Winslow Blood Substitutes

1. Auflage 2005
ISBN: 978-0-08-045414-6
Verlag: Elsevier Science & Techn.
Format: EPUB
Kopierschutz: 6 - ePub Watermark

E-Book, Englisch, 576 Seiten

Blood substitutes are solutions designed for use in patients who need blood transfusions, but for whom whole blood is not available, or is not safe. This interest has intensified in the wake of the AIDS and hepatitis C epidemics. Blood Substitutes describes the rationale, current approaches, clinical efficacy, and design issues for all blood substitutes now in clinical trials. The many summary diagrams and tables help make the book accessible to readers such as surgeons and blood bankers, who have less technical expertise than the biochemists and hematologists who are designing and testing blood substitutes.* Includes chapters necessary to the understanding of blood substitutes, including history, toxicity, physiology, and clinical applications* Presents detailed descriptions of the various products that have been developed and have advanced to clinical trials, and some that are in earlier states of development

Professor Winslow received his M.D. degree and postgraduate training in internal medicine and hematology at the Johns Hopkins University and Hospital. He studied hemoglobin biochemistry at the Massachusetts Institute of Technology and Molecular Biology at the National Institutes of Health. His research, for more than 30 years, has been aimed at the intersection of the synthesis, structure and function of hemoglobin, in such areas as sickle cell anemia, high altitude physiology and hemoglobin-based oxygen carriers. Professor Winslow previously headed the Blood Research Division at the Letterman Army Institute of Research, responsible for the US Army's blood substitute program. Between 1991 and 1998, he was a Professor of Medicine, leading a blood substitute program at the University of California at San Diego (UCSD), supported by the National Institutes of Health. Professor Winslow has also served as a consultant to many private companies and has been an advisor for, among others, the Federal Aviation Administration (FAA), Food and Drug Administration (FDA), the Institute of Medicine of the National Academy of Science, the Pan American Health Organization, the National Institutes of Health, the Department of Defense and a number of foreign governments. He has written more than 200 scientific articles on clinical, physiological and biochemical aspects of hemoglobin and oxygen transport.

Autoren/Hrsg.

Winslow, Robert M.

Inhaltsverzeichnis

1;Cover;1
2;Blood Substitutes;4
3;Contents;6
4;List of contributors;10
5;Preface;14
6;Acknowledgements;16
7;Abbreviations;18
8;Introduction;22
9;Section 1: Background;24
9.1;1 Historical Background;26
9.1.1;INTRODUCTION;26
9.1.2;BLOOD CIRCULATION AND TRANSFUSION;26
9.1.3;WORLD WAR II;28
9.1.4;FIRST ‘BLOOD SUBSTITUTES’;29
9.1.4.1;Milk;29
9.1.4.2;Normal saline;30
9.1.4.3;Ringer’s solution;30
9.1.4.4;Gum saline;30
9.1.5;BLOOD PLASMA, SERUM AND ALBUMIN;30
9.1.5.1;Perfluorocarbons;31
9.1.6;CELL-FREE HEMOGLOBIN;32
9.1.6.1;Modified hemoglobin;33
9.1.6.2;Encapsulated hemoglobin;34
9.1.6.3;Synthetic heme;34
9.1.7;CURRENT STATUS;34
9.1.8;SUMMARY;34
9.1.9;REFERENCES;35
9.2;2 Transfusion Medicine;38
9.2.1;HISTORY OF BLOOD TRANSFUSION;38
9.2.2;ORGANIZATION OF BLOOD SERVICES;39
9.2.3;AVAILABILITY OF BLOOD;40
9.2.3.1;The blood donor;40
9.2.3.2;Frequency of donors in the population;40
9.2.3.3;Blood utilization and shortages;40
9.2.3.4;The shrinking donor pool: the safety vs. availability balance;41
9.2.4;RED BLOOD CELL COMPONENTS;41
9.2.4.1;Whole blood and red blood cells;41
9.2.5;RED CELL COMPATIBILITY;43
9.2.6;UNIVERSAL RED CELLS;44
9.2.7;RED CELL MODIFICATION;44
9.2.7.1;Other considerations;44
9.2.8;ADVERSE EVENTS ASSOCIATED WITH RED CELL TRANSFUSION;47
9.2.8.1;Disease transmission;47
9.2.8.2;Other adverse events;48
9.2.9;IMMUNOMODULATORY EFFECTS;49
9.2.10;THE COST OF RED CELLS;50
9.2.11;THE ROLE OF RED CELL SUBSTITUTES;51
9.2.12;REFERENCES;52
9.3;3 Regulatory Perspectives on Clinical Trials for Oxygen Therapeutics in Trauma and Transfusion Practice;55
9.3.1;GENERAL REGULATORY BACKGROUND IN THE UNITED STATES;55
9.3.2;CONSIDERATIONS FOR CLINICAL TRIALS IN TRAUMA;57
9.3.3;CONSIDERATIONS IN TRANSFUSION AVOIDANCE;59
9.3.4;SUMMARY;60
9.3.5;REFERENCES;61
10;Section 2: Physiological Basis;64
10.1;4 Clinical Physiology: Oxygen Transport and the Transfusion Trigger;66
10.1.1;INTRODUCTION;66
10.1.2;OXYGEN REQUIREMENTS;66
10.1.3;LOCAL REGULATION OF OXYGEN SUPPLY: THE MICROCIRCULATION;68
10.1.4;OXYGEN UPTAKE IN THE LUNG;69
10.1.5;THE ‘OPTIMAL’ HEMATOCRIT;70
10.1.6;OXYGEN DELIVERY, OXYGEN UPTAKE AND THE ‘CRITICAL OXYGEN’;70
10.1.7;BLOOD TRANSFUSION AND OXYGEN SUPPLY;71
