascular grafts and arterial
stents; temporary small bone fixation devices).
Today, biomaterial research has developed into a major interdisciplinary effort involving chemists, biologists, engineers, and physi-
cians. Biomaterials research has provided the clinician with a large number of new materials and new medical devices. As the biomaterials
device industry continues to grow, degradable polymers will increase at the expense of traditional biomaterials such as metals and
conventional, biostable polymers.
This volume consists of two parts: Part I: Polymers as Biomaterials and Part II: Medical and Pharmaceutical Applications of Polymers.
The fundamental questions of polymer synthesis, the types of polymers used for medical purposes, and modification of polymers to
increase their biocompatibility, are presented in the first part. The applications of the two major groups of biomaterials—natural biomate-
rials (polysaccharides, cellulose, chitosan, proteins, etc.) and synthetic biomaterials (polyesters, silicones, elastomers, etc.)—are also
reviewed. Part II deals with concrete utilization of polymeric biomaterials in the domains of tissue engineering, ophthalmic delivery,
vascular prostheses (grafts), dental and maxillofacial surgery, blood contacting, skin graft polymers, sensors in biomedical applications,
medical adhesives, medical textiles, and topical hemostat biomaterials.
The uses of polymers in the pharmaceutical domain fall into two areas: drug polymers and drug carrier polymers for controlled
release. Part II provides the groundwork for understanding the fundamentals of drug delivery including conventional, nonconventional,
and modulated systems; structure–property relations of selected supports and their role in drug delivery; delivery of drugs to sites such
as the gastrointestinal tract, lung, skin, tumors, and blood vessels; and marketing considerations in new drug delivery systems.
This book is truly international, with authors from Austria, Canada, Finland, France, Germany, India, Israel, Italy, Japan, the Nether-
lands, Portugal, Slovenia, Spain, Switzerland, Thailand, the United Kingdom, and the United States. I am grateful to all the contributors.

Severian Dumitriu

Copyright © 2002 Marcel Dekker, Inc.

Contents

Preface
Contributors

Part I. Polymers as Biomaterials

1. Polysaccharides as Biomaterials
Severian Dumitriu

2. Biomimetics
Weiyuan John Kao

3. Silicones for Pharmaceutical and Biomedical Applications
Haissam S. El-Zaim and John P. Heggers

4. Biodegradable Polymers as Drug Carrier Systems
Abraham J. Domb, Neeraj Kumar, Tzviel Sheskin, Alfonso Bentolila, Joram Slager, and
Doron Teomim

5. Biodegradable Biomaterials Having Nitric Oxide Biological Activity
C. C. Chu

6. Hydrogels for Biomedical and Pharmaceutical Applications
Akio Kishida and Yoshito Ikada

7. Mucoadhesive Polymers
Andreas Bernkop-Schnürch

8. Polymers for Tissue Engineering Scaffolds
Howard W. T. Matthew

9. Chitosan: Structure–Properties Relationship and Biomedical Applications
Alain Domard and Monique Domard

10. Chitosan-Based Delivery Systems: Physicochemical Properties and Pharmaceutical Applications
Radi Hejazi and Monsoor Amiji

Copyright © 2002 Marcel Dekker, Inc.

11. Immobilization of Active Biopolymers from Cold Plasma–Functionalized Surfaces for the Creation
of Molecular Recognition and Molecular Manufacturing Systems
Ferencz Denes and Sorin Manolache

12. Advances in Designed Multivalent Bioconjugates with Dendritic Structure
Bogdan Comanita

13. Biocompatibility of Elastomers
D. J. Chauvel-Lebret, P. Auroy, and M. Bonnaure-Mallet

14. Control of Cell–Biomaterial Interactions
Danielle C. Giliberti, Kyle K. White, and Kay C Dee

Part II. Medical and Pharmaceutical Applications of Polymers

15. Polymeric Systems for Ophthalmic Drug Delivery
O. Felt, S. Einmahl, P. Furrer, V. Baeyens, and R. Gurny

16. Dental and Maxillofacial Surgery Applications of Polymers
A. Bascones, J. M. Vega, N. Olmo, J. Turnay, J. G. Gavilanes, and M. A. Lizarbe

17. Biomaterials in Burn and Wound Dressings
Robert L. Sheridan, Jeffrey R. Morgan, and Rashid Mohammad

18. Dermocosmetic Applications of Polymeric Biomaterials
P. Corvi Mora and P. G. Baraldi

19. Textile-Based Biomaterials for Surgical Applications
C. C. Chu

20. Bioabsorbable Polymers for Medical Applications with an Emphasis on Orthopedic Surgery
Pentti U. Rokkanen

21. Polymers for Artificial Joints
Naohide Tomita, Kazuya Nagata, and Hiroshi Fujita

22. Polymeric Occluders in Tilting Disc Heart Valve Prostheses
G. S. Bhuvaneshwar, A. V. Ramani, and K. B. Chandran

23. Blood-Contacting Polymers
T. Avramoglou, J. Jozefonvicz, and M. Jozefowicz

24. Surface Modification of Dacron Vascular Grafts: Incorporation of Antithrombin and
Mitogenic Properties
Matthew D. Phaneuf, Martin J. Bide, William C. Quist, and Frank W. LoGerfo

25. Antithrombin–Heparin Complexes
Leslie R. Berry, Maureen Andrew, and Anthony K. C. Chan

26. Adhesives for Medical Applications
Iain Webster and Peter J. West

27. Glucose-Sensitive Hydrogel Membranes
Jin Ho Lee, Jung Ju Kim, and Kinam Park

Copyright © 2002 Marcel Dekker, Inc.

28. Polymeric Micro- and Nanoparticles as Drug Carriers
G. Barratt, G. Couarraze, P. Couvreur, C. Dubernet, E. Fattal, R. Gref, D. Labarre, P. Legrand,
G. Ponchel, and C. Vauthier

29. Liposomes in Drug Delivery
Yuan-Peng Zhang, Boris Čeh, and Danilo D. Lasic

30. Liposomes for Cancer Therapy Applications
Lawrence D. Mayer, Rajesh Krishna, and Marcel B. Bally

31. Systemic Cancer Therapy Using Polymer-Based Prodrugs and Progenes
Leonard W. Seymour

32. Anticancer Drug Conjugates with Macromolecular Carriers
F. Kratz, A. Warnecke, K. Riebeseel, and P. C. A. Rodrigues

33. Enzyme–Prodrug Therapies of Cancer
Richard J. Knox, Roger G. Melton, and Ronit Satchi

34. New Lipid/DNA Complexes for Gene Delivery
Kenneth W. Liang and Leaf Huang

35. Gene Delivery by Cationic Liposome–DNA Complexes
Nejat Düzgüneş, Sérgio Simões, Pedro Pires, and Maria C. Pedroso de Lima

36. Biological Stimulus-Responsive Hydrogels
Takashi Miyata and Tadashi Uragami

37. Biocompatible Polymers in Liver-Targeted Gene Delivery Systems
Edwin C. Ouyang, George Y. Wu, and Catherine H. Wu

38. Bioartificial Pancreas
Riccardo Calafiore

39. Transdermal Delivery of Drugs
B. B. Michniak and A. El-Kattan

40. Drug Delivery via Mucosal Routes
Nimit Worakul and Joseph R. Robinson

41. Bioadhesive Drug Delivery Systems
A. David Woolfson, R. Karl Malcolm, Paul A. McCarron, and David S. Jones

42. Recent Developments in Drug Delivery to the Nervous System
Dusica Maysinger, Radoslav Savic, Joseph Tam, Christine Allen, and Adi Eisenberg

43. Glucose-Mediated Insulin Delivery from Implantable Polymers
Larry R. Brown

44. Drug Targeting to the Kidney: The Low-Molecular-Weight Protein Approach
R. F. G. Haverdings, R. J. Kok, M. Haas, F. Moolenaar, D. de Zeeuw, and D. K. F. Meijer

Copyright © 2002 Marcel Dekker, Inc.

Contributors

Christine Allen McGill University, Montreal, Quebec, Canada
Mansoor Amiji Northeastern University, Boston, Massachusetts
Maureen Andrew Hamilton Civic Hospitals Research Centre, Hamilton, Ontario, Canada
P. Auroy Université de Rennes, Rennes, France
T. Avramoglou Université de Paris, Villetaneuse, France
V. Baeyens Centre Interuniversitaire de Recherche et d’Enseignement, Archamps, France
Marcel B. Bally BC Cancer Agency, Vancouver, British Columbia, Canada, and University of British Columbia, Vancouver, British
Columbia, Canada
P. G. Baraldi Ferrara University, Ferrara, Italy
G. Barratt UMR CNRS, Chatenay-Malabry, France
A. Bascones Universidad Complutense, Madrid, Spain
Alfonso Bentolila The Hebrew University of Jerusalem, Jerusalem, Israel
Andreas Bernkop-Schnürch University of Vienna, Vienna, Austria
Leslie R. Berry Hamilton Civic Hospitals Research Centre, Hamilton, Ontario, Canada
G. S. Bhuvaneshwar Sree Chitra Tirunal Institute of Medical Sciences and Technology, Thiruvananthapuram, India
Martin J. Bide University of Rhode Island, Kingston, Rhode Island
M. Bonnaure-Mallet Université de Rennes, Rennes, France
Larry R. Brown Harvard–Massachusetts Institute of Technology, Cambridge, Massachusetts
Riccardo Calafiore University of Perugia School of Medicine, Perugia, Italy
Boris Čeh University of Ljubljana, Ljubljana, Slovenia
Anthony K. C. Chan Hamilton Civic Hospitals Research Centre, Hamilton, Ontario, Canada
K. B. Chandran University of Iowa, Iowa City, Iowa
D. J. Chauvel-Lebret Université de Rennes, Rennes, France
C. C. Chu Cornell University, Ithaca, New York
Bogdan Comanita Institute for Chemical Process and Environmental Technology, Ottawa, Ontario, Canada

Copyright © 2002 Marcel Dekker, Inc.

P. Corvi Mora EUPHAR Group, Piacenza, Italy
G. Couarraze UMR CNRS, Chatenay-Malabry, France
P. Couvreur UMR CNRS, Chatenay-Malabry, France
Kay C Dee Tulane University, New Orleans, Louisiana
Ferencz Denes University of Wisconsin, Madison, Wisconsin
D. de Zeeuw University of Groningen, Groningen, The Netherlands
Alain Domard University Claude Bernard Lyon I, Villeurbanne, France
Monique Domard University Claude Bernard Lyon I, Villeurbanne, France
Abraham J. Domb The Hebrew University of Jerusalem, Jerusalem, Israel
C. Dubernet UMR CNRS, Chatenay-Malabry, France
Severian Dumitriu University of Sherbrooke, Sherbrooke, Quebec, Canada
Nejät Düzgüneş University of the Pacific, San Francisco, California
S. Einmahl University of Geneva, Geneva, Switzerland
Adi Eisenberg McGill University, Montreal, Quebec, Canada
A. El-Kattan Pfizer Inc., Ann Arbor, Michigan
Haissam S. El-Zaim University of Texas Medical Branch, Galveston, Texas
E. Fattal UMR CNRS, Chatenay-Malabry, France
O. Felt University of Geneva, Geneva, Switzerland
Hiroshi Fujita Kyoto University, Kyoto, Japan
P. Furrer University of Lausanne, Lausanne, Switzerland
J. G. Gavilanes Universidad Complutense, Madrid, Spain
Danielle C. Giliberti Tulane University, New Orleans, Louisiana
R. Gref UMR CNRS, Chatenay-Malabry, France
R. Gurny University of Geneva, Geneva, Switzerland
M. Haas University of Groningen, Groningen, The Netherlands
John P. Heggers University of Texas Medical Branch, Galveston, Texas
R. F. G. Haverdings University of Groningen, Groningen, The Netherlands
Radi Hejazi Northeastern University, Boston, Massachusetts
Leaf Huang University of Pittsburgh, Pittsburgh, Pennsylvania
Yoshito Ikada Suzuka University of Medical Science, Mie, Japan
David S. Jones The Queen’s University of Belfast, Belfast, Northern Ireland
J. Jozefonvicz Université de Paris, Villetaneuse, France
M. Jozefowicz Université de Paris, Villetaneuse, France
Weiyuan John Kao University of Wisconsin, Madison, Wisconsin
Jung Ju Kim Purdue University, West Lafayette, Indiana
Akio Kishida National Cardiovascular Center Research Institute, Osaka, Japan
Richard J. Knox Gnact Pharma Plc, Salisbury, England
R. J. Kok University of Groningen, Groningen, The Netherlands

Copyright © 2002 Marcel Dekker, Inc.

F. Kratz Tumor Biology Center, Freiburg, Germany
Rajesh Krishna* BC Cancer Agency, Vancouver, British Columbia, Canada, and University of British Columbia, Vancouver, British
Columbia, Canada
Neeraj Kumar The Hebrew University of Jerusalem, Jerusalem, Israel
D. Labarre UMR CNRS, Chatenay-Malabry, France
Danilo D. Lasic Liposome Consultations, Newark, California
Jin Ho Lee Purdue University, West Lafayette, Indiana
P. Legrand UMR CNRS, Chatenay-Malabry, France
Kenneth W. Liang University of Pittsburgh, Pittsburgh, Pennsylvania
M. A. Lizarbe Universidad Complutense, Madrid, Spain
Frank W. LoGerfo Beth Israel Deaconess Medical Center, Boston, Massachusetts
R. Karl Malcolm The Queen’s University of Belfast, Belfast, Northern Ireland
Sorin Manolache University of Wisconsin, Madison, Wisconsin
Howard W. T. Matthew Wayne State University, Detroit, Michigan
Lawrence D. Mayer BC Cancer Agency, Vancouver, British Columbia, Canada, and University of British Columbia, Vancouver,
British Columbia, Canada
Dusica Maysinger McGill University, Montreal, Quebec, Canada
Paul A. McCarron The Queen’s University of Belfast, Belfast, Northern Ireland
D. K. F. Meijer University of Groningen, Groningen, The Netherlands
Roger G. Melton Gnact Pharma Plc, Salisbury, England
B. B. Michniak University of Medicine and Dentistry of New Jersey, Newark, New Jersey
Takashi Miyata Kansai University, Osaka, Japan
Rashid Mohammad Shriners Burns Hospital, Massachusetts General Hospital, Boston, Massachusetts, and Harvard Medical School,
Cambridge, Massachusetts
Jeffrey R. Morgan Shriners Burns Hospital, Massachusetts General Hospital, Boston, Massachusetts, and Harvard Medical School,
Cambridge, Massachusetts
F. Moolenaar University of Groningen, Groningen, The Netherlands
Kazuya Nagata Industrial Technology Center of Okayama Prefecture, Okayama, Japan
N. Olmo Universidad Complutense, Madrid, Spain
Edwin C. Ouyang University of Connecticut Health Center, Farmington, Connecticut
Kinam Park Purdue University, West Lafayette, Indiana
Maria C. Pedroso de Lima University of Coimbra, Coimbra, Portugal
Matthew D. Phaneuf Beth Israel Deaconess Medical Center, Boston, Massachusetts
Pedro Pires University of Coimbra, Coimbra, Portugal
G. Ponchel UMR CNRS, Chatenay-Malabry, France
William C. Quist Beth Israel Deaconess Medical Center, Boston, Massachusetts
A. V. Ramani T.T.K. Pharma, Ltd., Bangalore, India

* Current affiliation: Bristol-Meyers Squibb, Princeton, New Jersey

Copyright © 2002 Marcel Dekker, Inc.

K. Riebeseel Tumor Biology Center, Freiburg, Germany
Joseph R. Robinson University of Wisconsin, Madison, Wisconsin
P. C. A. Rodrigues Tumor Biology Center, Freiburg, Germany
Pentti U. Rokkanen Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland
Ronit Satchi Center for Polymer Therapeutics, London, England
Radoslav Savic McGill University, Montreal, Quebec, Canada
Leonard W. Seymour University of Birmingham, Birmingham, England
Robert L. Sheridan Shriners Burns Hospital, Massachusetts General Hospital, Boston, Massachusetts, and Harvard Medical School,
Cambridge, Massachusetts
Tzviel Sheskin The Hebrew University of Jerusalem, Jerusalem, Israel
Sérgio Simões University of Coimbra, Coimbra, Portugal
Joram Slager The Hebrew University of Jerusalem, Jerusalem, Israel
Joseph Tam McGill University, Montreal, Quebec, Canada
Doron Teomim The Hebrew University of Jerusalem, Jerusalem, Israel
Naohide Tomita Kyoto University, Kyoto, Japan
J. Turnay Universidad Complutense, Madrid, Spain
Tadashi Uragami Kansai University, Osaka, Japan
C. Vauthier UMR CNRS, Chatenay-Malabry, France
J. M. Vega Universidad Complutense, Madrid, Spain
A. Warnecke Tumor Biology Center, Freiburg, Germany
Iain Webster Smith & Nephew Group Research Centre, York, England
Peter J. West Smith & Nephew Group Research Centre, York, England
Kyle K. White Tulane University, New Orleans, Louisiana
Nimit Worakul University of Wisconsin, Madison, Wisconsin, and Prince of Songkla University, Haad Yai, Thailand
A. David Woolfson The Queen’s University of Belfast, Belfast, Northern Ireland
Catherine H. Wu University of Connecticut Health Center, Farmington, Connecticut
George Y. Wu University of Connecticut Health Center, Farmington, Connecticut
Yuan-Peng Zhang ALZA Corp., Mountain View, California

Copyright © 2002 Marcel Dekker, Inc.

1

Polysaccharides as Biomaterials

Severian Dumitriu
University of Sherbrooke, Sherbrooke, Quebec, Canada

I. INTRODUCTION Applications, and Polysaccharides: Structural Diversity
and Functional Versatility, all edited by S. Dumitriu and
Polymers have found applications in virtually every disci- published by Marcel Dekker, Inc.
pline of medicine, ranging from simple extracorporeal de-
vices to intricately designed implants. Since each medical
application has its own highly specialized requirements, a II. BACTERIAL POLYSACCHARIDES
range of diverse materials with good biocompatibility but
different chemical and physicomechanical properties must Encapsulated bacterial diseases are still the most prevalent
be available. and serious infections in humans. There is increasing re-
Polysaccharides constitute an important component of search of the chemical basis of immunogenicity to capsular
life matter. Polysaccharides display a perfect biocompati- polysaccharides and prevention of bacterial infections
bility and biodegradability, which are the basic characteris- through immunization.
tics for polymers used as biomaterials. They have several The capsular polysaccharides of bacteria are attractive
characteristics not found in other natural polymers. Re- vaccine candidates because they constitute the most highly
cently, specific properties of antivirals, antitumorals, gene conserved and most exposed bacterial surface antigens.
modulators, etc., have been discovered for various classes They can be readily isolated and purified; they are non-
of polysaccharides. toxic; and they are immunogenic in humans (with few ex-
This chapter presents all polysaccharide classes with ceptions) (1). Another important feature is that capsular
applications as biomaterials and as pharmaceutical sys- polysaccharides can be chemically and physically defined,
tems. For the first group—polysaccharides used as bioma- which is necessary for control over their efficacy as human
terials—a special emphasis is given to the presentation of biologicals. In fact, the use of capsular polysaccharides as
membranes, implants, skin replacements, matrices for cel- immunoprophylactic agents against human disease caused
lular engineering (scaffolds), and hemostatic agents. The by encapsulated bacteria is now firmly established (2,3).
second group—polysaccharides used as pharmaceutical Efficacious vaccines composed of the capsular polysaccha-
systems—describes mainly the use of polysaccharides as rides of Nisseria meningitidis, Streptococcus pneumoniae,
components for drug conditioning and drug delivery sys- Haemophilus influenzae, and Salmonella typhi have been
tems fabrication. This chapter presents a review of the lit- developed as commercial products (Table 1).
erature based on the three books previously published: A new generation of highly successful semisynthetic
Polymeric Biomaterials, Polysaccharides in Medicinal glycoconjugate vaccines in which the polysaccharides were

Copyright © 2002 Marcel Dekker, Inc.

Table 1 Bacterial Polysaccharides droxyamino acid units or asparagine units of proteins. In
proteoglycans, polysaccharides are bound to polypeptides.
Pathogenic organism Reference
The crystal structure of the complex of an anti–Id Fab
1. Neisseria meningitidis with a Fab specific for a Brucella polysaccharide antigen
Group A 4 has previously been reported (33). To complement this
Group B 5 study, the binding characteristics and immunological prop-
Group C 5 erties of this Ab2 and two others raised with a second anti-
2. Streptococcus pneumoniae
Brucella antibody were investigated, including quantita-
Type 19F 6
Type 14 7
tive kinetic measurements by surface plasmon resonance
3. Hemophilus influenzae (34). Protective immunity to encapsulated bacteria is re-
Type b 8 lated to antibody response to polysaccharide (PS) antigen,
interactions with T and B cells, and host defense mecha-
nisms (35).
Klebsiella pneumoniae is one of the most frequently
conjugated (covalently linked) to protein carriers were de- isolated gram-negative pathogens in severe nosocomial in-
veloped (1). During the last 15 years, comprehensive fections. Alvarez et al. (36) have demonstrated the exis-
studies specially directed to the development of glycocon- tence of K. pneumoniae clinical isolates deficient in the
jugate vaccines as potential human vaccines have been re- lipopolysaccharide O side chain, the major factor for resis-
ported (Table 2) (9–11). tance to complement-mediated killing in this bacterial spe-
Complex carbohydrates are essential cell surface com- cies. These isolates are complement resistant, and their
ponents. Generally, the surface carbohydrates of bacteria mechanisms to resist complement were investigated by
are polysaccharides, either capsular polysaccharides or a selecting transposon-generated complement-sensitive mu-
part of cell wall lipopolysaccharides (LPS) (22–24). Bacte- tants. One mutant with a drastically reduced capacity to
rial cells are protected by capsules in inadvertent surround- grow in nonimmune human serum carried the transposon
ings (25–29). inserted in an open reading frame of a gene cluster in-
Capsular polysaccharides (CPS) are generally nega- volved in capsule synthesis. Four additional clinical iso-
tively charged (30). All structures of bacterial polysaccha- lates representing four different K serotypes were studied,
rides published until early 1982 have been recorded in a and results showed that capsular polysaccharide is a ma-
review (31). jor complement resistance factor in these O side chain–
Generally, bacterial polysaccharides have repetitive deficient isolates.
units that may consist of monosaccharides and octasac- Barnett et al. (37) compared responses to pneumococcal
charides and they may be linear or branched. conjugate and polysaccharide vaccines in 48 otitis-free and
Cell wall lipopolysaccharides of gram-negative bacteria 64 otitis-prone children. Pre- and postimmunization con-
consist of a lipid moiety, a core oligosaccharide, and a centrations of antibodies to pneumococcal serotypes 6B,
polysaccharide moiety which is made up from repeating 14, 19F, and 23F were measured by enzyme-linked immu-
units (32). Mammalian glycoproteins contain oligosaccha- nosorbent assay. Postimmunization mean concentrations
rides with different complexities, which are bound to hy- of antibodies to all four serotypes were significantly higher
for children receiving conjugate vaccine than for those
receiving polysaccharide vaccine; the difference in re-
Table 2 Synthetic Glycoconjugate Vaccines sponses was primarily due to a better response to conjugate
vaccine in the otitis-prone group. Significantly higher post-
Polysaccharide source Protein carrier Reference immunization concentrations of antibodies to all four sero-
Haemophilus influenzae Diphtheria toxoid 12,13 types and to one of the four serotypes were found in otitis-
Tetanus toxoid 14 prone children and otitis-free children who received conju-
Streptococcus pneumonia Tetanus toxoid 15 gate vaccine, respectively. Pneumococcal conjugate vac-
Cholera toxin 16,17 cine has the potential to reduce the incidence of disease
Pertussis toxin 16 due to vaccine serotypes, even among children with recur-
Neisseria meningitidis Tetanus toxoid 18 rent otitis media.
Bovine serum albumin 19 Protein antigens induce significant mucosal immuno-
Salmonella typhi Bovine serum albumin 20 globulin A (IgA) and systemic IgG responses when admin-
Cholera toxin 20
istered intranasally (i.n.) with the glyceride-polysorbate–
Tetanus toxoid 21
based adjuvant RhinoVax (RV) both in experimental

Copyright © 2002 Marcel Dekker, Inc.

animals and humans (38). The pneumococcal polysaccha- ysis is regenerated from cuproammonium solution of re-
ride conjugates (PNCs) induced significant systemic IgG fined cotton linters. Cellulose hollow fibers are regenerated
and IgA antibodies after i.n. immunization only when from cellulose acetate by deacetylation (45). Current ex-
given with RV and, for serotype 1, serum IgG titers were tensive efforts to improve hemodialysis membranes are
comparable to titers induced by subcutaneous immuniza- focusing on removal of β-microglobulin and improv-
tion. In addition, i.n. immunization with PNC-1 in RV elic- ing blood compatibility. The improvement of hemocom-
ited detectable mucosal IgA. These results demonstrate patibility of cellulose membranes is achievement by sur-
that RV is a potent mucosal adjuvant. face modification through uretanation, acylation/sulfation,
Zhong et al. (39) describe the generation, molecular chloroacetylation/sulfonation, and polyacylation (46–48).
structure, and protective efficacy of a human monoclonal Ishihara et al. (49) have synthesized a water-soluble
antibody (MAb) reactive with the capsular polysaccharide graft polymer composed of a cellulose and polymer having
of serotype 8 Streptococcus pneumoniae. In vitro studies a phospholipid polar group, poly(2-methacryloyloxyethyl)
revealed MAb D11–dependent complement deposition on phosphoacrylcholine (MGC) as a coating material on the
the capsule of serotype 8 organisms via either the classical cellulose hemodialysis membrane. The MGC could be
or the alternative complement pathway. In vivo, MAb D11 coated on the hollow fiber probe and the performance of
prolonged the survival of both normal and C4-deficient the probe did not decrease even after the coating. By re-
mice with lethal serotype 8 S. pneumoniae infection. cording rapid changes in the glucose concentration from
100 to 200 mg/dL, the time to reach 90% of the maximum
value was within 7 min. To determine the glucose concen-
III. CELLULOSE AND ITS DERIVATIVES tration in subcutaneous tissue, the hollow fiber probe modi-
fied with MGC was applied to human volunteers.
Polysaccharides currently used in medicine on a large scale Both cellulose diacetate and triacetate are used for he-
include cellulose, cellulose derivatives, heparin, dextrin, modialysis. The blood compatibility of the cellulose ace-
pullulan, hyaluronic acid, and alginate. tate membrane seems to be excellent if monolayer cover-
Cellulosics, regenerated cellulose and its methyl, ethyl, age of the surface with serum albumin is employed (50).
amino ethyl, and acetate-phthalate derivatives (40) have Collodion, a cellulose trinitrate derivative, was the first
been widely investigated as membranes in artificial kid- polymer to be used as an artificial membrane, and it played
neys, encapsulating materials for controlled drug delivery a central role in further investigations and applications
(41), sutures and bandages (42), and blood-compatible ma- (51,52). Cellophane and Cuprophan (53–57) membranes
terials (43), and are used mostly for blood purification, as replaced collodion later because of their better perfor-
anticoagulant, and as plasma expander in aqueous solution. mance and mechanical stability. However, due to their al-
leged lack of hemocompatibility, membranes made from
A. Blood Purification unmodified cellulose lost their market share. They have
been replaced by modified cellulosic and synthetic dialysis
1. Hemodialysis
membranes which show a better hemocompatibility than
Hemodialysis is a therapeutic treatment of chronic renal unmodified cellulose membranes. Most of the new mem-
disease to remove an excess of water and uremic toxins brane materials are also available in high-flux modifica-
from the patient blood by dialysis under the extracorporeal tions and for this reason are suitable as well for more ef-
blood circulation. The most important part of the hemodi- fective therapy modes, such as hemodiafiltration and
alysis system is the semipermeable membrane installed in hemofiltration. The success of hemodialysis as a routine
the dialyzer. The first semipermeable membrane was re- therapy is also the success of membrane development,
ported in 1944 using cellophane. Cellulosic membranes are because both a reproducible membrane production and
still used for the hemodialyzer, largely synthetic semiper- an unlimited availability of dialysis membranes have in-
meable membranes made of polysulfone (PS), polyacrylo- creased the number of dialyzed patients to about 1 million
nitrile (PAN), poly(methyl methacrylate) (PMMA), and worldwide in 1999 (58).
ethylene-vinyl alcohol copolymer (EVAL) (44). Dialysis membranes made from regenerated cellulose
The cellulosic hemodialysis membrane can be divided are under dispute because of their alleged lack of he-
into regenerated cellulose and cellulose acetate (di- and mocompatibility. The introduction of membranes from
triacetate). In the early years of hemodialysis therapy, flat-, synthetically modified cellulose, like cellulose acetate or
tube-, hollow fiber–type membranes were employed. At Hemophan, has proven, however, that hemocompatible
present almost 100% of hemodialyzers appear to be made membranes can be fabricated from cellulose by means of
from hollow fibers. The cellulose membrane for hemodial- chemical surface modifications (59,60). Diamantoglou et

Copyright © 2002 Marcel Dekker, Inc.

al. (59) have synthesized a series of cellulose carbamate lose is as a barrier for the prevention of surgical adhesions
derivatives to profit from the excellent hemocompatibil- (64). The use of oxidized cellulose (Surgicel) was largely
ity pattern of the urethane family. In vitro investigations unsuccessful in animal models in reducing surgical adhe-
on membranes made from these cellulose modifications sions in a reproducible fashion.
proved a direct relationship between the degree of modifi-
cation and hemocompatibility. This was proven for the fol- B. Drug Delivery Systems
lowing three representative hemocompatibility parame-
ters: complement C5a generation, thrombin–antithrombin Hydrophilic matrices based on polysaccharide carriers re-
(TAT) III formation, and platelet count (PC). As already main a highly popular design of sustained release dosage
shown for modifications made from cellulose esters, a form. Control of drug release from tablets containing poly-
direct dependency between improved hemocompatibility saccharide excipient system was found to be capable using
and the degree of substitution (DS) in the cellulose mole- a variety of different formulations and process methods to
cule could be found. provide a variety of different release modalities which
were capable of matrix-dimension independence. Control-
2. Plasmapheresis lability of drug release was achieved by manipulation of
the synergistic interactions of the heterodisperse polysac-
Plasmapheresis is a therapeutic treatment of blood to sepa- charides (65).
rate only plasma from the whole blood of a patient through Release data from ethylcellulose (EC) matrix tablets
extracorporeal circulation when the plasma contains patho- were analyzed to determine which release equation pro-
genic substances which are mostly high molecular weight vided the best fit to the data and to observe the effect of
proteins. The separated plasma is discarded and substituted drug solubility on the release mechanism(s) (66). Theoph-
with fresh plasma. The plasma separation is based on ultra- ylline, caffeine, and dyphylline were selected as nonelec-
filtration by hollow fiber membrane with pore size from trolyte xanthine derivatives, with solubilities from 8.3 to
0.1 to 0.5 µm, prepared from cellulose acetate, polyvinyl 330 mg/mL at 25°C. At high drug loading, drug was re-
alcohol, polyethylene, and polypropylene. leased by a diffusion mechanism with a rate constant that
increased with an increase in aqueous solubility. At low
3. Virus Removal drug loading, polymer relaxation also became a component
Cellulose is a very good candidate as the filter material of the release mechanism. However, its contribution to
since the cellulose surface exhibits the least protein adsorp- drug release was less pronounced as solubility decreased,
tion of the conventional polymer surfaces. The membrane becoming negligible in the case of theophylline.
is prepared by coagulation of the cuproammonium solu- Microcrystalline cellulose (MCC), sodium carboxy-
tion. It was proved that this filter with an average pore methylcellulose (NaCMC), hydroxypropylmethylcellulose
size of 35 nm could completely remove hepatitis C virus (HPMC), hydroxyethylcellulose (HEC), hydroxypropylcel-
(61,62). lulose (HPC), and ethylcellulose were used for the pro-
duction of time-controlled acetaminophen delivery sys-
tems using a spray-drying technique. The influence of fac-
4. Hemostasis
tors such as polymer concentration, inlet temperature, and
Oxidized cellulose has been used as hemostat. This is an drug/polymer ratio were investigated (67). Dissolution
acidic polysaccharide produced by oxidation of cellulose studies in pH 1 dilute HCl and pH 6.8 phosphate buffer
with periodic acid or nitrogen oxide. A more effective dissolution media showed that formulations consisting of
method for homeostasis is to use oxidized cellulose gauze 1% polymer with a drug/polymer ratio of 1:1 exhibited
together with a liquid-type hemostat. Wiseman et al. (63) the slowest drug release, with the spheroids coated with
evaluated two adhesion barriers composed of oxidized re- NaCMC and HEC showing the longest T50% values (45
generated cellulose (ORC) in a model of bowel surgery, and 53 min at pH 1 and 49 and 55 min at pH 6.8, respec-
with and without bleeding. They concluded that with he- tively). Slightly better sustained drug release in pH 6.8 dis-
mostasis both absorbable fabrics of ORC reduced adhesion solution medium was reached, showing the following
formation between the injured cecum and abdominal side trend: HEC ⬎ NaCMC ⬎ MCC ⬎ EC ⬎ HPMC. Concern-
wall. The effectiveness of INTERCEED Barrier, but not ing the additives, the trends in dissolution T50% of drug
nTC7, was reduced but not eliminated in the presence of revealed TA ⬎ SA ⬎ CA ⬎ OA ⬎ PVP ⬎ PA ⬎ DBS
bleeding. This confirms similar observations in models of in acidic pH 1 dissolution medium and PVP ⬎ OA ⬎
gynecologic surgery. TA ⬎ SA ⬎ PA ⬎ CA ⬎ DBS in phosphate buffer at pH
A particularly interesting application of oxidized cellu- 6.8 (67).

Copyright © 2002 Marcel Dekker, Inc.

Hydroxypropylmethylcellulose has been the most side linkages. Very few (1 → 6)-β-D-glycoside linkages
widely used hydrophilic drug carrier. Matrix tablets were seem to occur in this polysaccharide by the chemical (83)
prepared by wet granulation (68), slugging (69), or direct and enzymatic (84) methods. Curdlan is insoluble but
compression (70). The drug release was controlled through swells in water.
variations in the molecular weight of the polymer, drug
solubility, the drug/polymer ratio, the particle size of the A. Clinical Application of Curdlan
drug and polymer, and the addition of different additives
(71,78). Maeda and Chihara (85) and Sasaki et al. (86) reported
The available grades of HPMC have varied molecular that curdlan, lentinan, and other similar polysaccharides
weight, degree of substitution, and particle size. The drug inhibited the growth of Sarcoma-180. Moreover, Sasaki et
and HPMC particles sizes also influence the drug release al. (87) found that a serum factor is involved in the tumor
parameters, although to a lesser extent. The major disad- inhibition by curdlan. When peritoneal macrophages from
vantage of single-unit hydrophilic matrix systems such as normal untreated mice were incubated in vitro with serum
tablets or capsules has been the possibility of uncontrolled of mice treated with curdlan, they become cytotoxic to tu-
erosion as a result of mechanical stress during passage mor cells. This was attributed to two serum factors, a pep-
through the gastrointestinal tract, causing erratic drug re- tide (mw ⫽ 4500) and probably a peptidoglycan (mw ⫽
lease and absorption. 9000) found in serum after administration of the polysac-
A multiple-unit indomethacin delivery system based on charide.
HPMC as the hydrophilic carrier material was developed Morikawa et al. (88) showed that when curdlan is given
by a novel technique using the insolubility of cellulose i.p. to mice, it produces a high and persistent level of both
ether at elevated temperatures and the ionotropic gelation polymorphonuclear (PMN) leukocytes and macrophages.
of the polysaccharide, sodium alginate with calcium ions The activated PMN leukocytes were spontaneously cyto-
(79). toxic to mammary carcinoma cells in vitro.
In order to develop nasal powder preparations with Cellulose sulfate, curdlan sulphate, and sulfopropyl cur-
higher bioavailability for peptide delivery, the effect of a dlan have been found to exhibit strong anti–human immu-
combination of hydroxypropylcellulose and microcrystal- nodeficiency virus (anti-HIV) activity (89,90). Yoshida et
line cellulose used as base materials and microenvironment al. (91) showed that curdlan sulfate with a sulfur content
for the drugs in the preparations was examined (80). Sig- of 14.4% at concentrations as low as 3.3 µg/mL completely
nificant enhanced absorption of leuprolide, calcitonin, and inhibited infection by HIV.
FITC-dextran was attained by the addition of a small Antitumor active polysaccharide against Sarcoma-180
amount of HPC to MCC. It is suggested that MCC works was isolated by DEAE-Sepharose CL-6B and Sepharose
as an absorption enhancer by causing a locally high con- 4B column chromatography from the hot water–soluble
centration of drugs in the vicinity of the mucus surface. fraction of the mycelium of liquid-cultured Agaricus blazei
On the other hand, HPC works to increase retention of mill (92). This polysaccharide did not react with antibodies
drugs on the nasal mucus due to its gel-forming property of antitumor polysaccharides such as lentinan, gliforan,
(80). and FIII-2-b, which is one of the antitumor polysaccharides
The aqueous interaction of the sodium salt of ibupro- from A. blazei. Moreover, the analyses of 13C-NMR and
fen with the cellulose ethers ethyl hydroxyethylcellulose GC-MS suggested that this polysaccharide was prelimi-
(EHEC) and HPMC has been investigated in the concen- nary glucomannan with a main chain of β-1,2–linked
tration range 0–500 mM ibuprofen and 0.1–1% (w/w) D-mannopyranosyl residues and β-D-glucopyranosyl-3-
polymer by cloud point, capillary viscometry, equilibrium O-β-D-glucopyranosyl residues as a side chain. This poly-
dialysis, and fluorescence probe techniques (81). A combi- saccharide was completely different from the antitumor
nation of time-resolved and static fluorescence quenching polysaccharide obtained from fruiting body of A. blazei,
shows that micellelike ibuprofen aggregates are formed in β-1,6-glucan.
the solution. The average aggregation number of pure ibu-
profen micelles in water is about 40.
V. GUAR GUM

IV. CURDLAN Targeting of drugs to the colon, following oral administra-
tion, can be accomplished by the use of modified biode-
Harada et al. (82) and Saito et al. (83) showed that more gradable polysaccharides as vehicles. Guar gum (GG) was
than 99% of the linkages in curdlan are (1 → 3)-β-D-glyco- crosslinked with increasing amounts of trisodium trimeta-

Copyright © 2002 Marcel Dekker, Inc.

phosphate (STMP) to reduce its swelling properties for use microspheres were prepared by crosslinking with glutaral-
as a vehicle in oral delivery formulations, especially drug dehyde. Nifedipine was loaded into these matrices before
delivery systems aimed at localizing drugs in the distal por- and after crosslinking in order to study its release patterns
tions of the small bowel (93). Swelling of GG in artificial (97). The mean particle size of the microspheres was found
gastrointestinal fluids was reduced from 100- to 120-fold to be around 300 µm. The molecular transport phenome-
(native GG) to 10- to 35-fold depending on the amount of non, as studied by the dynamic swelling experiments, indi-
crosslinker used, showing a bell shape dependency. As a cated that an increase in crosslinking affected the transport
result of the crosslinking procedure GG lost its nonionic mechanism from Fickian to non-Fickian. The in vitro re-
nature and became negatively charged. lease study indicated that the release from these micro-
Functionalizing of GG crosslinked products (GGP) spheres is not only dependent upon the extent of crosslink-
as possible colon-specific drug carriers was analyzed by ing, but also on the amount of the drug loaded as well as
studying (1) the release kinetics of preloaded hydrocorti- the method of drug loading (97).
sone from GGP hydrogels into buffer solutions with or Guar gum tablet formulations were prepared and evalu-
without GG-degrading enzymes (α-galactosidase and β- ated under a variety of in vitro dissolution conditions. The
mannanase) and (2) direct measurements of the polymer’s formulations, along with Dilacor XR (diltiazem), were ad-
degradation in the cecum of conscious rates (94). The ef- ministered to a group of eight fasted, healthy volunteers in
fect of a GG diet on α-galactosidase and β-mannanase ac- a four period crossover study (98). Dissolution of diltiazem
tivity in the cecum of the rat and GGP degradation was also from guar gum tablets was essentially independent of stir
measured. It was found that the product GGP-0.1 (loosely speed under normal conditions (USP Apparatus II).
crosslinked with 0.1 equivalents of STMP) was able to pre-
vent the release of 80% of its hydrocortisone load for at
least 6 h in PBS, pH 6.4. In vivo degradation studies in VI. PULLULAN
the rat cecum showed that, despite the chemical modifica-
tion of GG, it retained its enzyme-degrading properties in Although many fungi are known to produce exopoly-
a crosslinker concentration–dependent manner. Eight days saccharides with an interesting range of chemical and
of GG diet prior to the study increased α-galactosidase physical properties (99), most of the research effort has
activity in the cecum of the rat threefold compared to its been directed to the α-glucan pullulan, produced by Aureo-
activity without the diet. basidium pullulans (100). Bernier (101) first described
A novel tablet formulation for oral administration using the production of two exopolysaccharides by Pullularia
guar gum as the carrier and indomethacin as a model drug (A. pullulans), a heteropolysaccharide and a neutral glu-
has been investigated for colon-specific drug delivery us- can. These contain α-(1-4) and α-(1-6) glucosidic link-
ing in vitro methods (95). Drug release studies under con- ages.
ditions mimicking mouth-to-colon transit have shown that Pullulan is a polysaccharide with high liver affinity.
guar gum protects the drug from being released completely Considering this property, interferon–pullulan conjugation
in the physiological environment of stomach and small in- was promising for interferon (IFN) targeting to the liver
testine (95). Studies in pH 6.8 phosphate-buffered saline with efficient exertion of its antiviral activity therein (102).
(PBS) containing rat cecal contents have demonstrated the The cyanuric chloride method enabled the preparation of
susceptibility of guar gum to the colonic bacterial enzyme an IFN–pullulan conjugate that retained approximately 7–
action with consequent drug release. 9% of the biological activity of IFN. Pullulan conjugation
Also, it has been shown that the swelling of guar gum enhanced the liver accumulation of IFN and the retention
is affected by concentration of the drug and viscosity grade period with the results being reproducible. When injected
of the polymer. This study examines the mechanism of intravenously to mice, the IFN–pullulan conjugate en-
behavior of guar gum in a polymer–drug matrix (96). The hanced the activity of 2-5A synthetase in the liver. The
swelling action of guar gum, in turn, is controlled by the activity could be induced at IFN doses much lower than
rate of water uptake into the matrices. An inverse relation- those of free IFN injection. In addition, the liver 2-5A syn-
ship exists between the drug concentration in the gel and thetase induced by conjugate injection was retained for 3
matrix swelling. This implies that guar gum swelling is days, whereas it was lost within the first day for the free
one of the factors affecting drug release. The swelling be- IFN–injected mice.
havior of guar gum is therefore useful in predicting drug A chelating residue [diethylenetriamine pentaacetic
release. acid (DTPA)] was introduced to pullulan (103). This
Poly(vinyl alcohol)–guar gum interpenetrating network DTPA–pullulan could conjugate with IFN through Zn2⫹

Copyright © 2002 Marcel Dekker, Inc.

coordination on mixing these three components. Intrave- transplanted mice using 3H-liposome, the tumor/serum ra-
nous injection of the IFN–DTPA–pullulan conjugate with dioactivity ratio in mice injected with 1-AL/CHP liposome
Zn2⫹ coordination induced activity in the liver of an antivi- was higher than that of mice injected with other liposomes.
ral enzyme (103). Liver targeting of IFN by this conjuga- These observations suggest that 1-AL is effective as a cell
tion technique based on Zn2⫹ coordination opens a new recognition element. As a result, 1-AL/CHP liposome is
method of IFN therapy. considered to be a good carrier of anticancer drugs for the
Gu et al. (104) and Wang et al. (105) reported a novel active targeting of tumor cells (107).
formula of hydrophobized polysaccharide nanoparticles Insulin spontaneously and easily complexed with the
which can deliver a HER2 oncoprotein containing an epi- hydrogel nanoparticle of CHP in water (108). The com-
tope peptide to the MHC class I pathway. A protein con- plexed nanoparticles (diameter 20–30 nm) thus obtained
sisting of the 147 amino-terminal amino acids of oncogene formed a very stable colloid (108). The original physiolog-
erbB-2/neu/HER2 (HER2) was complexed with two kinds ical activity of complexed insulin was preserved in vivo
of hydrophobized polysaccharides, cholesteryl group– after i.v. injection.
bearing mannan (CHM) and cholesteryl group–bearing Suzuki and Sunada (109) have investigated the influ-
pullulan (CHP), to form nanoparticles (CHM-HER2 and ence of water-soluble polymers on the dissolution behavior
CHP-HER2). CHM-HER2 and CHP-HER2 were able of nifedipine from solid dispersions with combined carri-
to induce CD3⫹/CD8⫹ CTLs against HER2-transfected ers. All the solid dispersions of nifedipine were prepared
syngeneic fibrosarcoma cell lines. In addition, vaccina- by the fusion method using nicotinamide and four differ-
tion by CHM-HER2 complexes led to a strongly enhanced ent water-soluble polymers: hydroxypropylmethylcellulose
production of IgG antibodies against HER2, whereas vac- (HPMC), polyvinylpyrrolidone (PVP), partially hydro-
cination with HER2 proteins alone resulted in a produc- lyzed polyvinyl alcohol (PVA), and pullulan. HPMC, PVP,
tion of antibodies at a marginal level. Mice immunized and PVA dissolved in the fused liquid of nicotinamide and
with CHM-HER2 or CHP-HER2 before tumor challenge operated efficiently on the amorphous formation of nifedi-
successfully rejected HER2-transfected tumors. The com- pine in solid dispersions. In dissolution studies, the drug
plete rejection of tumors also occurred when CHM-HER2 concentration for these dispersions increased to more than
was applied not later than 3 days after tumor implanta- twice the intrinsic drug solubility. The rank order of the
tion. drug concentration was HPMC ⬎ PVP ⬎ PVA. However,
The effect of liposomal adriamycin with tumor recogni- since pullulan did not dissolve in the fused nicotinamide,
tion molecule, 1-aminolactose (1-AL), on AH66 hepatoma nifedipine was present as a crystalline state in the solid
transplanted into nude mice was investigated by Ichinose dispersion; the supersaturation behavior of the drug was
et al. (106). Adriamycin (ADM) was encapsulated in lipo- scarcely observed (109).
some coating with CHP to increase the stability in the
blood stream. 1-Aminolactose (1-AL) was assembled to
the outer layer of CHP-coated liposomal ADM as a tumor VII. DEXTRIN AND CYCLODEXTRIN
recognition molecule. In an in vivo therapeutic study, 1-
AL/CHP-coated liposomal ADM restrained tumor growth Dextrin consist of an α-(1→6)-linked glucan with
more when compared with CHP-coated liposomal ADM. branches attached to O-3 of the backbone chain units. The
Thus, 1-AL/CHP-coated liposome seems to be a carrier of degree of branching is approximately 5%. Recently, enzy-
ADM to tumor cells. matic hydrolysis combined with chemical and nuclear
Yamamoto et al. (107) synthesized CHP bearing 1- magnetic resonance studies have enabled the ratio of single
aminolactose and introduced a saccharide, cholesteryl pul- to multiple branches to be elegantly elucidated (110).
lulan bearing 1-aminolactose (1-AL/CHP), to an outer The molecular size is a pivotal importance for each of
layer of the conventional liposome as a cell recognition the pharmacological properties of dextrin, for example,
element. Lectin recognized the β-galactose by aggregation colloid osmotic pressure, viscosity, cell surface adsorption,
of 1-AL/CHP–coated liposome (1-AL/CHP liposome). and steric exclusion principles (111,112).
The uptake of this liposome to AH66 rat hepatoma cells The effects of dextrin on hemostasis have been re-
was greater than in liposomes without 1-aminolactose in viewed (113,114). Although it is generally agreed that the
vitro. Furthermore, 1-AL/CHP liposomal adriamycin coagulation mechanism remains normal after infusion of
showed a stronger antitumor effect in comparison with a standard clinical dose of dextrin (115,116). Dextran ap-
other types of liposomal adriamycin in vitro. When in vivo pears to be adsorbed to the surfaces of the vascular endo-
tumor-targeting efficacy was investigated in AH66 tumor– thelium and various cells (117,118).

Copyright © 2002 Marcel Dekker, Inc.

