Table Of ContentAdvances in Blood Substitutes
From reviews of previous Blood Substitutes volumes--
"Overall, this volume offers concise and state-of-the-art overview of the
subject, and as such the medical practitioner, hematologic specialist and
investigator in blood substitutes will find it useful. "
- The Quarterly Review of Biology, 1996
"This book is a good reference for all those who are interested in physiology of
circulatory systems and the researchers and technologists who are interested in
synthetic substitutes for biological materials."
- Journal of Cytology & Genetics, 1996
"There is now a concerted aim by both industry and academia to achieve the
complete solution to the safe blood transfusion problem by the development of
artificial blood substitutes. These efforts are summarized in this collection of
essays edited by Winslow, Vande griff and Intaglietta. "
- European Review, 1996
Advances in Blood Substitutes
Edited by
Robert M. Winslow Kim D. Vandegrift Marcos Intaglletta
University of California, San Diego
Volume 1 Blood Substitutes: Physiological Basis of Efficacy
Winslow, Vandegriff, Intaglietta, editors
ISBN 0-8176-3804-0
Volume 2 Blood Substitutes: New Challenges
Winslow, Vandegriff, Intaglietta, editors
ISBN 0-8176-3878-4
Volume 3 Advances in Blood Substitutes: Industrial
Opportunities and Medical Challenges
Winslow, Vandegriff, Intaglietta, editors
ISBN 0-8176-3980-2
Advances in
Blood Substitutes
Industrial Opportunities
and Medical Challenges
R. M. Winslow, M.D.
K.D. Vandegriff, Ph.D.
M. Intaglietta, Ph.D.
Editors
Springer Science+Business Media, LLC
Robert M. Winslow KimD. Vandegriff Marcos Intaglietta
School of Medicine School of Medicine Dept. of Bioengineering
University of California University of California University of California
San Diego, CA 92161 San.Diego, CA 92161 San Diego, CA 92161
Library of Congress Cataloging-in-PubHcation Data
Advances in blood substitutes: industrial opportunities and medical
challenges I R.M. Winslow, K.D. Vandegriff, M. Intaglietta, editors.
p. cm.
Includes bibliographical references and index.
ISBN 978-1-4612-7363-9 ISBN 978-1-4612-1976-7 (eBook)
DOI 10.1007/978-1-4612-1976-7
1. Blood substitutes. I. Winslow, Robert M., 1941
n. Vandegriff, KimD. m. Intaglietta, Marcos.
[DNLM: 1. Blood Substitutes. 2. Hemoglobins--metabolism.
3. Fluorocarbons. 4. Polyethylene Glycols. 5. Oxygen--metabolism.
WH 450 A2441 1997]
RMI71.7.A38 1997
615'.39--dc21
DNLMlDLC
for Library of Congress 97-22453
CIP
Printed on acid-free paper
© 1997 Springer Science+Business Media New York
Originally published by Birkhauser Boston in 1997
Softcover reprint of the hardcover 1s t edition 1997
Copyright is not claimed for works of U.S. Government employees.
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Special requests should be addressed directly to Springer Science+Business Media, LLC.
ISBN 978-1-4612-7363-9
Typeset by Ren6e Schad
987 6 5 432 1
Table of Contents
List of Contributors ...................................... Vll
List of Discussants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. IX
Foreword . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. xi
Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. xiii
Chapter 1
Blood Substitutes: 1996 in the Literature
Robert M. Winslow, M.D. ............................. 1
Chapter 2
Blood Substitutes and the Intestinal Microcirculation:
Extravasation and Ultrastructural Alterations
Ann Baldwin, M.D. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
Chapter 3
A Discussion of Pharmacoeconomics Applied to
Blood Substitutes
Pamela Bassett, D.M.D., M.B.A. . ...................... 38
Chapter 4
Tumor Microcirculation: Role in Drug and
Nutrient Delivery
Rakesh K Jain, Ph.D. . ............................. 46
Chapter 5
The Pressor Effect of Hemoglobin -- Good or Bad?