10.1.7.1;Acute blood loss (shock);71
10.1.7.2;Chronic anemia;72
10.1.7.3;Hemodilution;72
10.1.8;THE ‘TRANSFUSION TRIGGER’;73
10.1.8.1;Clinical transfusion triggers;74
10.1.8.2;Physiological transfusion triggers;75
10.1.8.2.1;Hematocrit/hemoglobin concentration;75
10.1.8.2.2;Mixed venous PO[sub(2)];75
10.1.8.2.3;Oxygen consumption (VO[sub(2)]);75
10.1.8.2.4;Oxygen extraction ratio;76
10.1.8.2.5;Hemodynamic instability;76
10.1.8.2.6;Blood loss;76
10.1.8.2.7;Symptoms;77
10.1.8.2.8;Other signs of ischemia;77
10.1.8.3;Individualized transfusion triggers;77
10.1.9;REFERENCES;78
10.2;5 The Role of Oxygen and Hemoglobin Diffusion in Oxygen Transport by Cell-Free Hemoglobins;81
10.2.1;INTRODUCTION;81
10.2.2;OXYGEN DIFFUSION AND ITS BARRIERS IN THE CIRCULATION;82
10.2.2.1;Physical chemistry of diffusion;82
10.2.2.2;Oxygen diffusion in vivo;83
10.2.3;FACILITATED DIFFUSION OF OXYGEN BY OXYHEMOGLOBIN;83
10.2.3.1;Facilitated diffusion of cell-free hemoglobin;84
10.2.4;RATE LIMITING STEPS OF IN VIVO GAS EXCHANGE;85
10.2.5;FACILITATED OXYGEN TRANSPORT AND VASOCONSTRICTION;86
10.2.6;FACILITATED DIFFUSION AND HYPEROXYGENATION OF ARTERIOLES;87
10.2.7;SUMMARY;89
10.2.8;REFERENCES;90
10.3;6 Oxygen Transport Properties of Hemoglobin-Based Oxygen Carriers: Studies Using Artificial Capillaries and Mathematical Simulation;93
10.3.1;INTRODUCTION;93
10.3.2;IN VITRO SIMULATION OF OXYGEN TRANSPORT;93
10.3.2.1;Mathematical simulation of oxygen transport;93
10.3.2.2;Flow regimes;94
10.3.3;CURRENT STATE OF OXYGEN CARRIER STUDIES IN ARTIFICIAL CAPILLARIES;95
10.3.4;CURRENT STATE OF MATHEMATICAL SIMULATION STUDIES;96
10.3.4.1;Capillaries of 25 µm diameter;96
10.3.4.2;Capillaries of 4 µm diameter;96
10.3.5;EXAMPLES OF EXPERIMENTS AND SIMULATIONS;97
10.3.5.1;Capillaries of 25 µm diameter;97
10.3.5.2;Capillaries of 10 µm diameter;98
10.3.5.3;Capillaries of 57 µm diameter;99
10.3.5.4;Capillaries of 4 µm diameter;99
10.3.6;IMPLICATIONS FOR IN VIVO OXYGEN TRANSPORT;100
10.3.7;SUMMARY;102
10.3.8;REFERENCES;104
10.4;7 Mechanisms of Oxygen Transport in the Microcirculation: Effects of Cell-Free Oxygen Carriers;105
10.4.1;INTRODUCTION;105
10.4.2;THE DISTRIBUTION OF OXYGEN IN THE CIRCULATION;106
10.4.3;OXYGEN DELIVERY AND CONSUMPTION;106
10.4.4;ANEMIA AND HYPEROXIA;108
10.4.5;THE HEMOGLOBIN – OXYGEN EQUILIBRIUM CURVE;108
10.4.6;TISSUE RESPIRATION;110
10.4.7;SUMMARY;112
10.4.8;ACKNOWLEDGMENTS;113
10.4.9;REFERENCES;113
10.5;8 Shear Stress, Mechanotransduction and the Flow Properties of Blood;114
10.5.1;INTRODUCTION;114
10.5.2;SHEAR STRESS AND THE RELEASE OF VASOACTIVE MEDIATORS;115
10.5.3;MECHANOTRANSDUCTION AND MECHANOSENSORS;115
10.5.4;THE ROLE OF THE GLYCOCALYX;116
10.5.5;CHANGES OF SHEAR STRESS IN THE MICROCIRCULATION;117
10.5.6;EFFECTS IN THE PLASMA LAYER;118
10.5.7;BLOOD SUBSTITUTES AND MECHANOTRANSDUCTION;119
10.5.8;ACKNOWLEDGMENTS;120
10.5.9;REFERENCES;120
10.6;9 Local Regulation of Blood Flow;123
10.6.1;INTRODUCTION;123
10.6.2;TISSUE OXYGEN SUPPLY AND DEMAND;124
10.6.3;CELLULAR METABOLIC FEEDBACK;127
10.6.4;OXYGEN-SENSITIVE MECHANISMS;128
10.6.5;MECHANISMS OF FUNCTIONAL HYPEREMIA;128
10.6.6;MECHANICAL STIMULI FOR FLOW REGULATION;129
10.6.7;INTEGRATIVE ASPECTS OF FLOW REGULATION;129
10.6.8;ACKNOWLEDGMENTS;131
10.6.9;REFERENCES;131
11;Section 3: Clinical Applications;134
11.1;10 Clinical Indications for Blood Substitutes and Optimal Properties;136
11.1.1;INTRODUCTION;136
11.1.2;TRAUMA/RESUSCITATION;136
11.1.3;ELECTIVE SURGERY;138
11.1.4;RED CELL INCOMPATIBILITY;139
11.1.5;ISCHEMIC DISEASE AND ANGIOPLASTY;139
11.1.6;EXTRACORPOREAL ORGAN PERFUSION;139
11.1.7;CELL CULTURE MEDIA;139
11.1.8;HEMATOPOIETIC STIMULATION;139
11.1.9;CARDIOPLEGIA;140
11.1.10;SICKLE-CELL ANEMIA;140
11.1.11;TUMOR THERAPY;141
11.1.12;CHRONIC ANEMIA;141
11.1.13;RESEARCH;141
11.1.14;REQUIREMENTS FOR A BLOOD SUBSTITUTE;141
11.1.14.1;Oxygen capacity;142
11.1.14.2;Oxygen affinity;142
11.1.14.3;Viscosity;142
11.1.14.4;Plasma retention;143
11.1.14.5;Colloid osmotic pressure;143
11.1.14.6;Storage stability;143
11.1.15;REFERENCES;144
11.2;11 Crystalloid Solutions;147
11.2.1;INTRODUCTION;147
11.2.2;PHYSIOLOGICAL PRINCIPLES;148
11.2.3;DISTRIBUTION VOLUMES OF WATER, SODIUM AND PROTEIN;148
11.2.4;KINETIC DISTRIBUTION VOLUMES OF FLUIDS;149
11.2.5;CRYSTALLOID SOLUTIONS;152
11.2.6;USE OF CRYSTALLOID FLUIDS IN SURGICAL PROCEDURES;153
11.2.7;USE OF CRYSTALLOID FLUIDS FOR REPLACEMENT OF BLOOD LOSS;154
11.2.8;OTHER EFFECTS OF CRYSTALLOID INFUSION;154
11.2.9;SUMMARY;156
11.2.10;REFERENCES;156
11.3;12 Hemoglobin-Based Oxygen Carriers as Resuscitative Solutions for Trauma;160
11.3.1;INTRODUCTION;160
11.3.2;REQUIREMENTS FOR COMBAT CASUALTY CARE;160
11.3.3;RELEVANT PROPERTIES OF HBOCs FOR TRAUMA AND COMBAT CASUALTY CARE;162
