Advances 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

Volume 2

Volume 3

Blood Substitutes: Physiological Basis of Efficacy Winslow, Vandegriff, Intaglietta, editors ISBN 0-8176-3804-0

Blood Substitutes: New Challenges Winslow, Vandegriff, Intaglietta, editors ISBN 0-8176-3878-4

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 School of Medicine University of California San Diego, CA 92161

KimD. Vandegriff School of Medicine University of California San.Diego, CA 92161

Library of Congress Cataloging-in-PubHcation Data

Marcos Intaglietta Dept. of Bioengineering University of California San Diego, CA 92161

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

Printed on acid-free paper

97-22453 CIP

© 1997 Springer Science+Business Media New York Originally published by Birkhauser Boston in 1997 Softcover reprint of the hardcover 1 st edition 1997

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ISBN 978-1-4612-7363-9

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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. Department of Physiology College of Medicine University of Arizona Tucson, AZ 85724-5051

Pamela Bassett, D.M.D., M.B.A. 666 Fifth Avenue, 37th Floor New York, NY 10103

Marvin L. Birnbaum, M.D., Ph.D. Departments of Medicine & Physiology University of Wisconsin - Madison Madison, WI 53792

Elaine K. Daily, R.N., B.S., F.C.C.M. Blood Substitutes Baxter Healthcare Route 120 & Wilson Road Round Lake, IL 60073

John W. Eaton, Ph.D. Baylor Medical College Department of Pediatrics One Baylor Plaza Houston, TX 77030

Stephen F. Flaim, Ph.D. Biological Sciences Alliance Pharmaceutical Corp. 3040 Science Park Rd. San Diego, CA 92121

Barbara Friensenecker, M.D. Department of Bioengineering University of California, San Diego La Jolla,CA 92093-0412

Marcos Intaglietta, Ph.D. Department of Bioengineering University of California, San Diego La Jolla,CA 92093-0412

Rakesh Jain, Ph.D. Edwin L. Steele Laboratory Massachusetts General Hospital and Harvard Medical School Boston, MA 02114

Heinz Kerger, M.D. Department of Bioengineering University of California, San Diego La Jolla,CA 92093-0412

Kari L. Murad, Ph.D. Department of Pathology (A-81) Albany Medical College 47 New Scotland Avenue Albany,NY 12208

Robert J. Przybelski, Ph.D. Blood Substitutes Baxter Healthcare Route 120 & Wilson Road Round Lake, IL 60073

Ronald J. Rohlfs, Ph.D. Department of Medicine School of Medicine University of California, San Diego Veterans Affairs Medical

Center (111-E) 3350 La Jolla Village Drive San Diego, CA 92161

Hiromi Sakai, Ph.D. Department of Polymer Chemistry Advanced Research Institute for Science

and Engineering Waseda University Tokyo 169, Japan and Department of Bioengineering (0412) University of California, San Diego Room 5608, Eng Bldg Unit 1 La Jolla, CA 92093-0412

viii

Mark Scott, Ph.D. Department of Pathology (A-81) Albany Medical College 47 New Scotland Avenue Albany,~ 12208

Vladimir P. Torchilin, Ph.D. Department of Radiology Harvard Medical School and Chemistry Program, Center for Imaging

and Pharmaceutical Research Massachusetts General Hospital 149 13th Street Charlestown, MA 02129-2060

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 Contributors

Robert M. Winslow, M.D. Department of Medicine School of Medicine University of California, San Diego Veterans Affairs Medical

Center (1ll-E) 3350 La Jolla Village Drive San Diego, California 92161

Jeffrey Tze-Fei Wong, Ph.D. Department of Biochemistry Hong Kong University of Science

and Technology Clear Water Bay Kowloon, Hong Kong

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 Colorado State University Fort Collins, CO (2)

Joeseppe Bonaventura Duke University Medical Center Durham, NC (4,6,11,13,14)

Giles R. Cokelet University of Rochester Rochester, NY (4, 6, 8, 12)

Maria Gawryl Biopure Corporation Cambridge, MA (2)

Armando Gonzales Veterans Affairs Medical Center San Francisco, CA (5, 14)

John Hearst Cerus Corporation Concord, CA (7,9)

John Hess U.S. Army Bethesda, MD (7, 11, 12)

Rhoda E. Hirsch Albert Einstein College of Medicine Bronx, NY (2, 4)

Paul Johnson 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)

Enzo Liguori Army Hospital of Rome Rome, ITALY (1)

Mark Lortie University of California, San Diego La Jolla, CA (2)