Robert J. przybelski, M.D., Elaine K Daily, R.N., B.S.,
F.C.C.M., and Marvin L. Birnbaum, M.D., Ph.D . ........ 71
Chapter 6
Perflubron-based Emulsion: Efficacy as Temporary
Oxygen Carrier
Stephen F. Flaim, Ph.D. ............................. 91
Chapter 7
The Other Blood Substitute:
Antigenically Inert Erythrocytes
Mark D. Scott, Ph.D., Kari L. Murad, Ph.D.,
and John W. Eaton, Ph.D. . ......................... 133
vi Table of Contents
Chapter 8
Hemoglobin Encapsulation With Polyethylene
Glycol-modified and Unmodified Vesicles:
Systemic and Microvascular Hemodynamics
at 80% Blood Substitution
Hiromi Sakai, Ph.D., Amy G. Tsai, Ph.D., Marcos
Intaglietta, Ph.D., and Eishun Tsuchida, Ph.D. . ....... 151
Chapter 9
Hemoglobin Oxygen Affinity and the Design of
Red Cell Substitutes
Robert M. Winslow, M.D. and
Kim D. Vandegriff, Ph.D. ........................... 167
Chapter 10
The Mechanism of Tissue Oxygenation and the
Design of Oxygen Carrying Plasma Expanders
Amy G. Tsai, Ph.D., Barbara Friensenecker, M.D.,
Hiromi Sakai, Ph.D., Heinz Kerger, M.D., and
Marcos Intaglietta, Ph.D. ........................... 189
Chapter 11
Colloid Osmotic Effects of Hemoglobin-based
Oxygen Carriers
K£7n D. Vandegriff, Ph.D., Ronald J. Rohlfs, Ph.D.,
and Robert M. Winslow, M.D. . ...................... 207
Chapter 12
Dextran-Hemoglobin
Sheung-Pun Tsai, Ph.D. and J. Tze-Fei Wong, Ph.D. . ... 233
Chapter 13
Modification of Molecules and Particles With
Polyethylene Glycol (PEG): Long-circulating
Pharmaceuticals
Vladimir P. Torchilin, Ph.D. ........................ 251
Chapter 14
The Reaction of Nitric Oxide with Cell-free Hemoglobin
Based Oxygen Carriers: Physiological Implications
Ronald J. Rohlfs, Ph.D., Kim D. Vandegriff, Ph.D.,
and Robert M. Winslow, M.D. . ...................... 298
Index ................................................ 328
List of Contributors
Ann L. Baldwin, Ph.D. Rakesh Jain, Ph.D.
Department of Physiology Edwin L. Steele Laboratory
College of Medicine Massachusetts General Hospital and
University of Arizona Harvard Medical School
Tucson, AZ 85724-5051 Boston, MA 02114
Pamela Bassett, D.M.D., M.B.A. Heinz Kerger, M.D.
666 Fifth Avenue, 37th Floor Department of Bioengineering
New York, NY 10103 University of California, San Diego
La Jolla,CA 92093-0412
Marvin L. Birnbaum, M.D., Ph.D.
Departments of Medicine & Physiology Kari L. Murad, Ph.D.
University of Wisconsin - Madison Department of Pathology (A-81)
Madison, WI 53792 Albany Medical College
47 New Scotland Avenue
Albany,NY 12208
Elaine K. Daily, R.N., B.S., F.C.C.M.
Blood Substitutes
Baxter Healthcare Robert J. Przybelski, Ph.D.
Route 120 & Wilson Road Blood Substitutes
Round Lake, IL 60073 Baxter Healthcare
Route 120 & Wilson Road
Round Lake, IL 60073
John W. Eaton, Ph.D.
Baylor Medical College
Department of Pediatrics Ronald J. Rohlfs, Ph.D.
One Baylor Plaza Department of Medicine
Houston, TX 77030 School of Medicine
University of California, San Diego
Veterans Affairs Medical
Stephen F. Flaim, Ph.D. Center (111-E)
Biological Sciences 3350 La Jolla Village Drive
Alliance Pharmaceutical Corp. San Diego, CA 92161
3040 Science Park Rd.
San Diego, CA 92121
Hiromi Sakai, Ph.D.
Department of Polymer Chemistry
Barbara Friensenecker, M.D. Advanced Research Institute for Science
Department of Bioengineering and Engineering
University of California, San Diego Waseda University
La Jolla,CA 92093-0412 Tokyo 169, Japan and
Department of Bioengineering (0412)
University of California, San Diego
Marcos Intaglietta, Ph.D. Room 5608, Eng Bldg Unit 1
Department of Bioengineering La Jolla, CA 92093-0412
University of California, San Diego
La Jolla,CA 92093-0412
viii List of Contributors
Mark Scott, Ph.D. Robert M. Winslow, M.D.
Department of Pathology (A-81) Department of Medicine
Albany Medical College School of Medicine
47 New Scotland Avenue University of California, San Diego
Albany,~ 12208 Veterans Affairs Medical
Center (1ll-E)
3350 La Jolla Village Drive
Vladimir P. Torchilin, Ph.D. San Diego, California 92161
Department of Radiology
Harvard Medical School and
Chemistry Program, Center for Imaging Jeffrey Tze-Fei Wong, Ph.D.
and Pharmaceutical Research Department of Biochemistry
Massachusetts General Hospital Hong Kong University of Science
149 13th Street and Technology
Charlestown, MA 02129-2060 Clear Water Bay
Kowloon, Hong Kong
Amy G. Tsai, Ph.D.