11.3.4;INTRAOPERATIVE TRIALS;163
11.3.5;PRE-HOSPITAL RESUSCITATION;164
11.3.6;PLASMA VOLUME EXPANSION;164
11.3.7;CARDIAC OUTPUT;165
11.3.8;OXYGEN UPTAKE VERSUS OXYGEN DELIVERY;167
11.3.9;HYPOTENSIVE RESUSCITATION;167
11.3.10;NEW FORMULATIONS;168
11.3.10.1;Conjugated hemoglobins;168
11.3.10.2;Hypertonic saline–HBOC combinations;169
11.3.11;SUMMARY;169
11.3.12;REFERENCES;170
11.4;13 Surgical Hemorrhage;173
11.4.1;INTRODUCTION;173
11.4.2;POTENTIAL CLINICAL BENEFITS OF HBOCs IN SURGICAL CARE;173
11.4.3;POTENTIAL ROLE OF HBOCs IN SURGICAL CARE;174
11.4.4;EXCEPTION FROM INFORMED CONSENT FOR TRAUMA TRIALS;175
11.4.5;CLINICAL EVALUATION OF TETRAMERIC HEMOGLOBIN IN TRAUMA;176
11.4.6;CLINICAL SAFETY OF POLYHEME™ IN TRAUMA;177
11.4.7;CLINICAL EFFICACY OF POLYHEME TRAUMA CARE;178
11.4.7.1;Reduction of allogeneic RBC transfusions;178
11.4.7.2;RBC non-availability: acute hemorrhagic shock;180
11.4.8;THE NEXT GENERATION OF HBOCs FOR SURGICAL CARE;181
11.4.9;ACKNOWLEDGMENTS;182
11.4.10;REFERENCES;182
11.5;14 Clinical Trials in Cardiac Surgery;184
11.5.1;INTRODUCTION;184
11.5.2;HEMOGLOBIN SOLUTIONS;184
11.5.2.1;Diaspirin crosslinked hemoglobin (DCLHb) in cardiac surgery;184
11.5.2.2;PolyBvHb (HBOC-201);185
11.5.2.3;o-Raffinose polymerized hemoglobin;186
11.5.3;PERFLUOROCARBON EMULSIONS;186
11.5.4;SUMMARY;187
11.5.5;REFERENCES;188
11.6;15 Hemodilution;190
11.6.1;INTRODUCTION;190
11.6.2;MECHANISMS OF ADAPTATION TO REDUCED HEMOGLOBIN;190
11.6.2.1;Viscosity-dependent increase in cardiac output;190
11.6.2.2;Myocardial perfusion and contractility;191
11.6.2.3;Oxygen extraction response;191
11.6.3;MICROCIRCULATORY CHANGES AND TISSUE OXYGENATION;192
11.6.3.1;Microcirculatory adaption to ANH;192
11.6.4;TISSUE OXYGENATION;193
11.6.5;BRAIN FUNCTION IN DILUTIONAL ANEMIA;194
11.6.6;PLASMA VISCOSITY;194
11.6.7;EXTREME HEMODILUTION;194
11.6.8;HYPEROXIC HEMODILUTION;195
11.6.9;SUMMARY;196
11.6.10;REFERENCES;196
11.7;16 Clinical Hemodilution;199
11.7.1;INTRODUCTION;199
11.7.2;INDICATIONS FOR ACUTE NORMOVOLEMIC HEMODILUTION;200
11.7.3;PHYSIOLOGICAL COMPENSATORY MECHANISMS;201
11.7.3.1;Cardiac output;201
11.7.3.2;Tissue oxygenation;201
11.7.4;HEMODILUTION PROCEDURES;201
11.7.4.1;Calculation of blood volume withdrawal;201
11.7.4.2;Practical aspects of hemodilution;201
11.7.4.3;Technique of preoperative hemodilution;202
11.7.4.4;Monitoring;202
11.7.5;EFFICACY OF HEMODILUTION;204
11.7.6;ADJUNCTS TO ANH;204
11.7.6.1;Erythropoietin (EPO);204
11.7.6.2;Hyperoxia;205
11.7.6.3;Hypervolemia;205
11.7.6.4;Blood substitutes;205
11.7.7;SUMMARY;205
11.7.8;REFERENCES;206
11.8;17 Potential for Blood Substitutes in Tissue Ischemia;209
11.8.1;INTRODUCTION;209
11.8.2;PERIPHERAL ARTERIAL OCCLUSIVE DISEASE;209
11.8.2.1;Rest pain;209
11.8.2.2;Ulcers and gangrene;210
11.8.3;TREATMENT AVAILABLE FOR CHRONIC CRITICAL LEG ISCHEMIA;211
11.8.3.1;General management;211
11.8.3.2;Increase transmural pressure;211
11.8.3.3;Improve the local microcirculation;212
11.8.3.4;Other treatments;213
11.8.3.5;Amputation;213
11.8.4;POTENTIAL FOR BLOOD SUBSTITUTES IN THE TREATMENT OF CCLI;213
11.8.4.1;Theoretical possibilities;213
11.8.4.2;Improving functional capillary density;213
11.8.5;SUMMARY;214
11.8.6;REFERENCES;215
12;Section 4: Toxicity and Side Effects;216
12.1;18 Redox and Radical Reactions of Hemoglobin Solutions: Toxicities and Protective Strategies;218
12.1.1;INTRODUCTION;218
12.1.2;OXIDATIVE MECHANISMS;219
12.1.3;HEMOGLOBIN AND CELL-SIGNALING PATHWAYS;221
12.1.3.1;HIF-1a transcription factor regulates oxygen homeostasis in cells;221
12.1.3.2;HIF-1a, a possible oxygen sensor for assessment of various oxygen-carrying blood substitutes;222
12.1.4;ANTIOXIDATIVE PROTECTIVE STRATEGIES;222
12.1.5;SUMMARY;224
12.1.6;REFERENCES;225
12.2;19 Pro-Oxidant Activity of Hemoglobin and Endothelial Cytotoxicity;227
12.2.1;INTRODUCTION;227
12.2.2;PRO-OXIDANT ACTIVITY OF HEMOGLOBIN;228
12.2.2.1;Heme moiety of hemoglobin;228
12.2.2.2;Redox cycling reactions;228
12.2.2.3;Other pro-oxidant mechanisms of hemoglobin;229
12.2.3;HEMOGLOBIN-MEDIATED ENDOTHELIAL CYTOTOXICITY IN VITRO;230
12.2.3.1;Heme- and ferryl Hb-induced cytotoxicity;230
12.2.3.2;Redox cycling of hemoglobin enhances lipopolysaccharide-induced cytotoxicity;232
12.2.4;PRO-OXIDANT ACTIVITY OF HEMOGLOBIN AND VASCULAR TOXICITY IN VIVO;233
12.2.5;REFERENCES;234
12.2.6;SUMMARY;234
12.3;20 Renal Toxicity;238
12.3.1;INTRODUCTION;238
12.3.2;HISTORY AND BACKGROUND;238
12.3.3;CURRENT STATE OF KNOWLEDGE;239
12.3.3.1;Renal hemoglobin transport and toxicity for tubular cells;239
12.3.3.2;Heme oxygenases;239
12.3.3.3;Histopathology;240
12.3.4;HEMOGLOBIN TOXICITY TO RENAL VASCULATURE;240
12.3.4.1;Extravasation;240
12.3.4.2;Hemoglobin effects on vascular function;241