Whereas native dextrin is immunogenic in humans Cyclodextrins have the potential to enhance drug re-
(119), lower molecular weight fractions in the clinical range lease by increasing the concentration of diffusible species
were not found to be immunogenic (120,121). The antigenic within matrix. Guo and Cooklock (137) used a range of
determinants on the dextrin chain appear to correspond additives including CDs to increase the solubility of the
to segments of two to seven glucose units (121,122). poorly water-soluble opoid analgesic, buprenorphine,
pH-sensitive dextran hydrogels were prepared by acti- and modify its release from buccal patches composed of
vation of dextrin (T-70) with 4-nitrophenyl chloroformate, poly(acrylic acid), poly(isobutylene), and poly(isoprene).
followed by conjugation of the activated dextran with 4- By inclusion of guest molecule inside the cavity of CDs,
aminobutyric acid and crosslinking with 1,10-diaminode- side effects decreased. Inclusion in CDs can reduce the
cane (123). The crosslinking efficiencies determined by bitterness of femoxetine (138), reduce the local irritation
mechanical measurements were in the range of 52–63%. of pirprofen (139), and decrease the ulcerous effect of
Incorporation of carboxylpropyl groups in dextran hy- phenylbutazone (140) or indomethacin (141). In the case
drogels led to a higher equilibrium and faster swelling un- of active ingredients exhibiting a poor bioavailability due
der high pH conditions. The swelling reversibility of hy- to water nonsolubility or low solubility, but without ab-
drogels was also observed after repeated changes in buffers sorption problems, the improvement in apparent solubility
between pH 2.0 and 7.4 (123). can improve the bioavailability (142,143). Other examples
Cyclodextrin (CDs) are naturally occurring homochiral of using CDs to promote drug release through dissolution-
oligosaccharides composed of from 6 to 13 α-1,4-linked erosion mechanisms are given by Giunchedi et al. (144)
D-glucopyranose units. They possess annular structures and Song et al. (145).
whose wide and narrow hydrophilic ends are delineated by Because of their ability to enhance the stability, solubil-
OH (2) and OH (3) secondary and OH (6) primary hy- ity, or bioavailability of drugs, CDs have been the subject
droxyl groups, respectively, whereas their hydrophobic an- of studies concerning every administration route: oral
nular interiors are lined with methyl and methylene groups (146–158); rectal (159–163); dermal (164–178); ocular
and ether oxygens. Interest in CDs stems from their ability (179–182); nasal (183–188); pulmonary (189–191); par-
to partially or completely include a wide range of guest enteral (192–196); intracerebral (197); intrathecal (198),
species within their annuli to form inclusion complexes, and epidural (199,200) administration. Recently, modified
also referred to a host–guest complexes (124–130). The CDs (201–212) were prepared either to allow the direct
bonding between the CDs and guests is solely secondary in formation of targeting agents (213–217) or to enable them
nature; nevertheless, the inclusion complexes can exhibit to be targeting agents.
considerable thermodynamic stability (131).
Cyclodextrins are potentially very interesting as the for-
mulator in pharmaceutical technology. These cyclic oligo-
VIII. STARCH
saccharides have the ability to form noncovalent com-
plexes with a number of drugs and in so doing alter their A. Microspheres and Microcapsules
physicochemical properties. In addition, the primary and
secondary hydroxyl group of the native (α, β, γ) cyclodex- Starch, in its native and modified form, has been subjected
trins are potential sites for chemical modifications (132). to extensive study over the past 40 years. Early interest in
Cyclodextrins have remarkable properties in improving starch was associated with the food and paper industry,
stability, solubility, and bioavailability of drugs after oral textile manufacture, and medicine. Crosslinked starch and
administration (133,134). Natural CDs undergo enzymatic starch networks have both the required biodegradability
degradation along the gastrointestinal tract, which proba- and a relatively high mechanical and chemical stability.
bly occurs mainly in the colon (135). No definitive results Starch microspheres were prepared using epichlorohy-
of acute toxicity have been published because the highest drin as a crosslinking agent. Recently the need for three-
doses administered to animals do not result in any mortal- dimensional matrices with controlled release properties for
ity (133). Because CDs are most often used to enhance the pharmaceutical and agrochemical uses has increased inter-
solubility and consequently the bioavailability of poorly est in starch gelation (218–223).
water-soluble active ingredients, intravenous administra- The condensation mechanism of epichlorohydrin with
tion is among the most interesting parenteral routes. Inclu- amylose involves epoxide ring opening, mediated by the
sion of a guest molecule in the cavity of CDs constitutes nucleophilic attack of the alkali amylose, and subsequent
a protected state of the included molecule. This protection chlorine displacement and epoxidation (224,225). The
is especially effective in the solid state, with respect to the starch–epichlorohydrin reaction follows second order ki-
oxygen from ambient air (136). netics, first order with respect to epichlorohydrin as well

Copyright © 2002 Marcel Dekker, Inc.

as starch. The activation energy for the reaction is 38 able α-1,6 bonds related to the presence of amylopectin
kJ/mol and the temperature coefficient K323/K303 is 2 (226). in the raw starch, (2) glycerol diether, and (3) monoether
The crosslinking of starch with epichlorohydrin under groups, all of these being likely to block the activity of α-
homogeneous and heterogeneous condition was studied amylase.
with a particular view of measuring the extent of the side A novel silicone polymer-grafted starch micropar-
reaction, where starch was substituted to give a monoether ticle—starch microparticles (MPs) grafted with 3-(trie-
derivative (227). The extent of this reaction was strongly thoxysilyl)-propyl–terminated polydimethylsiloxane (TS-
dependent on the reaction conditions (temperature, time, PDMS)—was developed that is efficacious both orally and
molar ratio of all reactants). Depending on these condi- intranasally (229,230). Unlike most other microparticle
tions, 5–25% epichlorohydrin was bound as glycerol systems, this novel system does not appear to retard the
monoether substituent by starch. The degree of swelling release of antigen or to protect antigen from degradation.
of the crosslinked starch was linearly dependent on the The results indicate that a unique physiochemical relation-
water/starch molar ratio in the reaction mixture (227). The ship occurs between protein antigen and silicone in a starch
crosslinking of starch proceeded with remarkable efficiency matrix that facilitates the mucosal immunogenicity of anti-
when epichlorohydrin was applied in the vapor phase. gen. This leads to predominance of Th2 antibody response
An interfacial crosslinking process was applied to hy- (229,230).
drosoluble starch derivatives: hydroxyethyl starch and car- The efficacy of temporary arterial emmobilization using
boxymethyl starch (223). All crosslinked polysaccharide degradable starch microspheres combined with hyperther-
microcapsules were characterized by a total resistance to mia was investigated in rabbits bearing VX2 tumors (231).
digestive media. Microsphere injection caused a marked decrease of tumor
Shefer et al. (224) characterized the structure and mor- blood flow and pH. During heating, there was a marked
phology of starch networks formed by two distinct meth- increase of the maximum temperature in tumor tissue com-
ods using cross-polarization magic angle–spinning 13C- pared with normal muscle. Tumor growth was suppressed
NMR spectroscopy (CP-MAS 13C-NMR) combined with 330% times at 3 weeks after hyperthermia alone and 270%
wide angle x-ray diffraction measurements. The first step times following combined treatment with microspheres
in the process involves the gelatinization of amylose using and hyperthermia. Damage to normal muscle tissue was
sodium hydroxide. After the addition of NaOH solution mild (231).
(6.6% w/w) the resonance lines of the amylose were broad- Evaluation of reticular endothelial system–specific
ened. Broadening can be caused by distribution of isotropic magnetic starch microspheres (MSMs) as an i.v. contrast
chemical shifts due to the loss of crystallinity (224). The agent for MR imaging in a model of experimental liver
loss of crystallinity during this process is also observed in metastases has been studied. A loss of liver signal intensity
the wide angle x-ray diffractogram of a sample following was obtained at all MSM dose levels. No metastases were
treatment with NaOH. detected in the precontrast images. The optimal detection
The amorphous nature of the networks formed follow- rate of hepatic metastases was reached with the T1-
ing the reaction of amylose with epichlorohydrin is also weighted spin-echo (SE) sequence at a dose of 1.0 mg
supported by x-ray diffraction analysis. The resonance of Fe/kg b.w. MSM and the diameters of the smallest lesions
the C6 carbon in the network formed is of weaker intensity depicted were 1 mm (232). The use of MSM dramatically
and is shifted downfield by about 1 ppm from about 61.4 increased the detection of experimental hepatic metastases.
ppm in the native amylose molecule to 60.4 ppm in the
crosslinked network. The secondary OH(2) and OH(3) of B. Starch Derivatives
the native amylose at 5.0–5.4 ppm appear in the cross-
1. Hydroxyethyl Starch
linked network spectrum. This indicates that both crosslink
points as well as glycolic functional group (4.7 ppm) are Hydroxyethyl starches (HES) are high-polymeric com-
formed (224). These observations suggest that epichloro- pounds obtained via hydrolysis and subsequent hydroxy-
hydrin crosslinks and reacts monofunctionally at C2, C3, ethylation from the highly branched amylopectin con-
and C6 (224). Their swelling degree, reflecting the number tained in maize. The glucose units can be substituted at
of glycerol dieter bridges in the polymeric network, and carbon 2, 3, and 6 leading to various substitution patterns.
the number of noncrosslinking monoglycerol ether groups This pattern is described by the C2/C6 hydroxyethylation
corresponding to a side reaction of epichlorohydrin with ratio. The higher the degree of substitution and the C2/C6
starch were determined (228). Degradation by α-amylase ratio, the less the starch is metabolized. The in vitro molec-
was surface controlled and could be modulated by the in- ular weight, the degree of substitution, and the C2/C6 ratio
troduction in the polymeric network of (1) nonhydrolyz- are the main determinants of the in vivo molecular weight,

Copyright © 2002 Marcel Dekker, Inc.

which is clinically relevant. Hemorrhagic complications kinetics of ACS with those of HES in 32 patients (ASA
that occur after infusing larger volumes of HES can be physical status I and II) undergoing elective surgery. In
avoided with a starch of low in vivo molecular weight contrast to hydroxyethyl starch, this new agent undergoes
(233). Furthermore high molecular weight HES macromol- rapid and nearly complete enzymatic degradation.
ecules lead to a distinctive decrease in fibronectin concen-
tration that reflects saturation of the reticuloendothelial 3. Carboxymethyl Starch
system (RES). Another advantage of low in vivo molecular
weight HES is its rather short half-life. Patients with an Claudius et al. (240) determined effects of sodium carbox-
increased bleeding risk, microcirculatory disturbance, or ymethyl starch (CMS) on the antimicrobial activity of van-
affected RES should receive HES with low in vivo molecu- comycin. In particular, the in vitro activity of vancomycin
lar weight. In the future, HES should be mainly character- against two clinically relevant bacteria, Staphylococcus
ized by the in vivo and not the in vitro molecular weight. aureus and Enterococcus faecalis, was studied in the pres-
Artificial colloids affect hemostasis. Particularly, HES ence of varying concentrations of sodium CMS. From two
solutions may have detrimental effects on hemostatic independent studies conducted using an agar dilution
mechanisms (234). method, it appeared that the binding of vancomycin to so-
Hydroxyethyl starch is frequently used as a volume ex- dium carboxymethyl starch had no effect on the in vitro
pander in critically ill patients. Hofbauer et al. (235) in- antimicrobial activity of vancomycin.
vestigated whether HES influences the chemotaxis of
polymorphonuclear leukocytes (PMNs) through endothe- IX. FUCAN SULFATES
lial cell monolayers by using a test system that allows the
simultaneous treatment of both cell types; HES was shown Marine algal sulfated polysaccharides have been found to
to significantly reduce the chemotaxis of PMNs through possess various pharmacological activities, i.e., antibacte-
endothelial cell monolayers. rial, antiviral, antitumor (241,242), immunosuppressive,
The effects of HES on blood coagulation were investi- antilipemic, antihemostatic, and anticoagulant (243). Fu-
gated in 20 patients undergoing surgery to determine can sulfates are a type of sulfated polysaccharide occurring
whether its use places recipients at risk of hemorrhage or in brown marine algae.
thrombosis (236). The partial thromboplastin times are sig- The anticoagulant activity of fucan sulfates (244) was
nificantly prolonged; factor VIII activities and fibrinogen mainly assayed by activated partial thromboplastone time,
levels are decreased. After infusion of HES, no significant which expresses the intrinsic pathway of blood anticoagu-
differences were detected in platelet count or prothrombin lation; prothrombin time, which explores the extrinsic
time. A decreased platelet aggregation was also found after pathway; thrombin clotting time; and repilase clotting time
the infusion of HES (236). methods (245). The anticoagulant components of brown,
Jamnicki et al. (237,238) compared the effects of pro- red, and green algae are found in fucan sulfates. They all
gressive in vitro hemodilution (30 and 60%) on blood comprise a family of polydisperse heteromolecules based
coagulation in 80 patients receiving one of two different on fucose, xylose, glucuronic acid, galactose, mannose,
6% HES solutions using thrombelastography (TEG). The and half ester sulfate. They differ in sugar composition and
newly developed solution has a mean molecular weight of sulfate content, and thus in structure (246–249).
130 kD and a degree of substitution, defined as the average The correlation between the sulfate and uronic acid con-
number of hydroxyethyl groups per glucose moiety, of 0.4 tents and the anticoagulant activity of fucan sulfates was
(HES 130/0.4); the conventional solution has a mean mo- confirmed by a study on fucan sulfate from Ecklenia kur-
lecular weight of 200 kD and a degree of substitution of ome (250). It has also been reported that fucoidans (pure
0.5 (HES 200/0.5). Both HES solutions significantly com- fucans) from F. vesiculosus (251), Eisenia bicyclis (252),
promised blood coagulation, as seen by an increase in reac- Hizikia fusiforme (253), Laminaria angustata (254), and
tion time and coagulation time and a decrease in angle P. canaliculata (255) showed antithrombin activity.
alpha, maximal amplitude, and coagulation index (all p ⬍
0.05).
X. LECTINS
2. Acetyl Starch
Lectins are proteins or glycoproteins of nonimmune origin
Acetyl starch (ACS) is a new synthetic colloid solution for capable of binding to one or more specific sugar residues
plasma volume expansion and is now undergoing phase 2 and mediating a variety of biological processes, such as
clinical trials. Behne et al. (239) compared the pharmaco- cell–cell and host–pathogen interactions, serum glycopro-

Copyright © 2002 Marcel Dekker, Inc.

tein, and innate immune responses. Currently, over 200 Hyaluronan (sodium hyaluronate) and hyaluronan de-
three-dimensional structures of lectins from plants, ani- rivatives (hylans) have been developed as topical, in-
mals, bacteria, and viruses and their complexes are avail- jectable, and implantable vehicles for the controlled and
able (256–262). localized delivery of biologically active molecules (283).
Excellent recent reviews on the structure and interactions Hyaluronan is the original lastoviscous, biocompatible
of lectins are available (263–272). Thus, lectins possess polysaccharide developed for use in eye surgery and visco-
various specificities that are associated with their ability surgery, orthopedic surgery, rheumatology, otology, plas-
to interact with acetylaminocarbohydrates, aminocarbohy- tic surgery, and veterinary medicine (284,285). Hyaluronic
drates, sialic acid, hexoses, pentose, and many other carbo- acid, either by itself or mixed with fibronectin, may be a
hydrates (258,273). Lectins from plant sources were the potentially optimal bioimplant for the surgical manage-
first proteins of this class to be studied (274–277). Human ment of vocal fold mucosal defects and lamina propria de-
foods of both plant and animal origin contain a variety of ficiencies (e.g., scarring) from a biomechanical standpoint
simple and complex carbohydrates as well as lectins. Both (286).
saccharides and lectins have the capacity to interfere with Hyaluronic acid in the range of Mw 1300 kD may prove
bacterial and viral attachment to epithelial cell surfaces beneficial in minimizing bacterial contamination of surgi-
within the alimentary canal, as has the major mucosal im- cal wounds when used in guided tissue regeneration sur-
munoglobulin, secretory IgA. It is well known that the lec- gery (287). The 1.0 mg/mL concentration of high molecu-
tin from jack fruits can bind to serum IgA1, but secretory lar weight HA had the greatest overall bacteriostatic effect,
IgA also possesses oligosaccharide receptors for bacterial inhibiting the growth of all six bacterial strains tested.
lectins in fimbriae and can agglutinate E. coli by this anti- Among the bacterial strains studied, HA was found to have
gen nonspecific mechanism (264). no bactericidal effects, regardless of concentration or mo-
Membrane lectins of certain cells are capable of inter- lecular weight.
nalization of their ligands, and hence glycoconjugates spe- An animal model study was conducted to compare the
cifically recognized by these lectins can be used as carriers efficacy of recurrent topical applications of hyaluronic acid
of metabolite inhibitors and drugs (278). Galactose-termi- and gentamicin ointment for the treatment of noninfected,
nated glycoproteins and neoglycoproteins have been used mechanical corneal erosions (288). Rabbit eyes treated
to carry antiparasitic (279) and antiviral drugs (280,281). with hyaluronic acid showed a significantly enhanced rate
The potential for using lectins as a means of ‘‘anchor- of epithelial defect closure compared with untreated eyes
ing’’ a drug delivery system to the mucosal surfaces of the and a similar rate to that achieved with gentamicin oint-
eye has been investigated (282). In this study the acute ment. In the eyes treated with hyaluronic acid a normal,
local dermal irritancy of these lectins, in terms of their po- multilayered epithelium was observed 48 h after complete
tential to cause inflammation and tissue necrosis, was healing, whereas the gentamicin-treated eyes showed an
investigated. There was no evidence of tissue necrosis, imperfectly layered epithelium, with irregularity of the cu-
edema, or Evans blue infiltration with any of the lectin boidal cells.
solutions administered. The rabbits did not display any Through the esterification of the carboxyl group of the
signs of discomfort such as scratching or continued groom- glucuronic acid moiety, polymeric prodrugs of hyaluronic
ing throughout the experiment. Histological examination acid have been prepared by several groups (289–291).
of the injection sites revealed little sign of any inflamma- Two drugs made up of HA derivatives have recently be-
tion, such as heterophil migration, edema, or tissue dam- come available for patients in whom simple analgesics and
age. It was concluded that these lectins demonstrate mini- conservative nonpharmacological therapy have failed. Les-
mal acute irritancy, and will therefore be taken forward for lie (292) reviews the epidemiology, pathogenesis, diagno-
formulation and in vivo studies. sis, and medical management of osteoarthritis of the knee,
with an emphasis on the physiologic and pharmacological
mechanisms of HA. Health care providers may administer
XI. HYALURONIC ACID, HYALURONAN, HA via intra-articular injection in primary care and rheu-
AND HYALURONAN DERIVATIVES matologic or orthopedic settings or they may refer their
patients to specialists for consultation.
Hyaluronic acid (HA) is a natural mucopolysaccharide Hyaluronic acid grafted with poly(ethylene glycol)
which consists of alternating residues of D-glucuronic acid (PEG) (PEG-g-HA) were synthesized. The materials char-
and N-acetyl-D-glucosamine. Hyaluronic acid functions as acterization, enzymatic degradability, and peptide (insulin)
the backbone of the proteoglycan aggregates necessary for release from solutions of the copolymers were examined
the functional integrity of articulate cartilage of the knee. (293). Insulin was preferentially partitioned into the PEG

Copyright © 2002 Marcel Dekker, Inc.

The biological cific diameter.72 ⫾ 0. In vitro histologic findings showed that mesen.50% w/w). a specific membrane receptor frequently overex. chondroitin sulfate (maxi- tives decreased (294). did not elicit any inflammatory response and Leakage rate of insulin from copolymer containing be. ally. and hyaluronan) onto coral has CD44. Due to these peculiar properties.29 ⫾ 0.20. (maximum adsorption 1. cans makes this material potentially useful in osseointegra- gard to the amount of bone and cartilage formed. conformational change of insulin was effectively pre. Subsequently rabbit son to previously used injectable biomaterials and expands autologous cells were cultured in this hyaluronan-based the arsenal of therapeutic tools in the field of soft tissue scaffold and implanted in a full thickness osteochondral augmentation. 6. tion in bone metabolism or periodontal therapy (298).07 mg/20 mg of coral. mg/20 mg of coral. the com- number of cells loaded per unit volume of implant. Coradini et al. 3. (294) covalently biocompatibility of the biomaterial. static interactions with calcium sites of coral that are de- The hyaluronic acid–based delivery vehicles are superior pendent on pH and blocked in the presence of large to porous calcium phosphate ceramic with respect to the amounts of salt. The structure evaluation of the com- HA solution. With the aim of producing a biomaterial for surgical chymal progenitor cells adhered and proliferated onto the applications. Inc.70 ⫾ appeared to be almost completely internalized into MCF7 0. erties of the ideal filler material. dermatan sulfate.90 ⫾ 0. Fluorescence microscopy showed mum adsorption of 0. chondroitin sulfate. phase in a PEG/HA solution system.06 thereafter. The tion (296). Leakage of insulin that the biomaterial. This material presents several advantages in compari- tors first were characterized in vitro. been investigated (298). linked isodium butyrate to HA (a component of the extra. expressing CD44 standard and variant isoforms. lesion. Hyaluronan is not adsorbed onto gran- esterification of the carboxyl groups of the glucuronic acid ules of coral. Granules of natural coral of spe- pressed on the tumor cell surface (294). Its major advantages as a drug carrier con. hyaluronic acid–based vehicles have the advantage of Several biomaterials are available for the purpose of degradation/resorption characteristics that allow complete soft tissue augmentation. but none of them has all the prop- replacement of the implant with newly formed tissue. and bination of granules of natural coral with glycosaminogly- HYAFF 11 sponges are superior to the ceramics with re. and heparan sulfate cells. of HA gels for dermal implantation give the physician new dimensional scaffolds as a culture vehicle for mesenchy. was completely degraded within 4 months after implanta- tween 7 and 39% by weight of PEG were similar.45% w/w) is adsorbed more than highly sulfated chon- provement of the antiproliferative activity up to DS ⫽ 0. paran sulfate.72 ⫾ 0. the antiproliferative effect of the ester deriva. The adsorption of glycosaminoglycans (heparin. The test of contact cytotoxicity showed a very good longer period of time. the alginate–hyaluronate association has hyaluronan-derived scaffold. possibilities of effective treatment in this field (299). The new composite biomaterial made from hydroxyap- vented in PEG-g-HA solutions. Stabi- mal progenitor cells was investigated (296). Two biomaterials based on hyaluronic acid modified by 3. highly sulfated chondroitin sist of its high biocompatibility and its ability to bind sulfate.10 mg/20 mg of coral.06 mg/20 mg of coral.60% that after 2 h of treatment fluorescein-labelled compounds w/w). lized. and particles of formulation for ophthalmic or arthritis treatment. inorganic component are closely anchored in the structure To increase the availability of sodium butyrate over a (297). face.60% w/w) (298). Crossed techniques were used to Copyright © 2002 Marcel Dekker. The percentage adsorption of polyanions onto (HYAFF 11 and ACP sponges) were tested as osteogenic coral depends mainly on their charge density. with sulfate or chondrogenic delivery vehicles for rabbit mesenchymal groups being more important than carboxyl groups. droitin sulfate species (maximum adsorption 0. The prolifera. although insulin was dena.06 mg/20 mg of coral. genitors. with or without mesenchymal pro- from the copolymers was dependent upon the PEG content. he- cellular matrix). having high con- activity of hyaluronic acid–butyric ester derivatives was tent of calcium (⬎98%) and a homogeneous surface ad- evaluated in terms of the inhibition of the growth of the sorb glycosaminoglycans with different capacity. bone marrow–derived progeni.50% w/w). 4. . The recent development The tolerability and safety of hyaluronan-based three. After 6 days of treatment. The progenitor cells and compared with a well-characterized adsorption of glycosaminoglycans is driven by electro- porous calcium phosphate ceramic delivery vehicle (295). In vivo data demonstrated been investigated (300). Heparin MCF7 cell line and compared with that of sodium butyrate. (maximum adsorption of 0. atite and collagen conjugated with hyaluronic acid has tured in storage of both phosphate buffered solution and been studied (297). Such a heterogeneous-structured polymeric posite showed more dense arrangement due to the forma- solution may be advantageous as an injectable therapeutic tion of collagen hyaluronic acid conjugate. Addition. 3. nonanimal hyaluronic acid gel is well tolerated and tion patterns and extracellular matrix production of rabbit effective in augmentation therapy of soft tissues of the and human mesenchymal. dermatan sulfate (maximum adsorption of 0. between 100 and 500 µm. we observed a progressive im.

In addition. Alginate Hydrogel With the aim of producing a biomaterial for surgi- cal applications. Viscometry measurements using segments show substantial enhancement (approximately the capillary technique or the Couette flow. Pass and Hales rides in dilute solutions. Oral administration of calcium I (MM 30%. MG 37%) than with alginate liposomes. ALGINATE num. Due to the presence of carboxylate The sodium alginate from Sarassum fulvellum showed groups. result in desegregation of the calcium alginate complex. alginate hydrogels without buffering of stomach acid may lutions up to 20 mg/mL. chroism (333). alginate is a polyelectrolyte at neutral pH. thixotropic gels exist at calcium levels that. in a regular 2(1) con. together with 50%) of c. An increase in enteric pH to 6. free energy of complexation was divided into two contri- nate). irreversible hydrogels the primary event in network formation is dimerization of have found multiple applications as food additives. which is an appropriate pH for pancreatic buffering in the duode- XII. Several antacids can buffer gastric fluid at pH 4. GG 30%. Inc. in an butions: one arising from the specific interactions between alginate with a high proportion of L-guluronic acid blokcs.316).5. the case of more con- (303) have investigated the effect of the cation on the en. modeled theoretically (327. and other techniques (310–312) have shown that tions. structure. Previous studies of alginate gelation other solvents. Due to their solubility profiles. ellipticity in the presence of excess of K⫹. Crossed techniques were used to have been investigated by circular dichroism (c. and Mn (317). and in biotechnology (320–326). namely. the buckled ribbon structure of the polyguluronic acid. in cos- poly-L-guluronate chain sequences.) (302) assess the existence of polymer interactions in aqueous so- and rheological measurements. Buffering of gastric fluid with antacids would be The alginates is a copolymer composed of D-mannuronic necessary in order to facilitate release of drugs from cal- acid (M) and L-guluronic acid (G) arranged in MM and cium alginate into small intestine—the most appropriate GG blocks interrupted by regions of more random distribu. in medicine. The gels are not thermoreversible.1% w/w (308). approached by rheological measurements in the flow Calcium alginate has been one of the most extensively mode. tumors. in the presence of divalent ions at concentration of ⬎0. 13C-NMR spectro. the behavior of the polymer associations appeared investigated biopolymers for binding heavy metals from as a compromise between those of individual polysaccha- dilute aqueous solutions (304–307).d. have been studied by means of circular di- scopic studies have been made on alginate solutions under. in a wide range of temperatures and dilu- by c. such as Sarcoma-180. The interactions of alginates of various compositions This observation has led to the well-known proposal of with basic polypeptides. ginate II (MM 33%. A. GG 20%.328).314) with specific chelation of Ca2⫹ ions The complexation of complementary polymers has been between the participating chains (315). as well as in of the system (309). tion of M and G units. metics. formation (313. Specific intermolecular cooperative interactions Several authors have modeled the association of biological occur between calcium and glucuronate blocks owing to polymers (329–332). centrated solutions and containing 20 mg/mL alginate was thalpy of dilution of alkali metal salts of alginate. and living cells. Alginate–Polyelectrolyte Complexation calcium to alginate over which thixotropic gels are formed depends on the alginate type.d. the alginate–hyaluronate association has Interactions of alginate with univalent cations in solution been investigated (319). content of D-mannuronate sequences in all alginates is al- The rigid structure and large pore size of these gels are most identical.d. evidenced the moderate with smaller changes for other univalent cations: Li⫹ ⬍ significance of interactions between the two polysaccha- Na⫹ ⬍ K⫹ ⬎ Rb⫹ ⬎ Cs⫹ ⬎ NH4⫹ (302). drugs. . poly(L-lysine) and poly ‘‘egg-box’’ junction zones (308. application of this system. The alginates used differ from each other going sol–gel transition induced by four different divalent in the content of L-guluronate and mixed sequences. Cu. MG 50%) and the nearly zero effi- Copyright © 2002 Marcel Dekker. Poly-L-guluronate chain lutions up to 20 mg/mL. complexing functional groups and a second arising from would be holding the alginate chains in a permanent gel configurational changes of the system upon complexation. assess the existence of polymer interactions in aqueous so. Ehrlich ascites carcinoma and IMC carcinoma (318). proteins. Co. The cations: Ca. and the solids content Irreversible hydrogels are insoluble in water.5 will occur in the ileum. circular dichroism investigations. the pH. Alginate forms gels rides (319). The ratio of B. The lower complexation efficiency with al- useful for the encapsulation of enzymes. In this analysis the total For high M alginates (high D-mannuronic acid algi. with one a considerable antitumor activity against various murine charge per repeating unit in the coil conformation (301). (Lys-Ala-Ala).

The ability of these alginates to achieved in this study (333). previously been suggested that alginate rich in mannuronic complexing L-guluronate sequences in the alginate struc. arguing able in the course of interaction. salt (e. and lets of Langherhans in alginate–poly(L-lysine) capsules liver. The release rate useful for enteric targeting of nucleic acids as gene transfer could be described as a first-order or square-root time agents. 0. which is characterized by a charge density be assumed that antigen leakage from the capsules occurs. Inoculation of mice with microspheres containing provides an effective protection against cell-mediated im. and modified oligo- process depending on the drug load. polylysine–pectin particulates is expected to combine the The biodegradable microspheres based on sodium algi- advantages of bioadhesion. it can (Lys-Ala-Ala). High G–alginate nan chain. encapsulation process. (337). at pH 3. and ideally should allow the transplanta. both the plasmid DNA and bovine adenovirus type 3 mune destruction. new opportunities for drug therapy (338–340). When protein drugs (myoglobin) polylysine. by Wheatly et al. This particulate system may have poten. Microencapsulation of is.. Alginates interacted as no evidence was found for capsules breaking in vivo. it may be suggested that the induce an antibody response in the recipient or act as an L-guluronan chain is more rigid. such as organic sol. ingly. bacterial β-galactosidase (LacZ) gene under the control of tial use as a carrier for drugs that are poorly absorbed after either the cytomegalovirus (CMV) immediate-early pro- oral administration (334). chlorothiazide. a final layer of poly(L-lysine). (BAd3) resulted in a significant increase in LacZ expres- Copyright © 2002 Marcel Dekker. spleen. ble (336). and polylysine helped to strengthen the particulates.9) melt over the same temperature range as lution. . mid DNA expressed LacZ in the intestine. and pectin. layers. absorption enhancement. as expected for an ionic net- vent. plexation (336). but on aging they become thermosta- in solution. and mannitol was the model for assessing microcapsules. Use of alginate– nucleotides (341). Use C. with poly(Lys-Ala-Ala) rather intensively. as applied to encapsulation of bio- gopeptides. less adaptable to the adjuvant to antibody responses against antigens leaked changes in the surrounding medium than the D-galacturo. The gels are also stable in 7M urea.. such as elevated temperatures. carriers for DNA intercalaters. Alginate and pectin were also found to en. Calcium Alginate as a Matrix for Delivery of pectin specially helped in forming a more robust particu. isoelectric point of gelatine. It has are due to the presence of considerable amounts of non. Inc. and D-galacturonan is conformationally adapt. (e.e. The polyionic complex based on alginate were used to Mice inoculated orally with microspheres containing plas- included the animal cells (335). i. The difference Alginate and proteins were also used in polyionic com- in efficiency of interaction of L-guluronan and D-galactur. against hydrogen bonding or hydrophobic interactions. and were suspended in sodium alginate solution and sprayed indomethacin were used as the model drugs for in vitro into buffered calcium chloride solution to form crosslinked assessments. L-Guluronan maintains the rigid twofold symmetry gelatine (30–40°C). The drug-loaded capsules were coated with paracellular drug absorption across Caco-2 cell mono. from the capsule was investigated (335). and nate were used to encapsulate plasmid DNA containing the sustained release. the encapsulation of DNA and its derivatives may be 2 cell monolayers by about three times. capsules are less immunogenic than high M capsules. Be- The influence of charge density of a polycation on com. Alginate and pectin served as the core polymers. was conducted Drug delivery particulates were prepared using alginate. ciency with alginate III (MM 33%. moter or the Rous sarcoma virus (RSV) early promoter. MG 20%) tion of islets in the absence of immunosuppression. acid (high M) is more immunogenic than alginate rich in ture (333). active macromolecules such as protein.3M NaCl) or by raising the pH to above the ten employing either harsh chemicals. Theophylline. Accord- hance the paracellular absorption of mannitol across Caco. On the basis of the results of complexation guluronic acid (high G). but Many of the present controlled-release devices for in the enhanced thermal stability can be eliminated by high vivo delivery of drugs involve elaborate preparations. or extreme conditions.. one-third that of poly(L-lysine) (333). cause encapsulation did not protect against the generation plexation was studied with the sequentially regular poly of antibodies against islet-like cell clusters (ICC). These conditions have the potential to destroy the activity A systematic study of the alginate–polycation micro- of sensitive macromolecule drugs.g. such as proteins or oli. GG 47%. Freshly prepared gels of gelatine with al- onan with poly(L-lysine) results from the difference in the ginate or pectate below the isoelectric point of gelatine conformational flexibility of their polyanionic chains in so. of. work (336).g. of Nucleic Acids late that was more resistant in acidic pH and modulated the release profiles of the encapsulated model drugs in the Advances in the design of genetically targeted agents offer alkaline pH.

For many drug candidates a ionically complexed membranes on alginate beads. guanidine membranes coating alginate result in a molecu- sion by plasmid DNA both in vitro and in vivo (342). and in diseases. Co- adenoviruses are capable of augmenting transgene expres. The effect a polymer concentration of 5 mg/mL. Testing of bead weight Present and future applications of alginates are mainly changes during formation. nanospheres. D.e. and 112 postimplantation. Calcium alginate has and alginate leakage.352). and 112 days postimplantation. tection was found to be comparable to high molecular taining only the plasmid DNA. attempt to achieve modified drug release (350). and simulated gastroin. . linked to the most striking feature of the alginate molecule. e.1 kDa) (345). ficacy. Alginate–poly(L-lysine)–alginate microcapsules An exchange of calcium for sodium within the bead lique.. Homo. nology. 28. tually treating neurodegenerative diseases with this tech- stranded DNA was released from chitosan coated beads. Our results suggest that weight poly(L-lysine) membranes (197. trolled drug release (349). respectively. beads formed using external and internal calcium gelation methods. DNA recovery efficiencies as of the brain at various times postimplantation was exam- high as 94% were achieved when the initial alginate/DNA ined.0) showed that high i. sustain effect. Immunohistochemical bead matrix within which DNA can be immobilized for staining of the implanted brains showed that on days 7. lar weight cutoff sufficient to retain DNA and exclude 31- Chitosan and poly(L-lysine) membranes.4 mg/mL and planting microencapsulated cells for the purpose of even- in the presence of sodium ions. million cells per hour were implanted into the right lateral Highly pure DNA was recovered from beads through me. high G content. hGH weight ratio was 1000 (343). or minimize toxicity. At chitosanase concentrations of 1. It appears that either membrane capsules has been successfully used to treat rodent genetic material would be stable for in vivo application. 20% of the total double. sion compared to those inoculated with microspheres con. in vivo application. The presence of cal. was detected at high levels around the implantation site Alginate gels produced by an external or internal gela. a sol–gel transition in the presence of multivalent ca- alginate concentration. pharmaceutical applications (347. Polymeric de- lysine) and chitosan. ethidium bromide. drolysis by lysozyme. Less than 2% of the membrane nant cells immunologically protected with alginate micro- weight was hydrolyzed. core liquefaction in citrate. especially in con- Co-guanidine membranes were shown to form intact. Inc. or proteinase (343). Ross et al. The properties of alginate gels suggest gels (internal gelation) result in the lowest bead shrinkage biomedical and pharmaceutical uses. such as microspheres. retaining all the DNA. DNA was encapsulated (345). ventricles of mice under stereotaxic guidance. regardless of the composition of alginate. 56. mice were implanted similarly with nontransfected but en- and use of DNA spin columns to separate DNA/alginate capsulated cells. The livery systems. coating algi. Calcium Alginate as Microparticles for Drug geneous gels formed by internal gelation absorbed half and Drug Proteins Delivery Systems as much DNAse as compared with heterogeneous gels formed by external gelation. and trypsin. At 7. chitosanase. Ca2⫹.2 and 7. Calcium branes were all shown to be dependent on both polymer alginate offer an alternative approach. Recovery of double. serving modified in vivo drug release is desired to improve ef- as an alternative to the commonly used polymers. CaCl2 concentration.g. weight carcinogen. were almost totally inert to the enzymatic hy. while providing access to the low molecular nate beads. poly(L.348).. and level of DNA protection from nuclease diffusion and the polymeric films. testinal (GI) conditions (pH 1. 56. The level of DNA pro. Delivery of hGH to the different regions mixtures in a citrate buffer. have been extensively researched in an degree of DNA complexation with co-guanidine mem. (346) have reported the delivery of particular in the protection of DNA during gastrointestinal recombinant gene products to the brain in rodents by im- transit. of drug/polymer weight ratio. chymo. and also at lower levels in the surrounding regions. kDa DNAse. while tion technique were studied so as to determine the optimal control mice showed no signal. and homogeneous tions. The highest level of The release rate of nicardipine HCl from various algi- DNAse exclusion was possible within beads coated with nate microparticles was investigated (351. and stranded DNA after nuclease exposure for 60 min reached curing time on parameters such as the time for 50% of 90% of that initially encapsulated. storage. Control chanical membrane disruption. hGH was localized in the stranded DNA was over 97 and 80%. The encapsulation yield of double. concentration and coating time. gene human growth hormone (hGH) at 95 ⫾ 20 ng per cium stabilized the alginate bead. the drug to be released (t50%) and the drug entrapment Copyright © 2002 Marcel Dekker. Somatic gene therapy using nonautologous recombi- trypsin. for tissues around the implantation site. These characteristics appear best been extensively studied and employed in a number of suited for stabilizing DNA during GI transit (344). enclosing mouse C2C12 myoblasts expressing the marker fied the alginate core releasing DNA.

Phase three was calcium–pectinate was highly brittle. and vigorous infiltration of mononuclear cells was observed in an approximately linear relationship existed among them the brain bordering the alginate beads 1 week after implan- (355). tumor microenvironment by genetically engineered cells Calcium-induced alginate gel beads containing chitosan could theoretically be of considerable therapeutic impor- salt (Alg-CS) were prepared using nicotinic acid (NA). cal product (50 and 75% for CR granules containing natu- Copyright © 2002 Marcel Dekker.59%. of CS content. (358) have investigated the growth char- drug for hyperlipidemia. with the total amount of pesticide leached using the techni- pared are suitable for intramammary therapy. A three- due to diffusion and erosion mechanisms at pH 7–7. and erosion tests were carried out for the lease (CR) properties (359). The study revealed prepared (354) using a gelation of alginate with calcium that optimal crosslinking efficiency was achieved in 1% cations. The control of the drug for different time inter. The insecticide/nematicide carbofuran was incorpo- pared (356). The basic formulation (sodium characterization of the prepared beads. depending on the viscosity grade of the algi. Calcium alginate beads containing ampicillin were pre. Several proteins have been identified with the poten- the following order: in pH 1. The effect on carbofuran release rough surface. In general. Inc.2) or physiological brown seaweed. a tance. phase approach was developed to establish the critical cur- Pellets of calcium–alginate. . The dried particles alginate 1. was studied by vals depended on the molecular weight of the polymer immersion of the granules in water under shaking (359). curs in a micromilieu consisting of both tumor and normal due content of the alginate used. used. and investigated its two functions acteristics of cells encapsulated in alginate. Morphological studies and drug contents. Beads with high guluronate A continuous delivery of such inhibitory proteins to the content gave the best controlled results. Calcium– of in vitro drug release characteristics was used as the alginate pellets were found to be viscoelastic. A bile acid concentration the uptake amount increased. sodium alginate with calcium ions. the brain.5.2 is the result of the high solubility of vascularization process. Even after 4 months in vivo a substantial amount dium was taken into Alg-CS. sis of various pellets indicated that both strength and resil.2–4. the release was indomethacin–calcium alginate gel discs (357). caused by the incorporation of natural and acid- nate used. while marker of optimal crosslinking efficiency. Bead performance was evaluated in vitro for dif. treated bentonite in alginate formulation. efficiency were evaluated with analysis of variance. The fast tial of interfering directly with tumor cells or with the neo- release rate in pH 1. texture analy.2 ⬎ pH 6. and ing parameters. When Alg-CS sulated cells proliferated and formed spheroids within the was placed in bile acid solution it took bile acid into alginate in the in vitro cultures and after implantation into itself. The Ionotropic gelation by divalent metal interaction was release of drug from alginate microparticles took place by employed of indomethacin–sodium alginate dispersion both diffusion through the swollen matrix and relaxation with calcium ions to induce the spontaneous formation of of the polymer at pH 1. About 80% of taurocholic acid dissolved in the me. in rated in alginate-based granules to obtain controlled re- vitro release. TAM in acidic medium (354). and BT4C. Tiaramide release was dependent both on its Growth and progression of malignant brain tumors oc- solubility in dissolution medium and the guluronate resi. and beads were also subjected under an extractor for 48 h (357). Three different cell lines. based on achieving fully dried gel discs by drying to con- Alginate gel beads containing tiaramide (TAM) were stant weight at 21°C under an extractor. however. reduction of the leached amount of carbofuran compared The results obtained show that the ampicillin beads pre. rate.61%. the third phase involved the optimization of the air drying ience profiles were in the order of calcium–alginate ⱖ time of the gel discs. tion time (phase two) had to be determined. calcium–pectinate. tation (358). However. The release rate was in cells. According to increment of of living cells were observed within the alginate beads. Furthermore. Nicotinic acid was rapidly released from which is an immunoisolating substance extracted from Alg-CS in diluted HCl solution (pH 1. carbofuran 0. an optimal concentra- ing in an aqueous medium for site-specific drug delivery tion of calcium chloride (phase one) and crosslinking reac- in the gastrointestinal tract (353). to coating. stabilization calcium–alginate–pectinate ⬎ calcium–pectinate. In phases one and two. water) was modified were characterized by irregular shape and a smooth or by addition of sorbents. thereby inhibiting tumor growth. 293.5. were encapsulated in alginate. The amount of NA that may have antitumor effects.8 ⬎ water. Morphological studies showed that encap- saline without disintegration of the beads. which repre- in gastrointestinal tract: (1) NA release from Alg-CS and sents a potential delivery system for recombinant proteins (2) uptake of bile acids into Alg-CS. incorporated in Alg-CS increased according to increment NHI 3T3. The use of alginate-based CR formulations resulted in a ity was much lower in the case of acid-treated particles. Since curing involved crosslinking of the calcium–alginate–pectinate were produced via crosslink. Read et al. the pH change test showed that this capac. w/v calcium chloride solution for 24 h and air dried at 21°C ferent dissolution media.

This study offers a con. reducing carbofuran leaching in clay soils. Chalain et al.5-diphenyl-2H tetra. . F. Inc. hemorrhoidectomy effectively reduce postoperative pain ous surgical infections. gel-forming ma. sponge composed of chitosan and sodium alginate was pre- pared for wound dressing application (362). utilizing hydrogels have been used as cell carriers to regenerate car- human dermal fibroblast. split skin graft donor sites. and it has long been tion tissue formation and wound contraction for the AgSD known that more rapid wound healing occurs when a gel is plus dihydroepiandrosterone (DHEA)–impregnated PEC formed at the wound surface and dehydration is prevented wound dressing were faster than any other groups. such as The healing of cutaneous ulcers requires the develop. which would Drug-impregnated polyelectrolyte complex (PEC) reduce the risk of groundwater pollution. compared to more bulky anal packs (364). elastic. In vivo tests showed that granula- terials with hemostatic properties. Calcium alginate dressing was mixed with vancomycin. respectively). Calcium alginate dressings following dressing as a drug delivery system for the treatment of vari. calcium alginate. and film-forming properties of calcium alginate difficult and postoperative hematoma may reduce graft product. dressings can be of immense help in minimizing these Ueng et al. filling of large auricle. (360) investigated the calcium alginate technical problems. they are good candidates for burn and wound take. Alginates are highly absorbent.5-dimethyl-2-thiazolyl)-2. impermeable to bacteria. ral and acid-treated bentonite. the calcium alginate decreased fibroblast motility properties as elastin presence in the tissue. Kneafsey et al. and number of repeated in situ complex formations for the occlusive. This study demonstrates that the calcium pluronics as scaffold. might be needed for reconstructive surgery of the entire ment of a vascularized granular tissue bed. It should dressing in PBS buffer (pH ⫽ 7. Control of hemorrhage during excision and grafting is ability. The effects of calcium defects in damaged or deformed cartilages. and lyophilized or dressings provide a significant improvement in healing not lyophilized to form two types of antibiotic dressings. Alginate– that the calcium alginate tested may improve some cellular bentonite CR formulations might be efficient systems for aspects of normal wound healing but not others (361). showing a more organized arrange- decreased the proliferation of HMEC and keratinocytes. alginate on cell proliferation and migration may have been (367) describe modification of the basic techniques that mediated by released calcium ions. microvascular endothelial cell tilage in the nude mouse model. nate dressing to fibroblasts and HeLa cells was evaluated A prospective controlled trial was carried out to assess by the 3-(4.4) was dependent on the be adhesive. (306). Calcium Alginate Wound Dressing could be controlled by the number of repeated in situ PEC reactions between chitosan and sodium alginate. and poly(ethylene) and poly(propylene) cesses were modelled in vitro in the present study. but had no effect on keratinocyte motility. There was no Transplantation of isolated chondrocytes has long been significant effect of calcium alginate on the formation of acknowledged as a potential method for rebuilding small capillarylike structures by HMEC. These pro. Equilibrium water content and release of silver sulfadiazine (AgSD) E. In ment of the cells. exudate absorb. When using by HMEC (361). The calcium alginate on split skin graft donor sites (365). These results suggest lead to production of a large amount of elastic cartilage Copyright © 2002 Marcel Dekker. and the restoration Polymers and hydrogels such as poly(glycolic acid). Cytotoxicity of the calcium algi. and keratinocyte cultures to examine the effect suitability of three polymers for generating tissue engi- of calcium alginate on the proliferation and motility of neered elastic cartilage using autologous cells in an immu- these cultures. histologic features resemble those of alginate tested increased the proliferation of fibroblasts but native elastic cartilage. which seems to correlate to functional contrast. tissue defects by dermal regeneration. the healing efficacy of calcium alginate and paraffin gauze zolium bromide colorimetric assay. This study compared the (HMEC). The results suggested that the antibiotic dressings present no obvious toxic risk to their use as a drug delivery system. tion of larger amounts of cartilaginous tissue. wound dressing (362). Recent ad- venient method to meet the specific antibiotic requirement vances in tissue engineering permit us to focus on produc- for different infections. durable. and the formation of capillarylike structures nocompetent porcine animal model (366). Calcium Alginate as Tissue Engineering All antibiotic dressings released bactericidal concentra- tions of the antibiotics in vitro for the period of time New cartilage formation has been successfully achieved needed to treat surgical infections. Because of the biocompatibility. (363) have found calcium alginate management uses. The re- It is commonly accepted that the ideal wound covering lease of AgSD from AgSD-impregnated PEC wound should mimic many properties of human skin. of a continuous epidermal keratinocyte layer. by technology referred to as tissue engineering.

or after multiplication in may be applied to soft tissue augmentation—an area in monolayer for one (P1) or three passages (P3). In the algi- rate of proteoglycan synthesis. (372) have developed an in- (DBM) or a fleece of polylactic/polyglycolic acid (E210) bred rat model in which the subcutaneous injection of a and implanted in nude mice for 8 weeks. The newly hydrogel. particu- studies of tissue–biomaterial interactions in an in vitro en. Glicklis et al. hydrophilic nature. Inc. cells were visualized tures and matrix vesicles (370). which were further embedded in molded hy. Furthermore. Structural homogeneity of comparison of different materials in terms of both histo- the tissue. a standard alginate that was gelled before injection density (50 million/mL) enhanced collagen type II expres. (a synthetic hydrogel) were The percentage of collagen type II. and gregates. moted their functional expression. within a week the cells entiation. Further. Morphological data con. The constructs were then implanted sponges was efficient. pigs. was gelled following injection into animals (alginate post- rier. three seeding (50 million/mL) and the use of E210 as a carrier. re-expression of their differentiated function prior to im- Small fragments of auricular cartilage were harvested from plantation. pore sizes with diameters of 100–150 µm. the encapsulation method could prove useful for constructs became stiffer over a 12-week period. These results indicate that throughout the gel but did not extend processes or appear the alginate system represents a relevant model for studies to contribute to new tissue formation. sion testing indicated that the alginate and RGD postgel more. was found to be enhanced by high-density shape and volume of a construct. In constructs in which syn- a dense extracellular matrix containing filamentous struc. participated in the aggregation. under vacuum permits direct formed tissue was evaluated. a field that combines polymer scaf- ticular chondrocytes were suspended in alginate at den. During the culture nate pregel plus cells. microscopic. (368) and Demoor-Fossard et secreted the maximal albumin secretion rate of 60 microg al. and RGD postgel plus cells). Using this model. Adult bovine ar. larly in the cell-containing groups (372). Histo- time. positive-staining P3 compared over an 8-week period: a standard alginate that cells was generally higher when E210 was used as a car. Due to their drogel constructs made of alginate and type I collagen aug. and alginate-RGD. a form of polymer. to which sion. DNA measurements showed that the in nude mice and harvested 4 and 12 weeks after hetero. A novel BMP-2–derived oligopeptide. logically. It geneic fibroblasts suspended within each of these three was found that chondrocytes retained their spherical shape gels were also evaluated (alginate postgel plus cells. seeding P3 chondrocytes at the higher gel). vironment which more closely mirrors the cartilage matrix Bone morphogenetic proteins (BMPs) are unique mole- than other culture methods. Copyright © 2002 Marcel Dekker. as demon. Alginate which polymers and cell populations have been injected with cells was seeded in demineralized bovine bone matrix independently. there was significant firmed chondrocyte differentiation with the appearance of ingrowth of a fibrovascular stroma into the gel with frag- hypertrophic chondrocytes scattered in the alginate gel and mentation of the construct. Marijnissen et al. (371) have examined the behavior children undergoing ear reconstruction for microtia or ex. these culture conditions. uted to the nonadherent nature of alginate. into animals (alginate pregel). folds with isolated cell populations to create new tissue. but is known to induce cell dediffer. seeding hepatocytes onto the alginate mented with κ-elastin. Parallel groups that included cultured syn- were cultured in alginate beads for up to 20 days (370). forms of calcium alginate. the cell adhesion tripeptide RGD was linked covalently Chondrocytes from 21-day-old rat fetal nasal cartilage (RGD postgel). Tissue engineering. total cell number within the sponges did not change over 2 transplantation. be used to generate neocartilage in vivo. weeks. More than 90% of the seeded cells and ultrastructural levels (367). (369) investigated whether multiplied chondrocytes can albumin/10(6) cells/day (371). the high efficiency is attrib- In vitro multiplication of isolated autologous chondro. algi- and typical chondrocytic appearance. originated from porcine and human isolated chondrocytes. sities of 10 or 50 million/mL. Material compres- of chondrogenesis and endochondral ossification. . nate pregel and RGD postgel groups. the gel remained a uniform sheet surrounded by strated by the alkaline phosphatase–specific activity and a fibrous capsule in the alginate postgel groups. of freshly isolated rat adult hepatocytes seeded within a tirpation of preauricular tags and from ears of juvenile novel three-dimensional (3-D) scaffold based on alginate. geneic fibroblasts were included. rous structure (spongelike) with interconnecting pores. Marler et al. chondrocytes underwent differentiation. indicating that hepatocytes do not proliferate under bled native auricular cartilage at the gross. composed of freshly isolated as well as serially logic behavior and their ability to maintain the specific passaged cells. Enzymatically isolated elastic chondrocytes were The attractive features of this scaffold include a highly po- then agitated in suspension to form the chondronlike ag. The 3-D ar- cytes is required to obtain an adequate number of cells to rangement of hepatocytes within the alginate sponges pro- generate neocartilage. cules with a specific biological activity for inducing ec- A potential approach to facilitate the performance of topic bone formation when implanted with a suitable implanted hepatocytes is to enable their aggregation and carrier matrix. The resulting neocartilage closely resem.

and somatosensory-evoked potentials (SEPs). The alginate membrane can be prepared and placed and circular dichroism (381–385).390). molecular modeling (379). A number of polysaccharides interact with galactoman- However. Therefore Suzuki et al. the plant polysaccharides. the clinical use of these devices has been re. NSVNSKIPKACCVPTELSAI.387) and other groups (388–398). Regener. or agarose) have been innervation of motor and sensory nerves had occurred.393) have proposed a different Advantages include simple application and rapid repair. cial nerve guides for peripheral nerves and also could be Mixed junction zones were formed by interaction between used for repair of disrupted pathways in central nervous the xanthan and galactomannan backbones. An alginate mem. a gluing technique using alginate gel is a potential nans has indeed been demonstrated by electron microscopy alternative to the conventional nerve autograph technique. The pro. Eighteen weeks after surgery. Alginate membrane was proposed as a self-setting bar. tara. but the interpretation of at the bone defect during the surgical procedure. as attributed to intermolecular binding of the backbone of the demonstrated by recovery of compound muscle action galactomannan and the helix of the order polysaccharide potentials (CMAPs). From this evidence Morris et al. was coupled covalently to on alternate glucose residues with a charged trisaccharide alginate. but double helical models cannot be ex- livery of the morphogenetic signal of BMP-2 (373). Xanthans secondary structure has been ginate hydrogel composites were implanted into the calf studied by x-ray fiber diffraction (378) and analyzed be muscle of rats and harvested 3 or 8 weeks after surgery. well-accepted such intermolecular models. compound nerve action potentials (386. model for the gelation of xanthan and galactomannans. Cairns et al. The primary structure is a (1 → 4)-linked β-D. nans resulting in synergistic viscosity increases or gel for- stricted because a microsurgical procedure requires spe. or enzymatically ation was evaluated by electrophysiologic testing and his. when heated and allowed to glucan backbone (cellulose) substituted through position 3 cool. (380) suggested surface of the Na-Alg aqueous solution. which have been extensively investigated be Dea cialized techniques and expensive equipment. (375) interactions of polysaccharides in binary mixtures have of- developed a new gluing method. DSC. tive positions of xanthan side chains on either side of a sandwiched galactomannan molecule being staggered. some of these have been complicated by the nature of the cedure consists of two simple steps.389) (CNAPs). In conclu. side chain (377). Addition of the side chain Ectopic bone formation was observed in alginate hydrogel causes the backbone to change from a twofold ribbonlike linked with BMP-2–derived peptide. Inc. tion. charides (κ-carrageenan. The synergisms be- of rats was bridged with freeze-dried alginate gel. the bone defect filled with unreacted Na-Alg aqueous solu- tion (374). were observed favors the formation networks between pectin and alginate and the implanted alginate gel had disappeared. mation. Copyright © 2002 Marcel Dekker. furcelaran. the bone defect macromolecule.. keeping the inside of ing of side chains along the polymer backbone. includ. functional re. The structural Histologically. . The crosslinking of cellulose fibrils by galactoman- sion. XANTHAN GUM Xanthan is widely used in foodstuffs in the form of syner- gistic gels with gluco. these Xanthan gum is a widely used thickening agent in foods two types of polysaccharide per se and xanthan alone will and is a recent addition to the hydrophilic matrix carrier not form gels. The x-ray results indicate a repeat distance of 0. cluded (378. based on x-ray fiber diffraction studies on stretched gels. similarity of galacturonic acid and glucuronic acid blocks ing myelinated and unmyelinated fibers. such as op. (391). many regenerated nerve fasciculi. tween plant galactomannans (carob. (392. The order–disorder transition has first or- is filled with sodium alginate (Na-Alg) aqueous solution. is fully reversible.396). It is suggested that cellulose conformation to a fivefold helix (380–383).379). First. without sutures.52 nm (393). modified guar gum) and xanthan or certain algal polysac- tologic study. Then NSVNSKIPKACCVPTELSAI-linked al. XIII. A. der kinetics. with the rela- tissue that is amorphous and cannot be sutured (375).’’ including optical rotation. A alginate hydrogel linked with an oligopeptide derived from single helix stabilized by backbone–sidechain bonding has BMP-2 might provide an alternative system for topical de. whereas mixtures of xanthan with either of list (376). a single helix stabilized intramolecularly by ordered pack- brane is formed on the bone defect. The evidence for this and for similar (388. NMR. that uses ten been considered to be synonymous with intermolecular freeze-dried alginate gel. The majority of studies of xanthan in the literature have rier membrane that can be used for guided tissue regenera. Freeze-dried alginate gel is a promising material for artifi. A 7-mm gap in the sciatic nerve binding of the two polysaccharides. (387). been ‘‘molecular. and shows no thermal hys- Then calcium chloride aqueous solution is dropped on the teresis. Xanthan Gels Many materials have been used for artificial tubular prostheses to assist peripheral nerve gap reconstruction. et al. form thermoreversible gels (395. (386.and galactomannans (394). Synergistic erating microscope systems. been proposed.