Dave Mailett Rice University Houston, TX (9)

Herbert J. Meiselman University of Southern California School of Medicine Los Angeles, CA (1, 6, 7.' 10, 11, 12)

William Phillips University of Texas Health

Science Center San Antonio, TX (2, 8, 11, 13)

Vijay Sharma University of California, San Diego La Jolla, CA (14)

Lynn Ten Eyck University of California, San Diego La Jolla, CA (7)

Robert Woodson University of Wisconsin Madison, WI (6,11)

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

Preface

During the initial planning stages for this volume, our working subtitle was "New Directions", because we have become extremely excited over the past several years about how studying cell-free oxygen carriers has changed the fundamental way in which we think about oxygen transport. However commercialization of these products has accelerated also (two products are in Phase III clinical trials), and, we believe, the prospect of clinically available solutions is at least as exciting as the scientific advances. Hence, our hybrid subtitle is "Industrial Opportunities and Medical Challenges"

We believe that the scientific advances discussed in this volume will contribute significantly to future generations of products, and that these new thoughts and theories will become increasingly important as first­generation products are replaced by more sophisticated and cost-effective ones. This book, thus, represents new advances both in commercialization and in our understanding of the basic workings of blood substitutes as medical products.

A new feature added to this year's book is a discussion section at the end of each chapter. These discussions followed the presentations of these chapters at the 1997 "Current Issues in Blood Substitute Research and Development" course given in San Diego in 1997. Exciting new ideas arose out of these exchanges, and we hope that this addition to the book will stimulate new ideas in the readers as well.

The review of the 1996 literature by Winslow (Chapter 1) has become a staple of the course, providing a path to steer through the abounding literature on blood substitutes and related fields. The literature is broken into a number of useful categories that outrange the review from previous years, reflecting both the increasing interest in the field and the expanding indications and scientific evaluations under study.

Advances in product development are covered in diverse chapters ranging from pharmacoeconomics of blood substitutes by Bassett (Chapter 3) to the efficacy of a perfluorocarbon-based oxygen carriers by Flaim (Chapter 6) to strategies employed in developing a hemoglobin-based product for its pressor effect by Przybelski, Daily and Birnbaum (Chapter 5).

New technologies are introduced in chapters by Sakai et ai. (Chapter 8) on encapsulated hemoglobin using polyethylene glycol modified liposomes and by Scott, Murad and Eaton (Chapter 7) on polyethylene glycol modified red blood cells. The use of polyethylene glycol modification

xiv Preface

became a "hot topic" this year due to its inert and highly interesting chemical properties. This is advanced in more detail by Torchilin (Chapter 13) in the chapter on the chemistry of modification of molecules and particles using polyethylene glycol. An older, and somewhat related technology, that still looks very promising is revisited by Tsai and Wong (Chapter 12) in their chapter on dextran conjugated hemoglobin.

A new indication for tumor oxygenation is reviewed by Jain (Chapter 4), providing an in-depth and fascinating overview of tumor microcirculation and new developments in cancer therapy. The microcirculation is explored further in a chapter by Baldwin (Chapter 2) in which ultrastructural inflammatory effects and extravasation are addressed. These two chapters lead to new experimental approaches and reveal new avenues that are just under exploration in this field.

Several paradigms are reevaluated in this volume. A new theory on the oxygen delivery by hemoglobin-based oxygen carriers is developed in a mathematical model presented by Winslow and Vandegriff (Chapter 9). Rohlfs, Vandegriffand Winslow (Chapter 14) provide a chapter on nitric oxide binding to hemoglobin-based oxygen carriers and its physiologic implication. Tsai et al. (Chapter 10) challenge assumptions about viscosity in the efficacy of blood substitutes. Finally, Vandegriff, Rohlfs and Winslow (Chapter 11) challenge assumptions about colloid osmotic properties in the design of blood substitutes. All ofthese chapters develop new ideas that are aimed to help the field continue to grow in the coming years.

As in each of the two previous years, this book is dedicated to updating the current state of the art in blood substitute research and development. The recent success of moving products into advanced clinical trials has come out of years of rigorous work toward this end. We feel that this book reflects the excitement in the field as hard work is finally being realized in tangible goals.

This book is the result of the effort of an entire generation of blood substitute scientists. However, selection of authors and subjects for the current volume is our responsibility alone. We have tried to provide an interesting and exciting volume this year. We always look forward to the response the book receives.

Robert M. Winslow

Kim D. Vandegriff

Marcos Intaglietta