12.3.5;FUNCTIONAL CONSEQUENCES OF HEMOGLOBIN TOXICITY;241
12.3.5.1;Acute toxicity;241
12.3.5.2;Chronic renal hemoglobin toxicity;241
12.3.6;ACUTE RENAL FAILURE;242
12.3.6.1;Classification of human acute renal failure;242
12.3.6.2;Preconditioning;242
12.3.6.3;Animal models of acute tubular necrosis (renal failure);243
12.3.7;SUMMARY;243
12.3.8;FUTURE DIRECTIONS;244
12.3.8.1;Animal models of acute and chronic toxicity;244
12.3.8.2;Clinical trials;244
12.3.9;REFERENCES;245
12.4;21 Hemoglobin and Neurotoxicity;248
12.4.1;INTRODUCTION;248
12.4.2;IN VITRO EXPERIMENTS;248
12.4.3;IN VIVO EXPERIMENTS;250
12.4.4;TISSUE RESPONSE TO HEMOGLOBIN METABOLITES AND POSSIBLE NEUROPROTECTION;250
12.4.5;CLINICAL EXPERIENCE WITH HBOCs;252
12.4.6;REFERENCES;254
12.5;22 The Role of Inflammation in the Toxicity of Hemoglobin-Based Oxygen Carriers;256
12.5.1;INTRODUCTION;256
12.5.2;THE INFLAMMATORY RESPONSE;256
12.5.2.1;Cellular responses;256
12.5.2.2;Cytokines;257
12.5.2.3;Complement;257
12.5.3;BLOOD VESSELS;257
12.5.3.1;Reactive oxygen species;257
12.5.3.2;The intestinal mucosa;258
12.5.4;BLOOD SUBSTITUTES AND INFLAMMATION;258
12.5.4.1;Mast cells;258
12.5.4.2;Eosinophils;259
12.5.4.3;Complement;260
12.5.5;MICROVESSELS AND INTESTINAL MUCOSA;261
12.5.6;CLINICAL IMPLICATIONS OF INFLAMMATION DURING USE OF BLOOD SUBSTITUTES;262
12.5.7;ANTICIPATED FUTURE DIRECTIONS;262
12.5.8;SUMMARY;263
12.5.9;REFERENCES;264
12.6;23 Hemoglobin-Induced Myocardial Lesions;267
12.6.1;INTRODUCTION;267
12.6.2;BACKGROUND;267
12.6.3;ANIMAL MODELS;268
12.6.4;LESION CHARACTERISTICS;269
12.6.5;MECHANISM OF HEMOGLOBIN-INDUCED MYOCARDIAL LESIONS;271
12.6.5.1;Contaminants;271
12.6.5.2;Effect of a foreign protein;272
12.6.5.3;Heme;272
12.6.6;CO-MEDICAMENTS;272
12.6.6.1;Administration protocol;272
12.6.6.2;Chemical modification;273
12.6.6.3;Role of nitric oxide;273
12.6.7;SUMMARY;274
12.6.8;ACKNOWLEDGEMENTS;275
12.6.9;REFERENCES;275
13;Section 5: Perfluorocarbon-Based Oxygen Carriers;278
13.1;24 Fluorocarbon Emulsions as in vivo Oxygen Delivery Systems: Background and Chemistry;280
13.1.1;FLUOROCARBON CHEMISTRY;280
13.1.1.1;Unique chemicals;280
13.1.1.2;Stable and inert;281
13.1.1.3;Hydrophobic and lipophobic;281
13.1.2;OXYGEN DISSOLVING AND DELIVERING CAPACITY: GAS-LIKE LIQUIDS;282
13.1.3;PERFLUOROCARBON EMULSIONS FOR IN VIVOOXYGEN TRANSPORT;283
13.1.3.1;Optimal perfluorocarbons for clinical emulsions;283
13.1.3.2;Synthesis of PFCS;286
13.1.3.3;Optimal emulsifiers;287
13.1.3.4;Production of small, stable emulsion particles;287
13.1.3.5;Stability: counteracting molecular diffusion and coalescence;288
13.1.4;DEVELOPMENT OF INJECTABLE FLUOROCARBON EMULSIONS;289
13.1.4.1;Fluosol-DA related emulsions;289
13.1.4.2;Oxygent™;290
13.1.4.3;Oxyfluor;290
13.1.4.4;Miscellaneous emulsions;291
13.1.5;THE SEARCH FOR IMPROVED EMULSIONS;291
13.1.5.1;Fluorocarbon–hydrocarbon diblockstabilized emulsions;291
13.1.5.2;Phase-shift emulsions;292
13.1.5.3;Further research on fluorocarbon emulsions and applications;292
13.1.6;REFERENCES;294
13.2;25 Fluosol: The First Commercial Injectable Perfluorocarbon Oxygen Carrier;297
13.2.1;INTRODUCTION;297
13.2.2;ORIGINS OF FLUOSOL;297
13.2.3;CHEMISTRY, COMPOSITION AND PRODUCTION;298
13.2.4;PRECLINICAL STUDIES;299
13.2.5;CLINICAL TRIALS;299
13.2.5.1;Studies in Japan;299
13.2.5.2;Studies in North America;300
13.2.6;FAILURE OF REGULATORY APPROVAL OF FLUOSOL FOR THE TREATMENT OF ANEMIA;301
13.2.7;PERCUTANEOUS TRANSLUMINAL CORONARY ANGIOPLASTY;301
13.2.7.1;What is angioplasty?;301
13.2.7.2;Benefits of Fluosol in angioplasty: animal and clinical studies;302
13.2.7.3;Regulatory approval of Fluosol for clinical use as adjunct to angioplasty;302
13.2.8;OTHER APPLICATIONS FOR FLUOSOL;303
13.2.9;LESSONS LEARNED FROM FLUOSOL;304
13.2.9.1;Merits;304
13.2.9.2;Shortcomings;304
13.2.10;OTHER ‘FIRST-GENERATION’ EMULSIONS;304
13.2.11;REFERENCES;305
13.3;26 Perftoran®;309
13.3.1;INTRODUCTION;309
13.3.2;HISTORY AND COMPOSITION OF PERFTORAN;309
13.3.3;PRECLINICAL STUDIES;310
13.3.4;CLINICAL TRIALS WITH PERFTORAN;312
13.3.5;CURRENT USAGE OF PERFTORAN;312
13.3.6;CLINICAL IMPLICATIONS;314
13.3.7;THE FUTURE OF PERFTORAN;315
13.3.8;SUMMARY;315
13.3.9;ACKNOWLEDGMENTS;316
13.3.10;REFERENCES;316
13.4;27 Rational Development of Oxyfluor™;319
13.4.1;INTRODUCTION;319
13.4.2;EVOLUTION OF PERFLUOROCARBONS FOR OXYGEN TRANSPORT;320
13.4.2.1;Leland Clark;320
13.4.2.2;Green Cross and Fluosol®;320
13.4.2.3;HemaGen and Oxyfluor™;321
13.4.3;DEVELOPMENT OF OXYFLUOR™;321
13.4.3.1;The emulsification system;321
13.4.3.2;The perfluorochemical;323
13.4.4;OXYFLUOR REGULATORY STATUS;326
13.4.5;THE FUTURE OF OXYFLUOR AND HEMAGEN;329
13.4.6;REFERENCES;331
13.5;28 Oxygent™, A Perfluorochemical-Based Oxygen Therapeutic for Surgical Patients;333
