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TISSUE ENGINEERING INTELLIGENCE UNIT 5
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Michael N. Helmus ○
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Biomaterials in the ○
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Design and Reliability○
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of Medical Devices
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R.G. LANDES ○
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C O M P A N Y
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T
ISSUE
E
NGINEERING
I
NTELLIGENCE
U 5
NIT
Biomaterials in the Design
and Reliability of Medical Devices
Michael N. Helmus
Material Sciences Center
Boston Scientific Corporation
Natick, Massachusetts
LANDES BIOSCIENCE EUREKAH.COM
GEORGETOWN, TEXAS AUSTIN, TEXAS
Biomaterials in the Design and Reliability of Medical Devices
Tissue Engineering Intelligence Unit
Eurekah.com
Landes Bioscience
Copyright ©2002 Eurekah.com
All rights reserved.
No part of this book may be reproduced or transmitted in any form or by any means, electronic or
mechanical, including photocopy, recording, or any information storage and retrieval system,
without permission in writing from the publisher.
Printed in the U.S.A.
Please address all inquiries to the Publishers:
Eurekah.com / Landes Bioscience, 810 South Church Street
Georgetown, Texas, U.S.A. 78626
Phone: 512/ 863 7762; FAX: 512/ 863 0081
www.Eurekah.com
www.landesbioscience.com
ISBN: 1-58706-039-6 (hard cover version)
ISBN: 1-58706-086-8 (soft cover version)
While the authors, editors and publisher believe that drug selection and dosage and the specifications
and usage of equipment and devices, as set forth in this book, are in accord with current recommend-
ations and practice at the time of publication, they make no warranty, expressed or implied, with respect
to material described in this book. In view of the ongoing research, equipment development, changes in
governmental regulations and the rapid accumulation of information relating to the biomedical sciences, the
reader is urged to carefully review and evaluate the information provided herein.
Library of Congress Cataloging-in-Publication Data
Biomaterials in the design and reliability of medical devices / [edited by] Michael N.
Helmus.
p.; cm.—(Tissue engineering intelligence unit)
Includes bibliographical references and index.
ISBN 1-58706-039-6 (hardcover)
1. Biomaterials. 2. Medical instruments and apparatus. 3. Materials testing. 4. Bio-
medical engineering. I. Helmus, Michael Nevin. II. Series.
[DNLM: 1. Equipment and Supplies. 2. Biocompatible Materials. 3. Equipment
Design. 4. Materials Testing. WB 26 B6135 2001]
R856.B474 2001
610'.28--dc21 01-037183
Dedication
To my coauthors, coworkers, and colleagues and those special mentors in my
career: Drs. Don Gibbons, Roger Snyder, and Mr. Josh Tolkoff. However, the
most important are my family who have learned to live with my quirks and
humor—my wife Shoshana, and daughters Devorah, Esther, and Rivkie. And
in the memory of my parents who gave me the ability to pursue my dreams—
Herbert and Bernice Helmus.
CONTENTS
Preface................................................................................................viii
1. Overview and Introduction: Unique Aspects of Biomaterials
in the Safety and Efficacy of Medical Implant Devices...........................1
Michael N. Helmus
Materials Selection................................................................................1
Functional Requirements......................................................................2
Biomaterials and Regulatory Guidelines..............................................53
2. Standards and Guidelines for Biocompatibility of Medical Devices......74
Sharon J. Northup
Product Registration Requirements.....................................................74
Standards and Guidelines for Biocompatibility Testing.....................106
Chemical Characterization................................................................107
Risk Assessment.................................................................................113
Case Studies of Materials Toxicity Risk Assessment...........................117
Conclusion........................................................................................125
3. Regulation of Medical Devices...........................................................127
Barry Sall
U.S. Food and Drug Administration Regulation
of Medical Devices........................................................................127
4. Nonclinical Medical Device Testing...................................................144
Sharon J. Northup
Overview of Biocompatibility Procedures..........................................144
Sample Preparation...........................................................................146
Detailed Description of Biocompatibility Procedures........................148
Cytotoxicity......................................................................................149
Sensitization......................................................................................150
Irritation Assays.................................................................................152
Systemic Toxicity (Single and Repeated Dose Toxicity Including
Pyrogenicity).................................................................................152
Pyrogenicity......................................................................................156
Genotoxicity......................................................................................157
Implantation.....................................................................................160
Hemocompatibility...........................................................................162
Chronic Toxicity and Carcinogenicity...............................................164
Reproductive and Developmental Toxicity........................................165
Biodegradation..................................................................................165
Toxicokinetic Studies........................................................................166
Effectiveness Testing.........................................................................167
Externally Communicating Devices...................................................169
Implanted Devices.............................................................................169
Conclusion........................................................................................170
5. Failure Analysis: Learning for the Future from the Past .....................172
Michael N. Helmus