13. Protection against radicals is important because the rides used in the same way. scabrella. used as fiber source in numerous studies of the effects on lactomannans have lower temperatures of gelation in the gastric emptying. . in immunocomprom. the presence of the galactomannan from healing intestinal wounds. with 1. in 5 mM Pectin is a general term for a group of natural polymers NaCl) showed a Tg of 24°C for that of S. and in denture wearers. In the supine position no difference was found (Aflurax ticity of the xanthan solution related to the applied concen. with 2. with clarified human whole saliva resulted in proteolytic after 6 months the life table estimates were 48% of patients degradation of the peptide. In addition.7% (2. less substituted.1% (1. The pectin-based raft-forming antireflux agent Aflurax ised patients. The func. (410). Apparently. dry mouth syndrome (xerostomia).10). Commercial pectins are divided into low-ester pec- for locust bean gum (LBG) (M/G ⫽ 43). The positive effect of lecithin supplementation is of formulations containing N-CMC or carrageenan (403). influence on the enzymatic activity of the disordered xanthan chains in contrast to M/G ratios higher upper digestive tract. glucose in two ways: by delaying gastric emptying and by Examples of current or potential applications of xanthan increasing the intestinal barrier layer (407). was tested in a mixture with the bioadhe. brella. Polymerized galacturonic acid partially esterified with mined by viscoelastic measurements and microcalorime. On the other hand.5% of proteins. sca.9%) present in meal. For the lower values it involves only lent cations. to erode or dissolve mucosa is exposed to oxidative stress from the diet. tides in a retention-increasing formulation. A sustained effect of from S. (411) demonstrated a protective effect of cipients in tablets or clear blood fluid substitutes.7%. It was concluded that (M/G) on the temperature of gelation (Tg) and the gel xanthan is an appropriate vehicle for antimicrobial pep- strength of mixtures of galactomannan with xanthan is re. (401) (Idoflux) was examined. tin and high-ester pectins. Aflurax versus 6. scabrella increased slightly the temperature of the con.0%) on peptide histatin 5. and its short-term effect on the rate of gastric empty- the galactomannan. stomach content. The time to recurrence of heart- tration of the coupling agent. first regarding reduction of developed a formulation which will prolong the retention esophageal acid exposure and also as to its efficacy as time of antimicrobial agents at the site of application. Recently reported is that xanthan used in tablets cattle is enhanced by mixing with lecitin from soy oil re- yields a comparable kinetics in the release of drugs to those fining. A Tg of 40–50°C was found by Shatwell et al. Pectin is not degraded by en- mansson (400) reported a difference of 13°C Tg of two zymes secreted in the upper gastrointestinal tract and LBG samples.01). Russien et al. rats. ported (397). Kohen et al. parahybae. pectin against oxidative damages of the jejunal mucosa in tion of xanthan in tablets is similar to other polysaccha. (399) pectin. Coupling caused a reduction of the viscosity and elas. gastric ulcer. with M/G ⫽ 3 (40°C) and 5 (53°C). binding of divalent and triva- also on the M/G ratio. placebo 13.2%). pectin delays absorption of changed (397).6–13. and 20°C for the galactomannan of M. lowering serum cholesterol level. Pectin has been tures with xanthan. from the endo. in mix. parahybae (398) that occur as structural materials in all land-growing plants. based on the human fungicidal salivary times in the upright position were 3. explained by increased adhesion of pathogenic bacteria to Oral candidiasis frequently occurs in individuals with the pectin–lecithin complex (412). namely. citrus peels or waste from potato starch manufacturing) in loids. the however. in pharmaceutics (401. PECTIN sperm of Schizolobium parahybae (M/G ⫽ 30).9%) on placebo (p ⫽ 0. colon cancer. In the presence of xanthan the in remission on Aflurax versus 8% on placebo (p ⫽ 0. pectin consumption in the studies by Schwartz et al. colonic cell M. The influence of the galactomannan characteristic ratios degradation occurred more slowly. sive.402) or biomedical uses are as ex. did not show this effect. Pectin influences the viscosity of the ionic strength contribution of proteins (3. The xanthan/galactomannan systems (4: 2 g l(⫺1).5–14. gallstone. The antidiarrhea effect of pectin (in the form of dried dients compared to formulations not containing hydrocol.4% of protein. It appears that the more substituted ga. deter. Copyright © 2002 Marcel Dekker. Inc. slowly and thereby yield a delayed release of active ingre. the galactomannans ing may be explained in this way. glucose and insulin level. Lundin and Her. Two galactomannans were investigated: one highly substituted from the seeds of Mimosa scabrella (M/G ⫽ 11) and the other. than 3. methanol accounts for the major part of any commercial try. passes intact through the small intestine. proliferation. The mechanism of gelation depends bile acid binding. cannot be explained by increased viscosity of the Tm of xanthan alone or in a mixture being practically un. The maintenance treatment in patients with healed esophagitis activity against Candida albicans of a synthetic cationic (413). and as source of volatile fatty acids in the formational change (Tm) of xanthan. probably due to the colon (404–409). XIV. presence of xanthan. The median (interquartile range) acid exposure peptide dhvar 1. Incubation of the peptide burn with Aflurax treatment was prolonged significantly. and M.

different types of carbohy- bers (WSDF) guar gum. lipid reduction and IgA production–enhancing activities of The effect of dietary nondigestible carbohydrates (15% WSDF were dependent on their molecular sizes (418). oligofructose. mined in feces after 1. no significant increase in Ig production was number of tumor-bearing rats and a lower total number of apparent. In addition. rats. regular tumor measurements with a vernier caliper. a decrease in the level of phospholipids was only of the polymers with the cells is claimed. normal rats were fed for 3 weeks a diet con. (control) (420). mammary tumors in oligofructose-fed rats than in the hanced the Ig production of lymphocytes.414–417). although the increase in serum IgA level was liminary study on methylnitrosourea-induced mammary only observed in the rats fed on WSDF. crease by week 3 in rats fed 5% orange or apple pectin. nans against 1-nitropyrene–induced mutagenicity. comparable to gemfibrozil. Following treatment. 15% oli- When mesenteric lymph node lymphocytes were cultured gofructose added to the basal diet modulated this carcino- in the presence of various concentrations of guar gum or genesis in a negative manner (423). comannan.05). Hepatic cholesterol concentration declined significantly in the most studied physiological effect of pectin and other all pectin-fed groups. comparison with citrus pectin. of both tumor lines was significantly inhibited by supple- Histopathological examination revealed marked alteration menting the diet with nondigestible carbohydrates. Inhibi- tal cholesterol and triglyceride levels were significantly tion rates were dose-dependent and varied between 20 and lower in the rats fed with WSDF than in those fed with 50%. carcinogenesis in female Sprague–Dawley rats. partially hydrolyzed guar gum drates were investigated for their antimutagenic activity (PHGG). Pseudomonas aeruginosa. in liver and serum at the end of the experimental trials. and not on PHGG. organisms from the mutagenic attack (421). was also investigated (424). ginseng) and by the drug gemfibrozil were studied (419). nontoxic dietary treatment appears to be easy and risk free omatous plaques. and hepatic lipase activities. The growth Tg and erythrocyte superoxide dismutase were not changed. belonging to two tumor lines (TLT and EMT6). glucomannan. Inc. Although serum to. levels in liver and serum and its increase in feces could perimental animals have proven the serum cholesterol low. and that serum group fed the basal diet alone. On the other hand. In this study. without doubt. apple pectin exerts stronger bacteriostat- that has antilipid peroxidative property (419). of nonsoluble fibers have been described (422). applicable as an adjuvant factor in the classical a significant reduction of the hypercholesterolemia in a way protocols of human cancer therapy (424). containing food is assessed to decrease the risk of cancer The dietary effect of the water-soluble dietary fi. Lowering the serum cholesterol level is. The decrease of cholesterol terolemic and normolipidemic humans. Such in the aortic wall with the appearance of large multiple ather. and other ex. Within the screening pectin on the serum lipid level and immunoglobulin (Ig) pronounced antimutagenic effects were found for xyloglu- production of Sprague–Dawley rats was compared with can and different pectins and pectinlike rhamnogalacturo- that of water-insoluble cellulose (418). Both garlic and pectin were successful in for patients. and vere heartburn and erosive esophagitis. all WSDF feeding enhanced IgA Anticarcinogenic and tumor growth–inhibiting effects productivity in the spleen and mesenteric lymph node lym. In a pre- phocytes. . Garlic was the only treatment Among pectin. and 3 weeks of treatment. calis. Serum cholesterol only declined sig- soluble dietary fibbers. or pectin incorporated into the basal Experimental hypercholesterolemia and its modulation diet) on the growth of intramuscularly transplanted mouse by some natural dietary supplements (pectin. There was a lower glucomannan. Streptococcus fae- To investigate the effects of pectin on cholesterol me. and HDL cholesterol. and Escherichia coli in tabolism.5 or 5% apple or orange pectin or without pectin 17/34 on Aflurax versus 28/38 on placebo (p ⬍ 0. inulin. Cholesterol concentrations were deter- Aflurax significantly delays recurrence of moderate or se. These data suggest that WSDF indirectly en. explain the beneficial effect of including these fibbers in ering effect of pectin (404–408. protecting the observed in the rats that had been fed on guar gum or glu. 10–15 g/day leads to a decrease in the serum cholesterol Because a high daily consumption of polysaccharide- level of 10%. and tumors. The conclusion the diet to prevent some currently very frequent diseases from the last 25 years’ studies is that a pectin dosage of (420). and highly methoxylated (HM) against different standard mutagens. serum diet containing starch as the only carbohydrate. nificantly in apple-fed groups. 2. of the gastrointestinal system. tenance treatment. garlic. Numerous studies in hypercholes. The results were evaluated by Results of the study demonstrated that feeding the choles. ical action on Staphylococcus aureus. we used water- Copyright © 2002 Marcel Dekker. Concerning the mode of action. a direct interaction cellulose. The acid exposure was not significantly Cholesterol concentration in feces showed a significant in- reduced with pH monitoring (413). when used as main. erosive esophagitis was found in taining 2. The terol-enriched diet caused a significant increase in total. plasma MDA and post-heparin pared with that in animals of the control group fed the basal total. mean tumor surface in the experimental groups was com- LDL.

disintegrated in the colon. concentration fundamental aspects of the pathogenesis of HIT have been decrease in colonic mucus. cosaminoglycans. relating to was prepared by direct compression of pectin and pec. It was shown that the tablets tion and concentration of growth factors in the wound area. an ideal ingredient for colon-specific delivery. the type of droitin sulfate. The understanding of some the mechanisms un- related to fecal enzyme activities. and polygalacturonic acid gave carbohydrate backbone and the sulfation pattern of the viable cells that could be used for extracorporeal liver sup. polysaccharide are important for the emergence and level port (434). involve risk of bleeding. dissolution of pectin (429). Coacervate with gelatine per. Another unwanted control group at initiation stage of carcinogenesis. which may lead to depletion of these blood compo- also decreased. The side effect of heparin is its interaction with platelet func- concentrations of β-glucosidase and azoreductase were tion. Long-term treatments with heparin. (431. cium or by chemical means.432) protected a core tablet san–heparin membrane stimulated the increased stabiliza- with a coat of HM pectin. supple. The solubil. Consequently new therapeutic concepts imply the use of ity in the GI fluids is suppressed by crosslinking with cal. liver cells by coacervation of carboxymethylcellulose. some treatment recommendations can already be which contains the drug and is enclosed by an erodible drawn from these studies (439). soluble methoxylated pectin from apple. During the last decade. As the prophylactic use of hep- arin continues to increase. The diet. drugs with either indirect or direct antithrombin activity. the pH of the surrounding medium. The plug The discovery of new activities of heparin. combination with chitosan stimulates re-epithelialization ied by Meshali and Gabr (430) using a blend of pectin and in an in vitro model of human wound healing. family of sulfated glycosaminoglycans (GAGs). chon. chitosan. Although data of randomized trials are still release system based on an impermeable capsule body. HIT). Kratz et al. algal. which are Should heparin-induced skin necrosis develop. contribute an enormously important role PGE2 level in distal colonic mucus in 20% apple pectin– in the successful development of open heart surgery. angio- tinase in different ratios. or microbial polysaccharides. The drug sion. The effect of apple pectin on the colon car. has widened the scope of the pulsatile system were determined as a function of of potential uses of this GAG. In addition to the disintegration genesis (441). pectin/pectinase plug have been studied (428). . such as donaparoid sodium and the recombinant hirudin mits the formation of microglobules suitable for lepirudin. significantly decreased the tin sulfates. studies assessing various treatment regimens in HIT be- To develop an enzymatically controlled pulsatile drug came available. also resolved. and on the type of pectin. nents (thrombocytopenia. (444) have recently shown that heparin in The use of pectin in tablet formulations have been stud. Fecal to its antithrombotic and anticoagulant properties. of specific activities (445). Inc. drugs with pectin was shown to be applicable for sustained Some of the biological properties of heparin can be sim- release of water-soluble drugs (433). However. binding peptides into fibrin gels enhances neurite exten- and the addition of buffering or chelating agents. nurses must be aware that hepa- rin use may cause heparin-induced skin necrosis—a rare XV. The chito- chitosan. this discussion will Heparin is the most biologically reactive member of the focus on skin necrosis caused by subcutaneous heparin. HEPARIN but serious complication. Due fed rats were lower than those in basal diet fed rats. an example of designer matrices in tissue engineer- release was controlled by the enzymatic degradation and ing. Heparin and chondroi- mented by 20% apple pectin. cinogenesis may partially depend on PGE. were significantly lower than those in to hemorrhage. derlying the development of new. heparin β-glucuronidase activities in the apple pectin–fed group. Encapsulation of ulated by other GAGs or by chemically sulfated vegetal. missing. the human immunodeficiency virus (HIV) times of the plugs. inhibition of growth of smooth muscle cells (440). paradox thromboem- The resistance of pectin to degradation in the upper GI bolic complications in HIT led to the concept that thrombin tract and its complete dissolution in the colon makes pectin generation plays a key role in clinically manifest HIT. the lag times and the release profiles (442). as vation of dimethylhydrazine metabolism to carcinogens in well as short-term ones in the case of patients susceptible the colonic lumen. and tissue engineering (443). Although even more severe com- plications may occur from heparin use. Ashford et al. diseases (436–438). which are the most abounded sulfated gly- number of tumors and the incidence of colon tumors. Incorporation of heparin- pectin/enzyme ratio. heparin Copyright © 2002 Marcel Dekker. Coprecipitation of cationic which stimulated healing. widespread in animal tissue (435). In recent years results of the first prospective controlled-release products (425–427). is extensively used in the management of cardiovascular which has been considered a key enzyme for the final acti.

quire life-long anticoagulation. tion can be associated with a variety of postoperation clini- In recent years. LMWH had a similar or even a better (446.. the anticoagula- tions. In vitro and in vivo evaluation suggest that the lular interactions (457). were studied. bus formation (452–456). Patients with mechanical heart valves re- and basic FGF has been demonstrated in various publica. the development of blood-handling equipment Clinical procedures involving extracorporeal blood cir- (e.447). peutic approach. FGF. as well of organ failure which contribute to mortality in routine Copyright © 2002 Marcel Dekker. while heparin tions such as thrombosis and thromboembolism. and heparin. In all patient’s reaction to this complication have been presented these situations. Albumin pread- coagulant. Angiogenesis is a prerequisite for tumor expansion and Acute myocardial infarction and coronary angioplasty are metastasis. and various degrees of deep vein thrombosis and pulmonary embolism. both have lim. bonded PA than in the AO coupled to heparin. risk/benefit ratio than unfractionated heparin (UH) (451). compared with their GA-treated counterparts. Bioma. This reac- concern preventing even more widespread application. (448) have studied the inhibitory ef. Therefore. Crosslinked gels of albumin as nylacetate comatrix to develop a prolonged release form well as heparinized albumin gels. and cel- els (449). Heparin- itations (450). artificial heart devices) has been one of monary bypass. Inc. therapy must be discontinued immediately. such as increased pulmonary capillary (LMWH) have been tested in the prevention and treatment permeability.g. heparin-coupled PA and AO was significantly less when let aggregation and control of thrombin generation and ac. cardiovas. Polysulfated heparinoids exert a selective inhibitory provides adequate biological anticoagulation. culation are potentially complicated by the interaction of ographic catheters. Calcification tivity. linked gels of albumin to which heparin is immobilized. mers. are commonly used for postimplant complica. a potent antiplatelet drug. Inhibitory effects of heparin coupling on calcifica- ples demonstrated a significant reduction in calcium depo. Given the central role of platelets and 5 months (458). Randomized which is 100 times below the IC50 of suramin. the hemodialysis and cardiopulmonary bypass. exposure of blood to synthetic surfaces the most investigated areas in the past two decades. pulmonary artery (PA). tion with LMWH after mechanical heart valve replacement fects of suramin and the polysulfated heparinoids pentosan were studied (451). jugular vein (JV) and rabbit aorta erosclerotic plaques with resultant activation of platelets (RA) were implanted subcutaneously in weanling rats for and coagulation. intra-aortic balloon pumps. Aspirin is able to interact with antithrombin III. various blood systems with foreign surfaces. binding of basic fibroblast growth factor. The angiogenic potential of the heparin-bind. The effect of these drugs toward the bioprosthetic thetic vascular grafts. Therefore. studies are now needed to further evaluate this new thera- the administration of polysulfated heparinoids might be. an anti.625% glutaraldehyde Many of the acute coronary ischemic syndromes are crosslinked (GA) segments of porcine thoracic aorta (AO). tion of both molecules or by their covalent coupling. Zugmaier et al. bonded porcine pulmonary artery seemed to be the best Among the biomedical applications of synthetic poly. Heparin bonding was ineffective in pre- thrombin in arterial thrombosis. generally leads to activation of cellular and humoral blood terial thrombogenicity remains the single most important systems with activation of complement cascade. Anticoagulation activity with LMWH polysulfate. among all vascular bioprostheses in this study. dextran sulfate. and com- effect on heparin-binding angiogenesis factors at an IC50. scanning electron microscopic evaluation of retrieved sam. Calcium content of prevention and treatment focus on both inhibition of plate. low molecular weight heparins cal complications. It can be concluded that cross- released aspirin–heparin from the comatrix had a syner. and fucoidan on the action of after mechanical heart valve replacement appears feasible. sorbed onto surface reduce platelet adhesion. and suitable substrates for endothelial cell seeding. tion of bioprosthetic vascular grafts of different origin sition. anaphylactic reactions. gistic effect in inhibiting glutaraldehyde pretreated bovine are candidate sealants for prosthetic vascular grafts and pericardium calcification. which Aspirin. Heparin-bonded and 0. among the new targets presently under investigation with ing growth factors acidic fibroblast growth factor (FGF) various LMWH. come a novel approach to tumor therapy based on blocking Albumin has also been utilized with heparin preadsorp- angiogenesis. current strategies for its vention of calcification of JV and RA. preventing throm- and heparin were embedded in chitosan–polyethylene vi. triggered by spontaneous or mechanical disruption of ath. potential sealant of pros- (449). Although aspirin and unfractionated heparin are the inhibition was achieved to a greater extent in heparin- cornerstones of current treatment strategies. stability. angi. histological. In cardiopul- cular prostheses. results in heparin–albumin conjugates. Biochemical. . were studied with regard to in vitro calcification was investigated by in vitro and in vivo mod. Reports of one as in the treatment of stroke and unstable angina. pares favorably with UH anticoagulation.

improve measurement reproducibility and long-term po- Heparin-carrying PS (HCPS) is especially able to retain tential stability by considering the unique pseudo–steady the binding of heparin-binding growth factors (GFs) such state response mechanism of the polyion sensors devel- as vascular endothelial GF 165 or fibroblast GF 2. nontoxic. recent research has revealed that these sensors Various sugar-carrying polystyrenes (PS). and for agricultural purposes such as fungi- (462). trodes. such as for contact tin time. The growing importance of polymer membrane–based It has been extensively used as a biomaterial (474) due to potentiometric polyion sensors in biomedical research and its immunostimulatory activities. rin. The blood compatibility of the surface-modified cides (470). the material has been extensively used in the the polymerization of acrylic acid (AA) in order to prepare industry. human coronary smooth muscle cells. CHITOSAN by nonprofessional phagocytic cells.05). insects.468). such as fruit juices and followed by reaction first with insulin and then heparin beers (469). anticoagulant properties clinical measurements has brought up the question of how (475). is presented to explain the experimental results (464). oxygen plasma glow discharge to produce peroxides on its and demonstrates film-forming ability and gelation char- surfaces. boundary membrane surface with a high sample NaCl con- and human coronary endothelial cells have good adherence centration. These peroxides were then used as catalysts for acteristics. It is growth of various cells can be controlled by the HCPS also attempted to reduce long-term potential drifts by con- coating.). and platelet adhesion and activation. are glyco. unlike viable coelenterate. membrane inner filling solution side. endocytosed beads were trafficked to a lysosomal large amount of the crustacean exoskeleton is available as compartment. and chitin has been found in a wide range of natu- sine phosphorylation of a similar set of host proteins. Insu. fungi.466). fine powder. Indeed. which prevent phagolysosomal fu. and fiber. and the microspheres glucosamine and N-acetylglucosamine. These heparin sensors are The use of heparin-coated circuits resulted in reduction of irreversible. it was shown that coated microspheres specifically bound eukaryotic cells and were endocytosed XVI. flake. did endocytosis of Chlamydiae. Chitosan is usually were competitively inhibited by chlamydial organisms. antibacterial and antifungal action (476–481). as ral sources (crustaceans. from crustaceans (crab and crayfish). These results indicate that ibration procedure in order to avoid memory effects. however. and Copyright © 2002 Marcel Dekker. Inc. thereby retaining the bioactivity of molecules such tinuously stripping heparin out of the membrane at the as heparin-binding GFs. HCPS-coated surfaces con.4-D-glu- Endocytosis of heparin-coated beads resulted in the tyro. which con. Using polystyrene microspheres coated with heparin or heparan sulfate. for polyions such as heparin. Heparin may be stripped out of the phase skin fibroblast cells. ucts. Coated microspheres displayed properties of binding to eukaryotic cells that Chitosan is a polysaccharide comprising copolymers of were similar to those of Chlamydiae. activated partial thromboplas. Polymer in an extracorporeal circuit modifies the normal pattern membrane–based potentiometric sensors were developed of blood activation. wastewater (465. by similar pathways (461). Due to the fact that chitosan Poly(ethylene terephthalate) (PET) film was exposed to has a large molecular weight. . lens coatings or the contact lens material itself (471–473). These findings suggest that heparin-coated a byproduct of food processing. However chitosan is only manufactured chlamydial organisms. metals for the detoxification of hazardous waste (467. for the clarification of beverages. Human oped so far. beads and Chlamydia trachomatis enter eukaryotic cells biodegradable polysaccharide available as solution. A theoretical model trol selective growth of various cells (460). prepared from chitin (2-acetamido-2-deoxy β-1. behave quite differently than classical ion-selective elec- sist of synthetic styrene and sugar moieties. foremost as a flocculant in the clarification of a carboxylic acid group–introduced PET (PET-AA). and therefore may potentially reduce earlier to provide a rapid and direct method of analysis clinical complications in routine cardiac surgery (459). Mathison and Bakker (463. primarily because a sion. It is a natural. cosmetic industry. Thus. in the dental industry. pared by the grafting of poly(ethylene oxide) to PET-AA. and this characteristic is used to modify the cal- to the HCPS-coated plate. exhibits a positive charge. can). cardiac operations. etc.464) explored ways to conjugates that are able to attach to polymeric surfaces. mollusks. In addition chitosan has been exploited in the PETs were examined using in vitro thrombus formation. Application of biocompatible materials accurate and reproducible these sensors are. requiring a membrane renewal procedure be- systemic leukocyte activation of cardiopulmonary bypass tween measurements which currently prevents the sensors reflected by reduced leukocyte and neutrophil counts 24 h from being used for continuous monitoring of blood hepa- after operation (p ⬍ 0. as a chelating agent for harmful lin and heparin coimmobilized PET (PET-I-H) was pre. bead. annelids. for hair care prod- plasma recalcification time. and for ophthalmic applications.

These data support the alkoxide–based network (493). ing an anionic derivative of poly(ethylene glycol). When 50%. Biocompatibility and Bioadhesivity Recently. ionic strength. chitosan. and at 20 weeks were Chitosan has been proposed for the development of 64% of control levels. which is higher cholesterol levels were significantly lower in the chitosan. followed by adhesion and activation of platelets (504). Half were fed 30 poly(ethylene glycol) derivative to improve blood compat- chitosan tablets (45 mg chitosan per tablet) three times a ibility of chitosan.40 to 5. and temperature of the hydration cally problematic symptoms were observed.491). 498). Artursson et al. than that of sucrose (500). Copyright © 2002 Marcel Dekker. As a result it has been proposed that dietary supplementa. It was found that the interaction of chitosan with mucin New silica–chitosan hybrid biomaterials were produced decreases on increasing molecular weight.495). These hybrid materials dis- hypothesis that the mechanism of chitosan antibacterial played good blood compatibility in comparison with their action involves a crosslinkage between the polycations single component systems. modified by the complexation–interpenetration method us- sclerosis in individuals with hypercholesterolemia. respectively. When the area of aortic plaque in membranes and fibers for hemodialysis and blood oxy- the two groups was compared. antireactive. Chitosan as hemodialysis membranes promotes arch was observed in the chitosan-fed animals—42 and surface-induced thrombosis and embolization (501). chitosan surface was agent could be used to inhibit the development of athero. The result of patients with renal failure undergoing long-term stable he. patible with both healthy and infected human skin (499). Significant reductions in urea and creat. The enzy- philic drugs. Body growth was significantly greater blood comes in contact with biomaterial surfaces like in the chitosan-fed animals. genators. the modi- day. It is chitosans to increase the epithelial permeability. Chitosan caused leakage of glucose and lactate as the organic species to be incorporated into the silicon dehydrogenase from E. They found that a low degree of acetylation matic hydrolysis of chitin and chitosan leads to the produc- and/or a high molecular weight appear to be necessary for tion of N-acetyl-D-glucosamine and D-glucosamine. believed that the glucosamine plays an important physio- Chitosan ingestion effectively lowers serum choles. (485) and Schipper et al. me- The effects of chitosan have been investigated on 80 thoxypropyl(ethylene glycol) sulfonate (505). a highly significant inhibi. should be investigated further. found in various mammalian tissues (494. hepato- binds fat in the intestine. the pH. of Chitosan (486) reported that the structural properties of chitosans.0 g L-1). Animals were fed for 20 weeks on When chitosan was administered orally in mice. although the mechanism of the effect of rheological synergism and tensile stress testing (506). The influence of san ingestion (492). polymer for gastroadhesive formulations. such as degree of acetylation and molecular weight. are Chitin and chitosan are substrate for lysozyme. and increased serum hemoglobin levels (from 58. chitosan were investigated to assess the suitability of this inine levels in serum were observed after 4 weeks of chito. there is an initial adsorption of plasma proteins.82 ⫾ 2. The patients were tested after modified by complexation–interpenetration of anionic a control treatment period of 1 week. Orally administered chitosan liver and kidney and possesses anti-inflamatory. These data medium on the rheological properties were studied.19 mM) adhesion by the steric repulsion mechanism (505). Inc. also as a promoter of wound healing in the field of surgery using biopolymer chitosan and its heparinlike derivative (482–484). Chitosan lacks irritant or allergic effect and is biocom- tion with chitosan may inhibit the formation of atheroscle. and antihypoxic qualities (496– shown to lower blood cholesterol in animals and humans. the LD50 a diet containing 5% chitosan or on a control diet.14 ⫾ 4. logical role in in vivo biochemical processes. coli cells. A. fed animals throughout the study. rotic plaque (490. and suggests that the To improve blood compatibility. and has been protective. When in contact with blood. Ingestion of chitosan effectively reduced total serum fied surface can resist plasma protein adsorption and cell cholesterol levels (from 10. During the treatment period. and wound dressing materials tion of atherogenesis in both the whole aorta and the aortic (501–503). of chitosan and the anions on the bacterial surface that changes the membrane permeability. This study shows a direct cor. It is known terol (487–489). Blood was found to be in excess of 126 g/kg. The suggest that chitosan might be uneffective treatment for mucoadhesive performance was assessed in vitro by means renal failure patients. blocking absorption. relation between lowering of serum cholesterol with chito. . no clini. an enzyme very important for its absorption enhancement of hydro. skin substitute.1 Mucoadhesive properties of three viscosity grades of to 68 ⫾ 9. Oligosaccharides of chain length less than that glucosamine takes part in detoxification functions of five residues are ineffective. san and inhibition of atherogenesis.2 ⫾ 12. this study shows that chitosan surface can be permanently modialysis treatment (492).

Toxicity of chitosan also depends on its high charge a wound healing product for human use containing chito- density but appears to be less affected by the molecular san as an excipient. and particle size (525. chitosan has been added Chitosan acetate films. Water-soluble chitin was prepared by controlling de- ator (513). any cytotoxicity in cell culture tests of human skin fibro- Earlier. Chitosan Use as a Matrix for Drug Delivery tion in the acceleration of infiltration of polymorpho. while the lower layer is an antimi. On day 3 postwounding. molecular (516. . espe- absorbing wound exudate. Neither Az-CH-LA nor its hydrogel showed zation (510). The 3M company has marketed TEGASORB. Inc. for use as absorption ies. From the in vitro release stud. Chitosan has been reported as a wound healing acceler. (524) showed that chitosan hydrochloride chitin hydrogel material. and its for Wound Healing effectiveness was compared with that of fibrin glue. for sustained release (520–522) and to improve dissolution tive. The wound treated with water- nounced on day 9 and 15. degree of deacetylation. Because violet light irradiation to photocrosslinkable Az-CH-LA of the biocompatibility. and smooth muscle cells. weight. those of chitin and chitosan. III. sisting of two layers: the upper layer a carboxymethyl– Kotze et al. coronar endothelial cells. they are good can. ating effect on wound healing in rats was compared with nohistochemically. lated trachea. Granulation was more pro. The appear. followed by the production of collagen by fibroblasts (513). investigated the tricking effect of cartilage preparations in These results suggest that the photocrosslinkable chitosan accelerating wound healing.526). on postwounding day 3 and in the chitosan group on post- wounding day 6. The forming properties of chitosan products. Prudden (511) and Allen and Prudden (512) had blasts. produced an insoluble hydrogel within 60 s (518). exudate absorbability. and chitosan glutamate are potent absorption enhances in crobial impregnated biomaterial. Its acceler- of wound healing was evaluated histologically and immu. Table 3. glue. as an excipient in pharmaceutical products are listed in Loke et al. and slow lysozyme degradation (514).508). the loading concentration was optimized to deliver suf. which were tough and protec. A photocrosslinkable chitosan to which both azide and lactose moieties were introduced (Az-CH-LA) was B. (515) have prepared wound dressing con. wound-healing accelerator. The hydrogel layer acts acidic environments. binding strength of the chitosan hydrogel prepared from didates for burn and wound management uses (509). The phenomenon was later at. adhesive in medical use. Systems nuclear cells at the early stage of wound healing. and the process through alkaline and ultrasonic treatment (519). These results suggest chitosan has a func. It was concluded that there is a need as a mechanical and microbial barrier and is capable of for chitosan derivatives with increased solubility. collagen I. the chitosan hydrogel ing and promote tissue growth and differentiation in tissue more effectively sealed air leakage from pinholes on iso- culture. and hair follicles were almost healed at 7 days ance of mitotic cells occurred numerously in the control after initial wounding. the chitosan. enhancers aimed at the delivery of therapeutic compounds ficient antimicrobial drug into the wound area to sustain in the more basic environment of the large intestine and the antimicrobial activity for 24 h. Application of ultra- should mimic many properties of human skin. lated small intestine and aorta and from incisions on iso- late cell proliferation and histoarchitectural tissue organi. Compared to the fibrin glue. Immunohistochemical typing of soluble chitin solution was completely re-epithelialized. high of poorly soluble drugs (523). cially at neutral and basic pH values. Chitosan and Its Derivatives as Biomaterials prepared as a biological adhesive for soft tissues. Copyright © 2002 Marcel Dekker. Cotton fiber type chitosan (DA ⫽ 18%) was gree of deacetylation and molecular weight of chitin applied on open skin wounds for 15 days. Intro- duction of the lactose moieties resulted in a much more It is commonly accepted that the ideal wound covering water-soluble chitosan at neutral pH. As a pharmaceutical excipient. C. colon. developed here has the potential of serving as a new tissue tributed to the presence of N-acetyl-D-glucosamine. had the advantages of good oxygen permeability.517). The efficiency of chitosan in tablets was dependent on ting granulation tissue formation and re-epithelialization chitosan cristallinity. The water-soluble chitin was treated wounds showed histologically severe infiltration found to be more efficient than chitin or chitosan as a of polymorphonuclear cells. 30–50 mg/mL of Az-CH-LA was similar to that of fibrin Chitosan may be used to inhibit fibroplastia in wound heal. and IV showed increase of the production granulation tissues in the wound were nearly replaced by of type III collagen in the chitosan group. fibrosis. Chitosan also shows a biological aptitude to stimu. Chitosan may facilitate wound healing by stimula. and film. The applications of chitosan water absorptivity. weight (507.

Inc.8 (p ⬍ 0. several microsphere drug formula- gastric environment from a directly compressible tablet tions have matured beyond the stage of promising investi- formulation. ing and drug release of drug-loaded chitosan microspheres terions. (ket) was chosen as the model drug to be encapsulated. NC) indicated that the degree viable pharmaceutical products approved for widespread of N-deacetylation of chitosan significantly affected drug human use. cules. . Table 3 Chitosan as a Pharmaceutical Excipient Table 5 Hydrophobic Counterions for the Ionotropic Gelation of Chitosan Conventional formulations: Gels Polycation Hydrophobic counterions Films Chitosan–NH2 Octyl sulfate Emulsions Lauryl sulfate Direct compression tablets Hexadecyl sulfate Wetting agent Cetylstearyl sulfate Coating agent Controlled release matrix tablets: Microspheres and microcapsules Transmucosal drug delivery in globules (Table 4) (528).198).. 750. Microspheres and Microcapsules Sabnis et al. a real ionotropic gel 2. Using chitosan solution (pH ⬍ 6). Chitosan–NH2 Low molecular weight Using sodium diclofenac (SD) and fluorescein isothiocya- Pyrophosphate nate-labeled bovine serum albumin (FITC-BSA) as model Tripolyphosphate compounds. and crosslinking solution having pH ⬍ 6. The system con- Poly(aldehydocarbonic acid) sists of chitosan (CS) microcores entrapped within acrylic Xanthane microspheres.000. Using more hydrophobic coun- Vaccine delivery terions (Table 5) it is possible to prepare hydrophobic car- DNA delivery riers (532). Chitosan microspheres are produced. gel formation will Influence of chitosan molecular weight on drug load- occur with a number of different multivalent anionic coun. and in the any of the pHs studied (p ⬎ 0. (527) studied the potential utility of chito- san (I) in inhibiting diclofenac sodium (II) release in the Over the past decade. size range of 45–300 µm. [Fe(CN)6]3⫺ any harmful crosslinkage treatment.0001). The ionic strength of the disso. Inc. The NH2 groups of chitosan are proton.000. D. was efficiently entrapped within CS microcores us- Copyright © 2002 Marcel Dekker. Prepared chitosan microparticle delivery systems can mod- Chitosan crosslinked with high molecular weight coun.0001). was Table 4 Possible Counterions for the Ionotropic Gelation proposed (534).000 molecular weight were employed. These microparticles were obtained with of Chitosan different types of chitosan and various core/coat ratios.2 and 6. ated and an ionic crosslinking occurs. either release at pH 1. the properties of these new microparticles for Tetrapolyphosphate the entrapment and controlled release of drugs and proteins Octapolyphosphate were investigated. Ketoprofen is formed (528). By adding a chitosan solution dropwise into a was studied (533). Chitosans of 70. Sodium diclofenac (SD). terions (529–531) results in capsules (Table 4). spherical. ulate ket release within 48 h. An increase in the by an emulsification–crosslinking process or by use of pH of the dissolution medium resulted in an increase in complexation between oppositely charged macromole- drug release (p ⬍ 0. Analyses of variance model was tested using gational agents in preclinical and clinical trials to become SAS (SAS Institute. High molecular weight A new system which combines specific biodegradabil- Poly(1-hydroxy-1-sulfonate-2-propene) ity and pH-dependent release is presented. used as a model Pectin drug. The microparticles were stable at low Hexametaphosphate pH and thus suitable for oral delivery without requiring [Fe(CN)6]4⫺. Polycation Counterions with the particle size in all cases being smaller that 70 µm. The resulting crosslinked chitosan microspheres lution medium did not significantly affect drug release at were characterized by being smooth. such as cellu- lose acetate butyrate (CAB) or ethyl cellulose (EC). while A new microparticulate of chitosan controlled-release crosslinking with low molecular weight counterions results system.000. consisting of hydrophilic chitosan microcores en- trapped in a hydrophobic cellulosic polymer.

nanospheres. a radiophar- els was observed following the oral administration of these maceutical drug for cancer therapy. and varying the formulation conditions (different coadhesive DL-lactide/glycolide copolymer (PLGA) pH values and concentrations of PEO-PPO) and the stage nanosphere system to improve peptide absorption and of protein incorporation into the nanoparticle formation prolong the physiological activity following oral ad- medium. and tetanus and diphtheria Kawashima et al. proteins. linked chitosan microspheres that contained cisplatin. are a suitable vehicle for the deliv- rate. which considers the dissolution of the for Cancer Therapy Eudragit coating. cae (PS4A). (537) investigated the production of linking.49%). A pharmacologically active block copolymer (PEO-PPO) nanoparticles and their po. The use and vaccines were studied by Calvo et al.9 µm) and they were encapsulated within Eu. The mech. Seven factors and three levels for group of chitosan when its oxidation to dehydroascorbyl each factor that might affect the formulation of micro- palmitate takes place during microparticle preparation. was determined by capsules that contain 20 IU of insulin and sodium glyco. of microsphere drug carriers could represent a more ratio- anism of protein association was elucidated using several nal approach to specific cancer therapy. Copyright © 2002 Marcel Dekker. apy has led to the investigation of alternative. spheres were selected and arranged in an L27(3(13)) or- This preparation method produced microparticles charac. A marked absorption of in. which were produced by an emulsion-chemical thus permitting covalent bond formation with the amino crosslinking technique. The hypoglycemic effect started from 8 h after of Ho(NO3)3 ⫻ 5H2O/head) was intrahepatically adminis- the administration of chitosan capsules when the capsules tered to male rats. as compared with the capsules rats and mice (544). Microspheres and Microcapsules with Insulin with a mucoadhesive polymer such as chitosan. The desired PLGA nanospheres with elca- tonin were prepared by the emulsion solvent diffusion method to coat the surface of the resultant nanospheres 1. insulin is presently nanospheres showed higher mucoadhesion to the everted administered parenterally. and excretion in cholate (PA% ⫽ 3. specific delivery of peptides including insulin. (540) produced glutaraldehyde cross- teral routes for the delivery of insulin in an attempt to im. thogonal experimental table. These findings suggest that oration method (535). uted throughout the body as a function of the physicochem- Novel CS and CS/ethylene oxide–propylene oxide ical properties of the molecule. sulin and a corresponding decrease in plasma glucose lev. ministration. as evaluated by the transit time experi- L-100 and Eudragit S-100 using an oil-in-oil solvent evap. nonparen. The difficulties in achieving a intestinal tract in saline than the other polymer-coated normal physiological profile of insulin by injectable ther. ery of these immunostimulants from Mycobacterium vac- Tozaki et al. (539) have developed a novel mu- toxoids. An insulin delivery system has ilar microspheres were prepared by Jameela and Jayakrish- been widely investigated as an alternative to subcutaneous nan (541) containing mitoxantrone. studying its absorption. The chitosan-coated rent lack of alternative delivery routes. . Chitosan nanoparticles. titumor agents (543). A combined mechanism of 2. and radioactive concentrations in blood. To determine the effects of chito- containing only lactose or only 20 IU of insulin (PA% ⫽ san in 166Ho–chitosan complex. The fate of 166Ho–chitosan complex.62%). ing spray-drying and then microencapsulated into Eudragit entered the colon. The size of the CS microcores was chitosan capsules may be useful carriers for the colon- small (1. (542) described an orthogonal experi- chitosan microparticles containing insulin by interfacial mental design to optimize the formulation of cisplatin crosslinkage of chitosan solution in the aqueous phase of (CDDP)-loaded chitosan microspheres (namely. Microspheres and Microcapsules release is proposed. Nishioka et al. Wang et al. (536). the swelling of the CS microcores and the dissolution of SD and its further diffusion through the Intravenously administered anticancer drugs are distrib- CS gel cores. Drug release was injection for the treatment of diabetes. distribution. terized by high loading levels of insulin. dragit microspheres (size between 152 and 233 µm) form- ing a multireservoir system. and sodium alginate. Inc. readily prepared without the ing the drug in about 80 h at an almost constant release use of organic solvents. the formulations might find application as an- livery with chitosan capsules. CDDP- a water/oil dispersion in the presence of ascorbil palmitate. poly As a consequence of poor oral bioavailability and the cur.75 mg 1. concentration is reached in the tumor tissue at the expense tential for the association and controlled release of proteins of massive contamination of the rest of the body.8–2. Sim- prove glycemic control. completely releas. 166Ho alone (0. (acrylic acid). found to be effectively controlled by the degree of cross- Bugamelli et al. bovine serum albumin. (538) studied the colon-specific insulin de. DAC-MS). ments with chitosan capsules.

Their po- soluble chitosan and a laminin-related peptide. The HC release administered intratumorally twice in mice bearing subcuta.1. the double-stranded DNA was hydrolyzed after 40 min of tion to the other organs and tissues.3-tetramethyluronium tetrafluoroborate spheres covalently linked with citric acid and loaded with (TBTU) method. ASA–containing chitosan capsules. (547. incorporating 1200 µg of natural gadolinium. sone acetate alone. tration were higher than after administration of the drug DNA was immobilized within alginate matrix using in carmellose suspension. and only slight radioactivity was de. rates from chitosan microspheres were influenced by the neous B16F10 melanoma. (550) investigated the influence of chito- and the smaller Gd dose than that administered in past Gd. and then mem- were examined. Microspheres and Microcapsules radiographs after intratumoral administration of 166Ho– with Antiinflammatory Drugs chitosan complex showed that radioactivity was localized at the site of administration without distribution to the An inclusion complex composed of hydrocortisone acetate other organs and tissues (544). the tumor growth in significant improvement of the dissolution rate for HC.. administered group. The radioactive concentrations in tissues brane coated with chitosan or poly-L-lysine. indomethacin are prepared (551). antiin- NCT trials. The thermal neutron irradiation drug/polymer ratio in the manner that an increase in the was performed for the tumor site.and single-stranded DNA.e. and bones. Less than 1% of total double-stranded DNA re- tected from the liver. testinal tract protection. mained unhydrolyzed within chitosan. release data from all samples showed administration. with 25–40% of the drug being released in the first hour pressed compared to that in the gadopentetate solution– compared with about 5% for pure HC. urinary and fecal excretion. in order to establish high drug sis in mice.3. Membrane and the whole-body autoradiography images showed that thickness increased with decreasing polymer molecular most of the administered radioactivity was localized at the weight and increasing degree of deacetylation of chitosan administration site. croparticles are able to pass the epithelial layer. pharmacokinetic model were in good agreement with ex- tory effect of the peptide on experimental metastasis in perimental data obtained after oral administration of 5- mice. The effect is dependent on the (545).548). HC inclusion complex.or poly-L-lysine– sults strongly suggest that 166Ho is retained at the admin. Inc. Also. dem. Auto- 3.32 ⫻ 1012 neutrons/cm2 8 h after the second gadolinium creased. the Chitosan microspheres were also used as support for diisopropylcarbodiimide/1-hydroxybenzotriazole method. This study demonstrated the potential use. a pharmacokinetic Therefore. However. a small spacer. HPβCD as a physical mixture were incorporated into chi- ticles. (HC) and hydroxypropyl-β-cyclodextrin (HPβCD) was The potential of gadolinium neutron–capture therapy prepared by the spray-drying method (549). and radioactive distribution an external or an internal calcium source. remains to be shown. flammatory drug prednisolone sodium phosphate (PSP) fulness of Gd-NCT using gadolinium-loaded nanoparticles across the epithelial barrier. Four methods were tried to achieve a cou. pling reaction. the antiinflammatory drugs in order to assure the gastroin- the water-soluble carbodiimide. In this way the chitosan micro- azole-1-yl)-1. with the fluence of release rate was observed when the drug loading was de- 6. spleen. Hydrocorti- (Gd-NCT) for cancer was evaluated using chitosan nano. was model of colon-specific drug has been validated by use of intercalated in chitosan by the TBTU method to facilitate 5-aminosalicylic acid (5-ASA) as a model antiinflamma- its coupling with the peptide. integrity of the intercellular cell contact zones and the mi- Hojo et al. but all four methods were unsuccessful. Autoradiographs after intratumoral administra. or HC with particles as a novel gadolinium device (545). and the 2-(1H-benzotri. bases). Conjugation of the peptide tory drug (552). it actually potentiated the antimetastatic effect. The nanopar. poly- chitosan. and have tential benefit under inflammatory conditions like in in- examined its inhibitory effect on experimental metasta. doses at the region of interest. coated beads. These re. san microspheres on transport of the hydrophilic. The simulation curves obtained from the with the larger chitosan molecule did not reduce the inhibi. lungs. The concentrations of onstrating that chitosan may be effective as a drug carrier 5-ASA in the large intestinal mucus after drug adminis- for peptides. (546) have prepared a hybrid of a water. These results strongly exposure. despite radioresistance of melanoma Mooren et al. Chitosan membranes did not offer suf- tion of 166Ho–chitosan complex showed that radioactivity ficient DNA protection from DNase diffusion since all of was localized at the site of administration without distribu. tert-butyloxycarbonyl-Gly. suggest that 166Ho is retained at the administration site only when it forms a chelate complex with chitosan. . flammatory bowel disease. corresponding with an increase in DNA re- istration site only when it forms a chelate complex with siduals (i. nucleotides. the diphenylphosphoryl azide method. These findings suggest that Copyright © 2002 Marcel Dekker. the nanoparticle-administered group was significantly sup. double. were tosan microspheres by spray-drying (549). After the irradiation.