13.5.1;INTRODUCTION;333
13.5.2;EMULSION CHARACTERISTICS;333
13.5.3;NON-CLINICAL SAFETY;334
13.5.4;CLINICAL SAFETY;334
13.5.5;PRECLINICAL EFFICACY;335
13.5.6;POTENTIAL CLINICAL APPLICATIONS;335
13.5.6.1;Tissue oxygenation and hemodilution;335
13.5.6.2;Cardiopulmonary bypass;336
13.5.6.3;Shock and trauma;336
13.5.6.4;Decompression sickness;337
13.5.6.5;Organ preservation;337
13.5.6.6;Tumor oxygenation;337
13.5.6.7;Sickle cell disease;337
13.5.7;PHASE II CLINICAL STUDIES;337
13.5.7.1;General surgery;337
13.5.7.2;Cardiac surgery;338
13.5.8;PHASE III CLINICAL STUDIES;338
13.5.8.1;General surgery;338
13.5.8.2;Cardiac surgery;339
13.5.9;FUTURE CLINICAL DEVELOPMENT;341
13.5.10;ACKNOWLEDGMENTS;342
13.5.11;REFERENCES;342
14;Section 6: Hemoglobin-Based Oxygen Carriers;346
14.1;29 The Structural and Functional Properties of Hemoglobin and their Relevance for a Hemoglobin-Based Blood Substitute;348
14.1.1;INTRODUCTION;348
14.1.2;THE STRUCTURE OF HEMOGLOBIN;349
14.1.3;DERIVATIVES WITH HEME LIGANDS;349
14.1.4;SUBUNIT INTERFACES AND TETRAMER–DIMER DISSOCIATION;350
14.1.5;COOPERATIVE OXYGEN BINDING;350
14.1.5.1;Structural basis of cooperativity;353
14.1.5.2;Models of cooperativity;354
14.1.6;STEREOCHEMICAL CONSEQUENCES OF LIGAND BINDING;354
14.1.7;CONTROL OF OXYGEN AFFINITY;355
14.1.8;NON-HEME LIGANDS: H[sup(+)], Cl[sup(-)], CO[sub(2)] AND 2,3-DPG;356
14.1.9;NITRIC OXIDE;357
14.1.10;AUTOXIDATION;359
14.1.11;ACKNOWLEDGMENTS;360
14.1.12;REFERENCES;360
14.2;30 Hemoglobin Modification;362
14.2.1;INTRODUCTION;362
14.2.2;REACTIVITY OF HEMOGLOBIN;363
14.2.3;AMINO-TERMINAL MODIFICATION;364
14.2.3.1;Carbamylation;364
14.2.3.2;Carboxymethylation;364
14.2.3.3;Acetaldehyde;364
14.2.4;MODIFICATION AT THE 2,3-DPG BINDING SITE;364
14.2.4.1;Pyridoxal derivatives;364
14.2.4.2;lysine EF6(82)ß modification;365
14.2.4.3;2-Nor-2-formylpyridoxal 5'-phosphate;365
14.2.4.4;Other 2,3-DPG pocket crosslinkers;366
14.2.4.5;aa-CROSSLINK (LYSINE G6(99) a[sub(1)]–LYSINE G6(99)a[sub(2)]);366
14.2.5;SURFACE, MULTISITE POLYMERIZING REAGENTS;367
14.2.5.1;Glutaraldehyde;367
14.2.5.2;Other polyaldehydes;368
14.2.5.3;Diimidate esters;368
14.2.5.4;‘Zero-link’ polymers;368
14.2.6;CONJUGATED HEMOGLOBIN;368
14.2.7;RECOMBINANT HEMOGLOBIN;369
14.2.8;HEMOGLOBIN SOURCES;369
14.2.9;REFERENCES;371
14.3;31 Designing Recombinant Hemoglobin;375
14.3.1;INTRODUCTION;375
14.3.2;GENETICALLY CROSSLINKED HEMOGLOBIN;375
14.3.3;OXYGEN DELIVERY;376
14.3.4;THE HYPERTENSIVE SIDE EFFECT;378
14.3.5;NO DIOXYGENATION BY OXYHEMOGLOBIN;382
14.3.6;EXPRESSION OF rHB IN E.COLI;383
14.3.6.1;Apoglobin stability and expression;383
14.3.6.2;Hemoglobin assembly;385
14.3.6.3;Comparative mutagenesis of apoHb;386
14.3.6.4;Alpha hemoglobin stabilizing protein (AHSP);386
14.3.6.5;Heterologous heme transport genes;387
14.3.7;SUMMARY;389
14.3.8;ACKNOWLEDGMENTS;390
14.3.9;REFERENCES;390
14.4;32 Design, Conformational, Functional and Physiological Characterization of Recombinant Polymeric Heme-Proteins;396
14.4.1;INTRODUCTION;396
14.4.2;DESIGN OF RECOMBINANT HEME PROTEIN POLYMERS;397
14.4.2.1;Homogeneous polymers;397
14.4.2.2;Heterogeneous polymers;398
14.4.3;BIOCHEMICAL PROPERTIES;399
14.4.3.1;Heme affinity and autoxidation rate;399
14.4.3.2;Stability;399
14.4.3.3;Oxygen affinity;400
14.4.3.4;Nitric oxide affinity;400
14.4.4;PHYSIOLOGICAL PROPERTIES;401
14.4.4.1;Plasma retention time;401
14.4.4.2;Exchange transfusion;401
14.4.4.3;Focal cerebral ischemia;402
14.4.5;ENDOTHELIAL PERMEABILITY (EXTRAVASATION);402
14.4.6;SUMMARY;404
14.4.7;ACKNOWLEDGMENTS;405
14.4.8;REFERENCES;405
14.5;33 aa-Crosslinked Hemoglobin;407
14.5.1;THE NEED FOR A BLOOD SUBSTITUTE;407
14.5.2;PRODUCTION;409
14.5.3;CHARACTERIZATION;409
14.5.4;PHARMACOKINETICS;411
14.5.5;VASOCONSTRICTION;412
14.5.6;HEMODYNAMICS;413
14.5.7;MICROCIRCULATION;413
14.5.8;ENDOTHELIUM;414
14.5.9;OXYGEN TRANSPORT;415
14.5.10;OXIDATION;415
14.5.11;CENTRAL NERVOUS SYSTEM;415
14.5.12;REFERENCES;416
14.6;34 DCLHb and rHb1.1;420
14.6.1;‘TETRAMERIC’ MODIFIED HEMOGLOBINS;420
14.6.2;DCLHb;421
14.6.2.1;Composition;421
14.6.2.2;Manufacture;422
14.6.2.3;Physicochemical characteristics of DCLHb;424
14.6.2.4;Product history;425
14.6.3;RECOMBINANT HEMOGLOBINS;426
14.6.3.1;Composition and nomenclature;426
14.6.3.2;Manufacture;426
14.6.3.3;Product history;428
14.6.4;RETROSPECTIVE;430
14.6.4.1;Conflict of Interest statement;432
14.6.5;REFERENCES;432
14.7;35 Clinical Studies with DCLHb;436
14.7.1;INTRODUCTION;436
14.7.2;PRECLINICAL CARDIAC LESIONS;436
14.7.3;PHASE I STUDY;437
14.7.4;PHASE II STUDIES;437
14.7.4.1;Hemorrhagic shock study: first entry into patients;437
14.7.4.2;Low-dose surgery studies;438
14.7.4.3;Hemodialysis;438
14.7.4.4;Intensive care unit studies;439
14.7.5;PHASE III STUDIES;439
14.7.5.1;Cardiac surgery: the pivotal efficacy study;439