6. Product Development in a Small Company Environment..................178
Roger W. Snyder
Records and Record Keeping.............................................................179
Testing..............................................................................................181
Materials and Components...............................................................182
Prototyping.......................................................................................184
Vendor Relationships........................................................................185
Sterilization and Shelf Life.................................................................186
Production Facilities..........................................................................187
Conclusion........................................................................................189
7. Tissue Engineering Constructs and Commercialization.....................191
Kelvin G.M. Brockbank
Case Studies: Development of Effective Transport Solutions
and Devices to Enable Product Distribution.................................194
Development of Methods to Increase Product Shelf-life....................195
8. Testing of Biomaterials Modified
with Bioactive Molecules: A Case Study.............................................198
Katherine S. Tweden
Characterization of the Nature and Uniformity
of the Modification.......................................................................199
Quantitation of the Modification......................................................202
Assessment of the Biological Activity In Vitro...................................202
In Vitro Challenges...........................................................................204
Manufacturing Ruggedness...............................................................204
Assessment of the Biological Activity In Vivo....................................205
Immobilization of an RGD-Containing Peptide: A Case Study.........206
Materials...........................................................................................206
Results...............................................................................................209
Appendix: Selecting Contract Labs.....................................................223
Barry Sall
Index..................................................................................................224
EDITOR
Michael N. Helmus
Material Sciences Center
Boston Scientific Corporation
Natick, Massachusetts
Chapters 1, 5
CONTRIBUTORS
Kelvin Brockbank Roger Snyder
Organ Recovery Systems Technical Services
Charleston, South Carolina and Regulatory Affairs
Chapter 7 LVAD Technology, Inc.
Detroit, Michigan
Sharon Northup Chapter 6
Northup Regulatory Toxicology
Service Katherine Tweden
Highland Park, Illinois HeartStent Corporation
Chapters 2, 4 Brooklyn Park, Minnesota
Chapter 8
Barry Sall
Worldwide Regulatory Affairs
Services
PAREXEL International
Corporation
Waltham, Massachusetts
Chapter 3, Appendix
PREFACE
T he implant was injection molded from a new elastic block copolymer.
Water absorbed to the slightly hydrophilic backbone of the soft segment.
Though the material passed all biocompatibility and safety tests, it did
leach a slightly cytotoxic additive resulting in a mild chronic inflammatory re-
sponse. White cells loomed and adhered to the surface. The cellular response over
time resulted in the continual bathing of the material with low concentrations of
lytic enzymes and a slightly acidic pH. The corner of the device was subject to a
tensile bending stress. Below the surface of the implant, a craze, the beginnings of
a microcrack had formed. The presence of water and the slightly acidic pH com-
bined with the mild catalysis of the enzymes result in a slow but continuing deg-
radation of the soft segments. As the implant experienced cyclic loading, microcracks
coalesced. The onslaught of time continued, a crack formed. Joe was at work, his
eyes opened wide....
Is this a Robin Cook nightmare in the making? The responsibility of medical
device designers and engineers is to eliminate the sites of failure and to test the
device and its materials of fabrication to demonstrate its ultimate safety and efficacy.
The nightmare could occur if testing fails to account for synergistic interactions
from chronic loading, aqueous environments, and biologic interactions. Testing
methodologies are readily available to assess accelerated effects of loading in
physiologic-like environments. This combined with the sub-chronic effects of
animal implants is a potent tool in assessing durability. It is difficult to predict the
chronic effects of the total biologic environment. The ultimate determination of
safety comes not only from following the details of regulations, but with an
understanding of potential failure modes and designs that lower risk of these
failures. This is our challenge.
Biomaterials are an integral part of medical devices, implants, controlled
drug delivery systems, and tissue engineered constructs. Extensive research efforts
have been expended on understanding how biologic systems interact with
biomaterials. Furthermore, efforts are now focused on how biologic interactions
can be controlled by bioactive surfaces, nano-textures, nano-engineered surfaces,
and hybrid systems containing cells. Meanwhile, controversy has revolved around
biomaterials and their availability in traditional medical devices as a result of the
backlash to huge liability resulting from such controversies as silicone gel escape
from mammary prostheses and fragmentation of a temporomandibular joint im-
plant fabricated from a composite of FEP (fluorinated ethylene polypropylene)
and carbon fiber. Congress has passed the Biomaterials Availability Act to help
address availability issues and the National Research Council has convened a
Biomaterials Roundtable to address a wide range of technical and regulatory is-
sues relating to improving biomaterials, testing, and availability for developing
new medical devices and technology. This book specifically addresses the unique
role of biomaterials in medical device design and the use of emerging biomaterials
technology in medical devices. Unique challenges faced by small medical device
businesses with respect to biomaterials, availability and testing are also addressed.
Case studies in a small medical device environment are given. The case study
given for bioactive materials is an excellent example of the challenges and
innovativeness required in testing new materials. This book is a bridge between
the academic and industrial worlds and provides guidelines and sources of infor-
mation not readily tabulated in current texts.
Michael N. Helmus