Therefore. . sponges with fast drug release. and the conse- The formation of microcapsules which contain rose. The results indicate that the chemically modified destruction. In addition A biodegradable drug delivery system of a gentamicin- semi-interpenetring polymer network hydrogels have been loaded chitosan bar with sustained antibiotic effect is de- produced between chitosan–polyethylene oxide diacrylate scribed (571). Using tartaric or citric chitosan. microspheres effectively inhibited bioprosthetic tissue cal. and a cylinder model cutting technique was used to chitosan–polyethylene oxide (562). CHIT-LYVS-GDI) were 4. nisolone was used as a model drug. coefficients of Ru(NH3)6(3)⫹ and dopamine in the films ing several pathological conditions associated with bone (568). By the attachment of hydrophobic palmi. in vitro. The use of acetic or formic acid enabled the production of stable foams and soft and elastic sponges. were prepared from a water-in-oil Miyazaki et al. selective. as Local Injection and flow injection analysis. solvent evapora- crosslinked by UV irradiation (561). Pred- the oil droplets and (2) addition of a cationic biopolymer. of fast. The rate of drug release was crosslinked. CHIT-LYVS. The bar san (565) and the attachment of C10-alkyl glycosides to implanted in the proximal portion of the rabbit tibia pro- chitosan (566). elastic. transport and ion exchange properties of such polymeric structures (CHIT. The microspheres with the most retarded release rate. the hematoma. acid resulted in unstable. the bar showed significant antibacterial activity. Approximately 11% gentamicin was released Noncovalent crosslinking has been used to prepare from the bar in the first 24 h. was found that the degree of deacetylation and the chitosan lial cell culture. and diethyl squarate (559) have hyde. quent effect on the drug liberation were investigated (570). and fective than other 5-ASA formulations for treatment of co. Combined crosslinking. our pharmacokinetic model of colon-specific drug delivery Thin films of a biopolymer chitosan (CHIT) were cast can accurately evaluate this colon-specific delivery system on glassy carbon electrodes.4 buffer at 24 h. physical properties. Microspheres and Microcapsules studied using cyclic voltammetry. the genta- Copyright © 2002 Marcel Dekker. Various formulation variables were studied for the suitability of dried chitosan gels as vehicles for the their effect on the release rate profile of these bone-seeking sustained release of the poorly soluble drugs such as indo- agents (553). The process is based Chitosan was dissolved in different acid solutions and on two steps: (1) formation of oil-in-water emulsions using chitosan–gelatine sponges were produced by frothing up lecithin as emulsifier. Inc. glyoxal (558). Bisphosphonate released from chitosan content were important for the release properties. a water-soluble chitosan higher concentration was produced in local bone and in derivative has been produced (567). Gels tic acid were used. crosslinked with glutaric dialdehyde (GDI) (568). on the resulting sponge. The influence of the acid type used to dissolve chitosan cification in the rat subdermal model. and disintegrating uble chitosan–lecithin complex. (565) investigated emulsion. The results showed that the chitosan matrix supported a fast ion transport as demon- Local implantation or injection of microspheres containing strated by aqueous-like values of the apparent diffusion bisphosphonates for site-specific therapy may aid in treat. in conditions that favor the formation of an insol. Chitosan microspheres containing two antire. it is possible to manipulate the mechani- been employed in the fabrication of chitosan hydrogels. The gentamicin released from chitosan-based gels by the O. (569) and Kristl et al. and glutaraldehyde prepare the chitosan bar. duced a low blood concentration of gentamicin. Hydrogels formed from chitosan are usually covalently allowing low drug release. chitosan is an attractive new coating for the development sorption and anticalcification agents. soft.and N-acetylation of chito. pamidronate and su. Polymer coating of micromatrices yielded methacin. papaverine hydrochloride. mary oil is herewith described (554). Elastic but harder sponges from stable foams were obtained when hydrochloric or lac- E. thus imparting negative charges on the polymer solution and then freeze-drying the foam. Sustained diffusion of gentamicin crosslinked chitosan combined with silk fibroin (563) or into the surrounding medium was seen using a release test polyacrylic acid (564). Crosslinking agents such as glutaraldehyde decreased by crosslinking the polymers with glutaralde- (555–557). In all bone tissue around the bar. but a much toyl groups to glycol chitosan. glyoxal crosslinked tion. and lidocaine. carbohydrate sceleroglucandialdehyde (560). It drug delivery system was found biocompatible in endothe. and reversible sensors. and the gel showed zero order release into pH 7. beroylbisphosphonate. cal properties and the drug liberation rate by using differ- Chitosan has also been covalently crosslinked with the ent acids to dissolve chitosan (570). ifer Yellow VS dye (LYVS) onto chitosan chains. modified by grafting Luc- and that 5-ASA–containing chitosan capsules are more ef. The ion litis in rats. rotating disk electrode.

simple polyelectrolytes in solution EDTA was covalently bound to the primary amino groups may be linked together by multivalent ions to form gels or of chitosan (574. and immunologic activity. 37°C and provided significant extension of drug release. ing. In addition to the negative bacteria. The porosity was increased by produc- with chitosan gel or membrane. hydrogen bond- avoids a second operation for removal of the carrier. or even on the same Under the formation of amide bonds. bonds are distinctly directional and specific and are more san–EDTA conjugate. moieties on the same polymer chain. and turbidity of polymer solutions (583). and microenvi- corporated into chitosan hydrogel to prepare ointments. chitosan (600). strength. proteolytic activity of the zinc pro. the complexing agent monomer units. heparin–chitosan gel stimu. re- nesium. actions (579–583). which stabilizes the outer membrane of gram. were synthesized (574). The effect of heparin ionically linked to chitosan on the The binding of chitosan to alginate beads was studied stimulation of re-epithelialization of full thickness wounds quantitatively by using radioactive-labelled fractions of in human skin was investigated in an in vitro model (577). van der Waals forces. Capsules with a diameter of 500 Copyright © 2002 Marcel Dekker.593). pH. and also ointment viscosity. Whereas proteolytic activity of the coacervates (588. micin concentration exceeded the minimum inhibitory polymers gelled as the temperature was raised from 4 to concentration for the common causative organisms of os. creased by reducing the number average molecular weight lated 9/10 of the full thickness wounds to re-epithelialize of chitosan below 20. and with increasing pH. the range of FA ⫽ 0. Berberine (the main ingredient of Coptis spp. responsive polymers (Pluronic) to chitosan backbones.573).3 to FA ⫽ 0. intrapolymer complexes of poly- New mucoadhesive polymers. Polyelectrolytes of high teases carboxypeptidase A and aminopeptidase N was charge density may form relatively insoluble complexes.599). sulting in poly(cation)/poly(anion) pairs. (578) was to decreasing fraction of N-acetylations (FA) on chitosan.589).) was in. This or more complementary polymers and may arise from elec- system has an advantage over other systems in that it trostatic forces.000 Da and by increasing the porosity compared with only 3/10 of the wounds that were covered of the alginate gel. Many polymer complexes form as a result of (571). such as cooperative interactions. This antimicrobial activity of NaChito-EDTA can electrostatic forces. which are chitosan HCl. interpolymer complexes. as mechanochemi- The release rate of berberine was inversely proportional to cal devices (594). The physicochemical properties of the ointments and the Gel technology based on ionic crosslinked polysaccha- release profile of berberine were investigated. A recently developed chito. and none of the wounds ing homogeneous gels. has been tested for possible topical use action (584). hydrophobic interactions. conduc- acid group of EDTA are covalently linked to the amino tivity. The complex stability is dependent serine proteases trypsin. by proton transfer to complementary polymeric bases. rheology. Polymeric acids may form complexes be explained by its highest binding affinity toward mag. . Based on these test results together with the chitosan characteristics F. ampholytes have been studied (585–587). as controlled release systems (592. called polymer effects.575). ronmental effects (590). The binding of chitosan was also found to increase with One approach taken by Hoffman et al. The results rides is currently in use and of considerable interest for indicated that the viscosity of chitosan hydrogel increased potential application in the extraction with solvents (591). steric compatibility. in the oil industry (595–597). The formation of complexes may jugate gels have also been reported in which the carboxylic strongly affect the polymer solubility. Finally. teomyelitis for approximately 8 weeks (571). in several other biomedical applications (598. or combinations of these inter- Chitosan–ethylene diamine tetracetic acid (EDTA) con. ionic could not be inhibited. antibiotic. solvent. strongly inhibited by the chitosan–EDTA conjugate. and temperature. and by adding calcium chloride to incubated without gel or membrane or with heparin solu. neutralized with sodium hydroxide localized than any other type of weak intermolecular inter- (NaChito-EDTA). α-chymotrypsin. Hydrogen groups of chitosan (572. The binding of chitosan was markedly in- After 7 days of incubation. concerted interactions. the gentamicin-loaded chitosan bar seems to be a clinically Polymer complexes are formed by the association of two useful method for the treatment of bone infection. Inc. In these systems ity to bind bivalent cations that are essential cofactors for complexes may be formed between oppositely charged intestinal proteolytic enzymes. with an increasing amount of lactic acid or EDTA (576). The in the range of pH 4 to 6. tion alone. in synthesize hybrid copolymers by grafting temperature. The Characteristics of the macromolecule complexes are adhesive force of the conjugate was even higher than of largely based on their higher molecular weight. exhibiting a high capac. the chitosan solution during the membrane-forming stage. and elastase upon such variables as charge density. Chitosan–Polyelectrolyte Complexation of biodegradable.

Cap. To prepare spray-dried composite particles containing when the capsules were made more homogeneous. all the chitosan was located in a thin hydrophilic functions (R—COOH in case of polyanions alginate–chitosan membrane on the surface.608). solution of chitosan were concomitantly fed into the rotary Noncovalent crosslinked chitosan gel mixtures can be atomizer of a spray-dryer (601). Copyright © 2002 Marcel Dekker. slower rate of dissolution than chitosan at the correspond- tosan in the formulation. Inc. . fluid and second slowly release a wound-treating drug posite particles. polymers can be effectively controlled by glutaraldehyde The stability of alginate–chitosan capsules was shown crosslinking (609. 1). the suitable pH value (606).000 Da. an aqueous when the capsule diameter was reduced to around 300 µm solution of lactose and sodium alginate and the acetic acid (602). to depend strongly on the amount of chitosan bound to The complexation reaction between the polyions leads the capsules. the artificial intestinal fluid. The latter ef- acting calcium alginate beads in an aqueous solution of fect created an ‘‘ionic’’ reticular network that immobilized chitosan and calcium chloride (two-stage procedure). A water-insoluble hydrogel is formed by blocking the stage procedure). These cap. µm had a higher weight ratio of chitosan to alginate after sules with high mechanical strength were obtained after 24 h of binding than the capsules with the larger diameter shorter reaction times when the number average molecular of 1500 µm. and R′—NH2 for the polycations) and by the interaction sules were much weaker than the capsules made by re. which could form a rigid gel structure on (607. The prolongation of induction pe. The hydrogel has the property of incorporat- Figure 1. The induction period for drug Gelatine forms polyionic complexes with chitosan at release to occur was increased with an increase in the de. san. xanthan and chito- a solution of sodium alginate into a chitosan solution (one.1 The complexation reaction between xanthan and chitosan. The drug release profiles prepared by the use of polyelectrolyte complexes of chito- of dry-coated tablet with SD(L/AL-CS) indicated a long san and polyanions such as carboxymethylcellulose (603) induction period followed by a rapid drug release phase in and xanthan (604. These complexes show a gree of deacetylation of chitosan and in the amount of chi. When the capsules were made by dropping to structural changes in both polymers. between the macromolecular chains (Fig. ing pH. weight of the chitosan was reduced to around 15.610). the polymers. The release profile and biodegradability of both the tablet surface.605). and alginate–chitosan complex [SD(L/AL-CS)]. Therefore a combination of chitosan and gelatine riod was attributed to the formation of an insoluble ion in a sponge will first lead to an absorption of the wound complex between sodium alginate and chitosan in the com.

75. The complexation efficiency readily reaches 90% of the available chitosan and the less deacetylated chitosan (DA ⫽ 34%) forms a stable hydrogel having the highest chitosan/xanthan ratio.5 56 Chitosan Mna acetylation (%) yield (%) (%) 4.1–1 µm). from which we can polymeric substrates to the regions where the immobilized notice that water constitutes. Similar results tion: 0. in its matrix. of the elaborate network.5 21 the Absorption of Water by the Chitosan–Xanthan Hydrogel 2. In fact.0.65 g/g.9 2560 6.9 97. we have studied the influence of the pH of the chitosan solution on the yield of complexation with xanthan. due to the drying and cutting proce- dures used. 3 for typical gel samples (24. in 0. The results are shown in Table 6. Additionally. 2).81 ⫻ 10⫺3 M0.3 457 691. biological products (611–615). sage that the gels are quite porous and that formation of The decomposition of the chitosan–xanthan hydrogel fibrilar structures takes place.2 M NaCl solution at 25°C.93.1 M 25°C.2M.617).875 27.2 and 9. solution. [η] ⫽ 1. ing a significant amount of structural water as well as the capacity of stabilizing.2 M NaCl solution at a Determined by intrinsic viscosity [η] ⫽ 1. Figure 4 shows the presence of loose drogels are shown in Fig. acetic acid/0.1 M acetic acid/0. care has to be exercised in the interpretation Scanning electron microscope (SEM) images of the hy. We notice a poor complexation at low pH due to strong ionization Figure 1.0 98.2 84.5 36 Degree of Complexation αmax 3. Recently.93.325 28.390. as in the case for the the samples for TEM inevitably leads to modifications of xanthan–CMC complex (616).2 M.350 28.75% xanthan). which impedes its reaction with the at different pH conditions. determined by measuring the intrinsic viscosity. in 0. concentration of the hydrogel. Mn chitosan ⫽ 122. The images convey the mes. we have studied the complexation reaction between xanthan and chitosan by determining the yields and the structure of the complex as well as its swelling capacity.5 98 691.2 the hydrogel whereas the fibrils have a typical dimension of 10⫺7 m (100 is stable no matter the ionic concentration present (Fig. which allows the passage of the hydrogel are shown in Table 7. of the micrographs. The channels present in the depends on the pH and the ionic concentration of the buffer gels have a pore size between 10⫺7 and 10⫺6 m (0.8 81. determined Note: pH ⫽ 5. In the pH range between 1. in all cases. the largest weight enzymes are lodged.3 82 452.5 60 5. 3b).2 Evaluation of chitosan–xanthan complex stability of the amine groups. nm).2 1805 191.25% aggregates of fibrils probably resulting from the rupture chitosan.930 28. The large swelling capacity Transmission electron microscope (TEM) images of the of these hydrogels does not lead to their disintegration hydrogels are shown in Fig. have been reported for the complexation of chitosan with carboxymethyl cellulose (CMC) and alginic acid (616. the higher the amount of xanthan needed to form a stable hy- drogel. buffer solution concentra- carboxylic groups present in the xanthan. The surface of the microsphere has a homogeneous The swelling characteristics and the water content of porous structure (Fig. observed via scanning electron microscopy (SEM). Since the preparation of when prepared as microspheres. the sample. Time: 48 h. Copyright © 2002 Marcel Dekker. buffer acetate 0. the lower the DA. Inc. 4. . The aggregates are formed of fiber fragments Table 6 Influence of the pH of the having typical diameters of 50 to 100 nm in agreement Chitosan Solution on the Yield of Its Complexation with Xanthan pH Xanthan complexation yield (%) Table 7 Influence of the Molecular Weight of Chitosan on 1.81 ⫻ 10⫺3 M0.5 992 Note: Ratio CH/X ⫽ 0.

The CH-X complex did not show a cytotoxic effect re- gardless of degradation time periods and concentration used (Fig. in turn. 75. 60. This effect was more evident at higher concentration (10 mg/mL).75% xanthan) 48.000⫻. Figure 1.5 Effect of CH-X particles on L-929 cell viability par- vation (618–621). Production of IL-1β was enhanced after macro- phage incubation with CH-X particles. The TNF-α. Nitric oxide production and efficacy as ticles (direct contact). 5) (623). Production of TNF-α by macrophages was stimulated by CH-X particles for the concentration of 1 mg/mL. 75. Inc. A concentration of material near the external surface of the sample is also evident.75% xanthan). 30. The ‘‘open spaces’’ (pores) are quite developed toward the cen- ter of the sample. 6). (a) Image of external surface. with the SEM observations. while the concen- tration did not affect the secretion level (Fig. .4 Transmission electron microscope images of typical gels (24.25% chitosan.000⫻. and they are known to induce other cells such as T lymphocytes to proliferate and synthesize proteins and additional factors which.25% chitosan. and NO secre- tion as markers for macrophages activation were assessed. an immune effector molecule has been also demonstrated in murine models (622). enhance macrophage acti.3 Scanning electron microscope images of typical gels (24. Our study (b) demonstrated clearly that macrophages incubated with Figure 1. (a) Figure 1. Cytokines and nitric oxide (NO) are also secreted by the macrophages as indicators of the inflammatory re- sponse. Copyright © 2002 Marcel Dekker. IL-β.000⫻. Evaluation of their bicompatibility was carried out with L929 fibroblasts cell line to determine the cytotoxicity and with J774 macrophages cell line to assess the inflammatory response. (b) image of internal section.

which can lead to the entire resorption inflammatory reaction is essential for preparing the wound of the hydrogel. . the transmembrane permeability of the capsules prepared pair and deposition of new matrices. Macrophages also play an important role in the phago.7 Effects of CH-X extract products on NO2⫺ secretion around CH-X particles (P) after 2 weeks implantation in rat sub- by J-774 macrophages. for the production of a new extracellular matrix.9 LM micrograph (156 ⫻) showing dense fibrosis for- mation with blood vessels (arrows) and inflammatory reaction Figure 1. Longer reaction times did not improve healing process (Fig. model used indicated a phagocytosis of the CH-X particles cytosis of the material and its degradation in vivo.8 TEM micrograph showing fibroblast adhering along of the particles could be not phagocytosable. carboxymethyl cellulose as a polyanion. using chitosan.6 Effect of CH-X particles on IL-1β secretion. CH-X particles (P) after 8 weeks of implantation in rat subcutane- Secretion of TNF-α and NO (Fig. and the presence of collagen attests to the decreases with time. In vivo studies based on light micros. 7) is influenced in ous tissue. The encapsulation is based on the electro- tract the fibroblasts into the wound to initiate the recon. Their presence is with chitosan and CMC (616). Cytokines Shioya et al. The permeability slightly shown in Fig. Figure 1. The objective of copy observations showed a recruitment of specific cell this investigation was to identify the factors which control populations responsible for the preparation of wound re. Degradation study on the animal Figure 1. The size Figure 1. (616) developed the encapsulation method and growth factors released by the inflammatory cells at. Inc. the same way by CH-X extract products with a slight sensi- tivity for TNF-α secretion. static interactions of chitosan as a polycation with sodium struction process. 9). 8. The by macrophages. Copyright © 2002 Marcel Dekker. CH-X particles were activated to produce IL-1β. cutaneous tissue.

synthesis. The anions (628). modulators of cell morphology. lease patterns of all chitosan gel beads in pH 6. 1. In 2. competition be. individually. more readily to chromaffin cells than gelatine. Morphological examinations re- phosphate (MPK) to form a series of water-insoluble vealed that the chromaffin cells survived for at least 2 macromolecular complexes (MC) in aqueous solution at weeks with collagen–chitosan scaffolds. These coagulation curves indicate attachment was examined (635). dized cellulose) with increase in the extent of modi- fication F. albumin. The amount and molecular weight of chitosan tosan) did not have a significant effect on insulin response. . that the chromaffin cells attached to collagen-blended chi- tine. At low It is known that glycosaminoglycans are involved in cell– sodium chloride concentration. the capsule membrane (616). its free amino groups ratio of the reacting group of MPK to that of GC. polymer ratio. and gelation) to in- the carboxylic acid groups on the cellulose predominates. Chitosan nanoparticles enhanced the nasal absorp- 1. The lower molecular weight of chitosan may to be diffusionally based. or MGC in the reaction mixture at the beginning Rat hepatocytes seeded onto glutaraldehyde-crosslinked and end of the coagulation. or interpolymer complexation. Chitosan as Scaffolds The addition of NaCl has two opposing effects on the ab- sorption of chitosan on oxidized cellulose (624). The complexation mechanism of effect (623) and then prevent the chitosan from reacting chitosan beads gelled in pentasodium tripolyphosphate or with CMC. improved bovine adrenal medullary chromaffin cell attach- Glycol chitosan (GC) and methyl glycol chitosan ment characteristics. In parallel with permeability. cules leading to an increase in the equilibrium adsorption. vivo. movement. leading to a gradual decrease in the equilibrium adsorption collagen-blended chitosan matrices were found to attach of chitosan (624). having struc- At higher sodium chloride concentration. GC ⫹ were crosslinked by glutaraldehyde to increase its strength. tissue engineering studies. Morphological evidence showed mal conditions for the complex between chitosan and gela. tural similarity to glucosaminoglycans. was modified using tween Na⫹ ions and cationic groups on the chitosan for several proteins (collagen. due to the swelling or matrix erosion. tosan substrate integrated well with the hydrogel matrix polymer concentration. The drug re- chanical strengths because of a lower density of interpoly. reacted with potassium meta. The equilibrium adsorption rates of chitosan on oxi. thus lower per. different hydrogen ion concentration (GC-MPK and MGC. chitosan (GA–chitosan) gel could attach with stability to Enzymatic-hydrolyzed chitosan was employed to pre. Inc. Insulin-loaded chitosan nanoparticles were prepared by dized cellulose substrates were determined and are plotted ionotropic gelation of chitosan with tripolyphosphate as a function of carboxylic acid group content (624). the surface. In vitro. reaction time.2 medium seemed to be non-Fickian diffusion controlled meability. Increased substrate surface area due to increased vivo absorption studies in animals have been carried out swelling on immersion in water because of increase to evaluate the nasal absorption–promoting activity of chi- in the hydrophilic character of the substrate (oxi- tosan using insulin as a model peptide (629–630). polyphosphoric acid solution was ionotropic crosslinking branes formed by chitosan with salt also have lower me. Since chitosan gel was the dependence of hydrogen ion concentration on the mole too fragile to use for cell culture. crease surface area and improve biocompatibility. The permeability increases phoric acid gel beads using a polyelectrolyte complexa- with an increase in the salt concentration. ionic strength—were essentially coincident with chitosan– Collagen-blended chitosan substrates produce significantly polysaccharide complexes. and function (631–633).8 seemed mer bridge. and and survived for at least 2 weeks under in vivo conditions. and probably act as duction of the hydrodynamic volume of the chitosan mole. and then release a very small amount of lactate dehy- Copyright © 2002 Marcel Dekker. whereas release profiles in pH give a more compact membrane structure. hance the nasal absorption of insulin was investigated in tent may arise from two effects (624): a conscious rabbit model by monitoring the plasma glucose levels. All of the optimal conditions—pH. Increased electrostatic interaction between poly- tion of insulin to a greater extent than an aqueous solution anion (oxidized cellulose) and polycation (chi- of chitosan. The effectiveness of chitosan as a scaffold of hepatocyte MPK) systems (626). retaining its spherical form. CaCl2. blended matrices (634). which can be considered for neural (MGC) were. cell and cell–matrix interactions. The ability of chitosan nanoparticles to en- increase in absorption with increase in carboxyl group con. the same as in pare chitosan–tripolyphosphate and chitosan–polyphos. temperature. differentiation. the capsule mem. cause a reduction in the effective charge by a shielding 6-mercaptopurine (627). Chitosan. Adding salt may tion method for the sustained release of anticancer agent. respectively. the dominant effect is re.or albumin- Remunan-Lopez and Bodmeier (625) investigated opti.

was controlled by varying initial loading content of PDGF-BB performed (643). a liver-specific sion and promotes contraction of a collagen lattice com- function. Bovine primary articular ported for a few cell types. Chitosan-Based Vector–DNA Complexes rial can support the chondrocytic phenotype. than those on the collagen-coated surface. limited mitosis. trimethylchitosan.N- material to support chondrogenesis. Inc. he.N-trimethylchitosan–galactose conjugate. combined chondroitin sulphate-A (CSA) and chitosan. cell at. chondrocytes. noglycan sulfation may be a contributing signal for pheno- The quality of articulate cartilage engineered using a typic transformation during wound healing (638). and they showed fibers of the collagen–chitosan mixture to be the released much more lactate dehydrogenase than those on thickest and with altered organization. and bony regenerative receptor-mediated endocytosis. Scanning electron microscopy of the cellular lattices patocytes on a collagen-coated surface spread flat. on the chemical composition of the biomaterial and whether that biomate. Hepatocytes on GA–chitosan also that chitosan sulfation markedly enhances fibroblast adhe- retained higher urea synthesis activity. The formation of a polyelectrolyte com- to obtain optimal therapeutic efficacy. the results suggest that glycosami- to an effective bioartificial liver support system. chitosan derivative having recognizable saccharide resi- vestigated (637). in part. to develop a novel bio. lytic peptide was administered in the upper small intestine The ability of cultured human foreskin fibroblasts to and colon of rabbits. For fabrication of chitosan biophysical characteristics of chitosan-condensed DNA sponge. A selected complex containing a beneficial to enhance periodontal bone regeneration (637). proliferation capacity. (641) have found chitosan presents some chitosan. in order to target cells With an aim of improving bone regeneration.N. smaller than 100 nm. Acknowledg. which indicated good cellular then the possibility of its application as a gene delivery adaptability. chitosan could easily be chemically modified duction. cell–polymer construct depends. By analogy to the in vivo results indicate that chitosan is a promising biopolymer as sequence of hyaluronan followed by sulfated glycosami- a scaffold of hepatocyte attachment which can be applied noglycans in wounds. of complexes. Moreover. chito. form discrete. oligomers to condense plasmid was determined using TEM BB–loaded chitosan sponge significantly induced new and microtitration calorimetry. in defined conditions. or chemically modified chitosan (640). drogenase during the 5-day culture period. (636) Chitosan is a candidate nonviral vector for gene delivery.N. N. and reporter gene expression was bind and to contract lattices of collagen. These pared to the unsulfated material. including round morphology. G.N. These results suggested that chitosan bility of the resultant complexes were measured using laser sponge and PDGF-BB–loaded chitosan sponge may be light scattering (644). various (PDGF-BB) was developed. Histomorphometric analysis confirmed that PDGF. al- Copyright © 2002 Marcel Dekker. Degradation of the chitosan sponge was pro.N- chitosan sponge induced significantly high cell attachment trimethylchitosan–galactose conjugate were tested. such as lactose. strated marked increase in new bone formation and rapid Chitosan is a polysaccharide that demonstrates much calcification. formation of DNA particles with chitosan (639) glycosaminoglycan (GAG) analog. chitosan solution was freeze-dried. such as N. has been investigated for gene trans- bined with the polyanionic CSA such that ionic crosslink. collagen–chito. complexes were measured. PDGF-BB–loaded chitosan sponge demon. These results show the GA–chitosan gel. fer. while the diameter and sta- bone formation. By contrast. Chitosan may be com. and several transfection experi- and freeze-dried again. Release rate of PDGF-BB could be dues. Reporter gene ex- san. With the san sponge containing platelet-derived growth factor-BB aim of developing a chitosan-based vector system. PDGF-BB solution. tool was investigated. In order to achieve an efficient gene delivery via tachment. and and proliferation levels. Release kinetics of PDGF-BB. by coupling ligands. PDGF-BB was incorporated into ments mediated by chitosan and lactosylated chitosan were the chitosan sponge by soaking chitosan sponge into the performed (642). crosslinked. and collagen type II and proteoglycan pro. Sechriest et al. The ability of a com- ceeded at defect site and subsequently replaced with new mercially available chitosan and depolymerized chitosan bone. and collagen–chitosan sulfate was determined (638). expressing a galactose-binding membrane lectin. such as the abil- and maintain many characteristics of the differentiated ity to condense DNA and to form homogeneous population chondrocytic phenotype. potential as a gene delivery system. . pression was enhanced in defined intestinal tissues. a Therefore. Successful chitosan-mediated transfection has been re- ing results in hydrogel formation. such as HEK 293 cells (639). for Gene Delivery ing the supportive influence of tissue-specific matrix mole- cules on the chondrocytic phenotype. PDGF-BB–loaded plex with DNA and the cellular recognition of N. measured in defined intestinal tissues. the synthesis of a novel potentials of PDGF-BB–loaded chitosan sponge were in. when seeded onto a thin layer of CSA– Erbacher et al. focal adhesions to the material characteristics favorable for gene delivery.

Moreover. as well as ability to protect DNA from nuclease deg.1 ily in water at neutral conditions. agarose gel. Inc. Chitosan succinate and phthalate matrices showed pH- bically modified chitosan were studied by fluorescence dependent release profiles of the entrapped diclofenac so- spectroscopy and dynamic light scattering method (651). a protective effect for poly- Many cationic polymers (645–649) have been explored mer embedded peptides toward degradation by intestinal as nonviral vectors.1. the co-administration of chitosan that the highly purified chitosan fractions used were neither and its derivatives leads to a strongly improved bioavail- toxic nor hemolytic. 99. The combina.000 Da zyme inhibitors on the polymer.0% for N1.5. that they have ability to complex ability of many perorally given peptide drugs such as insu- DNA and protect against nuclease degradation and that lin. Highly purified chitosan fractions of peptidases can be achieved by the immobilization of en- ⱕ5000 Da (N1). of peptides on the path between the dosage form and the and N3. For. metallopepti- DNA. these de- deoxycholic acid groups per 100 anhydroglucose units was rivatives maintain the beneficial cosmetic properties of synthesized by an EDC-mediated coupling reaction. The attachment of hydrophobic groups to glycol chitosan sponses. drugs (653). but not of the gut. . A simple carbohydrate polymer glycol chitosan (degree Mao et al. Glycol chitosan modified by attachment food allergy. dases are inhibited by chitosan derivatives displaying com- radation (650). Chitosan–DNA interaction at a charge of plexing properties such as chitosan–EDTA conjugates. should yield an amphiphilic polymer capable of self- sized by complexing plasmid DNA with chitosan resulted assembly into vesicles. and indicates its prophylactic utility in treating labile molecules. and 98. respectively. (652) describe a new immunoprophylactic of polymerization approximately 800) has been investi- strategy using oral allergen gene immunization to mod. The observations these unique features. Chitosan Derivatives the presence of cholesterol. of a strategic number of fatty acid pendant groups (11–16 mol%) assembles into unilamellar polymeric vesicles in H. Copyright © 2002 Marcel Dekker.5 ⫾ 2.4. offers the possibility of fabricating a drug delivery system noparticles is effective in modulating murine anaphylactic suitable for the oral and intranasal administration of gut- responses. though levels of expression remained low. These polymers are therefore low molecular weight chitosan can be administered intra. methylation (CM-chitosan). all the absorption membrane can be strongly reduced. membrane-penetration enhancement of chitosan polymers Oral allergen gene immunization with chitosan–DNA na. To increase chitosan’s utility. even unmodified chitosan endosomal release. Whereas serine proteases (N3) were prepared and characterized in respect of their are inhibited by the covalent attachment of competitive in- cytotoxicity. These poly- in various pharmaceutical formulations. in contrast to pH 2 at which the matrices resisted plasmid DNA was confirmed by electrophoresis on an dissolution. may be the critical rate-limiting steps proved to display a permeation-enhancing effect for pep- in the uptake process. a presystemic metabolism 99. Both derivatives disolve eas- Hydrophobically modified chitosan containing 5. 5000–10. On the other hand. ability to cause hemolysis. ulate peanut antigen–induced murine anaphylactic re. tide drugs. By modifications meric vesicles efficiently entrap water-soluble drugs. useful excipients for the peroral administration of peptide venously without liver accumulation suggest there is po. In 1:1 was much greater than seen for poly(L-lysine). and ⱖ 10. On the one hand. of the primary amino group at the 2 position of this poly Investigations of chitosan citrate as a hydrocolloidal (β1 → 4-D-glucosamine). Based on chitosans showed rapid blood clearance. N2.000 Da (N2). and buserelin. Maximum drug release was observed under Charge complex formation between self-aggregates and pH 7. it has been N-derivatized sans as components of a synthetic gene delivery system by phosphonomethylation (PM-chitosan) or by carboxy- (650). the features of chitosan can even matrix material (657–659) and as the wall of a mcrocap- be optimized according to a given task in drug delivery sule (660) have been reported. For peroral peptide delivery these tasks focus on tion of strong complex stability and low in vivo expression overcoming the absorption (I) and enzymatic barrier (II) levels suggest that uptake and/or decomplexation. and addition. gated for its ability to form polymeric vesicle drug carriers.9 ⫾ 0. Oral administration of DNA nanoparticles synthe. Chitosan is used because the in transduced gene expression in the intestinal epithelium. systems. ability to complex hibitors such as the Bowman-Birk inhibitor. tential to investigate further low molecular weight chito. dium (655). These polymeric vesicles are found to be biocompatible and hemocompatible and capa- In the 1990s chitosan turned out to be a useful excipient ble of entrapping water-soluble drugs (656). calcitonin. because of the mucoadhesive properties of chito- complexation resulted of DNA degradation by DNase II: san and most of its derivatives. mation and characteristics of self-aggregates of hydropho. After intravenous injection.1 ⫾ 1. chitosan (654).

New 5FU. Lee. J. respectively. 1996. Thee (Eds. Structural char- MMC after intraperitoneal administration and their in vivo acterization of capsular polymer of strain Eagan. C. Henrichsen. 1994. R. 325–371. gamma irradiation of purified and highly deacetylated chi- tosan fibers and films at sterilizing doses (up to 25 KGB) I. Jr. Capsular polysaccharides of non-groupable chitosan (gly-chitosan). require the final products to be sterilized before use. J. J. and gly-chitosan-glu-MMC. J. Jennings. J. S. It was found that LCC solubilized taxol by forming micelles with J. H. gly-chitosan. J. In: Neoglycoconjugates: Preparation the Sarcoma-180 solid tumor inoculated subcutaneously. 41:155 (1983). R. The structure of the cross-reactive were found to be preliminary regulation factors for two. W. The viscosity average molec- ular weight of the polymer decreased with increasing irra- 5-Fluorouracil (5FU) has remarkable antitumor activity. Sood. with the intravenous injection. Lin. saccharides. named N-suc-chitosan-glu-MMC streptococci that cross-react with pneumococcal group 19. I. Chitosan-fixing 5FU at the 2 position through a hexamethylene spacer and carbamoyl linkages exhibits 1. cines. Lee. B. Immunol. J. Biol. to provide the hydrophobic moieties and carboxymethyl but N-suc-chitosan-glu-MMC showed significant tumor groups attached to hydroxy groups to provide the hydro. 133:2706 (1984). pp. A. P. C. Small-sized chitosan gel nanospheres. MMC and both the conjugates. R. 150:97 (1990). polymer–drug binding charac. 9. Koizumi. Irradiation in anoxia did not affect film order to provide a polymeric prodrug of 5FU with reduced properties significantly. celles in aqueous solution was examined (661). Immunol. Pon. Mar- tin. Baker. I. types 19 (19F) and 57 (19A) pneumococcal capsular poly- step hydrolysis of the polymeric drug. acid polysaccharide antigens of Neisseria meningitidis Chromofore-terminating peptides were coupled with CM. amide. J. 5FU or immobilizing 5FU derivatives (aminophenyl. The nance. H. The solubility of taxol in LCC mi. Inc. philic moieties [N-lauryl-carboxymethylchitosan (LCC)] the tendency to suppress tumor growth was observed in was newly synthesized. A. in which process the drug 5. 443–479. Lee. 255:6847 (1980). ester. amino acid composition of the spacer and the spacer length 6.). 2. For as human vaccines.663). J. 3. M. Capsular poly- mer of Haemophilus influenzae type b. and exhibiting high antitumor activity. This particle size was con- sidered effective for passive targeting for tumors. Jennings. W. Cristel. ized mainly by the plasma concentration time profiles of 8. Y. H. J. Chitosan has potential biomedical applications that may centration of taxol in the micellar solution was very high. on the group-specific antigens of Neisseria meningitidis Covalently drug-pendanted 6-O-carboxymethyl-chitin serogroups A and X. Sterilization of Chitosan particle sizes less than 100 nm. Chem. New York. C. 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In understanding the complex biological system. proteins/enzymes and various biolog. In the trum of biomimetics in this chapter by highlighting se- 1980s and early 1990s. the field of biomimetics expanded lected research investigations in which the knowledge of dramatically to such areas as antitumor pharmaceutics biological sciences has been adopted as a template in the (19–21). polyketone-derived phenols (17). For example. and much more. in the biological and engineering arena. However. the field of biomi. Biological the late 1990s and into the new millennium. the semantic definition is molecules were designed and synthesized by mimicking the ability to camouflage a substance with suitable contriv- the functional structure and synthesis pathway of natural ances similar to the environmental background with the compounds. namely. observed cellular functions. biomimetic methodologies were aim to elude a hostile observer. can be traced to the early 1970s when functional artificial and life sciences. Nonetheless. the author argues that (11). to formulate bio- chemical properties. The author will emphasize the complementary interrela- ses of proteins and nucleotides (24). such a definition employed to selectively synthesize antileukemic triptolides is insufficient and narrow. there is not a consensus in the defini- novel approach and new technology. mimetism should be broad and hence dynamic and encom- catechol estrogens (16). medicine. the root of biomimetics communities. biomimetic systems fundamentally function at the angstrom scale of Copyright © 2002 Marcel Dekker. Wisconsin I. camptothecin chromophores (15). the application of progesterone (12–14). sity and uniqueness of biology for potential methods to Although the biomimetic approach has been employed control biological behavior of a myriad of tissue engi. and to vitro and in vivo (1–10). cium phosphate coatings on metal alloys (26) and poly(L- dating the specific interaction among material physico. continue to be utilized in probing the molecular fundamen- biomaterial developments have begun to utilize the diver. Inc. study and development of novel molecules and materials. and such as synthetic peptide amphiphiles (28) and polymers physiological parameters such as mechanical forces in derived from molecular and microbiology (29–31). the development of receptor agonists and antago. nists (22. tion of ‘‘biomimetics’’ that is accepted by various science metic materials emerges. functional materials for biomedicine and bioengineering ical molecules. lactic acid)–co-apatite composites (27). 2 Biomimetics Weiyuan John Kao University of Wisconsin. engineering. the study of functional structures and synthe. passing. cyclical polyenes such as racemic 11α-hydroxy. Hence. However. Madison. chemistry. Based on these investigations. INTRODUCTION methodologies have been employed as an engineering tool to develop novel material processing methods such as cal- Current biomaterial research efforts mainly focus on eluci.23). and the elucidation tionship between biomimetic research and the pursuit of of biological pathways such as enzyme catalysis (25). The author will attempt to address the wide spec- D-glucose-derived (⫹)-biotin (18). tals and mechanisms of biology. . by various scientific disciplines to develop novel mole- neering and biomedical applications. As the result of this cules and materials.

IL1ra only II. Circulating IL1 receptor antagonist (IL1ra) is with potential biomedical values. hemodialysis polymer membranes may activate the molecule in solution were utilized as a guide in determin- phagocyte oxidative metabolism resulting in the highly ox. Investigations adopting these broad research princi. and the macro catalyzed the dismutation of O 2⫺ with a rate constant of scale of tissues. For ex. The idized low-density lipoprotein found in uremic patients. which all have important roles in the healing process ples of biomimetic macromolecules and novel biomaterials (1. The biomimetic ap.9. 1) (33). Inc. modulate host cell behavior (34). To formulate agonists. the low molecular weight metalloporphyrins micron scale of cells and protein matrices.1 ⫾ 0. ex. the glycine sequence of approximately the same length was native SOD molecule is highly unstable and has low bio. can pioneered by Yamamoto et al.e. as a unique structural designs can be deduced and mimicked model in the design of biofunctional molecules. and biochemistry. designed macromolecules chemistry. potent proinflammatory cytokine that upregulates cellular lecular synthesis and processing mechanism of biological function upon ligation with IL1 receptor type I (IL1RI) on systems and biological components can be elucidated and the extracellular membrane (35). further hypothesized that the resulting antagonist proach to develop molecules with SOD activity was first sequences. tumor necrosis factor α. Hence. hydride) was found to be 1. It has been proposed that IL1β complexes with Domain 3 of IL1RI by a strong elec- From the beginning of biomimetic research in the filed of trostatic interaction. cine linker was utilized to join the antagonist domain with Copyright © 2002 Marcel Dekker. resulting in no postli- BIOMIMETICS gation signal transduction (38). 2. the chrome-c. granulocyte/macrophage–colony stimulating factor (GM- ples will be presented in this chapter as illustrative exam. lease high levels of IL1β. The k cat value for the multifunctional chi- uniqueness of biological materials and systems is the meta. Using in vitro assay systems based on cyto. and 3 of IL1RI and initiates signaling pathways to upregulate cellular functions (37). pharmaceutical sciences. However.e. and meras with pH sensible sites and SOD-like active sites 3 of IL1RI to occur. which target Domains 1 and 2 of IL1RI.) for struct of metalloporphyrins and poly(styrene-co-maleic an- optimal function. Alternatively. moiety (i. The 10 7 –10 8 /M/s.37–40). a trimeric gly- (Fig. thus allowing the complexation be- dride) copolymers resulted in the formulation of novel chi. who demonstrated that the reaction of vari. The tertiary structures of the native IL1β and IL1ra ample. mera of metalloporphyrins and poly(styrene-co-maleic an- stable microstructure formed from the molecular to mac. minimum distance between each residue was approxi- Superoxide dismutase eliminates the highly reactive and mated using the structural coordinates archived in the hence destructive superoxide radicals and participates in SwissProt Database. tion.. CSF). have chosen sible scales of spatial resolution. By studying the hierarchical structure In the design of biofunctional molecules to study and of biological systems and biological constituents at all pos. the nano scale of macromolecules.e. IL1β ligates with Domain 1. Strong evidence suggests that radicals for the management of chronic inflammation. and tumor (19–21). Kao et al. etc. IL1β is a by currently available techniques. Kao et al. 2. an enhanced half-life circulation time. the natural antagonist for IL1β. hydride) bound to the warfarin site of albumin and showed chitecture and multifunctional properties of biological sys. and tism. (21) and continued by Ohse be converted to agonists by coupling a strong electrostatic and Nagaoka. a poly- the oxygen radical detoxification process. physical. based on the functional architecture of IL1β and IL1ra. mimetic materials. ing the spatial interrelationship between each residue. chemical.. whereas. molecular atoms. while the SOD ac- tems are utilized as foundations in the investigation of bio. the mo.4.1 pH roscale in order to attain a combination of required proper. tween the peptide macromolecule and Domains 1. This approach continues to this day. interleukin-1 (IL1). poly-lysine) to the terminal amino acid of the ous metalloporphyrins and poly(styrene-co-maleic anhy. In vivo studies demonstrated that the chimera con- ties (i. the fundamentals of the a family of active proteins.37–39). in vitro. availability and high immunogenicity. biological.1 ⫻ 10 6 /M/s at 8. utilized to link each amino acid at all possible orientations.and macroar.36). the intricate micro. structural. These residues are R (4) Of particular interest to biomedicine is the investigation on L(6) F (46) I (56) K (103) E (105) of IL1β and W (17) Q (21) Y (35) Q (37) superoxide dismutase (SOD) enzymes to catalyze oxygen Y (148) of IL1ra (35.. organs. Based on the measurement. bioactive molecules have been synthesized by studying the Antagonists were designed from known IL1β and IL1ra native functional structure and natural synthesis pathways amino acid residues showing strong avidity toward Do- of model molecules. BIOFUNCTIONAL MOLECULAR binds with Domain 1 and 2 of IL1RI. these amino acids are essential in ligand–receptor interac- cessive oxidative metabolism. main 1 and 2 of IL1RI (35. Both strategies phages (a primary class of phagocytic leukocytes) may re- embody the principle and the dynamic nature of biomime. Kao et al. IL1β-activated macro- applied to develop novel materials (32). . i. antagonist sequence. and macroorganisms (32). tivity was retained.

The trimeric glycine linker was the presence of autologous serum in the culture medium. Antagonists included those modeled after tured thereafter in the presence of autologous serum and the IL1β molecule: (IL1iant) RGGLGGFGGIGKGGEG. those modeled after the IL1ra GM-CSF release by adherent macrophages were observed molecule: (IL1ivant) WGGGQGGYGGQGGGYG and among all test samples and controls. IL1β-treated adherent macrophages on after antagonists developed via combinatorial chemistry tissue-culture polystyrene (TCPS) showed a higher GM- (40): (IL1viant) YWQPYALPL. At 18 h after the free (IL1vant) WGGYGGQGGYGGQG. a library of linear oli. with or without recombinant human IL1β or IL1ra at 25 resin methods with standard 9-fluorenylmethyloxycarbo. Ad- modeled after the IL1β molecule: (IL1i) KKKGGGRGGL herent macrophages treated with agonist IL1v showed a GGFGGIGKGGEG. Peptides thus formulated were desig. supernatants were collected at various time points for (IL1iiant) FGRGGLGGGIGKGGEG. pmol/mL. At 4 h after the peptide challenge.1 Structure of poly(styrene-co-maleic anhydride)–co-metalloporphyrin derivatives with superoxide dismutase activity. Inc. The GM-CSF GGGYWQPYALPL and (IL1vii) YWQPYALPLGGGK level of cells treated with IL1v remained comparable when KK. 33. and those modeled after antagonists gests that IL1v activates these gene expression factors re- developed via combinatorial chemistry (40): (IL1vi) KKK sulting in an increased GM-CSF production.) the poly-lysine domain. IL1ra. designed to introduce spatial flexibility between the poly. (Adopted from Ref. and (IL1iiiant) assay. It is known that IL1β upregulates those modeled after the IL1ra molecule: (IL1iv) KKKGGG GM-CSF release by human macrophages via the induction WGGGQGGYGGQGGGYG and (IL1v) KKKGGGWGG of AP-1 and NFκB gene expression factors. none. Figure 2. and that modeled peptide challenge. After 2 h. no differences in LGGRGFGGIGKGGEG. 2a). and other agonists. Human blood monocyte–derived macrophages were IL1ra was added simultaneously as the IL1v peptide indi- allowed to adhere on tissue culture polystyrene for 2 h in cating that the effect of IL1v in increasing GM-CSF release Copyright © 2002 Marcel Dekker. (IL1ii) KKKGGGFGRGGLGGGIG higher GM-CSF release than that treated with IL1β. Consequently. Cells were cul- nated as follows. and (IL1iii) KKKGGGLGGRGFGGIGKGGEG. . Simultaneously. The result sug- YGGQGGYGGQG. Peptides with scrambled amino acid sequences nyl chemistry (41). nonadherent cells were removed and adherent lysine sequence and the antagonist oligopeptide domain cells were challenged with free peptides at an optimal con- since chain mobility may impact the dynamics of ligand– centration of 50 pmol/mL that had been determined previ- receptor association. were also employed as peptide controls. adherent cells were also challenged gopeptides were formulated and synthesized using solid. KGGEG. Agonists included those CSF release than controls without treatment (Fig. ously.

95 were found among each test group indi. utilized known protease substrate pep- nificant differences in the GM-CSF release were observed tides (i.. low bioavailability. whereas. These two examples illustrate the uniqueness of a biomi- metic approach to develop synthetic molecules derived from naturally occurring precursors such as SOD and IL1 family proteins. sequence LGPA from collagenase. IL1vi. deleterious side ef- fects of the high dosage that is often required. However. namely. IL1-derived agonists have demonstrated potential in increasing hematopoietic stem cell proliferation. IL1-derived agonists and antagonists are currently under extensive investigation by pharmaceutical compa- nies and basic science research laboratories to improve the therapeutic value of native IL1β and IL1ra moieties (42– 44). 2b). the clinical value of these regimens has yet to be demonstrated due to high cost. antagonists.e. No sig. ample. approach to develop novel biomaterials containing biologi- nists derived from IL1-family proteins with or without recombi.05 versus values of ‘‘none’’ lular behavior in a variety of physiological systems such control. IL1β augments hematopoiesis and increases wound healing. IL1-derived an- tagonists have shown promise in decreasing the extent of acute and chronic inflammation in diseases such as rheu- matoid arthritis. engineered devices and novel therapeutic biomedical prod- ucts. the knowledge is necessary for the construction of tissue n ⫽ 4. and the pres- ence of natural agonists. These biomimetic molecules demonstrate enhanced biochemical and physical properties that can be employed to study biological systems and potentially im- prove clinical medicine. and modulating bone resorption by osteoclasts. cally derived functional moieties to modulate specific cel- nant human IL1β (* represents p ⬍ 0. West et al.05 versus values of ‘‘none’’ control. The overall differences at p ⬎ 0. For example. III. # represents p ⬍ 0. IL1ii. The BAB Copyright © 2002 Marcel Dekker.2 The release of GM-CSF by adherent human blood- derived macrophages (normalized to adherent macrophage den. IL1ra attenuates host inflammatory reaction.05 versus values of IL1β control. polyethyleneglycol–peptide) block copolymers.. suppressing chronic leukemia.e. Currently. orthopedic. or sequence NRV from plasmin) co- with both IL1β and one of the antagonists (Fig. Recombinant IL1β and IL1ra proteins have been investigated for their potential therapeutic values. NOVEL POLYMERIC MATERIALS sity) on tissue-culture polystyrene after 18 h incubated with (a) CONTAINING PEPTIDE/PROTEIN biomimetic agonists derived from IL1-family proteins with or BIOMIMETICS without recombinant human IL1ra (* represents p ⬍ 0. Hubbell and West have focused on the study and de- velopment of enzymatically degradable hydrogels that are by adherent macrophages was not neutralized in the pres. IL1ra. All values mean ⫾ s. Inc. These polymerized with polyethyleneglycols using dicyclohexyl- results indicate that the IL1-derived biomimetic antago.46). several laboratories have taken the biomimetic IL1iii. and modulating collagenase production. # represents p ⬍ 0.05). For ex- ence of the natural IL1β antagonist. neutralized by the presence of IL1β).05 versus values of IL1β control.m. or (b) biomimetic antago. and serum proteases. and IL1vii at p ⬍ 0. goal of these investigations is to obtain fundamental under- cating that the GM-CSF release mediated by antagonists was not standing of the complex biological–material interaction. no as cardiovascular. sequence between macrophages without treatment and those treated AAA from elastase. carbodiimide-based chemistry to formulate BAB (peptide– nists neutralized the ability of IL1β in increasing the re. IL1v values were larger than that of IL1i. treating septic shock. lease of GM-CSF by adherent macrophages. . and nervous. enhancing local wound healing. responsive to the local host environment (45. Hence. Figure 2. increas- ing B cell proliferation.

to provide bioactive sites for cell adhesion. Several macrophage-derived cy- (peptide–polyethyleneglycol–peptide)-containing hydro. tumor narcosis factor α are administered to patients suffer- glycol–peptide–polyethyleneglycol)-containing hydrogel ing from chronic inflammation in order to enhance the network grafted with the RGDs cell adhesion mediating wound healing process and attenuate inflammation (44). process. function. and structure of anti– increasing treatment time.7. Hence. jured patients and bone marrow transplant recipients to as- dation. growth regulation.4. a variety of cytokines.3. and fi- of the function–structure relationship between target pro. sist the recovery of hematopoiesis (42–44). tinucleated foreign body giant cells (FBGC) is unique to col–peptide–polyethyleneglycol) block copolymers were the macrophage phenotype. Some of the current biomate- foreign objects such as microorganisms and biomaterials rial development and research utilize the RGD sequence (1).5. Hydrogel networks were formulated via tion remain unclear. agents has yet to be demonstrated. apparent that such a design strategy to elicit a specific cel- phages recognize adsorbed proteins on the foreign surface lular function is limited by the redundancies that exist be- via several ligand–receptor superfamilies (4). Since the polymer construct degrades enzymati. and receptors on the cell surface must be obtained. Foreign body giant col–N-hydroxysuccinimide monoacrylate.v) β 1 and α v β (1. and the host foreign body reaction. to investigate and to partly control the biomolecular via biomaterials can be realized. Similar ibility. These bioresponsive materials allow the cesses of tissue healing. agents to modulate the function of other cell types in the initiator in 1-vinyl-2-pyrrolidone (47). When the ABA (polyethylene. For instance. Hydrogels were found to degrade in a protease. a clear understanding matrix proteins such as fibronectin. Macro.8) . Several cell membrane receptors on different teins and cell membrane receptors is crucial. . However. types of cells have been shown to complex with the RGD the ultimate challenge of eliciting specific cellular function cell adhesion motif of these matrix proteins. Furthermore. Inc. which might overcome the sequence of fibrinogen. The major function of blood-derived bronectin. the long-term clinical efficacy of treatments in- were found to adhere and migrate throughout the hydrogel volving the systemic administration of these bioactive matrix. motif was cultured with human dermal fibroblasts. target proteins must also be addressed. and 2-2-dimethoxy-2-phenyl acetophenone photo. For example. Pharmaceutics specific and dose-dependent fashion that increased with based on the property. the delivery of selected cytokines and growth factors produced degradation path within the hydrogel can be controlled by endogenous inflammatory cells is desirable and may spatially and temporally by varying the hydrogel chemical have potential therapeutic value in the fundamental pro- composition.8. or plasmin at various concen. type IV collagenase. triethanol. Copyright © 2002 Marcel Dekker. a more detailed under- mechanism of neurite extension and migration within a standing of the interplay between material-bound ligands similar polyethyleneglycol-containing. Other integrin receptors on a variety of cell phagocytic monocytes and macrophages is to mediate the types that recognize the RGD cell binding motif are normal host immune and inflammatory response against α (2. The process tween receptors and target proteins. growth factors. copolymers were reacted with acryloyl chloride to provide of adherent macrophage activation and fusion to form mul- photopolymerizable end groups. by utilizing biofunctional materials lies within the normal platelet surface glycoprotein IIb/IIIa recognizes the RGD host foreign body response. and the rate of material degradation underneath the giant eneglycol–N-hydroxysuccinimide monoacrylate and were cells has been shown to be markedly increased (50). and biocompat- study of cell migration mechanisms and function.5. methodologies are currently been utilized by Hubbell et Before the ability to control specific cellular function al.49).3. For example. tors on macrophages also recognize the RGD motif of fi- late cellular function. the redundancies that exist between receptors and peptides (48. to alter the inflammatory response and promote the healing porcine pancreatic elastase. Activated macrophages may release photopolymerization with block copolymers. ever. cells However. After the BAB inflammatory milieu (1). the molecular mechanisms involved in FBGC forma- drogel network.6. The presence of FBGCs is uti- formed by reacting the peptide with two amine groups such lized as a histopathology marker for chronic inflammation as lysine residues at the C terminus with polyethylenegly. Cell adhesive cells have been demonstrated on implanted biomaterials peptides such as RGDs were also reacted with polyethyl. Several characteristic macrophage functions are identi. ABA (polyethylenegly. Further- drogel system immobilized with enzymatically degradable more. IL1β and GM-CSF are given to in- trations was added to the hydrogel to commence degra. and other bioactive amine. vitronectin. How- subsequently grafted into the photopolymerized ABA hy. tokines and growth factors are utilized on a limited basis gels were hydrated to equilibrium. and integrin α 5β 1 and α IIb β 3 recep- bioactive functionalities in the material intended to modu. the localized cally in the presence of a specific enzyme substrate. brinogen. the In the development of biofunctional materials by mim. bioresponsive hy. tripeptide RGD sequence is found in several extracellular icking ligand–receptor interactions. it is fied as critical events in the foreign body response.

the improvement of clinical biomaterials. a hexamer of glycine (G 6 ) of approximately the mechanism of receptor–ligand recognition and postliga.59). 4) and the sequence PRRARV of the C termi- forces is critical for the development of biomimetic materi. G 3 PHSRNG 6 R GDG. respectively. designed methodologies to probe the molecular surement.4 Amino acid sequences PHSRN and RGD (in ball- lation of cellular function is vital for the future of tissue. engineered products. Kao in both possible orientations. PRRARV resides also binds directly with integrin recep- nologies and know-how are vital for the future of tissue tors (58.61) was used as a guide in the design of Several methodologies were utilized to examine the in. The follow- ing oligopeptides were synthesized: G 3 RGDG. nal heparin binding domain of fibronectin (53) were cho- als with specific cellular activity in the new field of cellular sen for exploration. and various physiological parameters such as mechani- cal forces. Specifically. 3). Figure 2. The network had been shown to medi- ate low levels (⬍30 cells/mm 2 ) of adhesion by human macrophages. Inc. arin binding domain of fibronectin in which the sequence ment of novel enabling technologies. The tertiary structure of rials. A clear elucidation of the mechanism involved in the (55) and RGD (56). peptides that included RGD and PHSRN. and FIII-10 modules. were synthesized using solid-resin methods with standard tin (53. LNQEQVSPD is a leader sequence and the cyclical RGDGRN sequence has been shown to bind with α v β 3 in- tegrin with high specificity and affinity (62). A terminal trimeric glycine domain (G 3 ) tion (52).3 Current research focuses on elucidating the complex mechanisms in the interaction among cells. Oligopeptides primary and tertiary structures of human plasma fibronec. materials. designed and employed biomimetic oligopeptides to PRRARV was studied using a G 6 linker. The hep- level between cells and material surfaces in the develop. G 3 RGDG 6 PRRARVG. Based on the mea- et al.’’ Manipu. A cyclic RGD peptide with an amino acid sequence of LNQEQVSPD(cRGDGRN) was utilized for comparison. G 3 RGDG 6 PHSRNG. Macrophage ad- Figure 2. however. The author acknowledges the critical cent loops of two connecting FIII modules and bind role of this type of fundamental research at the molecular synergistically to the same integrin receptor (57).52). the precise mechanisms involved in engineered products. the improvement of clinical biomate. of the central cell-binding domain of human plasma and the pursuit of novel biofunctional materials. materials. The resulting tech. and trimethylolpropane- triacrylate (51. In one of the studies. Synthetic peptides were formulated based on the was employed as a spacer in all peptides. and G 3 PRRARVG 6 RGDG. and human umbilical vein endothelial cells in serum- containing culture medium up to 10 days. which are located in the FIII-9 and the interaction among cells. G 3 PRRARVG. acrylic acid.. this association remain unclear.54). and the construction of biofunctional materials. fibronectin. considerations. tween these sequences was approximated using the struc- havior at protein and cellular levels under in vitro and in tural coordinates archived in the SwissProt Database vivo environments (1–10). The distance be- terrelationship between material chemistry and cellular be. although in this probe the effect of primary and tertiary structures of a case the G 6 linker was not selected based on any structural model protein (i. proteins/enzymes. proteins/enzymes. human neonatal foreskin dermal fibroblasts. G 3 PHSR NG. same length was used to link the two bioactive sequences tion cellular function (51. and-stick model) located in the FIII-9 and the FIII-10 modules. RGD and PHSRN are present on adja- engineering (Fig. respectively. fibronectin (60.52). Kao (sequence FINC HUMAN P02751). . Copyright © 2002 Marcel Dekker. The combination of RGD and et al. Peptides were immobilized onto a polymer network terpolymerized with polyethyleneglycol. Fundamental research at the molecular level results in the development of novel ‘‘enabling technologies’’ that are criti- cal for the development of biomimetic materials with specific cel- lular activity in the new field of ‘‘cellular engineering. Based on these findings. fibronectin) in ligand–receptor interac. the amino acid sequences PHSRN 9-fluorenylmethyloxycarbonyl chemistry (41). of the central cell binding various physiological parameters such as mechanical domain (Fig.e.