14.7.5.2;Pancreatitis;440
14.7.6;EUROPEAN PRODUCT APPLICATION FOR CARDIAC SURGERY;440
14.7.7;TRAUMA STUDIES: THE BEGINNING OF THE END;441
14.7.7.1;Stroke study;442
14.7.8;THE END OF DCLHb;442
14.7.9;LESSONS LEARNED;442
14.7.10;REFERENCES;443
14.8;36 Hemopure® (HBOC-201, Hemoglobin Glutamer-250 (Bovine)): Preclinical Studies;445
14.8.1;INTRODUCTION;445
14.8.2;PRODUCT CHARACTERISTICS;445
14.8.3;PHARMACOLOGICAL ACTION;446
14.8.4;PRECLINICAL STUDIES OF TISSUE OXYGENATION AND TRAUMA;448
14.8.4.1;Tissue oxygenation;448
14.8.4.2;Tumor oxygenation;449
14.8.4.3;Trauma, hemorrhage and/or shock;450
14.8.4.4;Controlled hemorrhage models;450
14.8.4.5;Uncontrolled hemorrhage models;450
14.8.4.6;Model of lethal whole body trauma;451
14.8.4.7;Hypotensive resuscitation;451
14.8.4.8;Brain oxygenation during hemorrhagic shock;452
14.8.5;CARDIOVASCULAR STUDIES;453
14.8.6;HEMODILUTION AND COMPLETE BLOOD REPLACEMENT;453
14.8.7;CARDIAC FUNCTION, OUTPUT AND METABOLISM;453
14.8.8;POTENTIAL INDICATIONS FOR HBOC-201;455
14.8.8.1;Extracorporeal membrane oxygenation;455
14.8.9;SUMMARY;455
14.8.10;REFERENCES;456
14.9;37 HBOC-201 (Hemoglobin Glutamer-250 (Bovine), Hemopure®): Clinical Studies;458
14.9.1;INTRODUCTION;458
14.9.2;PHASE I STUDIES IN HUMAN VOLUNTEERS;458
14.9.3;PHASE I/II STUDIES;461
14.9.3.1;Liver resection;463
14.9.3.2;Sickle cell disease;463
14.9.4;PHASE II STUDIES;463
14.9.4.1;Cardiac surgery;464
14.9.4.2;Abdominal aortic surgery;464
14.9.5;PHASE III STUDY;465
14.9.5.1;Orthopedic surgery;465
14.9.6;OTHER POPULATIONS AND CASE STUDIES;465
14.9.6.1;Abdominal aneurysm;465
14.9.6.2;Intraoperative myocardial ischemia;466
14.9.6.3;Autoimmune hemolytic anemia;466
14.9.6.4;HBOC-201 interference with clinical laboratory analyses;466
14.9.7;SUMMARY;467
14.9.8;REFERENCES;470
14.10;38 Polyhemoglobin-Enzymes as New-Generation Blood Substitutes and Oxygen Therapeutics;472
14.10.1;INTRODUCTION;472
14.10.2;POLYHEMOGLOBIN–CATALASE–SUPEROXIDE DISMUTASE;472
14.10.3;POLYHEMOGLOBIN–TYROSINASE;476
14.10.4;SUMMARY;479
14.10.5;REFERENCES;479
14.11;39 Surface Decoration of Hemoglobin with Polyethylene Glycol;481
14.11.1;PROTEIN MODIFICATION WITH PEG;481
14.11.2;HEMOGLOBIN MODIFICATION WITH PEG;481
14.11.2.1;Conjugation of hemoglobin with PEG chains;482
14.11.3;VASOACTIVITY OF PEG-MODIFIED HEMOGLOBIN;483
14.11.4;NEW PARADIGMS FOR THE DESIGN OF HEMOGLOBIN-BASED BLOOD SUBSTITUTES;483
14.11.4.1;Critical properties revisited;483
14.11.4.2;Validation of the new strategies;484
14.11.5;NEW PEG CHEMISTRY STRATEGIES;484
14.11.5.1;Thiolation-mediated maleimide chemistry;484
14.11.5.2;Structural and functional properties of Hb-PEG5K6;485
14.11.5.3;Vasoactivity of Hb-PEG5K6;486
14.11.5.4;Flexibility of the thiolation-mediated maleimide chemistry-based PEGylation protocol;487
14.11.6;MODIFICATION NEEDED TO NEUTRALIZE VASOACTIVITY;487
14.11.7;MOLECULAR SHIELDING BY PEG MODIFICATION;487
14.11.8;SUMMARY;488
14.11.9;ACKNOWLEDGMENTS;489
14.11.10;REFERENCES;489
14.12;40 Hemospan® (MP4), A Human Hemoglobin Modified with Maleimide-Polyethylene Glycol;491
14.12.1;INTRODUCTION;491
14.12.2;THE AUTOREGULATORY HYPOTHESIS;491
14.12.3;CHEMISTRY AND PHYSICAL PROPERTIES;492
14.12.3.1;Synthesis of MP4;492
14.12.3.2;Structure and physical properties of MalPEG-hemoglobin;493
14.12.3.3;Functional properties of MP4;494
14.12.4;NON-CLINICAL STUDIES;494
14.12.4.1;Fifty per cent controlled hemorrhage and resuscitation in pigs;494
14.12.4.2;Forty per cent hemorrhage and resuscitation followed by severe hemorrhage in pigs;495
14.12.4.3;Uncontrolled hemorrhage and resuscitation in pigs;496
14.12.4.4;Continuous exchange transfusion in rats;496
14.12.4.5;Microvascular response to hemodilution in Golden Syrian hamsters;496
14.12.4.6;Hemorrhage/resuscitation in rats;497
14.12.4.7;Pharmacokinetics and metabolism in animals;497
14.12.4.8;In vivooxidation;498
14.12.5;TOXICOLOGY/SAFETY;498
14.12.5.1;Acute and subacute toxicology;498
14.12.5.2;Central nervous system toxicity;499
14.12.5.3;Myocardial histology following 30 per cent blood volume exchange in primates;499
14.12.6;CLINICAL LABORATORY INTERFERENCE;499
14.12.7;CLINICAL INDICATIONS;500
14.12.7.1;Hemodynamic stabilization;500
14.12.7.2;Blood replacement after hemorrhage;500
14.12.7.3;Tissue oxygenation;500
14.12.8;CLINICAL TRIALS;500
14.12.9;SUMMARY;501
14.12.10;REFERENCES;502
14.13;41 Dextran–Hemoglobin;504
14.13.1;INTRODUCTION;504
14.13.2;HIGH YIELD OF DxHB;505
14.13.3;PROTECTION OF KIDNEYS;505
14.13.4;NON-ENTRY INTO LYMPH;505
14.13.5;OXYGEN AFFINITY;506
14.13.6;PHYSICAL STABILITY;506
14.13.7;IN VIVO STUDIES;506
14.13.7.1;Exchange transfusion;506
14.13.7.2;Hemorrhagic shock;506
14.13.8;POTENTIAL FOR DxHb;506
14.13.9;REFERENCES;507