Department of Bioengineering
University of California, San Diego
La Jolla, CA 92093-0412
Sheung-Pun Tsai, Ph.D.
Department of Biochemistry
Hong Kong University of Science
and Technology
Clear Water Bay
Kowloon, Hong Kong
Eishun Tsuchida, Ph.D.
Advanced Research Institute for Science
and Engineering
Department of Polymer Chemistry
Waseda University
3-4 Ohkubo, Shinjuku-ku
Tokyo 169, Japan
Kim D. Vandegriff, Ph.D.
Department of Medicine
School of Medicine
University of California, San Diego
Veterans Affairs Medical
Center (Ill-E)
3350 La Jolla Village Drive
San Diego, CA 92161
List of Discussants
The following discussion participants are in addition to the Contributors. Numbers in
parentheses are the Chapters in which Discussants participated.
Ruth Billings Enzo Liguori
Colorado State University Army Hospital of Rome
Fort Collins, CO (2) Rome, ITALY (1)
Joeseppe Bonaventura Mark Lortie
Duke University Medical Center University of California, San Diego
Durham, NC (4,6,11,13,14) La Jolla, CA (2)
Giles R. Cokelet Dave Mailett
University of Rochester Rice University
Rochester, NY (4, 6, 8, 12) Houston, TX (9)
Maria Gawryl Herbert J. Meiselman
Biopure Corporation University of Southern California
Cambridge, MA (2) School of Medicine
Los Angeles, CA (1, 6, 7.' 10, 11, 12)
Armando Gonzales
Veterans Affairs Medical Center William Phillips
San Francisco, CA (5, 14) University of Texas Health
Science Center
John Hearst San Antonio, TX (2, 8, 11, 13)
Cerus Corporation
Concord, CA (7,9) Vijay Sharma
University of California, San Diego
John Hess La Jolla, CA (14)
U.S. Army
Bethesda, MD (7, 11, 12) Lynn Ten Eyck
University of California, San Diego
Rhoda E. Hirsch La Jolla, CA (7)
Albert Einstein College of Medicine
Bronx, NY (2, 4) Robert Woodson
University of Wisconsin
Paul Johnson Madison, WI (6,11)
University of California, San Diego
La Jolla, CA (4, 9, 10)
Peter Keipert
Alliance Pharmaceutical Corp.
San Diego, CA (4, 10, 14)
Jack Levin
University of California, San Francisco
San Francisco, CA (2, 4, 9)
Foreword
Each chapter of this volume is a contribution from an expert in the field,
chosen by the editors to contribute to the 1997 "Current Issues in Blood
Substitute Research and Development" course given in San Diego, March
17-19. The contributors were selected because of their expertise in areas
which the editors believe to be critical to the advancement of the field, and
which reflect activity in "hot" areas of relevant research.
While there is a continuity in style for the annual course, each year brings
changes in emphasis and content. In previous years, we were often not
able to provide time for participants to present their views and opinions.
Consequently, this year we encouraged discussion after each presentation.
These sessions were recorded, transcribed, and are printed with the
chapters herein. We believe that the product is very close to the capturing
this year's course in print, and trust readers will enjoy reading the always
candid and often provocative remarks from the audience.
The price paid for inclusion of the discussion transcriptions was a delay in
publication. Each author was allowed to edit his/her discussion section as
well as the final version of the chapters prior to publication. The changes
are mainly for grammar, and we tried, when possible, not to alter the
conversational style of these interchanges.
While the discussions add an interesting component to the book, it also
necessarily increased the amount of work required ofthe authors, editors,
staff and assistants. The editors owe special thanks to Renee Schad,
Program Manager for the Blood Substitutes research program at the
University of California, San Diego, without whose assistance the creation
of this book would not have been possible. We also wish to thank Dr.
Ronald Rohlfs for his always enlightening comments and suggestions. We
gratefully acknowledge Shirley Kolkey and her assistants at Complete
Conference Management for their skillful organization of the course. We
also wish to acknowledge the continued support of the National Institutes
of Health (NHLBI), in particular, Dr. George Nemo and his staff.
Finally, we wish to thank all the authors and participants of the course.
Without their continued efforts, there would be no current issues
III
research and development of blood substitutes for us to update.
Robert M. Winslow
Kim D. Vandegriff
Marcos Intaglietta