α 4 .b known that the first 160 amino acids of integrin β 1 . spe- LNQEQVSPD(cRGDGRN) 290 ⫾ 83 a. or combinations thereof (Table in the presence of serum proteins (Table 2) (52).b 121 ⫾ 70 a β 3 reduced FBGC formation by about 70%. HSRNG. but not G 3 RGDG 6 P Note: All values ⫻10 macrophage/mm 2.05) versus tissue-culture FBGC formation. size) of FBGC formation on control a Values comparable ( p ⬎ 0. mean ⫾ s. namely G 3 PHSRNG 6 RGDG. Activated integrin β 1 or β 3 intracellular polystyrene controls. PHSRN. Each adherent cell with three or G 3 PHSRNG 6 RGDG 88 ⫾ 38 a 32 ⫾ 13 more nuclei per cell was defined as a FBGC. adhered to all peptide-grafted polymer networks with rela- tively subtle differences between adhesion mediated by RGD. Inc. (52) found Tissue-culture polystyrene 60 ⫾ 20 162 ⫾ 38 that serum fibronectin modulated macrophage adhesion Note: All values expressed in mean ⫾ s. Kao et al.b 88 ⫾ 30 a G 3 PRRARVG 6 RGDG 151 ⫾ 24 a.1 Adherent Macrophage Density on Polymer no antibody– and anti-β 3 neutralizing antibody–treated Networks Grafted with Fibronectin-Derived Biomimetic groups had a comparable FBGC density on TCPS (Table Peptides 3). hesion and FBGC formation in vitro assays (63) were per. G 3 PRRARVG 6 RGDG 17 ⫾ 9 19 ⫾ 7 tralizing antibodies were performed to ascertain ligand– LNQEQVSPD(cRGDGRN) 20 ⫾ 11 18 ⫾ 5 receptor specificity and identification.b 121 ⫾ 48 a neutralizing antibody was utilized. results in the necessary binding characteristic a Value different at 95% confidence level (p ⬍ 0.95) versus that of tissue-culture polystyrene surfaces in the presence of serum proteins. Under the FBGC culture condition described.m. PRRARV alone or in tandem specific manner. Macrophages controls. also utilized for confirmation. n ⫽ 3 to 5. Size on Polymer Networks Grafted with Fibronectin-Derived FBGCs containing up to 50 nuclei/cell formed consistently Biomimetic Peptides at 240 h of the FBGC Assay on tissue-culture polystyrene control surfaces. no FBGC formation G 3 RGDG 6 PHSRNG 271 ⫾ 28 a. domains stimulate cell migration. that determine the subsequent cellular event leading to b Value different at 95% confidence level ( p ⬍ 0.05) versus no grafted peptide controls. Antibody isotype negative controls were provided a substrate for FBGC formation that was statisti. are No grafted peptides 69 ⫾ 37 b 24 ⫾ 14 b critical in integrin–ligand recognition.e.b 97 ⫾ 29 a express α 2 . This re- 1) (52).. RGD or utilized in the FBGC culture assay to partly determine the PHSRN alone did not provide an adequate substrate for role of integrins and fibronectin-derived oligopeptides in macrophage fusion to form FBGCs.2 Macrophage-Derived FBGC Adherent Density and formed. and the extent (i. One notable exception was the peptide that contains Peptide 24 168 the PHSRN and the RGD domain in the optimal orienta- G 3 RGDG 378 ⫾ 59 a 155 ⫾ 83 a tion. n ⫽ 3 to 6. Furthermore. Table 2. with RGD in a single peptide formulation did not support portant. Briefly. β 1 integrin subunit was essential in macrophage sponse was highly dependent upon the relative orientation adhesion to peptide-grafted networks in a receptor–peptide between RGD and PHSRN. Average FBGC freshly isolated human blood-derived monocytes were in. neutralizing antibody was primarily by the direct interaction with integrins. PRRARV.e. the PHSRN modulating the function of adherent macrophages to fuse synergistic site and the RGD site in a single oligopeptide and form FBGCs.. These findings sug- Tissue-culture polystyrene 400 ⫾ 49 a 131 ⫾ 22 a gest that the association between this region of the integrin β 1 receptor and G 3 PHSRNG 6 RGDG. on which anti–integrin G 3 PHSRNG 243 ⫾ 30 a.b 220 ⫾ 140 a cifically the α-helix formed by residues 141 to 160. At 96 and 168 h. . When anti-β 1 G 3 PRRARVG 304 ⫾ 46 a. Peptide FBGC/mm 2 Size (⫻100 µm 2 ) cubated with samples in RPMI containing 20% autologous serum. It is also G 3 RGDG 6 PRRARVG 311 ⫾ 39 a.m.e.b 92 ⫾ 25 a was observed on any sample. whereas. and β 3 integrin subunits. β 1 . β 3 integrin subunit was less im. Competitive G 3 RGDG 6 PRRARVG 14 ⫾ 7 20 ⫾ 8 inhibition studies utilizing soluble free peptides and neu. no FBGC for- Culture time (h) mation was observed in the anti-β 3 antibody–treated group. Both integrin β 3 and β 1 sub- cally comparable to that on the positive control material units were found to play an importance role in mediating FBGC formation by macrophages adhered on peptide- grafted networks (Table 3) (52). modulate proliferation Copyright © 2002 Marcel Dekker. However. Macrophage adhesion to PRRARV was mediated FBGC formation. the medium was changed to RPMI G 3 RGDG 18 ⫾ 9 21 ⫾ 8 G 3 PHSRNG 14 ⫾ 9 27 ⫾ 9 with heat-inactivated autologous serum ⫹ 10 ng/mL of G 3 PRRARVG 15 ⫾ 9 17 ⫾ 4 recombinant human interleukin-4 ⫹ 5 ng/mL of recombi- G 3 RGDG 6 PHSRNG 16 ⫾ 7 19 ⫾ 5 nant human GM-CSF. Results showed that Table 2. Macrophages and FBGCs G 3 PHSRNG 6 RGDG 309 ⫾ 34 a.b 62 ⫾ 24 a. On most of the peptide-grafted network..

the promotion of protein serine/threo- inhibitor PSI. Cells treated with anti-integrin antibody. 48. fibrinogen. which in. . purified IgG isotype ascite) or anti–human integrin β 3 (25E11. tracellular matrix proteins.m. Inc. orientation between the peptide sequences in modulating and bovine serum albumin was employed as controls for macrophage and FBGC behavior was investigated. and NFκB 48 h.3 Macrophage-Derived FBGC Adherent Density on Polymer Networks Grafted with Fibronectin-Derived Peptides at 240 h of FBGC Culture No antibody Anti-integrin Anti-integrin Peptides treatment a β 3 treatment β 1 treatment G 3 RGDG 18 ⫾ 9 0 ⫾ 0 0 ⫾ 0 G 3 PHSRNG 14 ⫾ 9 0 ⫾ 0 0 ⫾ 0 G 3 PRRARVG 15 ⫾ 9 0 ⫾ 0 0 ⫾ 0 G 3 RGDG 6 PHSRNG 16 ⫾ 7 0 ⫾ 0 0 ⫾ 0 G 3 PHSRNG 6 RGDG 88 ⫾ 38 30 ⫾ 30 0 ⫾ 0 G 3 RGDG 6 PRRARVG 14 ⫾ 7 0 ⫾ 0 0 ⫾ 0 G 3 PRRARVG 6 RGDG 17 ⫾ 9 0 ⫾ 0 0 ⫾ 0 LNQEQVSPD(cRGDGRN) 20 ⫾ 11 0 ⫾ 0 0 ⫾ 0 Tissue-culture polystyrene 60 ⫾ 20 90 ⫾ 30 0 ⫾ 0 Notes: All values expressed in FBGC/mm 2. Treated cells were incubated the control of cellular behavior remains unclear. Surfaces without preadsorption nor im- association in modulating cellular function. and specifically protein kinase-C. such as fibronectin. or vitronectin. panetriacrylate. Furthermore. protein kinase-A inhibitor 14. macrophage adhe- eral concentrations to screen candidate signaling cascades sion was found to be independent of protein tyrosine ki- in regulating macrophage behavior mediated by fibronec. From cell adhesion assays. lavendustin A. except that on surfaces grafted with G 3 PHSRNG signaling and transcriptional events and the corresponding and G 3 PHSRNG 6 RGDG where cell adhesion was depen- inhibitor chosen for exploration included activated protein dent upon protein serine/threonine kinases at 48 h (Table tyrosine kinases inhibitor AG82. Freshly fibronectin and peptides.. purified IgG2a isotype ascite) neutralizing antibody at 60 µg/mL] was added to the culture at 96 and 168 h of the FBGC assay.05) than that of tissue-culture polystyrene and networks grafted with G 6 PHSRNG 6 RGDG. the exact interrela. results showed the following. derived biomimetic oligopeptides containing RGD and/or acteristic and signaling pathways of fibronectin–integrin PHSRN domains. Tissue-culture polystyrene. PCK inhibitor serine/threonine kinases but not protein kinase-A at 24 and EGF-R fragment. with fibronectin-derived oligopeptides. Table 2. the key role played by RGD. and tin and fibronectin-derived biomimetic oligopeptides. On networks immobilized bated with inhibitors of various signaling molecules at sev. the isolated human blood-derived monocytes were preincu. eneglycol-based networks were preadsorbed or immobi- utilized the aforementioned biomimetic fibronectin. however. PI-3K inhibitor wortmannin. nases and protein serine/threonine kinases at 24. MAPK inhibitor PD98059. mobilization were employed as negative surface controls. and gene expression. n ⫽ 3 to 6. acrylic acid.and polyethyl- ing macrophage adhesion and FBGC formation. The 120 h. a All values were significantly lower ( p ⬍ 0. lized with recombinant human fibronectin or fibronectin- derived oligopeptides to probe the structure–function char. For example. Specifically. On networks immobilized with fibronectin or albumin. macrophage adhesion was found to be dependent of pro- nine kinases inhibitor H-7.e. activated protein serine/threo. compen- Copyright © 2002 Marcel Dekker. leading to macrophage adhesion and focal tion in activating intracellular signaling events resulting in adhesion kinase formation. tein tyrosine kinases but not Src and dependent of protein 22 amide. induce the assembly of F-actin cy. Activated integrin receptors have been nine kinases. hibits Src-family kinases. and the spacing and Inhibitor vehicle was also utilized as additional controls. 4). Kao et al. with tissue-culture polystyrene or networks terpolymerized To yield insights into the mechanisms coordinated by with polyethyleneglycols. and localize the activity of focal adhesion ki. These cellular events may contribute to the Src is involved in integrin signaling upon ligation with ex- process of FBGC formation. shown to upregulate these selected signaling molecules un- toskeleton. mean ⫾ s. nase pp125 FAK. PHSRN. neu- tralizing antibody [anti–human integrin β 1 (JB1a. tionship between ligand–receptor architecture and associa. To determine the role of integrins in mediating FBGC formation. der a variety of ligand–receptor associations. and trimethylolpro- the interaction between integrins and fibronectin in mediat.

these results support the that was immobilized onto networks or tissue-culture poly. tein serine/threonine kinases. FBGC formation was dependent of pro- sine and serine/threonine kinases at 120 h. that macrophage adhesion was independent of protein tein tyrosine kinases but not Src and dependent of protein kinase-A by 48 h and was independent of both protein tyro- serine/threonine kinases but not protein kinase-A at 24 h. On tissue. AG82 inhibits protein tyrosine kinases. by 48 h. a p ⬍ 0. Furthermore. pro- Table 2. FBGC specifically protein kinase-C. n ⫽ 3 to 6. styrene was found to be independent of protein tyrosine rophage adhesion at 24 h (Table 5). A. Macrophage adhesion sion at 24 and 48 h. macrophage adhesion on fibronec. rosine and serine/threonine kinases. On networks immobilized bumin was found to be independent of both protein tyro. specifically protein kinase- culture polystyrene immobilized with fibronectin. H7 inhibits protein serine/threonine kinases. and PMA promotes protein kinase-C of protein serine/threonine kinases. sine and serine/threonine kinases by 120 h. and culture polystyrene immobilized with fibronectin. Inc. However. Taken together. Cell the necessary signaling characteristic for macrophage ad- adhesion on fibronectin-immobilized tissue-culture poly. sated protein tyrosine kinases inhibition in mediating mac.1 versus respective values of controls. n ⫽ 3 to 6. nine kinases in integrin signalings leading to macrophage tin-immobilized tissue-culture polystyrene was found to be adhesion mediated by fibronectin–integrin association. demonstrated the following. These results indicate that the crosstalk on tissue-culture polystyrene immobilized with fibronectin between protein tyrosine and serine/threonine kinases is was independent of protein tyrosine and serine/threonine different between adherent macrophages on fibronectin kinases by 120 h. with fibronectin. role of activated protein tyrosine kinases and serine/threo- styrene. Furthermore. On tissue- The promotion of protein serine/threonine kinases. Copyright © 2002 Marcel Dekker. Assays for FBGC adhesion on networks immobilized with fibronectin or al.5 Macrophage Adhesion on Networks and TCPS Immobilized with Proteins in Vitro 2h 24 h Networks/TCPS Control AG82 H7 AG82 ⫹ H7 AG82 ⫹ PMA Control AG82 H7 AG82 ⫹ H7 G82 ⫹ PMA Fibronectin 16 ⫾ 5 10 ⫾ 7 a 8⫾5 a 5⫾0 a 2⫾1 a 11 ⫾ 5 4 ⫾ 2 3 ⫾ 1 a a 3 ⫾ 1a 5⫾1 TCPS 12 ⫾ 8 11 ⫾ 1 13 ⫾ 6 4⫾1 6⫾2 10 ⫾ 6 6 ⫾ 3 4 ⫾ 2 5 ⫾ 1a 8⫾3 TCPS ⫹ FN 14 ⫾ 6 9 ⫾ 3 11 ⫾ 2 3 ⫾ 1a 4 ⫾ 1a 12 ⫾ 4 7 ⫾ 2 a 6 ⫾ 4 4 ⫾ 0a 5 ⫾ 1a Note: All values expressed in macrophage ⫻100/mm 2. Tissue-culture polystyrene (TCPS). AG82 inhibits PTK and H7 inhibits PSK. hesion and the subsequent development. Specifically.4 Macrophage Adhesion on Polymer Networks and TCPS Immobilized with Proteins or Fibronectin-Derived Oligopeptides in Vitro 24 h 48 h 120 h Networks/TCPS Control AG82 H7 Control AG82 H7 Control AG82 H7 Fibronectin 11 ⫾ 5 4 ⫾ 2a 3 ⫾ 1a 5 ⫾ 3 1 ⫾ 1a 1 ⫾ 1a 8 ⫾ 6 2 ⫾ 0 2 ⫾ 0 Albumin 11 ⫾ 3 5 ⫾ 3a 4 ⫾ 1a 5 ⫾ 3 1 ⫾ 1a 2 ⫾ 1a 6 ⫾ 4 3 ⫾ 1 2 ⫾ 1 G 3 RGDG 6 ⫾ 3 3 ⫾ 1 2 ⫾ 0 3 ⫾ 2 2 ⫾ 1 1 ⫾ 0 7 ⫾ 6 2 ⫾ 2 1 ⫾ 0 G 3 PHSRNG 6 ⫾ 4 3 ⫾ 1 2 ⫾ 1 4 ⫾ 1 1 ⫾ 1 1 ⫾ 0a 7 ⫾ 5 3 ⫾ 0 1 ⫾ 1 G 3 RGDG 6 PHSRNG 5 ⫾ 3 2 ⫾ 1 2 ⫾ 1 6 ⫾ 2 2 ⫾ 1 2 ⫾ 1 5 ⫾ 2 1 ⫾ 1 1 ⫾ 1 G 3 PHSRNG 6 RGDG 6 ⫾ 5 3 ⫾ 1 2 ⫾ 1 3 ⫾ 1 2 ⫾ 1 1 ⫾ 1a 6 ⫾ 4 2 ⫾ 0 0 ⫾ 0 TCPS 10 ⫾ 6 6 ⫾ 3 4 ⫾ 2 7 ⫾ 3 5 ⫾ 3 3 ⫾ 2a 4 ⫾ 1 3 ⫾ 1a 1 ⫾ 1 TCPS ⫹ fibronectin 12 ⫾ 4 7 ⫾ 2a 6 ⫾ 4a 10 ⫾ 3 4 ⫾ 2a 4 ⫾ 3a 5 ⫾ 2 3 ⫾ 1 2 ⫾ 0 TCPS ⫹ albumin 8 ⫾ 4 7 ⫾ 4 5 ⫾ 2 11 ⫾ 4 3 ⫾ 2a 2 ⫾ 1a 5 ⫾ 1 3 ⫾ 2 1 ⫾ 0 Note: All values expressed in macrophage ⫻100/mm 2. macrophage and serine/threonine kinases by 120 h. RGD and PHSRN appears to be significant pendent of protein serine/threonine kinases. mean ⫾ sem. dependent of protein tyrosine kinases but not Src and de.1 versus respective values of controls. mean ⫾ sem. It should be noted macrophage adhesion was found to be dependent of pro. did not compensate protein formation was found to be independent of both protein ty- tyrosine kinases inhibition in mediating macrophage adhe. Table 2. . but was independent of Src (Table 6). specifically in mediating this receptor–ligand association resulting in protein kinase-C but not protein kinase-A. a p ⬍ 0.

Albumin. example. SUBCELLULAR BIOMIMETICS most importantly the RGD and PHSRN domains of fibro- nectin. A point of development of unique biomimetic enabling technologies note. Such topographical biomimetics can Healy et al. or extracellular matrices with high reso- tions. The cellular re. Lavendustin A inhibits Src of protein tyrosine kinases and PKI inhibits protein kinase-A of protein serine/ threonine kinases. molding. Kao et al. Inc. tion was then directed point by point and layer by layer Copyright © 2002 Marcel Dekker. Fabrica- applications. tation to direct protein crosslinking by 2-photon photoacti- Specifically. fibrinogen. utilization of macromolecules and proteins as templates to positional spacing between the motifs. For mechanistic correlation between the role of protein func. only α v β3 integrin receptors were chosen as model proteins for fabrication in solution. this submicron architecture may play an important ena provides future researchers with necessary tools in the role in mediating cell adhesion and function. whereas. dimensional nanoarchitecture of 100–500 nm features. duced by a mechanism where the photoactivator directly tially manipulate local host environment for biomedical abstracts hydrogen atoms from protein molecules. inkjet. How- with integrin receptors to upregulate tyrosine kinases and ever. These findings represent a cron and subcellular scales needs further elucidation. tein kinase-C of tyrosine kinases showed a significant role IV. Table 2.6 FBGC Formation on Networks and TCPS Immobilized with Fibronectin by 240 h of FBGC Assay in Vitro Networks/TCPS Control Lavendustin A PKI Fibronectin 39 ⫾ 16 21 ⫾ 4 26 ⫾ 17 a TCPS 25 ⫾ 18 23 ⫾ 15 23 ⫾ 16 TCPS ⫹ fibronectin 9⫾5 7⫾2 17 ⫾ 13 Note: All values expressed in FBGC/mm 2. The resulting polymer network containing both RGD Goodman et al. a p ⬍ 0. Hence. that are vital for the advancement of cellular engineering Various three-dimensional fabrication methods such as and tissue engineered devices. utilized the inherent three-dimensional and FHRRIKA peptides mediated extensive adhesion. most cells are intimately associated with base- tional architectures in ligand–receptor recognition and the ment membrane matrices that have a complex three- postligation signaling events that control cellular behavior. governed cell adhesion at a longer culture time. the impact of biological organization at the submi- sion and FBGC formation.1 versus respective values of controls. serine/threonine kinases in mediating macrophage adhe. At the investigations illustrate the diversity and capability of a focal point of the lens where the photon density is suffi- biomimetic approach in the construction of biofunctional ciently high for 2-photon excitation. n ⫽ 3 to 6. and laser perforation have The incorporation of biospecific and biofunctional pep. α 2 β 1 and α v β 3 integrin receptors mediated the vation. 66). The cited Rose bengal was employed as the photoactivator. PROTEIN MATRIX AND in modulating FBGC formation mediated by fibronectin. biological systems are composed hierarchically. and mineralization of the extracellular matrix velop three-dimensional freeform fabrication of proteins by human osteoblast–like cells when compared to that of or synthetic polymers by conventional photochemically in- homogenous peptide surfaces and controls. cellular focal adhesion sites are about 250 nm in size. examples were given to illustrate the PHSRN domains of fibronectin. mean ⫾ sem. duced polymerization methods (70–73). crosslinking was in- materials to study fundamental cell biology and to poten. Similar to the strategy outlined above by Kao et al. and α v subunits in a temporally dependent manner. impregnation. be utilized in tandem with current clinically utilized mate- binding) peptides onto interpenetrating polymer networks rials or novel biofunctional materials as a part of the con- containing poly(acrylamide) and polyethyleneglycol (64– struction of fully biomimetic material constructs (67–69). . in the complexation develop biomimetic molecules and novel materials. been developed in an attempt to construct or reconstruct tides into polymeric networks has been adopted in other the unique topographical feature of protein layers. extracel- systems in the management of various pathological condi. showed the important role of RGD and In previous sections. lular membranes. and specifically the inter. confinement of nonlinear photo-optical processes to de- spreading. and alkaline phosphatase initial cell adhesion. A laser scanning sponse was found to rely on the participation of integrin confocal microscope was modified for near-infrared exci- α 2 . β 1 . grafted RGD and FHRRIKA (putative heparin. lution and accuracy. The fundamental understanding of these complex phenom.. hence.

complex systems are controlled by the structure and chem- ever.74–76). three dimensions are some of the existing technological sues. Furthermore. and or- methodologies to obtain a wide range of polymers. multilayer microstructure of biological systems to produce self-assembled amphiphilic structures. dered macroscopic growth. Inc. and inability to direct crystal growth in such as cellular membranes. mimetic materials. metal alloys. Features of less a hierarchical manner from the molecular to the centimeter than 200 nm. local ordering. Nanoparticles about 50 nm in diame- organizations in biological systems. Many incremental units are ics. or biologically derived materials with a packaged together to form unique composites (76). The process produces spe- been focused on the utilization of a myriad of synthetic cific minerals with defined crystal size. phase separation of chemical and/or biomineralization. current composite materials lack the com- thesized by varying the type of lenses. macromolecules. scale. comprise fibrous organic components embedded in a purification process through the accumulation of heavy soft organic matrix that are analogous to fiber. Biomineralization occurs within specific subunit compart- Currently. were syn. For example. function relationships and the construction of complex bio- ples illustrate the feasibility of mimicking the complex hi.or particle. within the solution and proceeded to achieve a desired. How. crete unit (i. self-assembled monolayer films.e. polydispersive molecular weight of eral. synthetic methodologies often result in heterogeneity istry of the interfaces between the organic substrate. erarchical structure of biological systems that expands Due to the specificity of biological synthesis pathways from the nano scale to subcellular levels in the study and such as biomineralization systems and protein and nucleic the partial control of biological functions. to synthesize calcium phosphate nanoparticles of a precise By studying the complex interrelationship of structural size distribution (84). These exam. molecules. These diverse physicochemical bulk and surface property. Furthermore. load-baring tissues such as ten. or tis. For example. biomaterial development and synthesis have ments or microenvironments. orientation. tissues.. is one important step in understanding basic structure– zyme linked fluorescence imaging in vitro. One exciting area synthesis and processing techniques to enhance the limita. microbiological and other biological tech- niques are currently being adopted and utilized in the con- struction and processing of novel biomimetic materials (77–83). micron and submicron structures fabri. The understanding of the strates fabricated from the native albumin molecule in structural organization and relationship between each dis- vitro. Several researchers are developing novel material hurdles that have yet to be overcome. The presence of proteins such as osteo- polymers. ter with a uniformed crystal size and structure were synthe- ers such as Baer and Hiltner pioneered the development sized on the extracellular membrane of bacteria of the Ci- of complex organic and inorganic composites that incorpo. metal ions as cell-bound insoluble metal phosphates. synthesized by mimicking biomineralization systems in- cation methods cannot incorporate or mimic the complex clude monolayer films. current synthetic fabri. extracellular matrices. BIOMIMETIC-DERIVED MATERIAL biosystems leads to several guiding principles that have PROCESSING METHODS significant implications for biology and materials sciences. biomaterial research. Clearly. of research attempts to utilize microorganisms as a mean tion of conventional synthesis and fabrication procedures. . that tendon has six discrete levels of structure organized in predetermined geometry and topography. and the lines were ten.. different levels of organization. com- biological functional assays. and supramolecular materials containing controlled microarchitecture and templates (76). elucidated nature of the phosphate formed depends on the type of Copyright © 2002 Marcel Dekker. low stability. demonstrated posite material research has focused on elucidating the that human platelets extensively adhered to lines fabricated microstructure–property correlation that includes the cou- from fibrinogen molecules in vitro. pling between the properties of an individual organic and fold narrower than the diameter of a platelet cell body. and medium. Baer et al. cated from alkaline phosphatase molecules demonstrated or extracellular matrix) that makes up a biological system a high level of enzymatic activity when assayed with en. acid syntheses. trobacter genus in the presence of calcium and phosphate rated some of the ordered microstructure found in nature ions. The bioactivity of plexity and sophistication necessary to achieve highly or- model proteins was maintained as determined by various dered and multileveled hierarchical structure. cells. large range of size distributions of polymer and pontin and catalysts is also critical for the control of ceramic particulates.e. phosphatase enzymes and has been utilized in the water don. The Citrobacter genus contains membrane-bound (32. The reinforced polymeric composites. However. min- and anisotropy (i. Some examples of novel biomaterials physical properties). analysis of a variety of mineralizing V. lack of control over multifunctional properties present in biological materials. Goodman et al. such as three-dimensional lattices. A inorganic component at various scales and in tandem at minimal level of platelet spreading was observed on sub. ceram. Hence.

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Today. unlike carbon. the practice of medicine had not seen cone is responsible for saving the lives of thousands of major changes for centuries. an elastic tube is PROPERTIES placed in the head of a child suffering from hydrocephalus in order to relieve the intracranial pressure caused by the Knowledge of the fundamental chemistry of the element excess of cerebrospinal fluid (CSF) in the cranial cavity. or intra-abdominal. Silicone has some unique chemical and physical cranial indwelling tubing is made of silicone. Since then bonds do not usually form.134). let us briefly review the chemistry and physical properties The first successful use of silicone in medical practice of silicone. silicone has made a major contribution. which implies low risk for interaction now used in many other surgical and nonsurgical proce- with the cells and chemicals in the body. tions for silicone in medical and pharmaceutical practice. intratho. still used sutures processed from the intestinal birth). Heggers University of Texas Medical Branch. In other words. Hydro- the mid-20th century. Nulsen and E. Spitz were cooperating with scientists from Dow Corning to develop a tube to be used in a hydrocephalic II. cone for medical applications. sili- Until the early 1950s. which can be either intravenous. It was these properties that in. Si is capable of forming four bonds and is known elastomeric. cephalic shunt is not the only procedure where the use of which proved to be one of the major inventions of the cen. carbon. flexible. all intra- tury. B. Before we go into the details of the different applica- spired scientists and physicians to consider the use of sili. El-Zaim and John P. E. It sustains high dures. also Copyright © 2002 Marcel Dekker. The tube had to be soft. Galveston. Around who otherwise would become mentally retarded. . health and how it can be responsible for disease. Silicon dioxide (SiO2). and its use extends to a variety of medical instru- temperature. for children borne with this birth defect (1 in 400–600 live example. Texas I. silicon (Si) and understanding how Si can be integrated in The shunt allows excess CSF to flow in one direction to biosystems are essential to understanding the role of Si in the drainage site. Inc. which suggests that silicone-based products ments and indwelling medical devices. Eugene Rochow invented silicone. Just like racic. stable Si—Si that was successfully used in the procedure. In this procedure. Before that time surgeons. as well as improving the quality of life of survivors walls of sheep or cows to sew wounds together. 3 Silicones for Pharmaceutical and Biomedical Applications Haissam S. It is inert. came about in 1956. At that time Doctors F. CHEMICAL AND PHYSICAL shunt procedure (68). All for its ability to polymerize and form network covalent of these requirements were met by the silicone elastomer structures (9. Silicone is properties. INTRODUCTION thousands of hydrocephalic shunt procedures have been performed using silicone elastomer. could be easily sterilized. and biocompatible with the human body. However.

63b. 1). they are compounds loxane groups. Poly- crust and is the natural source of Si used in manufacturing merization usually yields a mixture of silanol oligomers silicone. and can be molded ity of the molecules to slip past one another.) Figure 3. This process results in a fluid polysiloxane often termed an anes. Silicone is simply a generic term that refers to siloxane The polysiloxanes then are ‘‘capped’’ by trimethylsi- polymers (polysiloxanes). 63b. Further reaction with water yields called silica. The viscosity of the oil is a pri- stable under physiologic conditions. where atoms of silicon are is first accomplished by condensing two molecules of tri- linked together by oxygen in a fashion analogous to the methylchlorosilane to hexamethyldisiloxane via the addi- ether linkage of carbons by oxygen (36.1 The chemical structure of polydimethylsiloxane. and pensile from the Si molecule. . Figure 3. the relatively stable Si—O bond is further stabilized ‘‘oil. (From Ref. these compounds have widespread by substitution of alkyl groups as the two side chain groups industrial and consumer uses as dielectric fluids. the most common core structure of medical utility Polydimethylsiloxane.2 Chemical reaction depicting the formation of dimethylsiloxane from dimethyldichlorosilane in the presence of water. but also of the abil- with a variety of physical properties. which has a specific gravity is polydimethylsiloxane (PDMS) (Fig. is the most abundant mineral in the earth’s silanolsdimethylsiloxanes with terminal hydroxyls. 2 and 3). 63b. is the most commonly used fluid These highly hydrophobic compounds are chemically in medical practice (133). coatings. (From Ref. can be synthesized mary function of its molecular weight.48. a process termed equilibration (50). 4) and then reacting hexamethyldisilox- Si bond is correctly termed a siloxane bond and thus the ane with ailanol oligomers to produce silicones (Fig.) Figure 3.3 Generation of silanols with terminal hydroxyl groups from dimethylsiloxane with water. Originally this structure was also be conducted using other alkyl or aromatic side chain– Figure 3.’’ Consequently.89). Dialkylsiloxanes are prepared by the reaction of the methyl groups of silicones have little or no influence on dialkyldichlorosilane (generally dimethyldichlorosilane) this slippage. The pensile easily. (From Ref. thus the term silicone. Inc. The polymerization reactions described can with water (Figs. The Si—O— tion of water (Fig.) Copyright © 2002 Marcel Dekker. This of the structure (R1SiR2O)n . with n ⫽ 3 to 9 and cyclic siloxanes. (From Ref. 5). 63b.133). the basic silicone compound used in medicine. silicones are polysiloxanes (38.4 Condensation of two molecules of trimethylchloro- silane into hexamethyldisiloxane.104. Thus. which were CH3 groups. In polysilox.) misinterpreted as oxygen linked to Si with a double bond. In general. films. lower than that of water.

Soon after minor amounts of other substituents. groups. Elasticity occurs because polysiloxanes their intended use (7. During the 1960s and 1970s bonds. 1–2. or si. is a clear and highly viscous PDMS with Corning after undergoing the first human trial.11). This same property can be modified by changing the duce polysiloxanes. It was esti- ated by heat (heat vulcanization) or benzyl peroxide. with the ability to return to its original in collaboration with Dow Corning (28. Dow Corning introduced many improvements to enhance tuting vinyl groups for occasional methyl groups because the quality of the mammary prosthesis. ane is used to prepare medium and hard grade silicone elas- sist of covalently crosslinked polysiloxane networks and tomers. The problem encountered with the spongy implants of the adjacent regions to slip past each other. of silicone rubber sac filled with silicone gel was called a The basic ingredient to make silicone elastomers. When tension is released the polymer recoils. By changing the amount of filler added or phenylmethyldichlorosilane as the feedstock and equili. Highly crosslinked polymers will lose elasticity be. Silicone gels produced by this procedure con. . A lightly to look and feel less natural. BREAST AUGMENTATION IMPLANTS the ability of adjacent polymer regions to slip past each other and therefore will be influenced by the presence of Thomas Cronin and Frank Gerow.000–150.’’ or rubber elastomers. The most prosthesis was much greater for breast augmentation pro- common mechanism by which crosslinking occurs is by a cedures for cosmetic purposes (80%) rather than recon- radical attack on the alkyl groups pensile from the Si initi. the University of Texas. Polydimethylsiloxane is used to pre- resistance of the more bulky pensile groups to slipping past pare the soft grade silicone elastomers. Around the year 1960. were looking for an alternative to ane polymer is increased by crosslinking the polymeric the spongy breast implants commonly used for reconstruc- chains. two plastic surgeons at the bulky pendent groups. the crosslinked polymer will deform easily but will have sig. particularly vinyl Dow Corning introduced this new product to the market. the demand for mammary physical properties of the resultant elastomer. the polymer unwinds. but also as ‘‘gums. RTV silicones are provided as function of the length of the polymer chain and the degree intermediate components which require mixing before of crosslinking. to a silicone elastomer. Another type of silicone rubber is the room interpenetrating polymer networks swollen in a silicone temperature–vulcanizing (RTV) silicone rubber. In some cases.5 Production of silicone in a reaction between hexamthyldisiloxane and ailanol oligomers. the prevulcanized silicone is usually mixed with Silicone breast implants have been associated with a filler. struction procedures following mastectomy. whereas polysilox- each other.000 British women re- combine to form the carbon–carbon covalent crosslinking ceived breast implants (62). The mated that by the year 1992. strength.) modified chlorosilanes such as ethylmethyldichlorosilane imately 400 m2/g. Other companies joined Dow radical attack. Inc. A common filler used for this purpose is the submi. high temperature–vulcanized materials. Commercial PDMS are not only produced as fluids icones have much less tensile and tear strength than the or oils and gels. These will pro. Elasticity relies on III. (like other polymers) exist in highly coiled conformers. (From Ref. Other radicals in the silicone rubber determine the and to everybody’s surprise. but they was that after a period of time they hardened and started will not deform easily and hence are more rigid. ness. with increased viscosity because of the type of polymer used. As the material is stretched. 63b. mammary prosthesis and was later marketed by Dow licone rubbers. The physical rigidity of a silox. In order to increase its tear and tensile Corning to cash in on this rapidly growing market. which became a the double bond of this group is quite susceptible to free multimillion dollar product. one can change its degree of hard- brating with the homologous end groups. crosslinking is facilitated by substi. Figure 3.5 million North reactive intermediates containing carbon free radicals then American women and 100. This prototype shape when stress is released. two surgeons developed the first silicone breast implants nificant elasticity. which has a surface area of approx. tion of breasts among female patients undergoing mastec- cause uncoiling will be inhibited as a result of the inability tomy. complications such as capsular contracture. of lymph nodes draining the implant site. enlargement croscopic fumed silica. These sil- fluid. Unlike the other The strength and elasticity of polysiloxane elastomers is a type of silicone elastomers.93). occasional rup- Copyright © 2002 Marcel Dekker.

wheezing.’’ Some reports claimed an study was criticized for the lack of certain diagnostic valid- association with systemic. the pigment toms. in Copyright © 2002 Marcel Dekker. Pa- derma was the most common specific diagnosis (10. OPHTHALMOLOGY PROCEDURES that the number of reported cases exceeds 290 patients AND OPTIC DEVICES (62). The first report of an associa. Melanin in the pigment epithelium. edema. muscle twitching. which may be triggered by following the recommendations of two independent advi- bleed of the silicone gel through the outer bag. disease that fueled the debate over the safety of this pro. foul taste. 100). dry mouth. bruising. tients with retinal detachment are at serious risk of total 16. diarrhea. This of their product. headache. Further. tinnitus. dysethesia. epithelium is essential for the proper metabolism of the drug reactions. thors of this study themselves concluded that an associa- characterized immunological disorders. link of breast implants to a systemic connective tissue Only one retrospective cohort study. Inc. myalgia. dysphagia. neuronal layer of the retina.57). ture of the silicone gel sac. joint pain. palpitations. sei.76. probably autoimmune. Phys. hem. urinary symp.30. chills. located in gain or weight loss. the debris generated by the constant turnover of the outer tight skin. the back of the neuronal retina. Retinal detachment can be caused by numerous dis- The range of symptoms was very large and many of the ease conditions. and cancer. Sclero. including the layer of photo- skin rashes. a Department of Health advisory group in of the capsule. segments of the photoreceptors containing the photopig- zures. foreign material (18). emotional lability. Reported symptoms and signs include fatigue. The jury found that the the hole by external tamponade. dysmenorrhea. ity with potential bias due to differential over-report- tive tissue diseases (73. quired immunodeficiency syndrome (AIDS) (56. . series as well as several case–control and cohort studies done. dry eyes.. It supplies the retina with nu- angiomas. In 1991. periodontal it through the photoreceptors layer and therefore prevents disease. tremor. delayed wound healing. In addition.77). bone pain. an American jury found that silicone breast retinal reapposition was achieved by suturing a sponge or implants were responsible for the plaintiffs’ symptoms of a band to the sclera to produce a ‘‘buckle’’ which closes a mixed connective tissue disease. and the first documented cases were those of three patients in 1982. Capsular contracture. Traditionally. weakness. public awareness of the procedure works well in uncomplicated cases. Cytomegalovirus-induced retinitis is a cases did not fulfill conventional clinical and laboratory major cause of retinal detachment among patients with ac- criteria for a particular connective tissue disease. nausea.15. trients and is involved in phagocytizing and clearing out partial hearing loss. Analysis of published case implants. infections. The au- ing an association between breast implants and some ill.99.94). mouth sores. (26). dizziness. ing. It is estimated now IV. The drying effect of silicone in the while the battle between the litigants and the manufactur- surrounding soft wet tissue enhances the scar formation ers of the implants was raging inside the court and on the and is another possible contributing factor to the formation media front. reflection of light off the sclera. requested a halt on the use of silicone breast to be due to the natural attempt by the body to engulf the implants other than within clinical trials (27. however. pointed to a weak association (52). reduced smell. With this procedure the company was responsible as they misrepresented the safety retina resumes contact with the pigment epithelium. are separated from the pigment change. neuronal layers of the retina. This pseudocapsule is composed of fibrous Great Britain reported that there was no evidence of an tissue typically seen in the process of wound healing. is believed sory panels. parotid gland swelling. connec. published in the Journal of the American Medical Associa- cedure. freckling. as well as use of wetting agents such as provi. tion in 1996. hair loss. paresthesia. vascular abnormalities. skin papules. sue disorders among recipients of breast implants is no dif- It was not these complications but rather the possible ferent from that expected in the general population (101). increased sensitivity to light. have reduced the incidence of capsular contracture suggested that the cumulative incidence of connective tis- (45). tion between silicone breast implant and connective tissue disease dates back to 1964. captures light that makes fever. by Hennekens et al. ments. Several reports appeared in the literature suggest. nail changes. weight epithelium. insomnia. this as ‘‘human adjuvant disease. pigment receptors (rods and cones). heat intolerance. dry skin. Most of the reports tion between silicone breast implants and increased risk of described cases of a poorly defined syndrome referred to major connective tissue disease is unlikely. shortness of breath. cognitive Retinal detachment is a pathological process in which the dysfunction. and bacterial contamination issue rose steeply and the Food and Drug Administration. blurred vision. blindness unless the problem is corrected. constipation. After this trial. In 1994. increased risk of connective tissue disease in patients with ical changes and alterations of the nature of the silicone silicone breast implants (43).

either in the scrotum in males or the labia minora in paired vision. trol incontinence (59). The cuff is surgically implanted around the neck of deemed to be inoperable. at. a small when left untreated can lead to blindness. Various DEVICES forms of bioinjectable materials have been developed for this purpose. an experimental squeezing the pump several times. closing compress the urethra against the symphysis pubis.90. Side effects due to intraocular the bladder. injecting more fluid into it if necessary. forcing the fluid out of procedure to restore accommodation in primate eyes by the cuff and into the balloon. Transurethral or periurethral injection of biomaterials V. optical clarity. which requires removal of the Urinary incontinence is a common problem affecting preretinal membranes by vitrectomy. polysiloxane lenses coated with povidone are rou. paste has had relatively good results in the short term (24). Inc. and maintaining the surgeon’s view of the ing implantation the balloon can be further enlarged by back of the eye during surgery involving vascularized tis.5 years was reported with this tinely used for patients after cataract surgery (58). sympathetic nerve injury. complications. Follow- macular holes. sue. silicone seemed to be the perfect substance As early as the year 1947.41. brosis in the urethra and bladder granuloma balls (17). and very few are (98). That same year. An overall success rate least. urethra via a cutaneous tunnel were reported. and a stainless steel control assembly detachments are now routinely repaired.74. an external tampon. nence) or intrinsic sphincter deficiency (type III stress in- ride. balloon is implanted around the crura of the penis to con- nent internal tamponade. injection of autologous fat was tested and Copyright © 2002 Marcel Dekker. myelodysplasia. cuff and allow urine to flow. hexafluo.37.82. and infection. The inflated cuff cuts off the flow of urine in a silicone fill (21.88). ters have to be replaced within 3 to 4 weeks (130). which sphincter which consisted of a silicone rubber cuff. and hence hyper- biologically inert. manipulating the retinal edge in giant tears. Jo- sis’’ in human eyes (23). such as fi- with minimal phosphatic deposition. Drawbacks of this procedure included cost and is also used in manufacturing soft contact lenses. the patient could deflate the refilling the lens capsule with injectable silicone com. In 1962. Upon distention the balloon would branes. Silicone device. such as air. loss of urine during physical activities that increase intra- thelium together. sulfur. for longer-term main. Whereas sili. By In addition to the previous example. tissue erosion. Stress urinary incontinence. Since then the use of silicone has seph Kaufman described a procedure in which a silicone been extended to include providing temporary or perma. More recently. Gases. delaminating periretinal mem. The use of intraocular silicone is considered a major Brantley Scott and his colleagues developed an artificial breakthrough in the treatment of retinal detachment. 10–25% of women between the ages of 15 and 60 years ade must be supplemented with an internal tamponade in (64). Investigators felt the need for a substance abdominal pressure. In 1973. Last but not automatically restoring continence. Urinary incontinence may also occur material that is insoluble in tissue fluid seemed to be more as a result of spinal cord injury or following prostatectomy appropriate. for easy access. . Teflon paste injections revealed a low success rate of only cone catheters may be left indwelling for 8 to 12 weeks 38% and the occurrence of local side effects. Cibis was the first to report the incontinence by applying a constricting cuff around the use of liquid silicone (silicone oil) as a ‘‘vitreous prosthe. and perfluoropenthrane were tested and proved to be continence). latex or plastic cathe. Within minutes the cuff refills pounds is currently being investigated (87. The latter condition may be caused by effective in the short term. the pump is placed under the skin main long-term complications such as glaucoma and im. TREATMENT OF URINARY AND FECAL into the intrinsic sphincter was developed as a less invasive INCONTINENCE AND GENITOURINARY technique for the treatment of incontinence (8). Foaming or emulsification is responsible for the and. a balloon. Because of its long-term biotolerability and procedure in males (2. and surgical in- tenance of break closure and relief of retinal traction. of 70% for an average of 3. The balloon is positioned in the perivesical space nique. such as periurethral fibrosis. attempts to control urinary for this purpose. manner similar to that of the natural sphincter muscle. Injection of polytetrafluoroethylene (Teflon) Until the introduction of silicone-based prosthesis. tempts to replace any part of the urinary tract were plagued Long-term follow-up studies on patients treated with by the problem of phosphatic encrustation. which is the involuntary order to successfully bring the retina and the pigment epi. This can be avoided with a more complete women.131). or sometimes around the bulbous urethra of silicone can be avoided or reduced by proper surgical tech. a jury or trauma (75). that is could result from loss of pelvic support. and is amenable to surgical procedures mobility of the vesicourethral junction (anatomic inconti- to serve this purpose. is a common type.25.97). However. complex retinal detachment. Complex retinal pump. men. This condition with stable surface properties at aqueous interfaces.

Today. their introductions. ulnar head. structing the wrist using silicone joint prostheses or bone tion of PDMS paste is being investigated for treating prostheses made of silicone. sideration of both prosthesis designs and materials. Moderate success adjacent structures in the hand. stable implant in a chronic inflammatory response characterized by the arthroplasty with metacarpal cups or with soft tissue inter. degenerative arthritis and rheumatoid arthritis in the hand Small particles shed from HP elastomer implants are in- and wrist. persistent weakness of grip and in treating vesicoureteral reflux (61). which allows for the glid- with sublevatorial implantation of a silicone ring was re. de. cleated epithelial cells (42). who as well as autologous fat. and synovitis. However. Another use for silicone in nisms are not fully understood. moralizing. pioneered the field of silicone implant arthroplasty. Swanson. lunate. subluxation. Currently. however. scaphoid. eosinophils. tory cytokines and attract more immune cells. arthroplasty was introduced by Swanson. In very few cases. (92). In addition to hand orthopedic surgery. to aug- Copyright © 2002 Marcel Dekker. 107. Another possible application for this procedure is were implant fracture. a tunnel composed of a thin pseudocapsule in which tendon rected by medical or surgical means. large joints and long bones may require additional rein- neously in the penis. reconstruct larger joints such as the elbow (71. cone products are used to reconstruct the mandible.95).117– Silicone is also used in the making of penile implants 125). Inc. reconstruction of is a solid polysiloxane component that is inserted subcuta. growth fixation. A hinge spacer originally intended to im- The major problem encountered with collagen use is the prove the alignment and stability of resection and potential development of allergic reactions (3). Until the late 1950s. safe. silicone is com- terials continued until silicone rubber prostheses were in. and costly condition which may result from prostheses based on those original designs continue to be various causes. it is almost always associ. hand orthopedic surgery is in tendon transplantation (19). Silicone devices are often used in orthopedic gested by phagocytes which fail to clear these foreign par- surgery.109–125).84. success rates were not impres.20. Swanson and Niebauer became very popular soon after and effective procedure for the treatment of urinary incon. The purpose of this tunnel situations reconstruction of the contour deformity of the is to prevent the adhesion of the transplanted tendon to the anus is the only successful resort (86). ORTHOPEDIC AND RECONSTRUCTIVE matory response to small particulate debris of 10–100 µm SURGERY in diameter (5).35). One model of these implants with silicone components. Recently. This phenomenon is more commonly seen in association with high performance (HP) silicone elasto- Silicone prostheses play a major role in the treatment of mer than with the conventional silicone elastomer (125). but some of the problems encountered tinence. The metal hinge implants for the metacarpo. monly used in maxillofacial reconstructive surgery. Sili- troduced in the late 1960s and early 1970s (13. The condition is usually cor. injection of polydimethylsiloxane is a simple. and increasing deformity.85. Hunter’s Silastic rods are used to form of the anus and anal canal. the results from this study were not impressive (6. This results sive in attempts to achieve pain-free. Collagen. . widely used in arthroplasty. trapezium. intro- which calls for repeated injections. able silicone bag connected to a reservoir which is used The three major complications following silicone im- to pump fluid to the prosthesis when an erection is desired plant arthroplasty are fracture. ated with anorectal disorders that can deform the contour In this procedure. forcement. According to these carpophalangeal and interphalangeal joints. and giant multinu- positions (8). The plant arthroplasty (22). perianal injec. wrist.111. Silicone is also used in recon- ported by Hansen in 1996 (47). silicone phalangeal joint introduced in 1959 were not well tolerated lymphadenopathy has been reported following silicone im- due to bone resorption and metal corrosion (12. presence of lymphocytes. Frustrated macrophages release proinflamma- (45). whereas subluxation occurs mainly with the carpal implants (63). reports on duced other designs used in the treatment of arthritis in the use of silicone particles for treatment of urinary inconti. This led to careful recon- Soiling (fecal incontinence) is another distressing. and meta- nence appeared in the literature (61). in certain transplants are inserted later on. Niebauer and his colleagues introduced a Collagen has a good (46–77%) long-term (2 years) success hinged silicone joint with a dacron mesh covering for in- rate and is currently the most widely used injectable (4). search for better techniques and new biocompatible ma. are absorbed rather rapidly. ing function of the tendon. pinch. Silicone synovitis is an inflam- VI. Another model consists of an inflat. This may involve replacement of the head of the ulna used to treat male impotence. Although the pathophysiologic mecha. Designs by reports. Silicone can also be used to soiling. especially in operations to reconstruct the hand ticles away. Fracture commonly occurs in the wrist and metacarpopha- langeal implants.