14.14;42 Development of Non-Extravasating Hemoglobin-Based Oxygen Carriers;509
14.14.1;INTRODUCTION;509
14.14.2;FUMARYL-CROSSLINKED BOVINE HEMOGLOBIN;509
14.14.3;SEBACYL-CROSSLINKED TETRAMERIC HEMOGLOBIN (DECA);510
14.14.4;ADIPYL-CROSSLINKED BOVINE HEMOGLOBIN;513
14.14.5;ZERO-LINK POLYMERIC HEMOGLOBIN;513
14.14.6;OXYGEN DELIVERY BY HIGH AND LOW AFFINITY CARRIERS;516
14.14.7;SUMMARY;516
14.14.8;ACKNOWLEDGMENTS;517
14.14.9;REFERENCES;517
15;Section 7: Liposomes and Related Products;520
15.1;43 Liposome-Encapsulated Hemoglobin: History, Preparation and Evaluation;522
15.1.1;HISTORICAL PERSPECTIVE;522
15.1.2;PREPARATION OF LIPOSOMEENCAPSULATED HEMOGLOBIN;523
15.1.2.1;Lipid composition and charge;523
15.1.2.2;Particle size;524
15.1.2.3;Hemoglobin source;525
15.1.2.4;PEGylation of LEH;525
15.1.3;PROPERTIES;525
15.1.3.1;Oxygen affinity;525
15.1.3.2;Viscosity;526
15.1.3.3;Colloid oncotic pressure and isotonicity;526
15.1.4;ENDOTOXIN INTERACTION;526
15.1.5;CIRCULATION TIME;527
15.1.6;TOXICITY;528
15.1.7;OXYGEN DELIVERY;528
15.1.8;STORAGE STABILITY;529
15.1.9;SUMMARY;530
15.1.10;ACKNOWLEDGMENTS;530
15.1.11;REFERENCES;530
15.2;44 Hemoglobin Vesicles as a Molecular Assembly: Characteristics of Preparation Process and Performances as Artificial Oxygen Carriers;535
15.2.1;IMPORTANCE OF CELLULAR STRUCTURE;535
15.2.2;PREPARATION OF HEMOGLOBIN VESICLES;536
15.2.2.1;Virus inactivation and removal during hemoglobin purification;536
15.2.2.2;Encapsulation of concentrated Hb in HbV;537
15.2.3;REGULATION OF OXYGEN AFFINITY;538
15.2.4;STORAGE STABILITY;538
15.2.5;ENDOTOXIN;539
15.2.6;HEMOGLOBIN VESICLES AS OXYGEN CARRIERS IN VIVO;540
15.2.7;SUMMARY;540
15.2.8;ACKNOWLEDGMENTS;541
15.2.9;REFERENCES;541
15.3;45 Nanodimension Biodegradable Polymeric Membrane Artificial Red Blood Cells;544
15.3.1;INTRODUCTION;544
15.3.2;PROPERTIES OF HEMOGLOBIN POLYLACTIDE NANOCAPSULES;545
15.3.2.1;Particle size;545
15.3.2.2;Oxygen affinity, Hill coefficient and Bohr effect;545
15.3.2.3;Circulation half-life of hemoglobin nanocapsules;546
15.3.3;PEG-PLA COPOLYMER Hb NANOCAPSULES;547
15.3.3.1;Effects of molecular weight distribution of polyHb used in the PEG-PLA nanocapsules;547
15.3.3.2;Effects of higher concentrations of PEG-PLA (polyethelene-glyco-polylactide) copolymer combined with polyHb(17 : 1);547
15.3.3.3;Effects of higher molecular weight PLA for the PEG-PLA copolymer;548
15.3.3.4;Higher PEG-PLA concentration combined with higher molecular weight PLA;548
15.3.3.5;Effect of crosslinking the newly formed Hb nanocapsules;548
15.3.3.6;Effects of combination of all four factors to prepare Hb nanocapsules;548
15.3.3.7;Analysis of results;548
15.3.4;ENZYMES AND MULTIENZYMES;549
15.3.5;PREVENTION OF METHEMOGLOBIN FORMATION;549
15.3.5.1;Hb nanocapsules containing metHb reductase system;549
15.3.5.2;Hb nanocapsules permeable to reducing factors from plasma;550
15.3.5.3;Other red blood cell enzymes;551
15.3.6;IMPLICATIONS FOR BLOOD SUBSTITUTE DEVELOPMENT;551
15.3.7;ACKNOWLEDGMENTS;551
15.3.8;REFERENCES;551
15.4;46 Albumin-Heme: A Synthetic Heme-Based Oxygen Carrier;553
15.4.1;INTRODUCTION;553
15.4.2;RATIONALE FOR ALBUMIN-HEME;553
15.4.3;OXYGEN BINDING AND PHYSICOCHEMICAL CHARACTERISTICS;555
15.4.4;BLOOD COMPATIBILITY IN VITRO;555
15.4.5;IN VIVO EFFECTS;555
15.4.5.1;Blood pressure effects;555
15.4.5.2;Hemodilution;556
15.4.6;PRECLINICAL SAFETY;556
15.4.7;FUTURE RESEARCH;558
15.4.8;ACKNOWLEDGMENTS;559
15.4.9;REFERENCES;559
16;Index;562
16.1;A;562
16.2;B;562
16.3;C;563
16.4;D;563
16.5;E;564
16.6;F;564
16.7;G;564
16.8;H;564
16.9;I;566
16.10;J;566
16.11;K;566
16.12;L;566
16.13;M;567
16.14;N;567
16.15;O;567
16.16;P;568
16.17;R;568
16.18;S;569
16.19;T;569
16.20;U;569
16.21;V;569
16.22;W;569
16.23;Z;569
17;Color Plates;570

Leseproben

List of Contributors
Seetharama A. Acharya     (39), Albert Einstein Univ. School of Medicine, 1300 Morris Park Avenue, Bronx, NY, USA Paul Aebersold     (3), Division of Blood Applications, Center for Biologics Evaluation and Research, FDA, Rockville, MD, USA Abdu I. Alayash     (18), Center for Biologics Evaluation and Research – NIH Campus, FDA, Bethesda, MD, USA Vibhu Awasthi     (43), University of Texas Health Science Center at San Antonio, San Antonio, TX, USA Andrew D. Baines     (20), Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada Ann L. Baldwin     (22), Department of Physiology – College of Medicine, University of Arizona, Tucson, AZ, USA Andrea Bellelli     (29), Dipartimento di Scienze Biochimiche, Universita ‘La Sapienza’, Rome, Italy Jan Blumenstein     (41), Dextro-Sang Corporation, Toronto, Canada Liudmila A. Bogdanova     (26), The Institute of Theoretical and Experimental Biophysics of RAS, Pushchino, Moscow Region, Russia William S. Brinigar     (32), Department