Early attempts to strictures and fistulas resulting from a variety of causes use artificial valves were not very successful in the long including malignancy.60).106). bilateral vocal cord paralysis. . to provide support in the stenotic trachea.49. Hufnagel’s attempt set the stage for other laryngeal stent can be used alone or in combination with investigators to develop more biocompatible and safer the Safe-T-Tube to prevent and treat laryngeal stenosis. Silicone insufficiency. is used to prevent and ditis is the most dreaded complication of valve replace- treat anterior laryngeal stenosis limited to the anterior com. According to their method larynx that has an electric pharyngeal speech vibrator a catheter electrode with a metal guide wire was inserted which can be externally applied to the neck.126. Today.108). Such procedures represented a major in cases with cervical esophageal and hypopharyngeal challenge to the cardiac surgeon (34). This goal can be achieved by means of an artificial by Furman and Robinson (39). maintain. a life-threatening late complication of carcinoma of the leading cause of prosthetic valve infections (103). death may ensue tract and restores the ability to swallow so proper nutrition within few days. with intermittent laryngeal insufficiency. trauma. Staphylococci and gram-negative bacilli are tula. Valvular endocar- umbrella-shaped silicone prosthesis. Without treatment. and run due to the loss of flexibility of the material and to in- caustic indigestion (80). the esophagus and lung (83. CARDIOVASCULAR PROCEDURES reconstructed trachea or reconstituted trachea. The silicone Safe-T. a silicone device direct open treatment of valvular diseases became possible. docardtitis is less severe and may be responsive to antibiot- Since the first laryngectomy was performed in 1866.80. the method of shunt reconstruct the missing ear of patients with microtia esophageal speech by means of silicone tracheoesophageal (45. Deformed. The risk of infec- ESOPHAGEAL PROSTHESES tion can be greatly reduced by proper surgical techniques and by patient education on how to properly use. and subglottis (80). The prognosis for late valvular en- a matter of few months (31. called the Tracheal Cannula System is usually used (79). AND bacterial and fungal infections (55. The source of bacteria in early nosocomial in- missure of the vocal cords (80). The first method of pacing was described in 1958 region. Esophageal tube is used to bridge growth of tissue (14). However. environment. This required an alternative vibratory source to re. With the advent of extracorporeal circulation in 1954 and noma with glottic insufficiency. TRACHEAL. It is commonly used in cases with acute tracheal injuries. if necessary. The best approach to treat early valvular intake can be maintained (54). LARYNGEAL. a need to support a VIII. and neurological disorders the introduction of heart–lung machine by Gibbon (40). supraglottis. ment (32). calcified valves could not be completely fixed By diverting the saliva into the distal esophagus. The pace- Copyright © 2002 Marcel Dekker. The major risks associated with the silicone devices are VII. there are numerous heart when the glottic stenosis involves the midglottis. prostheses (33. His design consisted following laryngoesophagectomy and reconstructive sur. irradiation. infect or replace a contaminated device has been very effi- Tube is designed to maintain adequate tracheal airway and cient in preventing major complications. It can be kept in place for many years. several methods to restore speech have been attempted The idea of externally stimulating the heart with an (1. electric current was first conceived in 1952 by Paul Zoll place the larynx in the reconstructed pharyngoesophageal (135). A variety of devices used in the upper respiratory and di. valve prosthesis have the most consistently high success rate (102. an them consist of or contain silicone (34). early intervention to dis- gestive system are made of silicone. ment the chin of patients with microgenia and to all the speech restoration methods. ics alone. This procedure prevents When the patient presents with symptoms of acute septice- food and gastric refluxate from entering the respiratory mia secondary to valvular endocarditis.72). of into the right ventricle through a peripheral vein. a silicone.69). In cases such as obstructive sleep apnea. posterior valves available from different manufacturers and many of glottis.127). Inc. surgery.44).132). of a caged Lucite ball valve which he used to treat aortic gery of the cervical esophagus (78. Laryngeal keel. and clean their prostheses.53). as well as AND DEVICES many other procedures (78). by conservative procedures such as valvuloplasties and made salivary bypass tube greatly reduces the healing time calcium debridement. most of endocarditis is the institution of appropriate antibiotics fol- these patients succumb to respiratory problems and die in lowed by surgery (70). Silicone esophageal stents fection is believed to be patients themselves or their are used as a palliative therapy for tracheoesophageal fis. laryngeal carci. Charles Hufnagel was the first to the gap between the pharyngostome and esophagostome implant a valvular prosthesis (46. Also.

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which opens to delivery of a wide range of bioactive agents for human the ester alcohol (b.36).12–14).17).6). The most important biomedical applications of biodegradable polymers are in a. The II. The purpose of this chapter is to tallization of the polymerizing polymer occurs. around 1000 kD (26). safety. Lewis acid character of the tin cata- for more than three decades for a variety of medical appli. 4 Biodegradable Polymers as Drug Carrier Systems Abraham J. Injectable formulations containing micro- Over the past decade the use of polymeric materials for spheres of lactide/glicolide polymers have received the the administration of pharmaceuticals and as biomedical most attention in recent years. Extensive research has been devoted in Scheme 1). commonly synthesized by ring-opening melt polymeriza- ligament reconstruction (7).25). contact lenses. peptides and carbonyl group and reaction with the hydroxyl end group. Inc. They have been used for the delivery tion proceeds by tin catalyst activation of another dilactone of steroids (16. and Doron Teomim The Hebrew University of Jerusalem. anesthetics (21. The polymerization reaction was studied and several mechanisms were proposed including cationic (27–30). artificial heart valves. crys- organ regeneration (11). When polymerization temperature makers. Jerusalem. devices has increased dramatically. (Scheme 1) (37). Tzviel Sheskin. surgical dressings (8). dental tion of lactide and glycolide at 140–180°C for 2–10 h us- repairs. Alfonso Bentolila. Joram Slager. Domb. resulting review the chemistry. high molecular weight polymers. dures of the different biodegradable polymers actually Solid-state polymerization has been found useful for very available and to describe some of their release kinetics. The propagation reac- and animal use (15). and biocompatibility considerations. tracheal replacements (10). Synthesis the areas of controlled drug delivery systems (1–4) and in Linear lactide. Israel I. . and vaccines (23). properties. anionic (31–34). and is less than the melting point of polymer (⬃175°C). vascular grafts (9). The activated species reacts with the alcohol to the use of these polymers as carriers for controlled drug initiator to form an unstable intermediate. BIODEGRADABLE POLYMERS common polymerization catalysts are tin derivatives such A. lyst activates the ester carbonyl group in the dilactone (a. Copyright © 2002 Marcel Dekker. Linear polyesters of lactide and glycolide have been used In this mechanism. A hypothetical mechanism of the ring-opening polymerization of lactide using a tin 1. in Scheme 1). INTRODUCTION proteins (19). and coordination–insertion (35. and formulation proce- in solid-state polymerization as with poly(glycolide) (PG).22). cardiac pace- ing a catalyst (24. Neeraj Kumar. cations (5–8. Polyesters as tin octoate or tin hexanoate. Lactide and Glycolide Copolymers catalyst was suggested by Kissel et al.and glycolide-based polymers are most the form of implants and devices for fracture repairs (5. antibiotics (20). anticancer agents (18).

By us- ing only one form of the trialkoxide isopropyloxide (Al(O- iPr)3). The α-lactone polymerizes by ring-opening polymeriza- tion using an alcohol catalysis to give exclusively poly(α- Ring-opening rate for cyclic lactone can be increased by hydroxyalkanoic acid). In this method. Low molecular weight poly(lactic acid) (⬍3000 kD) can be synthesized by direct polycondensation of lactic or glycolic acid using phosphoric acid.000 can be obtained by the melt process when high purity monomers (⬎99. Inc. Scheme 1 Hypothetical mechanism of ring-opening polymer. particu- larly metal alkoxides. 37).25). Stannous octoate S″[CO2CH(″Bu)(Et)2]2 is commonly that sulfur dioxide and polymer were formed simulta- used because it has FDA approval as a food stabilizer (38). Polymers with a molecular weight as high as 500. La.L ⫹ D. The polymerization was preceded by thermal decompo- ization using tin octoate as catalyst. Zinc powder and CaH2 have also been evaluated as poten- tial nontoxic catalysts for copolymerization of poly(lactic acid) (PLA) with poly(ethylene oxide) (PEG) (40). Pure polymers in ⬎80% yield and molecular Alternatively.L. The aluminum trialkoxide–growing species belong to the most selective ones. Polymerization of L.44). Ti) alkoxides. neously. The aluminum alkoxide initiators are the most versatile and readily avail- able. namely. which did not receive much attention..D)-LA initiated with Al(O-iPr)3 is claimed to be the first example of fully controlled synthesis of high molecular weight PLA (45).9%) are used (37).000 were reported (49). its trimer. K. Fe.or Sn-based catalyst with carbonyl es. Since Sn(OCT)2⫺ promoted polymerizations are hardly controlled. Scheme 2 Polymerization of α-hydroxy acids using anhydro- sulfite cyclic derivatives of α-hydroxy acids. sition of (I) to give the sulfur dioxide and α-lactone (III). The formation of (III) was rate con- activation of a Zn.and (L. An interesting method of polymerization of α-hydroxy acids was offered by Tighe and coworkers (47–49).g. resorbable Fe(II) salts have been utilized as weights of MN ⫽ 20. Sn. the anhy- drosulfite (I) and the anhydrocarboxylate (II) cyclic deriva- tives of α-hydroxy acids are polymerized in refluxing diox- ane or nitrobenzene for 18–52 h with alcohol catalysis (Scheme 2). are continuously tested as initiators in the polymerization of lactides (41. Copyright © 2002 Marcel Dekker. Sm. in comparison with other metal (e. trolling. a variety of organometallic derivatives. (From Ref. and the subsequent polymerization was so rapid ter. initiators for lactide polymerization above 150°C (39). p-toluene sulfonic acid. Both monoalkoxides (R2-AlOR′) and trialkoxides (Al(OR)3) were applied by several groups (43. Lauryl alcohol is generally added to control the molecular weight of the polymer (24.42). and antimony trifluoride as acid catalysts (46). a perfect control of polymeriza- tion can be achieved. .

These branched polymers are degraded in cavity in the middle (shape of a red blood cell). to Tm ⫽ 230°C for PLA polymer is an important factor in polymer biodegradation stereocomplex of similar molecular weight) (54–56). PLLA have Tg of 57 and 56°C. Among reocomplex both for low and for height molecular weight them. which Blends of low and high molecular weight poly(DL. By casting a weight of 15. The physiochemical properties of optically active homo- nitrile only at elevated temperatures (from 52°C upwards). For high molecular weight PLA the reaction takes since only two helical turns are needed for complexation even longer.000 or molecules were used to prepare a range of branched struc. respectively. are intertwined forming ‘‘double strand’’ helices. and DL-lactic acid. penta. Branched lactide polymers prepared from the polymer. According to the latter view.55). On the other hand x-ray data suggested no the addition of low molecular weight polymer accelerated change in the 103-helical conformation. Steril- Scanning electron microscope (SEM) images revealed ization using γ-irradiation decreases the polymer molecular the formation of particles whose shape was influenced by weight by 30 to 40% (64). The copolymers branched with low-concentrated solution on mica crystals PLA stereo- 1 wt% of poly(vinyl alcohol) of 3. . The D. is purely amorphous. The PLA stereocomplex appears to be soluble in dichlo- erithritol.and D-helixes was suggested to cause Different interactions are known to be involved in com. preferably stereocomplex crystals are formed. wt% of small polyols like manitol. Polymers a monophasic character. crystals.000 to 676. The polymer characteristics are af- ferential scanning calorimetry (DSC) shows a shift of the fected by the comonomer composition. PLA of higher molecular weight. There is a difference in opinion as to whether the ylene oxide)-polylactide copolymers in a spherical form PLA stereocomplexes consist of 31-helixes (β-form) or were obtained from the block copolymerization of lactic 103-helixes (α-form). whereas the racimic PLA cipitate was obtained after 3 days. material with regard to design and performance.2–1 spheres were absorbed (55). Dif. and varies with the stereoregularity of the polymer.and L-helixes oxide) molecules (51). the packing of the L. Re- enantiomers in chloroform. This can be PEG have been synthesized and characterized by means achieved by pouring a solution of D. poly(glycolic acid). Also. Neither L-PLA or D-PLA gives a reaction on its own highly crystalline with a Tm of 170°C. has very different characteristics (63). It is suggested that com. If polymer was used of 150. as was also suggested in earlier found that PLA complex was formed in a solution of both reports for stereocomplexes of other polymers (59. higher molecular weight. the triangular shape (58). Inc. predicted 31-helix on acid on the end groups of three or four arm poly(ethylene the basis of computer calculations.000. lactic acid contains an asymmetric α-carbon atom PLA consists of heating a mixture of both enantiomers at with three different isomers as D-. 60°C in acetonitrile. Brizollara et al. Star poly(eth. MW ⫽ 100. up to 1 year.60). and poly(lactic-co-glycolic acid) are found as the best bio- mation was noticed. A quicker procedure was found reaction (61). the polymer archi- melting temperature of about 50°C (from Tm ⫽ 180°C for tecture. and xylitol had a weight average molecular romethane or hexafluoroisopropanol (HFIP). stereocomplexes of PLA containing by precipitating D-PLA and L-PLA together. and molecular weight. Polymer Properties isotactic PLA enantiomers in dichloromethane or chloro- form. Racimic PLA and plex formation takes place during precipitation from a sol. are packed in a hexagonal cell forming triangle-shaped lactide) were studied as carriers for drugs. less stereocomplex for. crystals (57). and their degradation is in general of higher molecular weight formed spheres consisting of faster than for the linear polymers (50). As expected. but PLLA is vent.000 to 46.or L-PLA. Poly(lactic acid) was soluble in aceto. The irradiated polymers con- Copyright © 2002 Marcel Dekker.51). respectively. acid) (PLLA) are the same. gel formation was in the PLA stereocomplex: 103-helix with a minimum of noticed which turned into a precipitate only after about 30 11 units and 31-helices with a minimum of 7 monomers days. L-. In concentrations ization of lactide and pentaerithritol as branching agent up to 10 mg/mL discs were formed either with or without were reported. the initial concentration of polymer.000 molecular complexes were obtained. of DSC and various microscopic techniques (62).and L-PLA in dichlo. the plex formation between two polymer molecules. polymers poly(D-lactic acid) (PDLA) and poly(L-lactic Within several hours the solution became turbid and a pre. It was helices are not intertwined. romethane into a nonsolvent like methanol or ether. Various polyol a fiberlike structure. The crystallinity of the D. cyclodextrine.000. and racemic PLA in various solvents under similar conditions (54. First.000 to 72. a three-dimensional network tures with different properties (37. The reaction proceeds very cently it has been reported that both conformations exist slowly at room temperature (53). As opposed to isotactic PLA weight range resulted in a tenfold increase in molecular several reports indicate the formation of triangle-shaped weight of 182. With Polyesters based on poly(lactic acid).000. When a film is casted from a solution of low molecular weight b. An easy procedure to obtain the ste. could be noticed in which the previously mentioned Copolymers of LA/GA 55 :45 branched with 0. ‘‘Frustration’’ of the release of drug from the blend formulation (52).

tetrahydrofuran.6-HD 70: 30 101. weight and distribution. Poly(glycolic acid) is insoluble in c.2 2.0 Poly(glycolic acid) PGA 50.000. plantation. PGA has a very high tensile (73) reviewed the biodegradation behavior of lactide/ strength (10. and the flexural ceeds in two phases: in the first phase the amorphous re- storage modulus as a function of temperature were deter. All specimens (2 ⫻ 10 ⫻ 15 mm) were prepared several biodegradable materials used in orthopedic devices in a similar way and allowed to hydrolyze at 37°C in dis- Table 4. a standardized set of experiments was de- A comprehensive review on the mechanical properties of signed. and then the crystalline regions in mined.5 3 20 160 Poly(orthoesters) t-CDM: 1.000 58 159 50 2.6 3.1 220 t-CDM: 1.000–20. which is comparable to those include chemical and configurational structure. mers with hydroxyvaleric acid. Poly(lactic acid) and its copolymers with less lactone have been summarized in a tabular or diagram than 50% glycolic acid content are soluble in common sol. which resulted in a decrease in molecular poly(e-caprolactone).000 84 — 19 800 4.000 54 170 28 1.8 2. Biodegradation common solvents. and ethyl acetate. mers are important factors in polymer biodegradation. tinue to decrease in molecular weight during storage at has been published (69).000 2 145 20 1.100 5. In its Lewis (70).1 180 Source: Ref. Inc. polyorthoester. as well as the biodegradation of various the mechanical properties and the release rate from the lactide/glycolide polymers.000 51 — 29 1. 68.2 and 16.000 59 178 48 3. tensile properties. termined by Siemann (66).500 2.5 P(HB-11%HV) 529. molecular of polystyrene and polyisoprene (67). format. poly(DL-lactic acid).000 psi) (65). The tensile and flexural strength room temperature. fabrication conditions.0 L-PLA 100. The thermal and mechanical properties of several tide polymers was described recently by Vert et al. The following polymers were compared: poly(L. The degradation of semicrystalline polymers pro- The thermal properties. This decline in molecular weight affects and modulus. (74. poly(hydroxybutirate) and copoly.1 Thermal and Mechanical Properties of Biodegradable Polyestersa Tensile Tensile Elongation strength modulus Polymer MW Tg (°C) Tm (°C) (MPa) (MPa) Yield (%) Break (%) Poly(lactic acid) L-PLA 50. Copyright © 2002 Marcel Dekker. poly(glycolic acid).000 ⫺62 57 16 400 7. The solubility parameters were The factors that may affect the polylactide degradation in the range of 16. but soluble in hexafluoroisopropanol and hexafluoroacetone sesquihydrate (HFASH). sity as well as the crystallinity and morphology of the poly- The solubility parameters of several polymers were de. Gopferich (71). vents such as chlorinated hydrocarbons.0 5. and degradation conditions ties of several biodegradable polyesters was reported (68).6-HD 35: 65 99.000 psi) and modulus of elasticity glycolide polymers. weight with no weight loss.0 80 Poly(trimethylene carbonate) PTC 48. A comprehensive investigation on the hydrolysis of lac- bonate).000 1.0 DL-PLA 107. . gions are hydrolyzed. (72). the ester bonds. of the polymers tested are summarized in Table 1 (68).7 6.5 17 Poly(η-caprolactone) PCL 44. the second. The polymers degraded by bulk hydrolysis of lactic acid).000 1 171 36 2.000 55 — 20 820 4.000 35 210 NA NA NA NA Poly(β-hydroxybutyrate) PHB 370.000 ⫺15 — 0.200 3.700 2. and Tracy highly crystalline form.75).900 4. and poly(trimethylene car. physical factors.3 L-PLA 300. site of im- A comparison study on the physicomechanical proper. The molecular weight and polydisper- (⬃1. (76). and polycapro- polymers.8. In these studies. Holland et al.

In vitro degradation was essentially the same. were 60 to 90% degraded in 15 weeks postimplantation. but faster. . and and the degradation rate decreased with the increase in MA DSC and x-ray scattering for thermal properties and crys. The degradation of several aliphatic polyesters in the The copolymer L-LA/DL-HBA degraded the least with form of microspheres in phosphate buffer solution at 37 a lag time of no weight loss for 5 weeks. The degradation of branched PLA was characterized as bulk erosion. biodegradable carriers for drug delivery systems.83). The polymers had a molecular higher water uptake than the branched polymers. chromatography (GPC) for molecular weight change. Polycaprolactones The successful use of lactide and glycolide polymers in d. semicrystalline PLA lost about 50% of its mechanical hydroxy acids of the structure strength after 18 weeks in buffer. The changes The polymers were prepared by direct condensation of in the polymer during hydrolysis were monitored by mandelic acid and lactic acid at 200°C under vacuum. and polymers of other α-hydroxy acids. pH change and lactic acid release.79) and that this phenomenon is based on a diffusion mechanism. The weighing for water uptake and weight loss. the linear PLA had a sence of catalysts (82. polyesters for this purpose. The biodegradation of low molecular most pharmacologically effective. weight of 5000 and Tg in the range of 20 to 37°C. content with no degradation observed for the MA homo- tallinity change. and coordination polymerization of ε- Copyright © 2002 Marcel Dekker. Degradation at 85°C resulted in a similar degradation drug for 15 weeks. Other research efforts suggest that PLA-derived mi- croparticles will degrade faster than nanoparticles derived from PLA (78. cationic. with poly(L-LA/DL-HICA) being the profile. while the corresponding branched PLA con. (LHRH) agonist were implanted in rats and released the mers. with no weight loss until about 30 weeks of hydrolysis. Other Copolymers of Lactic Acid absorbable drug delivery systems and medical devices and Low molecular weight homopolymers of D. polyhydroxybuty- rates. and suggested that size de- pendency exists for hydrolytic degradation of PLA sys- tems. PGA. indicat- ing minimal involvement of enzymatic degradation. On the contrary. These ample. weight PLA used in tablets for oral delivery of drugs was also studied (81). potentiometry and enzymatic assays for polymer after 15 weeks in buffer at 37°C. Vert et al. and dynamic mechanical Low molecular weight α-hydroxy acid copolymers tests for changes in mechanical properties (76).84). gel permeation copolymers containing 15 to 100% MA were amorphous. The branched materials degraded much faster than the refer. and PLGA degradation. composed of 70 mole% L-lactic acid and 30 mole% DL- mer. No adequate explanation was given for cylinders (2 ⫻ 10 mm) implanted subcutaneously in rats this phenomenon. Small tained only 2%. tilled water or isotonic phosphate buffer. The biodegradation of branched PLA with glucose or macromolecular polyol in rats is determined by weight loss (37).86). like the linear polymers (37). For ex. a. (77) demonstrated the complexicity of PLA. The most studied polymers in ported (82. Polymer cylin- and 85°C was reported (80). ders containing luteinizing hormone releasing hormone mers degraded faster than higher molecular weight poly. after 36 weeks the linear PLA contained about 21 polymers were evaluated in vivo for their capabilities as wt% water. Lower molecular weight poly. The poly. These poly- mers were developed originally as synthetic plastics to be degraded by microorganisms in the environment (85. were synthesized by direct polycondensation in the ab- ence linear PLA. this category are the polycaprolactones. Inc.L-mandelic absorbable sutures encouraged the evaluation of other acid (MA) and its copolymers with lactic acid were re. Synthesis Poly(ε-caprolactone) (PCL) has been synthesized from the anionic. 2.

only one alkoxide group (99). Polymer Properties (91. They are useful in im- with the increase in the lactide content in the polymer proving the phase morphology. the low molecular fragments and the small polymer parti- (B) cationic.1) and molecular weights above 50.92). Effective anionic reac. block and graft is insoluble in aliphatic hydrocarbons. the rapid biodegradation of PLA (95). Zn µ-oxo (89). polymer of 5000 miscible polymer blends. respectively. Inc.L and L. and λ-valerolactone and Ti. and 2-nitropropane. Et2O. stannous octoate. Like the lactide polymers. tors is shown in Scheme 3 (87). PCL and its copoly- mers degrade both in vitro and in vivo by bulk hydrolysis (101). and (C) coordination catalysts. BF3. diglycolide. and benzene ported by Feng and Song using bimetallic (Al. Biodegradation The biodegradation of PCL has been extensively studied in the past 30 years and several reviews are available (87. caprolactone.88). substituted caprolactones. The synthesis of polycaprolactones has been merization of ε-caprolactone (CL) and lactides (LA) recently reviewed (87. acylating agents. Block copolymerization of CL and LA was also re- and carboxylates in tetrahydrofuran. Degradable block copolymers with polyethylene glycol. toluene. The poly- mers degrade in two phases. alkyl sulfonate. The crystallinity of the polymer decreases with the and. the ultimate mechanical properties of im- increase in polymer molecular weight. The homopolymer formation can to yield polymers with a molecular weight range of 15. tained using coordination catalysts such as di-n-butyl zinc. like 2-propanol. accordingly. yield polymers with a narrow molecular weight distribu- tion (MW/MN ⫽ 1. hol. alkoxides) initiators (97. and alkoxides and halids of Al. In the first phase a random hydrolytic chain scission occurs. cles are carried away from the site of implantation by solu- Copyright © 2002 Marcel Dekker. block copoly- is 80% crystalline. The homopolymer melts at 59–64°C with a Tg rials with properties that are different from the homopoly- of ⫺60°C. and multicomponent systems are most often multiphase mate- alcohols.2-dichloroethane at 50°C CL and LA. cyclohexanone. Polycaprolactone was also obtained from the radi- Polycaprolactone is soluble in chlorinated and aromatic cal polymerization of 2-methylene-1. reactivity. The follow.L) and reported for each type of catalyst.000. and alkylating agents.000 polymer is 45% crystalline (101). FeCl3. Formation of large amounts cationic polymerization and include protic acids. allows the permeability of the PCL to be combined with rolactone polymerization using these three types of initia. (96). The kinetic equivalency of the degradation of PCL in buffer and in rabbit was demonstrated by measuring the polymer intrinsic viscosity for 60 weeks (87). Copolymerization with lactide increases the Tg mers or random copolymers (94).000 b. High molecular weight homopolymers and ran. hydrocarbons. . the interfacial adhesion (100). Polymerization occurs at 120°C under argon to were also reviewed (87). which results in a reduc- tion of the polymer molecular weight. alkali metal alkoxides. Lewis of homo-PLA is observed and has been attributed to the acids.000 be prevented by the addition of a small amount of an alco- to 50. and trimethyl. with the degradation rate affected by the size and shape of the device and additives. The anionic method of polymerization is most use. Because of the difference in ful for the synthesis of low molecular weight hydroxy.102). As an example.98).3-dioxepane (93). or the use of Al derivative that bears dom copolymers with lactides and other lactones were ob. alkoxide in toluene from one to three in the presence of silyl triflate. A schematic description of cap. whereas the 60. diethyl ether. increase in the mean degree in association of aluminum ing agents. nomers can only be achieved when CL is first polymerized Known cationic catalysts in organic synthesis affect followed by the lactide (99). Mg. and it In contrast to random copolymers. In the second phase Scheme 3 Polymerization of ε-caprolactone using (A) anionic. c. ε-caprolactone using aluminum isopropoxide as initiator tion systems are tertiary amines. Sn. the sequential polymerization of these two mo- terminated oligomers and polymers (90). Block copolymers of CL and LA were synthesized by Various initiators and polymerization conditions were ring-opening polymerization of lactides (D. have been used in 1.

Synthesis of 5-fluorouracil (5-FU) (110). In vitro of Alcaligenes eutrophus were determined using x-ray and release of 5-FU from poly(ethylene carbonate) pellets con- variable-temperature 13C NMR relaxation studies (108). bilization in the body fluids or by phagocytosis. They are linear thermoplas- tic polyesters of carbonic acid with aliphatic dihydroxy Poly(β-hydroxybutyrate) (PHB) is made by a controlled compounds. Properties and Biodegradation. Complete degradation and elimina. [n] ⬎ 3 dL/g) with a narrow polydis. No visible inflam- 3HV melts at 91°C. while weight (⬎100. and only an additional 15% of 5-FU were released around ⫺40°C in its ‘‘native’’ state within the granules. These data indicate that poly(ethylene mer with 4HB melts at 159°C. acid or tertiary amines to the polymer. The fer at 85°C. poly(propylene carbonate) remained intact after 60 days. caligenes eutrophus (106. mer eroded under these conditions.107): b.104). Block copolymers of trimethylene carbonate (TMC) and Copyright © 2002 Marcel Dekker. The producing organism occurs naturally. mer pellets were determined. which The hydrolytic degradation of HB polymers was studied results in a weight loss. The rate of higher fraction of 3HV and low molecular weight poly- degradation can be increased also by the addition of oleic mers were more susceptible to hydrolysis. sludge show the rate of degradation to be in the following Copolymers of aliphatic carbonates and lactide showed order: P(3HB-co-9% 4HB) ⬎ P(3HB) ⫽ P(3HB-co-50% excellent biocompatibility and mechanical properties. Random copolymers of 3HB and 4HV were pro. during the following 60 days. Polycarbonates Poly(ethylene carbonate) and poly(propylene carbonate) 3. bacterial fermentation.000. and the 1: 1 copolymer with carbonate) was degraded by enzymes. . and after 5 months 20 to 40% of the poly- degradation rate is significantly increased by copolymer. Copolymers having a ization or blending with lactide and glycolide. the biodegradability of polycarbonates has been stud- ied (110. Biodegradation Since the carbonate linkage may be labile to hydrolysis. Microspheres degraded slowly in phosphate buf- tion of PCL homopolymers may last for 2 to 4 years. both polymers did not degrade polymer melts at 177°C with a Tg at 9°C. 20% of the drug was released Polyhydroxybutyrate is an amorphous elastomer with a Tg in 2 h.111). taining 20% 5-FU was poor. P(3HB) homo. An optically active copolymer of 3-hydroxybu. persity and a crystallinity of around 50%. 3HV). Poly(β-hydroxybutyrate) have been tested as biodegradable carriers for the delivery a. which catalyzes the chain hydrolysis (103. The polymers are synthesized from the reaction of dihy- genes eutrophus (105): droxy compounds with phosgene or with bischlorofor- mates of aliphatic dihydroxy compounds by transesterifi- cation and by polymerization of cyclic carbonates: The copolymer compositions (0 to 95 mole% 3HV con- tent) can be controlled by the composition of the carbon These polymers have been synthesized from carbon diox- sources. (109). a. even after 40 days. the 91: 9 copoly.4 and 37°C. The PHB properties in the living cells matory reaction was noted at the implantation sites. 4. Better release profiles were The biodegradation of these polymers in soil and activated obtained when poly(propylene carbonate) was used. and the toxicity and weight loss of poly- b. The melting When pellets of the polymers were incubated in phosphate point depends on the polymer composition. buffer pH 7. Pellets of poly(ethylene carbonate) and poly(propylene carbonate) were implanted into the perito- neal cavity of rats. ganometallic compounds as initiators (111). Inc. Poly(ethylene carbonate) was The polymers are characterized as having a high molecular completely eliminated 15 days postimplantation. ide and the corresponding epoxides in the presence of or- duced from 4-hydroxybutyric acid and butyric acids by Al. Synthesis tyrate (3HB) and 3-hydroxyvalerate (3HV) has been pro- duced from propionic acid or pentanoic acid by Alcali.

and a homologous series of tyrosine-derived polymers is mers. Copolymers of glutamic acid and ethylglutamate were used for the delivery of naltrexone (129). Polymers carboxyanhydrides of γ-benzyl-L-glutamate and γ-ethyl- of 50. bonate) from tyrosine dipeptide as monomeric starting ma- ring. especially natu- ral proteins. Inc. Synthesis and Biodegradation The utilization of amide-based polymers. The poly- The molecular weights of the polymers were highly de. multifunctional hydroxy acids and amino acid have terial. (3) debenzylation of the intermediate. produced by Domb et al. biodegradability. crystallinity and controlled number of Poly(amino acids) are generally hydrophilic. Other Polyesters a direct melt condensation of the acids with the diols with Poly(dihydropyrans) were developed for contraceptive de. A series of polyesters. linked in a ratio of 30 wt% PPF to 70 wt% calcium carbon- ate–tricalcium phosphate mixture and were synthesized by 5. The mono. 1. poly(propylene fumarate) (PPF). protected trans-4-hydroxy-L-proline. The polymers were cross- They completely degraded in vivo in 1 year (112). however. acid groups in the polymer chains can be used to alter wa- mers with stannous octoate as catalyst at 160°C for 16 h: ter swellability and solubility of the polymers. The properties. and. . lactide were synthesized from the reaction of the mono. and poly(iminocar- Biodegradable polymers derived from naturally occur.119) with different aliphatic diols have also been evaluated as drug carriers. in the preparation of biodegradable matrices has been extensively investigated in recent years (121). Nathan and Kohn (125) have excellently reviewed the history of amino acid–derived polymers. Poly(propylene The polymers were soluble in common organic solvents fumarate) with acrylate and epoxide terminal groups was and had a weight average molecular weight of 90. and their deg- Copyright © 2002 Marcel Dekker. The structures of poly(N-acylhydroxyproline esters) been investigated by Lenz and Guerin (115). drug release. mers were synthesized in three steps: (1) synthesis of N- pendent on the purity of the cyclic monomers. duced. The synthetic ability to manipulate amino acid se- Poly(p-dioxanone) is clinically used as an alternative to quences has seen its maturity over the last two decades. and aspartic acid were polymerized into described in Scheme 4 (121). poly(lactide) in absorbable sutures with similar properties with new techniques and strategies continually being intro- to poly(lactide) with the advantage of better irradiation sta. (2) polyamidation of the benzyl blocked very pure monomers were used. Both polymers are water monomers. malic acid. and bio- tion process as follows: compatibility of this class of polymers have been reviewed (121. who prepared a polyester from N- controlled drug delivery. Microcapsules and microspheres of crosslinked collagen.2′- bis[5(4HO-oxazolones] and alkane diamines (128). Biocompati- bility evaluation in mice indicated that poly (β-malic acid) is nontoxic (115).000 were obtained in 93% polymerization yield when L-glutamate.127). Drug release time from these polymers was short. were first suggested by Kohn This polymer has not yet been developed as a carrier for and Langer (126. a new approach for biomate- rials based on amino acids. livery. less then 24 h. and tartaric acid (118.000. and albumin have been used for drug delivery (122).117). a polyester or polyamide using a ring-opening polymeriza. soluble.122). (120). Poly(amides) been studied (113). Re- cently. The in vivo and in vitro release of contraceptive steroids and antimalarial agents from polymer matrices has B. Poly(amides) such as poly(glutamic acid) and poly- bility during sterilization (114): (lysine) and their copolymers with various amino acids have also been studied as drug carriers (123. Biodegradable polyamides for use in controlled delivery of drugs were obtained from the reaction of 2. gelatin. Pseudopoly(amino acids). acid catalysis. based on the reaction product of fumaric acid (116.124).

Negligible weight loss was detected without the enzyme. The copoly- period of months and rates are comparable to the degrada- mer was biocompatible and completely degraded in 90 tion time of poly(L-lactic acid). Random copolymers of the α-amino acids N-(3-hydro- (A) Poly(N-acylhydroxyproline esters). were synthesized from the reaction of ethyl or phenyl phos- mer analogous to lactide (130). poly(CTTP). and bisphenol A as comonomer yielded polymers with a (lysine) graft. x ⫽ 15. and the polymers were completely dissolved in from several hours to several days as a function of polymer structure and enzyme concentration. Inclusion of the amino acid phorodichloridates and various dialcohols including bis- lysine provides an amino group that allows for further phenol A and poly(ethylene glycol) of various molecular modification of the PLAL system. Recently. In a further study. brittle to soft and tacky. Interfacial condensation using a phase transfer catalyst rivatives to increase the system’s functionality with a poly. in both in vitro radation rates are dependent upon hydrophilicity of the and in vivo experiments in rats (134).138). contacting biomaterials due to having a broad range of methyl-L-glutamate were synthesized from the reaction of physical properties that can be obtained. The degradation process involves hydrolysis of the ethyl esters followed by hydrolysis of the peptide bonds to produce glutamic acid. from hard and poly(γ-methyl-L-glutamate) and 2-amino-1-ethanol or 5. they have exploited the PLAL system by the reaction with lysine N-carboxyanhydride de. which enters the metabolic cycle. have incorporated phosphoester groups into poly(ure- from porous particles (132). Poly(phosphate Esters) Amino acids are attractive due to their functionality by which they provide a polymer. For example. copolymer containing 13 shown a high degree of tissue biocompatibility (135. In a recent report. Poly(phosphoester) has been studied as a potential biode- co-lysine) (PLAL) was synthesized using a stannous oc. Cook weights: and coworkers (131) have successfully attached a peptide sequence which promotes cell adhesion to PLAL. gradable matrix for drug delivery (137. poly(CTH). Scheme 4 Molecular structure of pseudopoly(amino acids). C. Leong et al. Naltrexone was released from the polymer in a relatively constant way for 30 days. x ⫽ 4. Degradation goes over a copolymer were used as a reservoir implant. drolysis of the pandent ester bonds and the imino–carbon- Tubular capsules of 18 :82 glutamic acid/ethylglutamate ate bonds of the backbone (136). mole% glutamic acid remained intact for more than 79 In vitro degradation of these compounds occurs due to hy- days. weight average molecular weight around 36. Poly(lactic acid-co-lysine) has been formu. poly(CTTE). while the 40% copolymer disintegrated in 7 days. days. thanes) (139). Leong et lated into microspheres that exhibit deep lung delivery al. . (B) Tyrosine-derived xypropyl)-L-glutamine and L-leucine were synthesized polyiminocarbonate. and used as carriers for naltrexone (134). Inc. poly(carbonates) are readily processible polymers that sup- The degradation rate increases as the glutamic acid con- port the growth and attachment of the cells and have also tent increases.136). poly(lactic acid. x ⫽ 1.000. designed inert bioma- amino-1-pentanol as follows (133): terial for controlled release applications by introducing Copyright © 2002 Marcel Dekker. The use of N-carboxyanhydride–activated amino acids was the first efficient method for production of amino acid homopoly- mers. Poly(urethanes) have been used as blood Copolymers of n-hydroxyalkyl-L-glutamine and γ. The polymers toate catalyst from lactide and a lysine-containing mono. Naltrexone was covalently bound through the 3-phenolic or the 14-tertiary hydroxyls to the polymer hydroxyl side chains via a car- bonate bond. The in vitro enzymatic degradation using pronase E as protease showed that these polymers degrade from the sur- face. Tyrosine-derived amino acids.

and medical applications of polyphosphazenes was published by Allcock (144). (147). (148. Allcock et al. Several polymer structures have been used as matrix carri- ers for drugs (141. Polyphosphazenes The uniqueness of the polyphosphazenes stems from the inorganic backbone (N C P). and car. 1. where the drug is covalently bound to the polymer backbone and released from the polymer by hydrolysis (143). polymers with 153). Inc. observed that the glycinato)phosphazene]. 8 to 20% cortisone was released after poral controlled release of many drug classes including 75 days in buffer solution. phosphate. they show a tendency to decrease the of the polymer backbone and thus pentavalency of the molecular weight and mass loss with release of small mole- phosphorus contributes a site for future functionalization cules. mers containing mixed substituent can be obtained from the sequential or simultaneous reaction with several nu- cleophiles (Scheme 6) (145). Amino acid ester–substituted polyphosphazenes phenyl side chains degrade much slower than those con. degradation studies on poly(phosphazenes) with different Phosphoester bonds are readily cleaved under physio. degrade the material depending on the amino acid present urethanes) leads to phosphates. The first excellent biodegradable material. bioerodible polymer was the ethylglycinato derivative Poly(phosphoester-urethanes) are obtained by the reac. terization. and degradation of polymer. Introduction of the side groups. A comprehensive review on the synthesis. The in vivo degradation of these polymers in rabbits was faster than in vitro. on diffusion. The reaction is carried out in general at room temperature in tetrahydrofuran or aromatic hydrocarbone solutions. Biodegradable poly(phosphazenes) that are insoluble in The polymers based on bisphenol A release drug for a water prior to hydrolysis have been employed in the tem- long period of time. and organometallic molecules (Scheme 6). release kinetics of poly(phosphoester-urethanes) were in. Poly- Scheme 5 Synthesis of poly(phosphoester-urethanes). The release of small molecules occurred through dif- (140). The degradation rate depends nonsteroidal anti-inflammatory agents and peptides (150– on the nature of the polymer side chain. poly[di(ethylalanato)phophazene]. alcohols. The release mechanism was dependent combinedly fusion and decomposition of polymer. In vitro chain extenders as shown in Scheme 5. The properties of the polymers depend on the nature of phosphoester linkage in poly(urethane). and ammonia (146). charac. Scheme 6 Synthesis and hydrolysis of polyphospazenes. which with certain organic side groups can be hydrolyzed to phosphate and ammonia. .149) synthesized three differ- bon dioxide. and poly[di(benzylalano)phosphazene]. glycine. amines. swelling. which hydrolytically degrades to tion of polydiols and di-isocyanates with phosphates as ethanol.142) or as a hydrolyzable polymeric drug. Copyright © 2002 Marcel Dekker. (R C NHCH2COOEt). and hydrolysis of poly(phosphoester. D. Hydrolytically degradable polyphospha- phosphoester linkage does not change the mechanical zene was obtained when amino acid and imidazole de- properties inherent in the poly(urethanes) and provides an rivatives were used as substituents (142. According to the fluenced by the side chains attached via the phosphoester order of polymers.146). have been used for controlled release of the covalently taining ethyl or ethoxyethyl side chains (138). which makes it an excellent biomaterial for ent poly[(amino acid ester)phosphazenes]: poly[di(ethyl- drug delivery applications. amino acid derivatives show that it takes several months to logical conditions. alkoxides. Synthesis and Biodegradation The polymers are most commonly synthesized by a substi- tution reaction of the reactive poly(dichlorophosphazene) with a wide range of reactive nucleophiles such as amines. Leong et al.

Andianov and coworkers have synthesized poly v-butyrolactone (165). These objectives could only be met if the polymer were truly surface eroding. An in vivo release study in rats using radio.5 to 2 h and then labelled progesterone demonstrated a zero-order release further heated at 180°C and 0. as follows (164): noxy groups (141). ate crosslinked polyphosphazene for temporal controlled Hydrolysis of these polymers regenerates the diol and release. These polymers order kinetics for at least 6 months (159). 4-methylphenoxy–substituted polyphospha- zene matrices were reported (141). For a surface-eroding polymer. To exhibit a hydroxyl group were bound to the polymer chain through such a phenomenon. by a transesterification reaction. and thus further work was discontinued (166). Swelling at were investigated as bioerodible implants for the release different pH values was controlled by varying the ratios of naltrexone and contraceptive steroids. and various drug–polyphosphazene conjugates have one alkoxy group has a greatly reduced reactivity. developed not related to Alzamer (168). Synthesis nanoparticles that present covalently coupled poly(ethyl- ene glycol) at their surface (156). Human clinical of the two side groups (158). another family of poly(orthoesters) was that would release contraceptive steroids by close to zero. provide a surface-eroding polymer if the interior of the ma- priate selection of amino acid side chain groups (155). Inc. trials of the steroidal implant revealed local tissue irri- tation. reaction. hydrogels. water-soluble polymers. This can been reviewed (144). could and rates of degradation have been controlled by appro. The synthe- for 30 days. objective was that the polymer erosion and drug release The general reaction can be schematically represented as should be concomitant so that no polymer remnants are follows: present in the tissue after all the drug has been released. drophobic with very labile linkages. the polymer has to be extremely hy- the hydroxyl group (154). it was envi- Poly(organophosphazenes) have been synthesized that sioned that polymeric devices with an orthoester linkage possess amino acid side groups.4 at 37°C. linkage. E. with a minimal amount of cross- mers. subdermally implantable. The trix is buffered with basic salts. the erosion process at the surface of the polymer should be Copyright © 2002 Marcel Dekker. Steroids having much faster than in the interior of the device. Recently. The poration. These proprietary polymers were first designated rate of hydrolysis can be slowed by the incorporation of as Chronomer and later as Alzamer. Poly(orthoesters) Recently the use of these polymers for the release of indomethacin in the prevention of reossification of experi- Poly(orthoesters) were invented during the pursuit of de. bioactive poly. ents by Choi and Heller (160–163). The mechanical properties in the backbone. This butyric acid would further catalyze the breakdown of polymer allowed drug molecules to be encapsulated into orthoester linkages leading to bulk erosion of the matrix. Subsequently. Almost 90% of the loaded progesterone was released in 30 days with about 60% released in 8 days when placed in phosphate buffer The general synthesis involved the heating of the reaction pH 7. Hence. poly(phosphazene) microspheres under mild environmen. These Alzamer materials oxybenzoate and methoxyethoxy side group. . An additional are prepared by the addition of polyols to diketene acetals. They were prepared hydrophobic side groups such as phenoxy or methylphe. sis of such polymers. The production of -hydroxy- Ca2⫹ ions for an ionically stabilized system (157). veloping a bioerodible polymer. assigned to Alza Cor- cally unstable and hydrolyze in room moisture (142). pH-sensitive hydrogels have been mer matrix to neutralize the generated acid and keep the synthesized by the formation of poly(phosphazenes) with hydrolysis process under control. Thus it was decided to incorporate basic salts into the poly- tal conditions. be achieved by using a cyclic structure as shown in the A number of approaches have been proposed to gener. The γ-butyrolactone rapidly hydro- [bis(carboxylatophenoxy)-phosphazene] crosslinked with lyzes to -hydroxybutyric acid. Various hydrophilic and hydrophobic poly. bonded anti-inflammatory agent naproxen. which is an acid-sensitive linkage. The in vivo and in vitro release of progesterone and bovine serum albumin (BSA) from imidazole. versatility of these polymers has been demonstrated by the formation of 200-nm diameter poly(organophosphazene) 1. mental bone defects was reported (167).01 torr for 24 h. The first poly(orthoesters) were reported in a series of pat- Imidazolyl-substituted polyphosphazenes are hydrolyti. requires an orthoester starting material in which mers. mixture to 110 to 115°C for about 1.

There seems to be a linearly decreasing rela- tionship between the Tg and percentage of 1. It was shown that the glass transition temper- ature of the polymer prepared from DETOSU can be varied from 25 to 110°C by simply changing the amount of 1.6-hexanediol. duces highly flexible polymers that have ointmentlike This can result in the loss of stiffness and rigidity of the properties even at relatively high molecular weights. This can be a good method for incorporating 2. there should be at least mentlike consistency at room temperature and is applicable one monomer which has a functionality greater than 2.4-cyclohexane dimethanol. Initial work was conducted with the monomer.000 (169). whereas bisphenol and one removed by at least three methylene groups with A in the presence of catalyst gave molecular weight only an alkyl orthoacetate as shown: around 10. could be incorporated into the prepolymer along with the hexanediol. and hydrophobicity can be readily varied by controlling molecular weight and the 3. The reaction is exothermic and proceeds to completion vir- tually instantaneously. (172) have re- cantly dependent on the type of diol and catalyst used for ported the family of poly(orthoesters) which can be pre- synthesis. Polymer Properties thermolabile drugs. properties such as viscosity. replaced the flexible to the difficulty in preparing trifunctional ketene acetals. ethylene glycol.8. it is possible for a ketene acetal corporated into the polymer without use of solvent. liquid at room temperature. or an alcohol to have a functionality greater than 2. diketene acetal. A linear. The prepolymer is an acetal with a diol and is a viscous aspiro [5. In a series of experiments.6-hexanetriol pro- Tg of the polymer would drop due to inbibition of water. where R ⫽ H. for 3. to obtain a solid poly(orthoester).4-cyclohexanetrimethanol triols were used to prepare the crosslinked polymer.6.10-tetra ox. Heller et al. The reaction is as follows: Scheme 7 Synthesis of crosslinked polyorthoesters.4-cyclohexane dimethanol from 100 to 0% (170). The general method used for the synthesis of cross- linked polymers was by reacting prepolymer with the triols or a mixture of diols and triols (Scheme 7) (171). and 1. Heller et al. Crosslinked Poly(orthoesters) size of the alkyl group R′. triol to a rigid one such as 1.6-cyclo. and biophenol A. The molecular weight of poly(orthoesters) were signifi. ever. Thus. one should be cautious with using compounds with hydroxyl functionality. Mechanical properties of the linear poly(orthesters) can be varied over a large range by selecting various composi- tions of diols.6-hexanediol gave pared by reacting a triol with two vicinal hydroxyl groups molecular weights greater than 200 K. as shown: Copyright © 2002 Marcel Dekker.6-hexanediol. Inc.1. However. 1. flexible diol like 1.6- hexanediol in trans-1. How- polymer. One could take advantage of this relationship in selecting the polymer for in vivo applications because in vivo the The use of flexible triols such as 1. triol. .5] undecane).9-bis(methylene 2. and the mixture can be crosslinked at temperatures as low as 40°C. the compound of interest hexanediol trans-1.4.2. This polymer has an oint- To prepare a crosslinked polymer. In where sensitive therapeutic agents such as proteins are in- case of poly(orthoesters). The diols investigated were 1. derived form pentaerythritol. Due In another experiment.

The reaction led to the decrease in Acid-catalyzed hydrolysis of these polymers can be concentration of phthalic anhydride. Incorporating acid anhydrides into the polymers. The pentaeryth. While. Polyanhydrides trolled release of tetracycline over a period of weeks in the treatment of periodontal disease (174). suberic acid. Alternatively.g. which are designed to erode within days (177). and pentaerythritol observed. (176) proposed the hydrolysis of poly (orthoesters) derived from 1. because of the polymer’s highly hydrophobic nature.8. Thus.9-bis(methylene-2.. basic excipients stabi. Using high-performance liquid chromatography matrix to accelerate the rate of hydrolysis uses this prefer.6-hexanetriol as follows: 4. Inc. if injection molding is necessary to fabricate the device. thus no autocatalysis is products are diol. the devices.6-hexanediol and trans-cyclohexane dimethanol to stabilize the interior of the matrix. lize the bulk of the matrix but diffuse out of the surface region. F. One should also consider the interaction between the incorporated anhydride as cata- lysts. or a mixture of diols. the hydrolysis duce a carboxylic acid and a triol. and infrared spectroscopy the formation of half phthalate ential sensitivity. vestigated as carriers in the design of controlled drug deliv- tain glycolide sequences and can be degraded hydrolyti. e. Depending on the reactants This initial hydrolysis is proceeded at a slow rate to pro- used during the synthesis of the polymer. was confirmed (178). Even though the polymer is relatively stable in trace amounts of moisture. a base is used esters of 1.4. and the drug during the thermal pro- The difference in the sensitivity of the hydrolysis of cessing. This approach has been used in the temporal con. This would include solution mixing strated by the zero-order release of 5-fluorouracil over a or powder blending followed by compression molding of 15-day period (173). 5. described A large number of biodegradable polymers have been in- the synthesis of self-catalyzed poly(orthoesters) that con. . they can be stored without careful ex- clusion of moisture. orthoester linkages in an acid versus alkaline medium has In one of the studies it was shown that phthalic anhy- been used to advantage in designing the orthoester-based dride reacted with the free hydroxyl end groups of the delivery systems. Ng et al. it is unstable to heat and undergoes disproportionation to an alcohol and ketene acetal. Polymer Processing ritol esters hydrolyze at a slower rate to pentaerythritol and the corresponding acetic or propionic acid. dipropronate or diacetate if 3. The preferred method for the matrices. The sequence The orthoester linkage is inherently unstable in the pres- of reaction is as follows: ence of water. then moisture must be rigorously excluded during fabrication. on the other hand. shear stresses (179).2. leading to increased controlled by introducing acidic and basic excipients into time for erosion of the matrix.5]undecane) was used (144). as demon. Wuthrich et al. The combination of moisture and heat can be fatal for the pro- cessing of poly(orthoesters). ery systems. Rate of hydrolysis can be increased by the fabricating the devices would be under low thermal and addition of acidic excipients. It has been generally recognized that the cally without excipient catalysis (175). matrix should undergo heterogeneous degradation to max- Copyright © 2002 Marcel Dekker.10-tet- raoxaspiro [5. the polymer. Polymer Hydrolysis The primary mechanism for the degradation of poly (orthoesters) is via hydrolysis. However.

185) and then followed by Yoda and less than 1 h. ers (182. mers were obtained using pure isolated prepolymers and plications in controlled drug delivery. active diacids. using a dry ice/acetone trap. Molecular weights in as the early 1900s. did not show any effect on polymer mo- extreme reactivity of anhydride linkage toward water. The dehydrative study was undertaken to determine the factors that affected coupling agent. It was found that the chloride was the most effective in forming polyanhydrides critical factors were monomer purity.187). The solvents employed can be a single solvent or a mixture of solvents like dichlo- romethane. The majority of the polyan. pyridine caused a decrease in molecular weight. This ten–Baumann technique. (180) envisioned the use of hydrophobic poly. of a dicarboxylic acid. Hill and Caroth. excess of 125. . For most practical applications high molecular monomer into the polyanhydride using a dehydrative cou- weight polyanhydrides are desirable. heating them at 180°C for 90 min with a vacuum of 10⫺4 tion and development of polyanhydrides dates as far back mmHg. temperature.000 Systematic development of polyanhydrides as substitutes to 240. sensitive monomers such as dipeptides and therapeutically quence of reaction involves first the conversion of a dicar. cally unstable renders them useful in drug delivery applica- Solution polymerization.5 to 3 mole%.000 when the concentration of cadmium acetate was for polyesters in textile applications was undertaken ini. Inc. such as p-tolu- were not suitable for textile applications because of the ene sulfonic acid. Bucher and Slade (181) reported the develop. boxylic acid monomer into a prepolymer consisting of a The solution polymerization is carried out by the Scot- mixed anhydride of the diacid with acetic anhydride. and ethyl ether. Hence. These polymers were dark brown in color. the inven. The se. In this method the solution of di- is achieved by simply refluxing the diacid monomer with acid chloride is added dropwise into an ice-cooled solution acetic anhydride for a specified length of time. The lecular weight. such as titanium and iron. Syntheses of polyanhydrides tions (187–189). benzene. They prepared and studied a number of inhibited the polymerization reaction and the polymers aromatic and heterocyclic polyanhydrides. chloroform. thesize polyanhydrides under ambient conditions for heat- hydrides are prepared by melt polycondensation. using melt polycondensation is useful to obtain high mo- lecular weight polymers but is not useful if the monomers a. earth metal oxides. Polymerization under vacuo to eliminate the acetic anhydride (190): takes place instantly on contact of the monomers and is essentially complete within 1 h. Significantly higher molecular weights were obtained ment of aromatic polyanhydrides composed of isophthalic in shorter times by using coordination catalysts such as acid and terephthalic acid. chloride monomer should be of very high purity. In 1909. Addition of a diacid solution dropwise to the diacid chlo- ride solution consistently produced high molecular weight polymers (192): The drawback of this homogeneous Schotten–Bau- mann condensation reaction in solution is that the diacid This procedure was used by most of the early investigators. Hence. N′N-bis[2-oxo-3-oxazolidinyl]phosphonic the polymer molecular weight (191). reaction time and with the degree of polymerization around 20 (193). The reaction is facilitated by using mer is obtained subsequently by heating the prepolymer an acid acceptor such as triethylamine. Other catalysts.183) reported a series of aliphatic polyanhydrides. imize the control over release process.000 were obtained. The poly. a systematic pling agent under ambient conditions. uct. However. The highest molecular weight poly- anhydrides in designing the surface-eroding matrix for ap. and ZnEt2⋅H2O (159). Subsequently. methods were developed to syn- Melt polycondensation. It is Copyright © 2002 Marcel Dekker. changed from 0. In the early 1980s. Acidic catalysts. Synthesis are thermolabile. An alter- The polyanhydride thus obtained was of low molecular native approach was the conversion of dicarboxylic acid weight. The weight average molecular weight varied from 90. acetic anhydride. with the reaction time of tially by Conix (184. and an efficient system to remove the byprod- Rosen et al. Miyake (186. cadmium acetate. It was found that the order of addition is very important in ob- taining relatively high molecular weight polyanhydrides. while the basic catalyst 4-dimethyl amino fact that they are extremely hydrophobic and hydrolyti.

For this type of copolymer C6H4EO(CH2)xECOE)n were prepared with x varying there is characteristically a minimum Tm between 5 to 20 from 1 to 10. such as sebacic acid. as determined by differential scan. Copolymers with a composi. in the case of the poly[bis(p-carboxyphenoxy)alkane] mer of highest concentration.. The propane (CPP). The melting To achieve a variety of degradation rates.. The degradation can be slowed by increasing the methy- mers were highly crystalline and the crystallinity of the lene groups into the backbone of the polymer. The advantage of the unsaturated polyanhy- drides is that they can undergo secondary polymerization Ring-opening polymerization. constant erosion kinetics. The de- Copyright © 2002 Marcel Dekker. In general. into the polymer. by the mono. The degradation rates of the mopolymers of sebacic acid (SA).3. series. and the ero- The melting point. the hy- ity as manifested by their crystalline melting points. bis(carboxyphenoxy)hexane (CPH) and degradation rates can be enchanced by incorporating the fumaric acid. sion rates (202). Hydrolysis of monomeric anhydrides is catalyzed NaH) and coordination-type inhibitors such as stannous- by both acid and base.5- such as dichloromethane and chloroform. A disadvantage omatic diacids (199). in presence of moisture to generate the dicarboxylic acids AlCl3 and BF3⋅(C2H5)2O] anionic (e. It is believed that the poor solubility of the oligomeric products. and the copolymers of SA with CPP. aliphatic polyanhydrides and their copolymers are aromatic monomers were prepared. However. bis(carboxyphenoxy) polyanhydrides can be altered in a number of ways.g. copolymers of two different water. sion rates underwent a decrease of three orders of magni- ning calorimetry. noxy) ethane anhydride] showed a tensile strength of 40 chloric acid. tricarboxylic acid or low molecular weight poly(acrylic omatic polyanhydrides display much lower solubility than acid) (203). the first step is preparation of the cyclic monomer and the second is polymerization of the cyclic monomers. The data on mechanical properties of polyanhydrides ization byproducts which have to be removed by washing are very limited. A systematic study on the tensile Coupling agents such as phosgene and diphosgene strength of the copolymers of CPP and SA showed that could also be used for the polyanhydride formation. increasing the CPP content in the copolymer or the mo- merization of sebacic acid using either phosgene or diphos. Polymer Hydrolysis coworkers prepared adipic acid polyanhydride from cyclic Anhydride linkage is extremely susceptible to hydrolysis adipic anhydride (Oxepane-2. Poly. the hydrolytic degradation rate of 2-ethylhexanoate and dibutyltinoxide (195–197). developed to improve the mechanical properties of the erogeneous base K2CO3 (194). increased the hydrophobicity of the polymer. lecular weight of the copolymer increased the tensile gene as coupling agents with the amine based hetero. For exam- copolymers was determined. Polymer Properties low pH conditions. bility compared to the corresponding homopolymers of ar- fore use and should be freshly prepared. strength (177). In an attempt to improve the Apart from the reactivity of anhydride linkage toward solubility and decrease the Tm.7-dione) using cationic [e. The washing by protic solvents may evoke kg/mm2 with an elongation of 17.g. . increasing the methylene groups from one to six tion close to 1:1 were essentially amorphous (198). These copolymers dis. of aromatic polyanhydrides are much tude. The fibers of poly[1. essential that the catalyst be ground into fine particles be. Inc. Ring-opening poly- of the double bonds to create a crosslinked matrix (200) merization (ROP) takes place in two steps. aliphatic aro- point of the aliphatic aromatic copolyanhydrides is propor. ulus of 505 kg/mm 2.2-bis(p-carboxyphe- with protic solvents such as methanol or cold dilute hydro. the aliphatic polyanhydrides.2% and a Young’s mod- some hydrolysis of the polymer. Albertsson and c. conditions in the solid state and in solution (204). in most cases. CH3COO⫺K⫹ and (201). aliphatic monomer. The results indicated that the homopoly. the ar. CPH. pedes the degradation of the core. higher than the aliphatic polyanhydrides. and fumaric acid. polyanhydrides increases with increase in pH. Increasing the value of x decreases the ero- mole% of the lower melting component (191). An in drophobic polymers such as P(CPP) and P(CPH) display depth x-ray diffraction analysis was conducted with the ho. under b. ple. Unsaturated polyanhydrides of the structure geneous acid acceptor poly(4-vinyl pyridine) produced [E(OOCECHCCHECO)xE(OOCERECO)y]n were higher molecular weights in comparison to nonamine het. Increased erosion rates were also observed The majority of polyanhydrides dissolves in solvents when poly(sebacic acid) was branched with either 1. of this method is that the final product contains polymer. polymers. formed at the surface of the matrix im- Almost all polyanhydrides show some degree of crystallin. found to undergo self-depolymerization under anhydrous played a substantial decrease in Tm and an increase in solu. matic homopolyanhydrides of the structure E(OOCE tional to the aromatic content.

The homopolymers are viscous showed good thermal resistance but were essentially insol. polyanhydrides points as a function of SA content. suggesting that inter. Several differ- materials rendering them questionable materials as a car- ent techniques have been developed for the preparation of rier in drug delivery systems. fatty acids. They anhydride polymerization. One must consider the thermal sta- anhydride. However. and the copolyanhydrides of the respective diacids. These chips are fed into the in- matic diacid is first converted to the diacetyl derivative jection molder to mold the drug–polymer matrix into the by refluxing the diacid in the presence of excess acetic desired shaped device. 2-buta- aromatic characteristics. polymerization reaction mainly affects the high molecular A typical example of such an aromatic aliphatic mono- weight fraction of the polymer. were pre. The depolymerization rate is found to follow a first-order kinetics. maleic. dride with glycine: drous conditions. low melting points. The same group also de- In addition to the previously discussed aliphatic aromatic veloped polyanhydrides containing ester groups (211). and hydrolytic properties. Polyanhydrides synthesized from nonlinear hydropho- pared from aromatic acid anhydrides and x-amino acids. drides thus synthesized were of relatively low molecular weight. vents. and flexibility to the the aromatic aliphatic monomer. The polyanhydride- tween drug and polymer at the high temperatures of injec- imides thus obtained are very soluble in polar organic sol- tion molding. and acetone (212). Another class of polyanhydrides are based on natural mal. imide-diacids. accelerate with temperature. The diacetyl derivative is polymerized either by bility of the polymer and potential chemical interaction be- melt polycondensation or in solution. The polyanhy- (206). In an attempt to im. bacic acid forms solid polymers with increasing melting prove the solubility in more polar solvents. microspheres from polyanhydrides. A systemic study was reported in none. The polymer and drug can be ground in a Micro Mill grinder. the drug can be mixed into the molten polymer to form small chips of For the synthesis of polyanhydride. and sebacic Varying the number of methylenic units in the α-amino acid possessed desired physicochemical properties such as acids provided the variability in the aliphatic character of low melting point. which the starting monomers. The depoly- merized polymer can be repolymerized to yield the original polymer. the aliphatic aro- drug–polymer conjugate. they showed melt transitions at tempera- The preferred method of drug delivery. These new polyanhydrides were devel. bic fatty acid esters based on ricinoleic. including hot-melt On similar lines. Other Polyanhydrides than the room temperature (210). in many in- tures of 245°C and above (209). The dimers of oleic acid and eurucic acid are One of these new polyanhydrides is polyanhydride. liquids. The polymers are solu- were synthesized using imide-diacids containing aliphatic ble in chlorinated hydrocarbones. d. Copolymerization with increasing amounts of se- uble in most organic solvents (208). oped to improve their physicochemical. Polymer Processing Drug-incorporated matrices can be formulated either by compression or injection molding. sieved into a parti- cle size range of 90–120 µm and can be pressed into circu- lar discs using a Carver press. This requires the development of cient data are available on the hydrolytic stability of these microcapsules or microspheres of the drug. Inc. tetrahydrofuran. polymer formed in addition to biocompatibility and biode- Copyright © 2002 Marcel Dekker. in drug delivery systems. . mechanical. Aromatic homopolymers mer is the one obtained by the reaction of trimellitic anhy- show no sign of depolymerization when stored under anhy. liquid oils containing two carboxylic acids available for imides. and a glass transition higher e. several These polymers are in the early stages of development and other modifications of the backbone of the polyanhydrides have not been characterized with respect to their suitability have been reported.or intramolecular anhydride interchange takes place during depolymerization. insuffi- stances. ther. is by injection. also referred to as copolyimides (207). hydrophobicity. Alternatively. Along with that. and increase with polarity of the solvent (204). another research group has developed microencapsulation (205) and solvent removal technique polyanhydrides containing amido groups.

the possible tissue–implant interactions must be almost two decades ago. terminated polymer. not the polymer itself. Lam and coworkers (216. After up to 7 days. In the case of biodegradable ma. BIOCOMPATIBILITY AND TOXICITY in rats. A detailed analysis of the polymeriza. PLLA is found as an excellent biomaterial and safe for in vivo use because its degradation product L-lactic acid is a natural metabolite of the body. increased local acidity due to its degradation can lead to irritation at the site of polymer implant. . macromolecules with lactide/glycolide was observed. Physical mixtures of polyan. The last section of this chapter reviews existing data densation to yield film-forming polymers with molecular about the biocompatibility and toxicity of the different weights exceeding 100. which alters its proven. One of the most successful trices. The properties of polyanhydrides were modified by the The feasibility of lactide/glycolide polymers as excipients incorporation on long chain fatty acid terminals such as for the controlled release of bioactive agents is well stearic acid in the polymer composition. cells were harvested from the abdominal cavity. No evidence of inflamma- minimal effect on the polymer molecular weight. microspheres for the controlled release of contraceptives Copyright © 2002 Marcel Dekker. but also the potential toxicity of its degra. irritation. sphere dosage forms (16–23). an adequate testing for with PLA films than with PTFE films in subcutaneous tis- safety and biocompatibility of the specific polymer matrix sues of rats. Inc. the final product is essentially a stearic acid– also being investigated. gradable polymers for drug delivery. caused by phagocytosed PTFE particles.000 (213). especially as injectable micro- taken into consideration. is the steroid-loaded injectable dation products. They injected intraperitoneally in mice as well as III. Many conventional pharmaceutical agents formulated Whenever a synthetic polymer material is to be utilized in lactide/glycolide polymer matrices were widely studied in vivo. Agrawal and Athanasiou have in- troduced a technique in which basic salts are used to con- trol the pH in local environment of PLGA implant (215). The polymers were synthesized by melt con. Since natural fatty acids are monofunctional. However some limited incompatibility of certain not form uniform blends. Thus. not only the possible toxicity of the polymer have lactide/glycolide drug delivery formulations. phology revealed the evidence of cell damage and death tact between the polymer and biological tissues is evident. used in each case is essential. It was observed Therefore. clinical results obtained. although implantable rod and pellet devices are stearic acid. reported upon implantation of lactide/glycolide polymer hydrides with triglycerides and fatty acids or alcohols did devices. polymers actually available for biomedical applications. a direct con. in terms of to be evaluated. or other adverse effects have been remains in the range of 5000. focused on the development of injectable microsphere for- tion reaction shows that up to about 10 mole% content of mulations. for the eventual human application of these bio. gradability. they would Most of the research work on the use of lactide/ act as polymerization chain terminators and control the glycolide polymers as matrices for delivery systems has molecular weight. that there was more pronounced inflammatory response medical implants and devices. Whereas higher amounts of acetyl The lactide/glycolide copolymers have been subjected stearate in the reaction mixture resulted in the formation to extensive animal and human trials without any signifi- of increasing amounts of stearic anhydride byproduct with cant harmful side effects (211). Polyesters 1. A. Even though PLGA is extensively used and represents the gold standard of degradable polymers. Lactide/Glycolide Copolymers Biocompatibility of monomer is considered as the founda- tion for biocompatibility of degradable polymer systems. and they are the most widely investigated biode- hydrophobicity and decreases its degradation rate (214).217) studied the particles of PLA with particles of polytetrafluoroethylene (PTFE) as control. Microscopic examinations of cell mor- In all the potential uses of polymeric material. which tory response.

antibiotics. be effective in lowering blood glucose levels in diabetic ous implantation of the beads containing the drug (226). site and a minimal tissue-encapsulating reaction. In one of these studies describing the presence of lactide/glycolide excipients and their acidic bi- clinical evaluation of a bead preparation containing 70% oerosion byproducts. Many animal and clinical trials with these sys. the studies carried effects were observed (236).and 4% D-lactic acid in subcutaneous screw in 41% of the patients. mer. days were also observed with interferon–lactide/glycolide tion of several factors: the reproducibility of the microen. in the form of mi- mer. containing insulin were reported to tion was reported in two of three subjects after subcutane. (13) studied in vitro and in vivo biocom- were predegraded in vitro (229). ported in several cases where the macromolecules lost For example a 90-day female contraceptive based on nor. mer showing long-term delivery of the macromolecule Lactide/glycolide implants containing naltrexone and (232. and guinea pigs. and anti-inflammatory com. The degradation of co. The delivery of therapeutic molecules to the brain has been limited in part due to the presence of the blood–brain 2. no toxic cules as proteins. the in vivo drug-release performance. crobeads and pellets. including This finding prevented further clinical testing of that par. The biocompatibility and toxicity of poly(caprolactone) sponse following implants of lactide/glycolide copolymer have mostly been tested in conjuction with evaluations of into the brains of rats. lide) and PCL in the form of MONOCRYLR sutures. Prior to implantation. (228) reported the use of a copolymer reactions at the implant site and a ‘‘liquidization’’ of the made of 96% L. Clinically. rats for about 2 weeks. Lactide/glycolide polymer implants. the size 2/0 monofilament sutures implanted subdermally Good biocompatibility data were also reported with in rats. a local inflammatory reaction at the site of implanta. no febrile epi- tissues of rats for up to 52 weeks. promising capsulation process. (218–221). In a prelimi- copolymer is largely a consequence of the mechanical nary 90-day toxicology study of Capronor in female rats trauma that occurs during surgery (231). naltrexone and 30% of a 90 :10 lactide/glycolide copoly. patibility and efficacy of block coplymer of poly(glyco- polymer was faster than the homopolymer while inflam. except for a bland response at the implant Regarding the encapsulation of bioactive macromole. After 6 months. hydrophilic polypeptides of low mo- other narcotic antagonist agents have also been extensively lecular weight (⬍5000) are considered quite stable in the studied (224–227). The biocompatibility of lactide/glycolide copoly- mer in the brain was examined regarding the gliotic re. In general. Poly(caprolactone) barrier. Inc. when incorporated in poly(lactide) films. MRI data show the presence of local Bergshma et al. inflammation at the implant site or deactivation of the mac- ticular formulation. monofilament size 2/0 sutures retain 50% of their strength pounds (211). No similar problems were reported romolecule. and no adverse effects. . polymer formulation (211). discs made from the copolymer and homopolymer PLA Bezwada et al. problems in achieving long-term release have been re- tems were performed showing very good biocompatibility. peptides. whereas homopolymeric PCL plastic drugs. bioactivity in vivo after a few days. Serious The lack of an inflammatory response was confirmed Copyright © 2002 Marcel Dekker. It was found that lactide/glycolide Capronor. Using mation was observed with both (230). lactide/glycolide as the excipient has undergone successful A complex interaction apparently occurs in vivo between Phase I and Phase II clinical trials in various geographic the acidic polymer and the hormone. and the safety of the hormone (LHRH) incorporated in lactide/glycolide poly- polymer (223). as in the case of ethisterone as the active hormone and 85: 15 DL. In vitro release stud- areas. and antigens. strength after about 1 week. On the other hand. results were obtained with luteinizing hormone–releasing reliability in the treatment procedure. Similar problems The success of the steroid microsphere system based on in maintaining biological activity for longer than 5–10 lactide/glycolide matrices is probably due to the combina. after about 52 weeks. sodes or sterile effusions were observed. demonstrating safety and efficacy of the formulation ies have shown that growth hormone can become insoluble in about 300 subjects (222). lactide/glycolide copolymer containing growth hormone. MONOCRYL sutures retain 50% of their original lactide/glycolide copolymer matrices containing antineo. and that Toljan and Orthner (235) published details of the clini- incident was related to some unique aspect of that product cal use of an interference screw made from PGL copoly- (226).233). were observed (234). with other lactide/glycolide polymer preparations. out so far show mixed biocompatibility results. which is an implantable 1-year contraceptive copolymer is well tolerated following implantation into the delivery system composed of a levonorgestrel-ethyl oleate CNS and that the astrocytic response to lactide/glycolide slurry within a poly(caprolactone) capsule.

Only a ural polymers remain attractive primarily because they are few of them have been synthesized and characterized. studies describing gelatin systems. . No inflammatory reaction at the implantation site was flammatory reaction elicited by the sponges even in the observed in any of the mice during the first 7 weeks. implantation of four posite tissue–tendon allografts. by implanting polyvinyl alcohol sponges impregnated with Although many examples on the use of albumin micro- the powdered polymer in rats. esters. over a 12-week period (246). represent one of the latest and therefore less vent of synthetic biodegradable polymers (237–239). Inc. Histological Besides the collagen’s biocompatibility and nontoxicity examination of the corneas 4 weeks after implantation for most tissues (242). poly(N-palmitoyl hydroxyproline ester) was tested collagen has been used in many biomedical applications in a seriers of biocompatibility tests (248). following ophthalmic surgery. Copyright © 2002 Marcel Dekker. rel. in animal tissues where it is normally present in the form of In an initial evaluation of hydroxyproline-derived poly- aligned fibers. ophthalmoscopic tests. mild inflammatory response in one cornea. and histopathology after necropsy. A a 2-year period (87).245). advanced biodegradable polymers for medical use. tween the dermis and the adipose tissue layer. com. In the Ames mutagenicity spheres were reported in the literature. eral laboratories for medical applications ranging from bio- and albumin. and as drug delivery systems espe. such as absorbable sutures. Animal necropsies performed at 16 and clude its reported biodegradation into natural products. and its nonimmunogenicity (244. compared The Capronor–polycaprolactone contraceptive delivery with albumin. implantation for the presently available pseudopoly(amino ces in drug delivery systems have focused on the use of acids). and they are now being actively investigated in sev- proteins (polypeptides or polyamides) as gelatin. no clinical tests have thus far been conducted. connective tissue. ides) group. particularly albumin and to a around the implant by week 14 and. belonging to the poly(am- continues to be an area of active research despite the ad. continue to be developed as drug de. residual aldehyde crosslinking agents. based on animal clinical and physical data no untoward effects when injected intravenously into mice such as blood and urine analysis. A absence of drug (243). 5-fluoro. thin but distinct layer of fibrous connective tissue appeared Noncollagenous proteins. and poor patient tol. nounced rapid joint swelling occurred after the second and cently carried out in different medical centers (87). atively inexpensive. B. its 56 weeks postimplantation showed no histopathological lack of toxicity. The exploitable features of albumin in. gelatin offers the advantages of a good his- system was also tested implanted in rats and monkeys in tory in parenteral formulations and lower antigenicity. occasionally. ited a pathological response in three of them and a very cially in the form of microspheres (241). tissue irritation due to tory cells in the area around the implants (249). Collagen is a major structural protein found degradable bone nails to implantable adjuvants (121). In the rabbit cornea bioassay. Nat. In a second biocompatibility study. and natural products of living organisms. However. biocompatibility study with gelatin microspheres reported tensive study. and capable of a multitude of chemical preliminary promising results were obtained showing no modifications (240). subsequent injections. several factors such as the possible showed no invading blood vessels or migrating inflamma- occurrence of antigenic responses. multinucleated giant cells were associated with the fibrous livery vehicles. Poly(amides) 1. Because of its unique structural properties. showed no significant In a second study. Despite this. resulting in a chronic in. sponge wound dressings. For example. pro- Phase I and II clinical trials with Capronor were re. cutaneously in mice in the dorsal area of the animals be- uracil and bleomycin crosslinked sponges made from puri. gross toxicity or tissue incompatibility upon subcutaneous Most of the investigations of natural polymers as matri. collagen. abnormalities (248). when albumin microspheres were differences between the test and control groups. Natural Polymers 2. compared to no swelling when gela- tin microspheres were injected in the same way (247). 10-mg implants of erance of ocular inserts have adversely influenced its use poly(N-palmitoyl hydroxyproline ester) were inserted sub- as a drug delivery vehicle (241). a few lesser extent gelatin. readily available. The mice fied bovine skin collagen were implanted in rabbit eyes to responses were examined up to 1 year postimplantation test their possible use in preventing fibroblast proliferation (248). there are only a few assay polycaprolactone was negatively tested (87). injectables for facial re. The results of this second. injected repeatedly into the knee joints of rabbits. small pieces of the polymer into four rabbit corneas elic- constructive surgery. more ex. Pseudopoly(amino Acids) The use of natural biodegradable polymers to deliver drugs The pseudopoly(amino acids).

crylate (DMAEM) onto the poly(phosphazene) surfaces syl–tyrosine hexylester–iminocarbonate). study. not statistically different from the response observed for Biocompatibility and safety testings of these polymers polyethylene and poly(lactic acid). or poly(DTH. absence male wistar rats. A roughened interface was observed which was pen- Pseudopoly(amino acids) containing aromatic side etrated by new bone as early as 2 weeks postimplantation. and the degree of calcification around palmitoyl hydroxyproline ester) elicits a very mild. by subcutaneous implantation in animals have shown mini- In vitro attachment and proliferation of fibroblasts on mal tissue response. The phazenes have been mentioned as good candidates for use pins were implanted transcortically in the distal femur and in heart valves. However. ganic polymers (256). at a later time compatibility of AAm-grafted samples was greatly en- point. and carcinogenic apposition throughout the 26-week period of the initial activities. in a subcutaneous rat model. Copyright © 2002 Marcel Dekker. . hanced while an opposite behavior for DMAA-grafted iminocarbonate) was almost similar with the response samples was observed. Inc. ally low number of inflammatory cells at the bone–implant formed to evaluate possible systemic toxic effects. The connection between hydrophobicity dent chain length. and proximal tibia of New Zealand white rabbit for up to 26 as coating materials for pacemakers or other implantable weeks. fluorescent marker. How. teratogenic. was visualized by UV illumination of sections labeled with imal models. Two different types of polyphosphazenes are of interest as derived poly(iminocarbonates). Thus. indicate that the poly(N. showing no roethylene) (Teflon). local the implants was ascertained by backscattered electron mi- tissue reaction typical of a foreign body response. more in vivo testing and clinical trials implant sites. allergic interface. or any mutagenic. plant. and tissue compatibility has been noted for classical or- carbonate) pins and compared them to commercially avail. Polyphosphazenes gree of mechanical strength (121). After 7 days of postimplantation. bone activity at the implant–tissue interface are needed (144). the lack of fibrous capsule formation. and an unusu- ever. rabbit and mouse. additional safety and toxicity tests need to be per. Poly- of mice. conventional poly(L-tyrosine) phosphazenes bearing fluoroalkoxy side groups are some served as a control (250). the biological response observed for poly(DTH. In this study. Graft polymerization with dimethylaminoethylmetha- compatibility of solvent cast films of poly(desaminotyro. but unlike Teflon polyphosphazenes gross pathological changes from visual inspection of the of this type are flexible or elastomeric. Silver et al. easy to prepare. blood vessel prostheses. In order to test the tissue compatibility of tyrosine. a (DMAA) and acrylamide (AAm) (254). Tissue around the implantation site was of gaint cells. active bond remodeling at the surface of the degrading im- dence for any significant pathological abnormalities. In addition to routine histological evaluation of the devices. Bio- for poly(DTH-iminocarbonate). The tissue re.L-lactic acid) served as controls. with Teflon (255). Such polymers are as hydrophobic as poly(tetrafluo- with poly(N-palmitoyl hydroxyproline ester). However. compatibility assay were very similar to those observed 252). and a low inflammatory cell count and was evaluated by histological examination after 25 days. hanced biocompatibility in comparision to nonmodified ing the significantly faster degradation rate of poly(DTH. high-density polyethylene (HDPE) and medical polyethylene glycols was heading to materials with en- grade poly(D. resulting croscopy. solvent cast films of bioinert materials: those with strongly hydrophobic surface poly(CTTH) were subcutaneously implanted into the back characteristics and those with hydrophilic surfaces. polymers (253). the PTFP was grafted iminocarbonate). of the most hydrophobic synthetic polymers known (251. The data obtained from this bio. these hydrophobic polyphos- able orthosorbR pins made of polydioxanone (136). (135) reported a comparative study on bio. heart pumps. and can be used as coatings for other materials. Poly(DTH-carbonate) exhibited very close bone reactions. implantation sites over a 1 year period. All studies with these samples were observed for poly(DTH-iminocarbonate). Large differences greater cell density and inflammatory response was noted in the biocompatibility of these materials were found. highly enhances their biocompatibility. similar in fact to the response reported tyrosine-derived polycarbonates was a function of the pen. The bone tissue response was characterized by in encapsulation of the foreign biomaterial without evi. Ertal and Kohn fabricated poly(DTH. chains of tyrosine in their backbone structure were also Bone growth into the periphery of the implant material was developed recently to investigate whether biodegradable visible at the 26-week time point. Surface modifica- iminocarbonate). one would expect a different response with hydrophilic monomers like dimethylacrylamide from this material. done by intraperitoneal implantation of thin films in adult sponse was characterized by a thin tissue capsule. Consider. C. In this tion of poly(trifluoroethoxy-phosphazenes) (PTFP) with study. These preliminary biocompatibility results from two an. polymers that incorporate aromatic components would combine a high degree of biocompatibility with a high de. In the next study.

and therefore further work tions (263). rabbit brains and was found to be essentially equivalent to vestigated as bioerodible inserts for the delivery of the nar. grown directly on the polymeric substrate. cell and cellular morphology were unchanged when either bo- toxicity. and isophthalic acid [poly(ISO: SA)]. under hydrolitic conditions without the danger of a toxic The polyanhydrides constitute so far the only class of response. both the cellular doubling time sponse experiments showing no evidence of irritation. animals were healthy in rat brain was also studied (261). if side groups attached to Polyanhydrides are a novel class of biodegradable poly- the polymer are released by the same process being excre. New types of poly(orthoesters) were developed. Polyanhydrides ammonia. In cotic antagonist naltrexone. Biopsy samples of the implant zone were histo. Johnson and Johnson) and absorbable gelatin sponge (Gelfoam. Gelfoam in terms of biocompatibility evaluations (262). glycine. backbone. a similar study conducted in monkey brains. but no New classes of polyanhydrides have been recently syn- data on the biocompatibility and safety of these materials thesized and are undergoing extensive preclinical testing. which in the presence of appropriate side groups is capable of undergoing facile hydrolysis to phosphate and E. The rea. Polymer films were subcutane. and ammonia. nor in the blood chemistry or hematology evalua- causing local tissue irritation. (257) studied sebacic acid for up to 8 weeks indicated relatively minimal poly[(ethyl-alanate)-co-(imidazole) phosphazene] deriva. Langone et al. In vitro tests measuring teratogenic poten- thesized (146). tested (264). These materi- periodontitis were not successful because ointmentlike als were implanted in rabbits intramuscularly.167). and copolymers 1:1 of SA with fatty acid dimer vitro adhesion to bovine teeth was demonstrated (173). fumaric acid (FA) [poly(FA: However. and for the delivery of the con. were reported.255). Ocular and muscle irritation stud- Copyright © 2002 Marcel Dekker. 20 :80 copolymer of bis-(p-carboxyphenoxy) propane and patibility tests (141. Exam- In vitro studies have shown that good control over re. The animals were killed after 30 cally to deliver an anticancer agent directly into the brain or 60 days. (FAD) [poly(FAD : SA)]. They are solid materials which erode hy. Polyphosphazenes of this type are potential can. including a wide range of biocompatibility studies. then the polymer can be eroded active molecules including drug peptides and proteins (1). surface-eroding polymers approved for clinical trials by didates as erodible biostructural materials for sutures or as the Food and Drug Administration. The steroidal ties were noted in the CT scans and magnetic resonance implant was tested in two separate human clinical trials image. giant cell formation. A series of biocompatibility studies reported on several Polyphosphazenes containing amino acid ester side polyanhydrides have shown them to be nonmutagenic and groups were the first bioerodible polyphosphazenes syn. The tissue reaction of and biological material surrounding to the polymers was the polymer was compared to the reaction observed with found to correspond to fibroplast collagen with only a few two control materials used in surgery. matrices for controlled delivery of drugs (144).259). subcutane- polymers with a relatively low viscosity are squeezed out ously. and in the cornea. Upjohn). . showing good biocom. Theoretically. for the treatment of brain neoplasms. has been in. despite good adhesive- a uniqueness that stems from the presence of the inorganic ness. Imidazoyl groups linked to polyphosphazene chains Subcutaneous implantation in rats of high doses of the are also hydrolized very easily. ples of these new materials are polymers of sebacic acid. Since this polymer was designed to be used clini- ously implanted in rats. No systemic effects of the implants were ob- with this formulation was discontinued (166. nontoxic (189). The phosphate can be metabolized and the am- monia excreted. studies in beagle dogs with naturally occurring SA)]. tial were also negative. mers under development as vehicles for the release of bio- table or metabolizable. Polyorthoesters flammatory reaction of the polymer was intermediate be- tween the controls (261). hydride polymers (189). or Alzamer. Growth of two types of mammalian drolitically to ethanol. no abnormali- traceptive steroid norethisterone (258. cells in tissue culture was also not affected by the polyan- These polymers were tested in subcutaneous tissue re. the Chronomer polyorthoester copolymer poly(CPP)–SA 50 :50 was also implanted in material from Alza Corporation. ity (260). served on histological examinations of any of the tissues sons for the local irritation were never properly elucidated. lease of tetracycline could be achieved and very good in poly(SA). The in- D. its biocompatibility logically examined. tissue irritation with no evidence of local or systemic toxic- tives for in vivo evaluation. Inc. phosphate. oxidized cellulose monocytes in the internal site. absorbable hemostat (Surgicel. In both cases. or tissue inflammation vine aorta endothelial cells or smooth muscle cells were (143. In their bioerosion reactions polyphosphazenes display of the pocket within about 1 day. A closely related polyanhydride As mentioned previously.154).

under the same conditions. polymer matrices without incorporated TAF 1. Academic Publishers. O. Rokkanen. van. Inc. J.7. No indication for postimplantation test site contami. Laiho. P. E. tems. Z. or infection of the implantation site minimal quantity of giant cells and encapsulated foreign were conducted daily. nation was noted. Biotechnology crosis and acute to subacute inflammatory reaction associ- 7:127–130 (1989). Carino. time periods (3. K. Y. up completely between 7 and 14 days after the implantation to eight of these wafer implants were placed to line the (265). P. Elmalak. a the various polymer implants tested and the control materi. Appl. 135–161. In particular. consisting of wa- als (265). S. comparison of the tissue reactivity along the three different Biomater. Vihtonen. no evidence of inflamma. A. S. V. The transparency and avascu. J. Vycryl implant in- suture (Ethicon) (265). Drug delivery and targeting. Gliadel has finally won approval from the FDA as therapy In similar animal experiments in which polyanhydride for the treatment of brain tumors. taining the chemotherapeutic agent Carmustine (BCNU). Amsterdam. there was a erodable microspheres as potential oral drug delivery sys- time-related reduction in the incidence and severity of ne. In keeping with the results of the earlier pre- frequent observations without having to gain surgical ac. testing is unsuitable for implantation (268). D. M.267). No of the polyanhydrides for human use. showed no adverse vascular response (268. K. Nature 386(6623):410–414 (1997). Kilpikari. surgical cavity created during the surgical debulking of the matory reactions (266. a time. ies were performed compared to the material controls were minimal subacute inflammation and mild fibrosis. cellular infiltration. R. J. Mathiowitz. C. U. In these studies. The rabbit cornea possesses brain tumor in patients undergoing a second operation for clear advantages over other implant sites for studying surgical debulking of either a grade III or IV anaplastic implant–host interactions due to the easy accessibility for astrocytoma. K. Shastry. and Vycryl. K. Biologically tion of a time-related healing process (i. Basset. A. More- over.264) reviewed here showing acceptability sites were observed during the study period (4 weeks). a Phase I and II clini- meaningful differences could be seen in reaction between cal protocol was instituted (270). J. Van Brunt. S. Montgomery. duced minimal fibrosis associated with the presence of bleeding. composites proposed for internal fixation of bone. suppl. swelling. Nature 392(6679. polyanhydride dosage form (Gliadel).). Polyan- The biocompatibility of a new class of polyanhydrides hydrides. G. Jacobs. 1997. Jong. No evi. Bio- Copyright © 2002 Marcel Dekker.):5–10 (1998). At the end of the study the animals material. The tissue reaction in the different treatment groups Mechanical properties of biodegradable polymers and showed a clear trend of healing with time. and D. Weiseman (Eds. clinical studies suggesting a lack of toxicity. A. matrices containing tumor angiogenic factor (TAF) were implanted in rabbit cornea. tory response was observed with any of the implants at any was used for the treatment of glioblastoma multiforme. Kost. M. dence for tissue necrosis was detected in any of the treated 2. tation. noted remnants of tissue reaction at the 21-day time period P. Chickering. In these clinical trials. M. Tamminmaki. Bostman. Ta-Shma.e. Chaturvedi. M. in all tested groups there was a clear indica. Vijayaragha- Generally. were sacrificed and a gross necropsy examination of the Based on the biocompatibility and safety preclinical tissues surrounding the implant site was performed. Langer. In Gelfoam. P. Heller. The cornea is a very sensitive indicator of inflam. Tormala. Teomim. Vainionpaa. O. I. Chang.261). and ingrowth of blood vessels delivery of BCNU from a poly(CPP-SA) 20 :80 wafer (Gli- from the perifery of the cornea or neovascularization. O. Surgicel. fer polymer implants of poly(CPP-SA) 20 : 80 and con- In the rabbit cornea bioassay. J. Novel drug delivery systems. no central or cess to the implantation site. the bulk of the polymers disappeared universally fatal form of brain cancer. Phase III among the different inflammatory characteristics such as human clinical trials have demonstrated that site-specific edema. J. and significant clinical signs or abnormalities of the incision monkeys (263. systemic toxicity of the treatment was observed during the larity of the cornea also enable the observer to distinguish course of treating 21 patients under this protocol. R. 4. Ringel.. pp. 1:57 (1990). C. and most importantly from the biocompatibility REFERENCES standpoint. P. 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poly(D. These new commercially signifi- in healing-impaired patients. cally during the past decade. 5 Biodegradable Biomaterials Having Nitric Oxide Biological Activity C. Inc. tyrosine-based polyarylates or polyiminocarbo- for biomedical engineering use have increased dramati. This approach oxide derivative from polyglycolide. linear aliphatic polyesters like polyglycolide and polylac- tions of nitric oxide: retardation of the proliferation of tide from poly(-hydroxyacetic acids). via so-called tissue engineering. they do not elicit per- The chemical incorporation of biologically active com.L-lactide-urethane). promoting wound healing ily of simple polyesters. Ithaca. toward the reconstruction of injured. diseased. cant biodegradable polymeric biomaterials include poly eases.g. and nitric oxide–related dis. biodegradable polymeric biomaterials are originated from terial has indeed one of the well-known biological func. Chu Cornell University. poly[bis(car- Copyright © 2002 Marcel Dekker. or aged tis- ity of this new class of biodegradable biomaterial was sues is one of the most promising fields in the future medi- tested by examining its ability to retard the proliferation cine. meric biomaterials extends the domain beyond this fam- sia in cardiovascular disorders. . The re. New York I. Hence. nates or polycarbonates. some of them have recently been found to be biochemical agents and synthetic aliphatic polyesters like able to regenerate tissues. polysaccharides. polyanhydrides. poly(ester- The interests in biodegradable polymeric biomaterials amides). C. of human smooth muscle cell in vitro. polyglycolide as the biodegradable biomaterials. The potential biomedical applications of several new synthetic and natural biodegradable poly- of this new biomaterial include the treatment of hyperpla. recent introduction smooth muscle cells. (orthoesters).. It was found that Although the earliest and most commercially significant this new class of biologically active biodegradable bioma. Second.6. through the interaction of their biodegradation with immu- sulting new biomaterial was characterized and its in vitro nologic cells like macrophages.2. The biological activ. First. 4-amino-2. surgical implants hydrolytic degradation property was studied to examine made from biodegradable biomaterials could be used as the release profiles of the chemically incorporated nitric temporary scaffold for tissue regeneration. they would be gradually absorbed by human body and do cessfully synthesized by using nitric oxide derivatives not permanently retain trace of residual in the implantation (e. poly(-caprolactone). INTRODUCTION biomaterials has two major advantages that nonbiodegrad- able biomaterials do not have. manent chronic foreign body reaction due to the fact that pounds into synthetic biodegradable biomaterials was suc.6-tetramethylpiperidine-1-oxy) as the sites. This is because this class of poly(-hydroxybutyrate).

vascular coupler for vessel anas. boxylatophenoxy) phosphazene]. however. nerve growth conduits. Because of this unusual property. deliver the desirable biological functions of nitric oxide is rounding tissues. and biodegra. reported rate suture placement. gen-rich blood reaches the heart (14). mechanical biological. All biodegradable wound HAVING NITRIC OXIDE FUNCTION closure biomaterials are based upon glycolide and lactide family. It is important to know. or to mediate able to modulate the release of nitric oxide according to host defense system to combat diseases. released by cells like macrophage and endothelial cells ever. polyglycolide (Dexon from Ameri. nitric oxide radicals stimulation like normal tissues. toxic species in diseases and their treatments. poly(glycolide-L-lactide) random copoly. Nitric oxide acts both as an essential regula- However. genic risk. type 1. we our wish for a variety of therapeutic purposes. and copolymers derived from amino nitric oxide function. (31. cardiovascular disorders. have also been experi. its site of synthesis. poly(glycolide. anastomosis ring for intesti. In this chapter. physical. Besides to play a very important role in a host of expanding biolog- wound closure application. Inc. ipate in the process of wound healing. few (8–30). Nathan et cal properties and their biodegradation rate. cytoprotective property in reperfusion injury. septic shock. biodegradable polymeric bio. oxidative stress. Some well-known exam. Nitric oxide is extremely la- tone) copolymer (Monocryl from Ethicon). tissue regeneration Nitric oxide and NO⋅-derived radicals are not normal and engineering. how. dial ischemia. This small biomolecule and its bio- poly(ester-ether) (PDS from Ethicon). these biomaterials are not biological messengers whose trafficking depend on spe- ‘‘alive’’ and cannot remodel and/or release cytokines upon cific transporters or channels. blood pressure. Biodegradable al. ical functions. intramedullary plug against low oxygen supply. and possible muta- biodegradable biomaterials: they do not ‘‘actively’’ partic. Biodegradable polymeric biomaterials. through nature.19. The earliest and most successful and frequent biomedi- cal application of biodegradable polymeric biomaterials II. elicit inflammatory and foreign body reactions and would diffuse randomly in all directions from the site of play a ‘‘passive’’ role in wound healing. such as the ability to modulate inflam. and poly(glycolide-caprolac.33–35). such as inflammation. These biomaterials. their wide acceptance in other parts of orthope. Existing science and technology are not matory reactions. . to name a few (18. mainly as compo. tion. Instead. pseu. acids and non–amino acids. like microvascular leakage. poly(amino acids).27. It would be ideal release. neurotransmission. that excessive dation properties can be found in other recent reviews (1– introduction of NO⋅ into body may have adverse effects 7). Levi et tomosis. sen- (orthoester). Nitric oxide and its radical derivatives have been known gical meshes for hernia and body wall repair. would describe the new biodegradable biomaterials having dopoly(amino acids).32). This suggests that the only way to tively participate in the biological functions with the sur. unstable free radical biomolecule with expanding known mer with 90-to-10 molar ratio (Vicryl from Ethicon). B cell destruction. Nitric oxide (NO⋅) is a very small but highly reactive and can Cyanamid). The details of the biomedical appli. and mentally used in the field of orthopedics. a condition known as myocar- during total hip replacement. that a new NO⋅-releasing nonsteroidal anti-inflammatory cations of biodegradable polymeric biomaterials and their drug has the benefits of accelerating gastric ulcer healing chemical. to facilitate wound healing. sitization or protection of cells and tissues against irradia- ularly totally resorbable composites. Elliott et al. antimicrobial property. For example. partic. rheumatic and autoimmune diseases. logical functions have recently become one of the most trimethylene carbonate) random block copolymer (Maxon studied and intriguing subjects as recently reviewed by from American Cyanamid). biological functions. ligament/tendon prostheses. for drug control/release devices. In other words. materials like Vicryl have been commercially used as sur. materials that are commercially satisfactory include those blood clotting. the only way to if these synthetic biomaterials could be engineered so that control the biological functions of nitric oxide is to control they could become alive after implantation and hence ac. several investigators (8–18). respiratory distress syndrome. which causes cold sores in humans (12). reported that nitric oxide is a potent antiviral compound polymeric biomaterials have been experimented as vascu. by widening blood vessels so that more oxy- nal surgery. tissue damage in cystic fibro- There is one common characteristic among all these sis. Copyright © 2002 Marcel Dekker. augmentation of defected al. antitumor activity ples in this application are polyanhydrides and poly with a high therapeutic index. BIODEGRADABLE BIOMATERIALS has been in wound closure (1). vascular stents. tory agent to normal physiological activities and as cyto- dic implants may be limited due to their inherent mechani. and stents in ureteroureterostomies for accu. also found that nitric oxide could protect human heart bone. Some of these bile and short lived (about 6 to 10 s). against two disfiguring poxvirus and herpes simplex virus lar grafts. to name a nents for internal bone fracture fixation like PDS pins.

A.2. the radical incorporated polyglycolide (PGA) must exhibit an electron paramagnetic resonance (EPR) spectrum that has the characteristic of nitroxide.2 Electron paramagnetic resonance spectra of TAM spins with nuclear spins. This measurement can provide fundamental in- formation of free radicals. Figure 2 is such an EPR spectrum of TAM-PGA. which describe the classical multiplicity of EPR spectram due to the interaction of the unpaired electron Figure 5.6-tetramethylpiperidine-1-oxy into the carboxyl chain ends their physical. An EPR characterization of nitroxyl radicals is based on the measurement of the signal intensity of an EPR spectrum.37). and mechanical properties are in- of linear aliphatic polyesters like polyglycolide.6.6. This relationship between free radical motion and the characteristic of its immediate environment would provide a useful means to study the release pattern of nitroxyl radi- cals that were chemically bound to biodegradable sub- strates.6-tetramethylpiperidine-1- oxy (TAM) as the source of nitroxyl radicals nitric oxide into synthetic biodegradable polyesters like polyglycolide or polylactide.2. This EPR spectrum shows a considerable broadening of linewidth when compared with an EPR spectrum of free TAM nitric oxide. Synthesis and Characterization We recently used a patented chemical method to incorpo- rate nitric oxide derivatives into a series of synthetic biode- gradable biomaterials (36. The amounts of the nitric oxide derivatives that can be incorporated into biodegradable biomaterials would depend on the molecular weight of the biomaterials. These nitroxyl radicals cannot move as freely as free nitric oxide due to the restricted PGA chain segmental mo- tion. such as linewidth. g value. thermal. nitric oxide derivatives could be released to the surrounding and the rate of release could be controlled by the nature of the biodegradable bio- materials. 2A) when compared with free TAM nitroxyl radical (Fig. Upon the hydrolytic degra- dation of the host biomaterials. 2. Inc. . Because TAM nitroxyl radicals were incorporated only Figure 5. 2B) is attributed to the viscous macromolecular environment surrounding TAM nitroxyl radicals that were chemically bound to PGA chain ends. radical (A) in conjugation with polyglycolide and (B) in free form. into the carboxylic chain ends of PGA macromolecules. significantly different from the parent PGA macromole- Copyright © 2002 Marcel Dekker. Figure 1 illustrates the chemical scheme of this patented method of incorporating 4-amino-2. The considerable broadening of the EPR spectrum of the TAM-PGA biomaterial (Fig. and hyperfine splitting con- stants.1 Chemical scheme for incorporating 4-amino. which largely depends on the immediate environ- ments of the free radicals. which bears a relationship to the tumbling motion of free radicals. Due to the free radical characteristic of Tempamine ni- troxyl radicals.

In addition. This lack of change in fundamental properties release pattern of TAM radicals from PGA.3 The kinetics of in vitro release of TAM nitroxyl radicals from TAM-PGA biomaterials in buffer media of original leased into the surrounding environment upon hydrolytic pH 7.4 The reversible one-electron reduction and oxidation Figure 5.44. Inc. however.6 The change in pH of the buffer medium used for reactions of nitroxyl free radicals. (c) pH 3.44 at 37°C. (b) pH 4.0.0. Figure 3 illustrates such an in vitro sion. In Vitro Hydrolytic Degradation Since the expected biological functions of the TAM-PGA must come from the nitroxyl radicals that would be re- Figure 5. the amount and the rate of release of TAM nitroxyl radicals should have a direct impact on the applicability of the newly synthesized TAM-PGA bioma- cules. is their degradation prod- ucts and their subsequent biological properties. The release of between TAM-PGA and parent PGA biomaterials should Tempamine nitroxyl radicals upon PGA hydrolysis fol- be beneficial because the similar processing conditions that have been used to fabricate PGA for a variety of clinical applications could also be used to fabricate the new TAM- PGA. B. Figure 5. degradation of PGA. Copyright © 2002 Marcel Dekker. (d) pH 3. Figure 5. The main difference between the parent and TAM-PGA. such as similar melting temperature and heat of fu.5 The effect of pH of the media on the EPR spectra intensity of TAM nitroxyl radical at 10 g/mL. The media was glycolic acid: (a) pH 7. terials to medicine.5. the knowledge of the well-known bio- degradation properties of PGA could be applied to estimate the release pattern of TAM nitroxyl radicals from PGA upon its biodegradation. . the in vitro release study of TAM-PGA at 37°C.