of Chemistry, Temple University, Philadelphia, PA, USA Maurizio Brunori     (29), Dipartimento di Scienze Biochimiche, Universita ‘La Sapienza’, Rome, Italy Enrico Bucci     (42), Biochemistry and Molecular Biology, University of Maryland Medical School, Baltimore, MD, USA Kenneth E. Burhop     (23), Medication Delivery, Baxter Healthcare Corporation, Deerfield, IL, USA Pedro Cabrales     (7, 8), Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA Thomas Ming Swi Chang     (38, 45), Faculty of Medicine, McGill University, Montreal, Quebec, Canada Keith W. Chapman     (40), Sangart Inc., and Department of Bioengineering, University of California, San Diego, California, USA. Pierre-Guy Chassot     (14), Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland Felice D’Agnillo     (19), Division of Hematology, Center for Biologics, Evaluation and Research Food and Drug Administration, NIH Campus, Bethesda, MD, USA Randal O. Dull     (32), Department of Anesthesiology, University of Utah, Salt Lake City, UT, USA Barbara L. Ellington     (21), Department of Neurosurgery, University of California San Francisco and San Francisco Veterans Affairs Hospital, San Francisco, CA, USA Bengt Fagrell     (17), Department of Medicine, Karolinska Sjukhuset, Stockholm, Sweden John A. Frangos     (8), La Jolla Bioengineering Institute, La Jolla, CA, USA Clara Fronticelli     (32), Anesthesiology and CCM, Johns Hopkins University, Baltimore, MD, USA Maria S. Gawryl     (36, 37), Research and Development, Biopure Corporation, Cambridge, MA, USA Elizabeth A. Goins     (43), Department of Radiology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA J. David Hellums     (6), Department of Bioengineering, Rice University, Houston, TX, USA Hirohisa Horinouchi     (46), Department of General Thoracic Surgery, School of Medicine, Keio University, Tokyo, Japan Yubin Huang     (46), Advanced Research Institute for Science and Engineering, Waseda University, Tokyo, Japan Marcos Intaglietta     (7, 8), Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA Bahram I. Islamov     (26), The Institute of Theoretical and Experimental Biophysics of RAS, Pushchino, Moscow Region, Russia Henrikh R. Ivanitsky     (26), The Institute of Theoretical and Experimental Biophysics of RAS, Pushchino, Moscow Region, Russia Paul C. Johnson     (9), Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA Natalia B. Karmen     (26), The Institute of Theoretical and Experimental Biophysics of RAS, Pushchino, Moscow Region, Russia Peter E. Keipert     (28), Sangart Inc., Sorrento Valley, San Diego, CA, USA Gregor Kemming     (15, 16), Clinic of Anesthesiology and Institute for Surgical Research, Ludwig-Maximilian-University, Munich, Germany Harvey G. Klein     (2), Department of Transfusion Medicine, Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, MD, USA Koichi Kobayashi     (44, 46), Department of Surgery, School of Medicine, Keio University,Tokyo, Japan Raymond C. Koehler     (21, 32, 42), Department of Anesthesiology and Critical Care Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA Teruyuki Komatsu     (46), Advanced Research Institute for Science and Engineering, Waseda University, Tokyo, Japan Marie Pierre Krafft     (24), Colloïdes et Interfaces, Institut Charles Sadron, Strasbourg, France George C. Kramer     (12), Department of Anesthesiology and Physiology, University of Texas Medical Branch, Galveston, TX, USA Herman Kwansa     (42), Department of Biochemistry and Molecular Biology, University of Maryland Medical School, Baltimore, MD,USA Laurence Landow     (3), Division of Blood Applications, Center for Biologics Evaluation and Research, FDA, Rockville, MD, USA Kimberly Lindsey     (3), Division of Blood Applications, Center for Biologics Evaluation and Research, FDA, Rockville, MD, USA Kenneth C. Lowe     (25), Department of Life Science, University of Nottingham – School of Biological Sciences, Nottingham, England, UK Eugene I. Maevsky     (26), Thermodynamics and Energetics of Biological Systems, Institute of Theoretical and Experimental Biophysics of RAS, Pushkino, Moscow Region, Russia David H. Maillett     (31), Department of Biochemistry and Cell Biology, Rice University, Houston, TX, USA Belur N. Manjula     (39), Departments of Physiology and Biophysics, Albert Einstein College of Medicine, Bronx, NY, USA Igor A. Maslennikov     (26), The Scientific-Productive Company ‘Perftoran’, Pushchino, Moscow Region, Russia Barbara Matheson     (42), Department of Biomedical Science, University of Maryland Dental School, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA Konrad Messmer     (15, 16), Institute for Surgical Research, University of Munich, Munich,...