.7 The hydrolytic release mechanism of TAM radicals from TAM-PGA biomaterials via alkaline and acid hydrolytic degradation. (B) Acidic hydrolytic degradation of the ester link- ages in polyglycolide backbone during the middle stage of im- mersion. It was well known that the nitroxyl free radicals could participate in one-electron reduction reaction in an acidic medium to yield relatively stable diamagnetic products. Because the conversion of TAM nitroxyl radical (i.e. Figure 4 shows such one-electron re- duction and oxidation reaction of free nitric oxide deriva- (B) tives. (A) (C) Figure 5. hydroxypiperidines structure (NOH). lowed a double exponential behavior in which significant amounts of nitroxyl radicals were released before 20 days followed by a gradual release thereafter. . (A) Initial alkaline hydrolytic degradation of the es- ter linkages in polyglycolide backbone during the early stage of immersion. (C) Acidic hydrolytic degradation of the amide linkage to free TAM radical from the polyglycolide substrate during the late stage of immersion. and oxo-piperidi- nium cations (NO⫹). chemical reduction of nitroxyl radical) to hydroxypiperine Copyright © 2002 Marcel Dekker. Inc.

ylic fragments of PGA segments (II in Fig. As hydrolysis time proceeded further. 6. the EPR spectra peak intensities were reduced accordingly.0 (EPR spectrum b in Fig.39x ⫹ 3.0018x ] in pH as for the number of spins versus time in Fig. The length of the PGA segment of the TAM-PGA frag- Copyright © 2002 Marcel Dekker. A comparison between Figs. The extent of this conversion and hence the number of spins of TAM would depend on the strength of acidity of the medium. The observed in vitro release pattern of TAM nitroxyl radicals from the TAM-PGA biomaterial and the close similarity between the TAM release pattern and the media pH reduction profiles suggested that pH must play a major role. 5) and 3.57 e⫺0. 7A) and the TAM-PGA fragments (Ia in Fig. EPR could not detect the presence of hydroxypiperine. (C) 55 days. the PGA fragments would eventually be degraded into glycolic acid or/and its cyclic dimers (glycolide) as the pH of the media became more acidic. This would suggest that more TAM nitroxyl radicals would be reduced to hydroxypiperine at a lower pH.5 during the first 14 days of hydrolysis. and there was a very little reduction in pH thereafter. we postulated the hy- drolytic degradation mechanism of TAM-PGA biomaterial as illustrated in Fig. and fewer TAM nitroxyl radicals would be remained in an acidic medium and exhibit weaker EPR signal. 5). 3 and 6 showed a remarkable similarity between the release pattern of TAM nitroxyl radicals and the profile of the reduction in pH of the degradation media. Figure 5 illustrates such an effect of pH on the peak inten- sity of EPR spectra of TAM nitroxyl radicals in glycolic acid media. TAM-PGA biomaterials experi- enced both alkaline and acid catalyzed hydrolytic degrada- tion as evident in the change of pH of the media (Fig. 3.4). (A) 3 days.83 e⫺0. Note the presence of split line hydrolysis of TAM-PGA were expected to be carbox.0 (EPR spectrum d in Fig. the nitroxyl group could also be easily po- larizable by acids toward its ionic resonance form resulting in an increased electron–nuclear coupling constant (hyper- fine splitting constant) since the spin density of the nitroxyl bond has been influenced by the proton activity in the acidic media. buffer (7. The acidifying of the degradation media can be demon- strated by the decrease in pH as shown in Fig.4 at day 0 to 3. The result indicated a similar double exponential reduction [y(x) ⫽ 3. 3).8 Electron paramagnetic resonance spectra of the deg- Alkaline hydrolysis would occur during the very early radation products from the in vitro hydrolytic degradation of stage (within a few days) because of the initial pH of the TAM-PGA in buffer media over a period of 55 days at 37°C. The pH of the medium was reduced from the initial 7. structure in an acidic environment would remove the free radical characteristic of TAM. Inc. . 7A). (B) 23 days. 7. and the spin numbers of TAM would continue decrease with time. As the pH of the media decreased from 7. Based on the well-known hydrolytic degradation mechanism of PGA biomaterial. The possible products of this early stage alka.44 to 4. In addition. Figure 5. peaks in A and B that are not there in C.

as imposed by the PGA long chain segments. This suggested that a more homoge- nism of TAM-PGA biomaterials shown in Fig. dation media). ments (Ia) would also be reduced via ester hydrolysis in might be at least two different segmental lengths with dif- both alkaline and acidic media till all the ester linkages ferent tumbling rate of TAM nitroxyl radicals (i. In other words. disappeared and the typical 3 EPR spectrum of nitroxyl Based on the proposed hydrolytic degradation mecha.e. 7. The largest EPR spectral amide linkages where the TAM nitroxyl radicals were feature of the first peak was observed at 23 days hydroly- attached to PGA were far more hydrolytic resistant than sis. In Vitro Biological Activity on Human eventually the amide linkages where the TAM radicals Smooth Muscle Cells were attached would be hydrolyzed to free TAM radicals (VII in Fig. Because the different A tensor and g factors).e. different m was easier than their polymeric counterparts and was re- in I or Ia. the tumbling hydrolysis proceeded further. 7C) until at the late stage of hydrolysis. shown in Fig. There was virtually no character on its first peak (i. we did not expect the formation of free up to 40 days of hydrolysis. which was a series of EPR spectra rized to be able to retard SMC proliferation in humans. This level of SMC retardation of PGA chain lengths (heterogeneity). this spectral feature of TAM radicals (VII in Fig.e. This is because NO has been theo- spectra shown in Fig.. should expect only one type of TAM nitroxyl radical (I 7.. would be the predominant products in the degra. This spectral feature could imply that there trol had been more than double (134% increase) during the was a mixture of TAM-PGA nitroxyl radicals with various same culture period. 8. 7C). however. At the late stage of hydrolysis.0 ⫻ 10 4 /2 mL. a mixture of TAM nitroxyl motion of free TAM nitroxyl radicals in aqueous solution radicals with different PGA chain length (i. the typical 3 EPR peaks of homogeneous nitroxyl radicals while the number of live SMCs in the culture medium con- in solution.. flected in the typical nitroxyl radical hyperfine spectrum.9 The effect of TAM-PGA on the proliferation of human smooth muscle. like VII or IIIa shown in Fig. . As from three different stages of hydrolysis time. The cell density at day 0 was 5. Due to the lack of restriction or Ia in Fig. TAM-PGA showed profound retardation At 3 days of hydrolysis. At the late stage of hydrolysis TAM nitroxyl radicals via the scission of the amide linkage (55 days). 9. The biological activity of TAM-PGA can best be illus- These different types of TAM radicals due to different trated by the level of retardation of smooth muscle cell PGA chain lengths attached might be evident in the EPR (SMC) in cell culture. This EPR spectral feature persisted for a long period ester linkages. there TAM-PGA biomaterial was found to be similar with free Figure 5. a spectral feature with change in the number of live SMCs in the culture medium splitted peaks) that was characteristically different from having TAM-PGA over the entire period of cell culture. radicals reappeared. 7A) in the very early stage of hydrolysis. two were scissioned (III or/and IIIa in Fig. Inc. one neous type of nitroxyl radical. its EPR spectrum had a unique of the proliferation of SMC in vitro. all PGA seg- ments of the TAM-PGA fragments were hydrolyzed and C. were present in the media. 7B). Copyright © 2002 Marcel Dekker.

ment of intimal hyperplasia after balloon angioplastic pro. In the anticancer ter. D. S. CRC Press. Hwang. Royal Society of Chemists. Hayashi. G. Shalaby. J. 3. . and syn. Nature 351:714–718 (1991). FL.S. Park. Mater. Although the inter- mediate and final degradation products from the hydrolysis ACKNOWLEDGMENTS of TAM-PGA biomaterials (I/Ia. E. Bioactive Spin Labels. Palmer. J. T. Scott. for his thesis upon which the bulk of nitroxyl radicals. Karupiah. TAM nitroxyl radicals at 1 µg/mL. Chiellini. it appears that Closure Biomaterials and Devices. be able to considerably sensitize tumor cells toward radia. 10. Cancer Res. 11. FL. wound closure materials with 7. Y. W. Inc. Thus. the same retardation of SMC proliferation as free TAM Dr. Pharma- therapy in cancer because nitroxyl radicals are known to col. POTENTIAL BIOMEDICAL 4. CRC Press.). troxyl radicals. M. The nitroxyl radical–incorporated biomate. Thus. Tannenbaum. O. and pharmacology. Higgs. H. S. therapy because a lower dosage of radiation could be used 12. the mod- the newly synthesized TAM-PGA biomaterials have the ified biomaterials may be used to control local inflamma- same biological function as free nitric oxide in terms of tory reaction induced by wounds or/and surgical implants. particularly at 100 g/mL. Boca Raton. T. von Fraunhofer. R. Germany. D. 1992. Wound at 1 µ/mL over the entire culture period. 1996. S. I. W. Technomic Publishing. M. C. C. Figure 9 also shows icals and superoxide anions because these nitroxyl radical– that any higher concentrations of TAM nitroxyl radicals labelled biomaterials could react with any reactive free in the culture media (⬎1 µg/mL) would appear toxic to radicals and neutralize them. The benefit will be lessened side effects of radiation chrome P-450 reductase. Lancas- thetic vascular grafts that would not clot. M. drug area. diseased tissues. a naturally occurring enzyme to neutralize su- The preliminary in vitro SMC culture data suggest that peroxide anions and other reactive radicals. 54:297–301 (1994). S. 1993. P. R. A. H. Amer. sites via the biodegradation release of the incorporated ni. New York. FL. E. Shalaby. of biologically active biodegradable polymers are the treat. Boca Ra- ton. Q. it appears that both the free TAM this chapter is based. U. dismutase. 13. CRC Press. Biomedical Polymers: Designed-to- APPLICATIONS Degrade Systems. W. K. 5:68 (1992). 43:109–142 (1991). Glatt. Snyder. the amounts of TAM that were incorporated into PGA 2. Biomedical Applications of Synthetic Bio- Some examples of the potential use of this new generation degradable Polymers. Since the level of retardation of SMC proliferation REFERENCES by TAM-PGA biomaterials at a concentration of 1 mg/mL was found to be similar to the pure TAM nitroxyl radicals 1. H. 1995. Berlin. 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They developed the first syn. Based on physical structural features. ionic charge. and the other is the phys- drogels increased year by year. On the other hand. multipolymer hydrogels. FUNDAMENTALS A. fied further into four groups: homopolymer hydrogels. Based on ionic charges. superior chemical and physical properties. anionic. cationic. Suzuka-shi. method. It basically involves two types of gel preparation. Inc. Japan I. One is the chemical crosslinking. to minimize protein adsorption and cell adhesion. rounding tissue. The lent bonds and weaker cohesive forces such as hydrogen most simple classification is hydrogels obtained from natu- and ionic bonds and intermolecular hydrophobic associa. ral products and hydrogels made of synthetic materials. The low interfacial tension between the hydrogels are classified as neutral. These networks are able to retain a large quantity of Peppas classified hydrogels in three ways: method of prep- water within their structure without dissolving. method introduces physical crosslinks between polymer searches. or am- hydrogel surface and the aqueous solution has been found pholytic hydrogels. The re. Mie. tion. the physical overview of hydrogels and focus on the ongoing re. 6 Hydrogels for Biomedical and Pharmaceutical Applications Akio Kishida National Cardiovascular Center Research Institute. Another classification is based on the crosslinking thetic hydrogel and the subsequent development of thera. The elastic nature of the hydrated hydrogels when used polymer hydrogels. Hydrogels are classified in several ways (Table 1). and interpen- as implants has been found to minimize irritation to sur. functional groups on and textbooks for historical and detailed information of polymer chains are bound with crosslinking agent or radia- hydrogels (2–4). hydrogels have Based on the method of preparation. In this chapter. . INTRODUCTION II. by Wichterle and Lim (1). In the former case. and physical structure features (5). chains through intermolecular force such as van der Waals Copyright © 2002 Marcel Dekker. Japan Yoshito Ikada Suzuka University of Medical Science. Due to their aration. or hydrogen-bonded structures. they are classified as amorphous hydrogels. etrating polymeric hydrogels. Osaka. co- als. Classification Hydrogels are a three-dimensional network of hydrophilic polymers held together by association bonds such as cova. semicrystalline search for an ideal biocompatible material was pioneered hydrogels. peutic soft contact lenses. Since then the research for hy. hydrogels are classi- received much attention for preparing biomedical materi. we deal with a brief tion to form insoluble gels. There are some reviews ical crosslinking.

or trifunctional crosslinking agent sorbent hydrogel. hydrophilic or hydrophobic groups may be available. for example. In order to improve the mechanical strength of Synthetic hydrogels. the crosslink structure works as the re- tractive force to pull back the polymer chain inside. There are three basic types of monomers and poly. amide. In many situa. Table 6. Most of the monomers and the polymer are hy- Classification Contents drophilic because the water-soluble groups contribute to Source Natural swelling. Inc. such as hydroxyl. weight of swollen gel swelling ratio ⫽ zable crosslinking agent. Physical crosslink association in. Hydrogen bonded Crosslink Covalent bond Intermolecular force C. and Anion ether group. chemical reactions.1 Classification of Hydrogels polymers. The radiation method utilizes electron beams. The water content of a hydrogel is expressed in B. weight of dry gel troduces physical crosslinks between polymer chains through intermolecular force. water content ⫽ tions. When the water content of chains to produce a crosslinking point (6). Preparation terms of percentage of water by weight: Hydrogels are prepared by various methods. Typical methods of preparing ⫻ 100 weight of water ⫹ weight of dry gel hydrogels are irradiation. their drogels. Peppas suggested that the swelling characteristic of hy- A wide variety of synthetic hydrogels can be manufac. To incorporate water into hydrogels. swelling ratio or water content is currently used in most cases. Copyright © 2002 Marcel Dekker. Among the neutral monomers and erties of hydrogels. hydrophobic portion is incorporated. Classifi. theory (11). This retractive force is described by the Flory rubber elasticity force and hydrophobic association. and superporous hy. since the equilibrium swell- source. and physical association. a property important in hemodialysis (10). Cationic hydrogels acquire positive charge. or ultraviolet light to excite polymer content between 38 and 75%. Properties Functions Biodegradable 1. x-rays. Another index which characterizes hy- and polymers with reactive functional groups in the side drogels is the swelling ratio. stimuli-responsible. various hydro- Electric charge Nonion philic groups can be applied. the hydrogel is called superad- linking requires a di. which Physical structure Amorphous has a favorable effect on the permeability of anions such Semicrystaline as phosphate. . For instance. Monomers with acidic groups are thought to Cation minimize calcification when the hydrogels is implanted Zwitter ion (8. acidic or anionic. wettability and mobility. most of hydrogel contact lenses have water gamma rays. and optical and mechanical prop- and basic or cationic. To describe the swelling behavior of hydrogels. The counterbalance of the expanding and re- cation by function of hydrogel is also useful. ing ratio influences the solute diffusion coefficient. drogels is a key for the use of hydrogels in biomedical and tured by selecting an appropriate polymer or monomer pharmaceutical applications. A wide vari. water may be present during the initial formation weight of water of the crosslinked structure. when 2-hydroxyethyl methacrylate (HEMA) is co- Copolymer polymerized with hydrophobic monomers. For in- Component Homopolymer stance.9). tracting force attains to equilibrium in a particular solvent ety of functional hydrogels have been proposed such as at particular temperature. biodegradable. expressed by the ratio of the chain or the chain ends. Chemical cross. hydrogels with Multipolymer superior tensile strength and machinability are obtained Preparation method Simultaneous polymerization Crosslink of polymer (7). Another chemical crosslinking weight of swollen sample over that of the dry sample: method is a simultaneous copolymerization–crosslinking reaction between one or more monomers using polymeri. surface mers used to create hydrogels: neutral. Water Content and Swelling Ratio Stimuli responsive Superabsorbent The polymer chains of hydrogels interact with the solvent Etc. molecule and tend to expand to the fully solvated state. the hydrogel is over 90%. On the other hand.

and so on. MEDICAL APPLICATIONS and when they move on a limited region. so that the hydrogel surface becomes slippery. Generally. through the lens will double when the thickness is halved. mind. it tance for medical application of hydrogels. The ionic character is mainly due to the pres- antithrombogenicity. Another factor OF HYDROGELS to be considered in the comfort of a hydrogel contact lens is the surface quality. 1-vinyl-2-pyrrolidone (NVP). HEMA. high Jackson and Fleming proposed five prerequisites for the water (⬎50% H 2 O) nonionic. hematuria (13).17). One example of this hydrogel formation is to react to high water content. The hydrogel contact lens is only comfortable when it has a large diameter. fortability of this type of contact lens. Simi. The oxygen permeability coefficient. Hydrogel contact lenses are a member time. Other hydrogel contact lens materials are methacrylic ings have been applied to catheters to protect the urethra acid. hydrogels problem. low water ionic. For instance. softness. Permeability The original material for hydrogel contact lens was poly (2-hydroxyethyl methacrylate) (polyHEMA) (1). and form a hydrophilic lubricious surface. Dk. than rubber or plastic lenses. ence of methacrylic acid. contains about 40% water of hydration. while it is responsible for higher poly(vinylpyrrolidone) with an isocyanate prepolymer on surface protein binding to the contact lenses. Hydrogel lenses have been classified by the U. is still the most frequently used material for contact lenses. oxygen permeation lenses are classified into two groups: soft (flexible) and through hydrogel has been investigated in detail for a long hard contact lenses. contact Wide varieties of hydrogel contact lenses have been de- lenses. and catheters exhibits a high faction coefficient. applicable to any lens type. 2. As A. As the dry surface of latex gloves tact lenses were developed to enhance oxygen transport. they leasing drugs and proteins for drug delivery systems are are more easily damaged and require more hygienic care core characteristics for each application. Contact Lens ance and protein penetration into the hydrogel. Hydrogels swell glyceryl methacrylate. thin edges. and re- other types and are easier to fit. Then the hydrogel-coated catheter provides protection to Food and Drug Administration (FDA) into four general the contacting urethral epithelium during the catheter use. Ultrathin fabrication is The mechanical friction between a catheter and the mu. however. the oxygen flux cosa tissue may injure the urethra and may cause micro. III. Because of this side effect. Inc. but there are some disadvantages.S. ultrathin low-water-content contact lenses are Contact lenses are used to correct the optical function of currently recommended. tion is a desirable property for good oxygen permeability. nentially with the water content. radiopacity. oxygen permeation for contact lens. rather thick poly- HEMA hydrogel contact lenses was found to be insuffi- Hydrogels have been used extensively for lubricating the cient for the corneal metabolism. water ionic. This ionic character contributes ity (14). Contact Of all the studies for permeability. (18). improved hydrogel con- surfaces of biomaterials. High hydra- a silicone drain (15). the eye with intimate contact to the eye (16. For daily- wear lenses. and sterilizabil. veloped. hydrogel coat. There has been little study about this Because of their extraordinary biocompatibility. as minor ingredients in hydrogel contact lenses (Table 2) providing a less frictional interface between the mucosa. while the ‘‘traditional’’ material. such as low tear toler- B. urinary catheters and surgical drainage systems. at the The permeability of target molecules is of utmost impor- equilibrium swelling in physiological saline solution. A variety of other mono- on contact with water and retain a significant proportion mers as well as a variety of crosslinking agents are used of water. The hydrogel lenses are made of with the important property of oxygen permeability in slightly crosslinked hydrophilic polymers and copolymers. dimethylacrylamide. nutrient and immuno- Hydrogel contact lenses are more comfortable than logical biosubstance transport for immunoisolation. hydrogels One method was to increase the water content by copoly- were applied to provide a low friction surface (12). On the other hand. and drug delivery systems. is a prop- Copyright © 2002 Marcel Dekker. Most of the available contact lenses were developed of soft contact lens group. wound dressings. . merizing with a more hydrophilic monomer. The oxygen per- within body cavities require surface lubricity to facilitate meability coefficient of hydrogel materials increases expo- insertion and removal. Lubricant the oxygen permeability of the original. drainage tubes used to evacuate collections of fluid method was to fabricate ultrathin lenses. and high optimal performance of a surgical drain: a slippery surface. less interaction of eyelid with hydrogel have been successfully used in a wide range of biomedical contact lens is one of the possible reasons for the com- applications that include lubrication for surgical gloves. groups (Table 2): low water (⬍50% H 2 O) nonionic. and the other larly.

nonionic healing by keeping a moist atmosphere.24) (Na. Dressing affect the drug release from hydrogels include the drug loading method. there dissolved drugs. As a barrier effect. In order to solve this thermal gelation and good nondenaturing effects on pro- contradiction. Poly(vinyl alcohol) posite wound dressings (22). such as poly(ethyl- Group 1: low water (⬍50% H 2 O). Intrasite (Smith & Nephew). ionic A. (PVA) is used for releasing bovine serum albumin in vitro tional Patent Hydro Med Science Division) was the first (32). possess all of these characteristics except high mechanical Pluronic polyols or polyoxamers are block copolymers strength. . and solute permeability (27. For a given contact lens. for several proteins including IL-2 (29. NDOAAm: N-(1. polymer foams. The swelling capacity of hydrogels in water. The success of various hy- Tetrafilcon HEMA/MMA/VP 43 9 drogel composites for wound covering depends on their Crofilcon DHPMMA/MMA 38 12 ability to protect against infection and to promote wound Group 2: high water (⬎50% H 2 O). nonionic ene glycol). There are many successful examples of hydrogel com. oxygen transmis. acrylamide. initiator. Drug Delivery System Etafilcon HEMA/MAA 58 28 Bufilcon B HEMA/NDOAAm 55 16 Hydrogels are currently being studied as controlled release Vifilcon MAA/HEMA/VP 55 16 carriers of drugs and proteins because of their good tissue Note: HEMA: 2-hydroxyethyl methacrylate. There are two general amide. and the polymer chain elasticity. reduces the tensile strength (21). rat intestinal natrituretic factor (31). and alginates. and other ingredients. adopted name Polymer % H2O Dk such as HEMA. the local partition of drugs. strength. In one method. tion of water into the polymer matrix and subsequent diffu- ficient of the material divided by the average thickness of sion of the drugs as determined by Fick’s Law. or agar. a secure wound cov. The initial release of the drug was attributed to diffu- hydrogel developed for use as a wound covering material. the overall Historically. VP: compatibility. the polymer matrix. should be tailored considering the aforementioned effects hydrogels. Physically crosslinked PVA gels have lich). number of tailored hydrogels for specific drugs is also ering is also necessary to prevent infection (21).28). Gelperm (26) (Geist. the metabolites (20). a hydrogel monomer is mixed with drug. In another method. FDA Biomedical) are currently available. the osmotic effect of been used in medicine for a long time. and crosslinker and is polymerized to entrap the erty characteristic of a material. sion of drug through water-filled pores near the surface of Vigilon (25) (Bard Home Health). drugs from the hydrogel delivery system involves absorp- sibility (Dk/L) is defined as the oxygen permeability coef. ionic IV.1-dimethyl-3-oxobutyl) acryl. methods for loading drugs into hydrogels as drug carriers. of poly(ethylene oxide) and poly(propylene oxide).S. loading level. Table 6. The exist a plenty of polymeric wound covering materials. easy manipulation under swelling condition. MAA: methacrylic acid. DHPMMA: 2. Hydrogels countless. drug loading. The release of these O 2 /mL mmHg).3-dihydroxypropyl methacrylate. which causes Copyright © 2002 Marcel Dekker. The Hydron (23. in cm) (19). and permeability of water and Due to an enormous number of drugs and proteins. composite blends of hydrogels and other teins. hydrocolloids. and drug release. Pluronic gels have been used as delivery systems polymers have been created. The hydrogel (in most cases lyophilized) is allowed to swell to dimension of Dk is generally written in ⫻10⫺11 (cm 2 /s)(mL equilibrium in a suitable drug solution. Some of these dressings Polymacon HEMA 38 9 have a multiple layer structure. and Biolex (Catalina been prepared by a freeze–thawing process. where D is the diffusion drug within the matrix. the lens (L. Inc. All these hydrogel wound dressings are composed of hydrophilic monomers. PHARMACEUTICAL APPLICATIONS Ocufilcon HEMA/MAA 44 16 OF HYDROGELS Bufilcon A HEMA/NDOAAm 45 12 Group 4: high water. The prerequisites as well as the physical properties of drugs. urease (30). (27) reviewed the detailed consideration of swelling. for a successful wound covering material are flexibility. gauze or nonwovens of cotton or wool have hydrophilic/hydrophobic balance. and release kinetics. grades of pluronics have a unique character of reversible ity. Lidofilcon A VP/MMA 70 31 Lidofilcon B VP/MMA 79 38 Group 3: low water.2 Classification of Contact Lens by U. a preformed coefficient and k is Henry’s law solubility coefficient. preparation of hydrogel matrix for a specific drug carrier They are subdivided into polymer films. Some typical examples are reviewed herein.S. Some which gives them advantageous permeability and flexibil. 1-vinyl-2-pyrrolidone. Nowadays. nonantigenicity. Kim et al. They reported that factors that C.30). U.

or xeno- gels have been also reported to effectively deliver EGF geneic. capsulate living cells with a semipermeable barrier which ceptor (40). noisolative barrier was made of hydrogels prepared from rally occurring polymers that have been modified to con. The properties required for corporation of IL-2 into a collagen pellet (47. but stricting transport of larger molecules and host immuno- sometimes the bioactivity of incorporated proteins was cytes. the host immune system should be prevented by the semi- teins from collagen matrices. oxygen. Most of these proteins are incorporated into ents. nutrients should be supplied at a sufficiently high rate ported. the square root of time in many cases. It is believed that the predominant shown to accelerate wound healing. agar. Among the many requirements to these matrices. Several different approaches to immunoisolation reduced by such ionic interaction. Basic capsules). tumor necrosis factor re. of the system are cylindrical or planar diffusion chambers vent the inactivation of proteins by alginate. permits bidirectional passage of small molecules (nutri- trone (41). the protein macrophage colony stimulating factor (GM-CSF) (54. hyaluronic acid (lysine)-alginate. and have been from collagen gel is thought to be a diffusion-controlled studied as protein-releasing matrices (33. properties or for control of the degradation time (42–44). though passage of components of Several groups have demonstrated the release of pro. and ported a gelatin microsphere delivery system containing the kinetics were reported to be difficult to control. The objective cells may be allowed to float FGF adsorbed to heparin-sepharose beads can keep its ac. in the gel showed a significant enhancement in the healing bFGF (56). The current types (acrylic acid) to the alginate hydrogel was shown to pre. Alginate V. re- a rapid diffusional release within a time of 2–3 days. In both cases. the protein underwent necessary to obtain gelatin–hydrogel. through the membrane. but glutaraldehyde that was applied to the site in a saline buffer solution. their The controlled releases of insulin (45) and nerve growth permeability may be the most important issue. typically poly excellent biocompatibility. In most cases. FUTURE PERSPECTIVES is one of most popular natural hydrogel matrices for drug release. structural densification of the hydrogel. The basic concept of immunoisolation is very simple: to blast growth factor (bFGF) (39). or from engineering thermoplastics.55). dimensional hydrogel matrix. tein pharmaceuticals. and urogas. the immu- Hyaluronic acid derivatives are a good example of natu.37) and to bone defects (38). whether allo. used 3% methylcellulose gels to deliver transforming hyde (52). Beck IFN-α. similar to synthetic polymer hydrogels. Collagen highly depend on the source of cells. or poly- and derivatization for enhancement of the rheological olefins (59–64).48). the growth factors were from the same species. Because of their high porosity. tured substance of collagen and is soluble in water under poration of chymotrypsin in poly(NVP) (PVP) hydrogels the physiological condition. epidermal growth factor (EGF). The addition of poly have been proposed and evaluated (58). Tabata et al. Gelatin-based matrices are studied in many as- growth factor β1 (TGF-β1) both to topical skin wounds pects. Hydrogels from natural products are also used as drug carriers. basic fibro. Gelatin is a dena- drogel as a protein-delivery system were done with incor. Modified hydrogel membrane barriers are fabri- a high molecular weight (MW ⫽ 5 to 6 ⫻ 10 6 ) and exhibits cated either from weak polyelectrolytes. One of the system because the in vitro release rates were linear with pioneer studies on the use of a chemically crosslinked hy.34). naturally occurring polysaccharides (alginate. Another (macrocapsules) and dispersions of spherical beads (micro- method is preincorporation with other polymers. In many studies. Oxygen and factor (NGF) (46) from hyaluronic acid esters were re. and TGF-β1 (57). The gelatin system was of skin wounds or bone defects when compared to protein shown to be a useful delivering matrix. An appropriate crosslinking is (35). freely within a capsule but are mostly supported on a three- tivity after incorporation into the alginate matrix (41). and granulocyte (36. Fujiwara et al. (50) and TGF-β1 (51) to experimentally induced wounds An allograft is a graft between different individuals in a mouse model. Ionically crosslinked alginate hydrogels have been A. In both cases. poly(acrylonitrile-vinyl chloride). reported in. The protein release cause of allograft rejection is activation of cellular immu- Copyright © 2002 Marcel Dekker. Inc. A similar the semipermeable membrane used in cell transplantation collagen system was used to release NGF (49). or chi- trol the degradation and release rates. Immunoisolation used to incorporate several different proteins for controlled release applications including TGF-β1 (39). Hyaluronic acid has tosan). . such was applied after modification by chemical crosslinking as polysulfone. permeability of the membrane. and bioactive cell secretions) while re- alginate hydrogels via ionic bonding to the polymer. The gelatin was often crosslinked with glutaralde- et al. such as the release of insulin (53). It crosslinking still remains as a potential problem in clinical means that the incorporated TGF-β1 was not denatured application if gelatin is crosslinked in the presence of pro- and worked appropriately.

The TGF-β1 could provide the maintenance of a chemical balance with the not be adsorbed onto the basic gelatin. there is still ambiguity in their ful tissue regeneration by the use of growth factors has not long-term effectiveness. new bone at the skull defect. nity by interactions of host T cells with a graft. The histological structure of the newly analog of the original organ by continuously supporting formed bone was similar to that of the normal skull bone. while hu. they tried to Gelatin hydrogels with a water content of 95 wt% that in- control the complement cytolytic activities by using poly corporated at least 0. very short half-life periods of growth factors in the body lar weight cutoff and its selectivity is characterized by the to sustain biological activities. also reported the sustained release of TGF- proliferation. a membrane which can physically hydrogels suitable for scaffold for tissue engineering inhibit the contact of host immune cells with the graft is (66–68). always been achieved. soft tissues at the skull defect site and does not induce bone lar events during the healing process. mers are well tolerated by living tissues and may serve as plement proteins for a long time.1 µg TGF-β1–hydrogel (95 wt%). whereas TGF-β1 in solution form was inef- B. newly formed bone membrane forms biohybrid organs. low interfacial ten- xenografts.57. a substrate for tissue formation. the use of porous hydrogels to assist tissue xenografts. by using gelatin as a basic material (56. hans. success- tion have been reported. Tissue engineering drogel degradation. providing a scaffold for cell adhesion and a space for cell Tabata et al. For the allograft applied to a recipient without sion with biological fluids. the semipermeable membrane must be de. in vivo efficacy. gradable hydrogel of acidic gelatin with an isoelectric out inactivating. Inc. Tissue engineering has been extensively studied by many played an important role in skull bone regeneration in- researchers in a wide area. Iwata et al. Tissue Engineering fective. which become a per. expected to effectively protect the graft from rejection. The agarose skull bone regeneration induced by TGF-β1–containing gel cannot effectively protect xenogeneic cells from the gelatin hydrogels (TGF-β1–hydrogels) is significant (57). munoisolative membranes applicable to xenografts is It has been widely recognized that growth factors challenging because of shortage of allogeneic donors. repair and axonal regeneration in the brain (69–71) and signed to be highly permeable to low molecular weight the spinal cord (72–75) has been investigated. not observed after treatment with TGF-β1–hydrogels. Hydrogels molecules. Tissue engineering. in the hydrogel and ions and metabolites of tissue fluids. Most xenogeneic recipients with microencapsulated Tabata et al. it is highly necessary diffusion coefficient of solutes. reported a series of growth factor release hamster islets in 5% agarose hydrogel could not demon. Thus. with a three-dimensional network of hydrophilic copoly- lecular weight biomolecules. Following the treatment with eration. Tissue engineering regeneration at the skull defect. regardless of the dose. In their hydrogel system. the viscoelastic behavior. which varied according to the water content. Al. The in vivo degradability of the hydrogels. . The swelling characteristics of hydrogels point of 5. The strate normoglycemia for more than 10 days. has been the most widely investigated TGF-β1 is released from the hydrogels as a result of hy- strategy in the recent biomaterials field. complexation for the enhancement of bone regeneration ter within the polymer network and also in the possibility activity (77). humoral immunity. The interest in hydrogel as a biomaterial for β1 by using a biodegradable hydrogel based on polyion soft tissue replacement existed in their ability to retain wa. greatly contribute to tissue regeneration at different stages though various membranes which allow xenotransplanta. However. To solve this problem. Overgrowth of regenerated bone and tissue reaction were Polymers play an important role in tissue engineering. One of the reasons for this is the A hydrogel membrane does not have a distinct molecu. the organ. When the hydrogel degrades too aims at restoring a tissue defect by inducing endogenous quickly. For In particular. surrounding tissue and allow the exchange between water moral immunity including antibodies and complement pro. (65) employed to contrive the dosage of growth factors for enhancing the a 5% agarose hydrogel to immunoisolate islets of Langer. of cell proliferation and differentiation. teins is thought to play a major role in the rejection of In addition. The development of im. bone regeneration at the rabbit skull defect site 6 weeks after treatment. such as antibodies and com. It is likely that hydrogel uses polymer devices with controlled macro. as well as duced by TGF-β1–hydrogels.0 by electrostatic interaction.and micro. it does not retain TGF-β1 or prevent ingrowth of tissue regeneration and manipulating the cascades of cellu. When acidic gelatin Copyright © 2002 Marcel Dekker.76–81). that degrades too slowly physically impedes formation of structures and chemical properties to achieve organ regen. but be able to prevent permeation of high mo. remained at the defect site without being resorbed 6 and manent part of the host organ by acting as the functional 12 months later. and structural stability make preformed antibodies. The TGF-β1 was adsorbed onto the biode- to retain the bioactive proteins such as growth factors with.1 µg of TGF-β1 induced significant (styrene sulfonic acid) (65). cell transplantation. Combination of cells and an immunoisolative 0.

Some polymers undergo strong conformational changes ing 125 I-labelled bFGF were implanted into the back of when only small changes occur in the environment. of the hydrogels decreased. The hydrogel degraded of sulfated polysaccharide seems to be promising. of the hydrogel. Hydrogels of Stimuli-Responsive Polymers In vivo release of bFGF from a biodegradable gelatin 1. changing the water content of hydrogels. The lower the by the polymer systems have mainly been observed in wa- Copyright © 2002 Marcel Dekker. The decrement profile longed with a decrease in the water content of hydrogels.9. (GEMA)–sulfate hydrogel has activity for activating genesis nor inflammation. water content of 125 I-labelled gelatin hydrogels. and the retention period was prolonged with a de. gelatin with the isoelectric point of 4. Overview hydrogel carrier was compared with the in vivo degrada- tion of hydrogel (79). irrespec- biodegradation. drogels were placed in a diffusion chamber and implanted ter contents of 90 and 95 wt% induced significantly high in the mouse subcutis for certain periods of time. C. bFGF-incorporating hy- Eight weeks after treatment. drogels were also reported. When bone regeneration compared with those with lower and hydrogels explanted from the mice were again implanted higher water contents and free TGF-β1. hydrogels incorporating 125 I-labelled TGF-β1 were im. activating ability of poly(GEMA)–sulfate. and histology for 21 days. and 500 ng) and im. In order to prepare the bFGF-reserving and -activat- was evaluated by biomicroscopy. active bFGF was released as a result of in vivo degradation dation will result in too short retention of TGF-β1 to in. This growth ported that heparin protects bFGF from proteolytic degra- factor was incorporated by polyion complexation into a dation and thermal inactivation (83). Control eyes and eyes receiving the hydrogel hydrogels with a crosslinking agent (85–87). The dried hydrogel Heparan sulfate and other sulfated glycosaminoglycans. are also present ent doses of bFGF (20. called stimulus-responsive polymers. pH. The ability of TGF-β1 incor. and ionic strength. The release profile was controllable by duce bone regeneration. the faster their of the hydrogel weight and gelatin radioactivity. of neovascularization became longer as the water content porated into acidic gelatin hydrogels to induce bone regen. To study the decrease of activ- eration was evaluated in a rabbit calvarial defect model. It has been re- a biodegradable vehicle for bFGF release (78). was hydrated with bFGF aqueous solution including differ. Corneal angiogenesis bFGF. tive of the water content. and radical polymerization of GEMA than 50 ng of bFGF demonstrated significant corneal angi. This indicates that significant neovascularization was still observed. Subcutaneous implantation of related well with that of gelatin hydrogels. 250. reached maximal growth on of polysaccharide model compounds. ity of bFGF when implanted. strongly potentiates biodegradable hydrogel prepared by crosslinking acidic its activity (84). The reserving and about day 7 and regressed from day 10 after implantation. ity remaining decreased with time. in the extracellular matrix and work as stabilizers for planted into a rabbit corneal pocket. It is possible that the slow degra. the bFGF radioactivity remaining decreased with as temperature. The gelatin hydrogel itself induced neither angio. of poly(GEMA) provided poly(GEMA) with a heparinlike Corneal angiogenesis. Acidic gelatin hydrogel was used as togenic activity for many cell types (82). The retention period of hydrogel biodegradation. and stabilizes its molecular conformation. Glu- with time after its implantation into the corneal pocket. The sulfation containing 20 ng of bFGF showed no corneal angiogenesis. 50. Rapid hydrogel degra. . the gelatin hydrogels with wa. These polymers are time. the radioactivity decreased both the weight of the hydrogels and the gelatin radioactiv- with time and the in vivo retention of TGF-β1 was pro. cosyloxyethyl methacrylate (GEMA) is a novel metha- Experimental eyes receiving the hydrogel containing more cryloyl monomer. Inc. indicat- the sustained release of TGF-β1 from the hydrogel with ing that most of the biological activity of bFGF was re- suitable in vivo degradability is necessary to effectively tained in the hydrogels. These results suggest that acidic bFGF and enhances the cell proliferative activity of bFGF. The in vivo retention of TGF-β1 was cor. ing matrix on the inner surface of porous materials. Among cytokines. indicating that bFGF-incorporating gelatin hydrogels into the mice in- TGF-β1 was released from the gelatin hydrogel as a result duced significant neovascularization. bFGF is a The polyion complexation is applicable for release of well-known heparin-binding growth factor which has mi- other growth factors. which occurred on the third or activity (88). poly(GEMA) was considered as one fourth day after implantation. the faster planted into the back of mice. of bFGF remaining in hydrogels was correlated with that The higher the water content of hydrogels. resulting in corneal neovascularization. which are functional analogs of heparin. corneal fluorescein angi. It was revealed that poly bFGF. gives highly water-soluble polymers [poly(GEMA)] and ogenesis. 125. Nonlinear responses crease in the water content of the hydrogels. dation of the hydrogel physically blocked TGF-β1– Other approaches for releasing growth factors from hy- induced bone regeneration at the skull defect. the use ography. When gelatin hydrogels incorporat. Hence. gelatin hydrogel releases bioactive bFGF with its biodegra- dation. such mice. It was concluded that biologically enhance its osteoinductive function. and its hydrogel The area of angiogenesis showed a dose dependency on for bFGF was investigated.

biocatalysts whose solubility is controlled by pH (94) or As a result. the repulsive have been used for the development of reversibly soluble force is eliminated owing to protonation of COO. As the hydration state was changed by a acid) with terminal acrylate groups were used for a nonad- decrease in the pH. The heat generated D. When spreading. followed by col- temperature (95–99). of designs for an insulin-delivery system that responds to These materials. Ionic hy. phase tran. cules to the polyanionic polymer poly(2-acrylamido-2- quired for the phase transition to occur. Novel Hydrogels by the exposure of γ-Fe 2 O 3 to a magnetic field causes the hydrogel to collapse. Glucose dehydrogenase was used fect the enzyme activity and substrate access to the enzyme here again for converting neutral glucose into gluconic molecule. ter. Water-soluble macromers based on block co- the matrix was exposed to glucose. Immobilized Biocatalysts induced change in the -COOH ionization of acrylic acid alters the repulsive force. As a stimulus that induces a volumetric lease from the hydrogel in the presence of either α-chymo- change in a hydrogel. When this reaction occurs inside the gel. trypsin or dextranase alone was completely hindered. presence of both enzymes. followed by a sharp decrease in the Hubbell et al. and insulin. thereby enabling the adhesion peptide to copoly- therapy was developed by using pH-responsive polymer. system.groups. interpenetrating polymer network (IPN) –struc- drogels are known to show a discontinuous volumetric tured hydrogels of gelatin and dextran were prepared with change above a certain threshold of an external stimulus lipid microspheres as a drug microreservoir. For exam. invertase and γ-Fe 2 O 3 in a poly(N-isopropylacrylamide (NIPAAm)-co-acrylamide) hydrogel. it is expected that the grafted PEG do- Copyright © 2002 Marcel Dekker. An appropriate balance of hydrophobicity and hydro. For the dual stimuli–responsive isms. There have been methyl-1-propanesulfonic acid). have been studying applications of a novel rate of sucrose hydrolysis. The development of a alizing the amine terminus of the peptide with an acrylate glucose-sensitive insulin releasing system for diabetes moiety. force by hydrophobic interactions over lower critical solu- sition of stimuli-responsive polymer can significantly af. tion. Hydrogels incorporated the peptide with a PEG crylamide]. ionic strength. ical properties and shows rapid electric field–associated multilayered hydrogels consisting of PEG-grafted dextran bending deformation. In sponse to electric field have also been developed using the these formulations. The problem of this system is extremely to magnetic fields has been produced by immobilizing slow response to the stimuli. Incorporation was achieved by function- used to control drug release (92). an electric field is utilized. Copolymer gels consisting of NIPAAm and acrylic acid were studied for constructing biomimetic actuators.107) and pulsa- chemical energy into mechanical energy in living organ.N-dimethylamino) ethyl methacrylate-co-ethyla. The polymer was mixed and compressed with spacer arm and incorporation of RGD-promoted fibroblast glucose oxidase. which mimic the conversion of tems: dual stimuli–responsive release (106. cooperative binding of positively charged surfactant mole- philicity in the molecular structure of the polymer is re. Drug Delivery topolymerization of poly(ethylene glycol) diacrylate was The swelling or shrinking of stimuli-responsive hydrogel derivatized with Arg-Gly-Asp (RGD)–containing peptide in response to small changes in pH or temperature can be sequences (101). appear to form an adherent hydrogel bar- rier that is highly effective in reducing postoperative adhe- sions in the models used. Hydrogels capable of mechanical re. photopolymerized in vivo in direct con- glucose were also developed using glucose oxidase. then insulin was released. the attractive force dominates. A wide range of stimuli-responsive polymers acid. For the pulsatile release system. A variety hesive barrier at the free surface on the treated wound site. tile release systems (108). NIPAAm produced the attractive When an enzyme is incorporated in a hydrogel. Biomimetic Actuators Yui and coworkers have proposed new drug release sys- Biomimetic actuators. 4. or concentration structured hydrogel prepared below the transition tempera- of organic solvent. tion temperature (32°C). a crosslinked hydrogel of poly(vinyl alcohol) chains whereas lipid microsphere release was observed in the entangled with poly(acrylic acid) chains has good mechan. Inc. have become of major interest lately (100). ple. a lot of reviews of this field (89–93). tact with tissues. The IPN- such as pH. The hydrogel obtained by pho- 3. A biocatalyst preparation sensitive lapse of the gel. A pH- 2. merize rapidly with the PEG diacrylate upon photoinitia- poly[(N. hydrogel prepared by poly(ethylene glycol) (PEG) diacry- late derivatives (101–105). The volume change of several hundred ture of gelatin exhibited a specific degradation-controlled times over and under the threshold is utilized to exert a lipid microsphere release behavior: lipid microsphere re- significant force. . temperature. (PEG-g-Dex) and ungrafted dextran were prepared. bovine serum albumin. it was oxidized to form polymers of PEG and poly(lactic acid) or poly(glycolic gluconic acid.

. Copyright © 2002 Marcel Dekker. Evolution of hydrogel poly- vivo (118) because it is assumed that devitalized cells and mers as contact lenses.123). Hydrogel. Cox. but the use of hydrogels under physiological condi. and hydrogels could be polymer–HAp composites by mixing (119). G. the larger amount of ions is supplied into a hy- lowered the performance of the materials by changing the drogel matrix from a solution in order to grow HAp nuclei bulk properties or causing thrombosis. Vol. and was revealed that there were two factors (the bound water has been observed not only in hydrogels but also in many content and the swelling ratio of a hydrogel) that affect kinds of biomaterials. 1962. There manner because of the multilayered structure in which are many kinds of hydrogels and many factors to study. E. Peppas. Menges. The inorganic material. for example. they reported that forma. p. hor- 2. M. Other Hydrogels pends on the HEMA content in the hydrogels and that their chemical structure was a more important factor in calcifi- Some hydrogels are currently used for biomedical applica. Hy- droxyapatite [HAp: Ca 10 (PO 4 ) 6 (OH) 2 ]. J. surface coatings. calcification. Woods. Wheeler.. If hydrogel–HAp composites can be formed. type of materials. vide useful data. the relationship between hydrogel tions is sometimes limited by calcification. San Diego. J. Ratner. is a biofunctional field. J. On the other hand. 1987. Imai et al. neering and drug delivery systems. which is one of the Hydrogels have been studied as biomaterials in the medical main components of calcified materials. Andrade. such as animal species. Chemical Society. heart valves vide a large number of nucleation sites for HAp on/in a (111. Schoen. In: Biomaterials Science. F. 1976. may con. regard to creating polymer–HAp composites has been trix based on aqueous polymer two-phase systems. Using various hydrogels that tions. B. Hydrogels in Medicine and Pharmacy. on/in a hydrogel. Hydrophilic gels for biological use. 783. 1996. A. some research (127) in and Sons. In some orthopedic and tissue adhesive continuous advances in biology and medicine will produce applications. 1. burger. age. Kokubo et al. cations. metic process and noted that a HAp layer with the desired 7.121). and so on. is another essential factor for calcium phosphate deposition 5. H. mains act as a drug reservoir dispersed in the dextran ma. who used PHEMA copolymer hydrogels. 31. found that the amount of calcified deposits de- E. New York. Over- films at a normal temperature and pressure in vitro (126). Eldlich. New York. Most studies of calcification have been done in F. However. A. American protein adsorption. D. Long-Term Effects Med.C. swelling ra- hydrogel layers did not. functional group. Press. A. D. Im- has revealed that the physicochemical aspect of materials plants 6:207 (1996). the main ob. many researchers have attempted to create further demand for biomaterials. tion of composite was good. and cellular debris are keys to calcification. a great deal of re. Hoffman. R.112). cation than hydrophilicity. 1987. Interscience. J. However. Recent research drug delivery systems. in the initial stage of calcification. Encyclopedia of Polymer Science thickness was formed on ceramic. and polymer and Engineering. the calcification mechanism (HAp formation) has not yet been clarified. FL. CRC (124. PEG-g-Dex hydrogel layers contained insulin. N. shear stress. and soft contact lenses (113). arti. Bikals. The done (122. H. Hydrogels for Medical and Related Appli- mone level. V. Kroschwitz (Eds.125). plasma spray a practical answer. Many possible factors. Watkins. Hydrogels. Inc. A. Boca Raton. S. carried hydroxyl groups. G. F. HAp formation (which is a dextranase.. metal. C. Lemons (Eds. F. 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g. research work in the field of 1. interactions of the polymer with the epithelium. typically of high serine and 3. prolonged. mucoadhesive polymers has strongly increased within the dence time of dosage forms on the mucosa can be last two decades resulting in numerous promising ideas. the resi. could be strongly improved polymers. which layer. Vienna. mers interesting tools for various pharmaceutical reasons: Because of all these benefits. academic research groups pioneered the degradation of orally given (poly)peptide drugs by concept of mucoadhesion as a new strategy to improve the luminally secreted intestinal enzymes (3.4). Furthermore. MUCUS GEL COMPOSITION ized on a certain surface area for purpose of local therapy or for drug liberation at the ‘‘absorption As mucoadhesive macromolecules adhere to the mucus gel window. Mucoadhesive poly. 2. 7 Mucoadhesive Polymers Andreas Bernkop-Schnürch University of Vienna. more profound basic knowledge. An overview reflecting peutic effect. The protein providing the basis for a high concentration gradi. These so-called mucins crospheres (2). Austria I. mucoadhesive polymers can guarantee threonine content that is glycosilated by oligosaccharide an intimate contact with the absorption membrane side chains that contain blood group structures. possess a linear protein core. and techniques based on a more and at a given target site in order to maximize the thera. drug delivery systems can be local. and for therapeutic effect of various drugs.8). core of many mucins exhibits furthermore N and/or C ter- Copyright © 2002 Marcel Dekker. II.’’ e. mucus structure are glycoproteins with a relative molecular coadhesive microspheres versus nonadhesive mi. for instance. Robinson and Bologna. which allows a sustained drug release strategies. mers are able to adhere on the mucus gel layer that covers such as a permeation enhancing effect (5.. inhibition of brush border membrane-bound en- ties are in many cases advantageous rendering such poly. . the status quo as well as future trends concerning mucoad- have reported that a polycarbophil gel is capable of hesive polymers should provide a good platform for ongo- remaining on the vaginal tissue for 3 to 4 days and ing research and development in this field. These mucoadhesive proper.6) or the various tissues of the body. thus provides an excellent vehicle for the delivery of drugs such as progesterone and nonoxynol-9 (1). Inc. for the ex- clusion of a presystemic metabolism such as the In the early 1980s. Mediated by mucoadhesive polymers. In addition. mass range of 1–40 ⫻ 10 6 Da. systems. the absorption of riboflavin. The most important component building up the in human volunteers by oral administration of mu. it is important to characterize first this polymeric has its absorption window in the stomach as well network representing the target structure for mucoadhesive as the small intestine. zymes (7. INTRODUCTION ent as driving force of drug absorption.

stress. Yes 16 ocular. eight different types of human mucins have been discovered and characterized. 1. Although Figure 7. The mucus layer based on secretory mucins repre- sents not only a physical barrier but also a protective diffu- sion barrier (9. gallbladder Yes 18 mucin of the stomach MUC7 Salivary 19 MUC8 Tracheobronchus. secretory and membrane.. Inc. pancreas 12 epithelial mucin MUC2 Secreted intestinal Intestine. mucins may gogues.and/or intermolecular di. however. on the other hand. which are listed in Table 1. tracheobronchus Yes 13 mucin MUC3 Secreted intestinal Intestine. ocular. loops in rats to be in the order of approximately 1–4 h sulfide bonds. This so-formed mucus layer. tem can remain on the mucosa in maximum. protein core. illustrated in Fig. glycosidic side in order to estimate how long a mucoadhesive delivery sys- chains. This presumptive structure of the mucus is (21).1 Schematic presentation of the three-dimensional the turnover time of the mucus gel layer seems to be crucial network of the mucus gel layer. Secretory mucins are secreted from mucosal a highly variable turnover time a time scale is therefore absorptive epithelial cells as well as specialized goblet quite complex and difficult to evaluate. Secreted mucins are continuously released from cells as well as glands undergoing immediately thereafter a polymerization process mainly based on an intermolecular disulfide bond formation. and the enzymatic activity of luminal proteases leading to bound forms. 11. be classified into two classes.