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Chemistry and Biochemistry of Oxygen Therapeutics: From Transfusion to Artificial Blood

ISBN: 978-0-470-68668-3
466 pages
September 2011
Chemistry and Biochemistry of Oxygen Therapeutics: From Transfusion to Artificial Blood (0470686685) cover image
Human blood performs many important functions including defence against disease and transport of biomolecules, but perhaps the most important is to carry oxygen – the fundamental biochemical fuel - and other blood gases around the cardiovascular system. Traditional therapies for the impairment of this function, or the rapid replacement of lost blood, have centred around blood transfusions. However scientists are developing chemicals (oxygen therapeutics, or “blood substitutes”) which have the same oxygen-carrying capability as blood and can be used as replacements for blood transfusion or to treat diseases where oxygen transport is impaired.

Chemistry and Biochemistry of Oxygen Therapeutics: From Transfusion to Artificial Blood links the underlying biochemical principles of the field with chemical and biotechnological innovations and pre-clinical development.

The first part of the book deals with the chemistry, biochemistry, physiology and toxicity of oxygen, including chapters on hemoglobin reactivity and regulation; the major cellular and physiological control mechanisms of blood flow and oxygen delivery;  hemoglobin and myoglobin;  nitric oxide and oxygen; and the role of reactive oxygen and nitrogen species in ischemia/reperfusion Injury.

The book then discusses medical needs for oxygen supply, including acute traumatic hemorrhage and anemia; diagnosis and treatment of haemorrhages in "non-surgical" patients; management of perioperative bleeding; oxygenation in the preterm neonate; ischemia

normobaric and hyperbaric oxygen therapy for ischemic stroke and other neurological conditions; and transfusion therapy in β thalassemia and sickle cell disease

Finally “old”and new strategies for oxygen supply are described. These include the political, administrative and logistic issues surrounding transfusion;  conscientious objection in patient blood management; causes and consequences of red cell incompatibility; biochemistry of red blood cell storage;  proteomic investigations on stored red blood cells; red blood cells from stem cells; the universal red blood cell;  allosteric effectors of hemoglobin; hemoglobin-based oxygen carriers;  oxygen delivery by natural and artificial oxygen carriers; cross-linked and polymerized hemoglobins as potential blood substitutes; design of novel pegylated hemoglobins as oxygen carrying plasma expanders; hb octamers by introduction of surface cysteines; hemoglobin-vesicles as a cellular type hemoglobin-based oxygen carrier; animal models and oxidative biomarkers to evaluate pre-clinical safety of extracellular hemoglobins; and academia – industry collaboration in blood substitute development.

Chemistry and Biochemistry of Oxygen Therapeutics: From Transfusion to Artificial Blood is an essential reference for clinicians, haematologists, medicinal chemists, biochemists, molecular biologists, biotechnologists and blood substitute researchers.

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List of Contributors xvii

Preface xxiii

1. Introduction 1
Richard B. Weiskopf

References 5

Part I. Oxygen: Chemistry, Biochemistry, Physiology and Toxicity 9

2. Hemoglobin Reactivity and Regulation 11
Stefano Bettati and Andrea Mozzarelli

2.1 Introduction 11

2.2 Oxygen Loading and Transport 11

2.3 NO Reactivity with Hb 15

2.4 Hb Oxidation 16

2.5 Nitrite Reactivity with Hb 16

2.6 Amino-acid Determinants of Hb Reactivity:

Natural and Engineered Hbs 17

2.6.1 Modulation of Oxygen Affinity and Cooperativity 17

2.6.2 NO Reactivity and Oxidation 18

2.7 Conclusion 18

Acknowledgments 19

References 19

3. The Major Physiological Control Mechanisms of Blood Flow and Oxygen Delivery 23
Raymond C. Koehler

3.1 Introduction 23

3.2 Autoregulation of Blood Flow to Changes in Perfusion Pressure 23

3.3 Metabolic Regulation of Blood Flow 26

3.4 O2 Transport 27

3.5 O2 Delivery 27

3.6 Endothelial Control of Vasomotor Tone 29

3.7 Effect of Cell-free Hb on Endothelial Function 31

3.8 Hypoxic Hypoxia 33

3.9 Carbon Monoxide Hypoxia 36

3.10 Anemia 36

3.11 Conclusion 39

References 39

4. The Main Players: Hemoglobin and Myoglobin; Nitric Oxide and Oxygen 47
Tim J. McMahon and Joseph Bonaventura

4.1 Introduction 47

4.2 Role of Mammalian Mb in O2 Homeostasis 47

4.3 What’s Missing in the Mb Knockout Mouse 48

4.4 Evolutionary Origins of Mb and the Nitrogen Cycle 49

4.5 Human Hb: Evolved Sensor of pO2 and Redox 49

4.6 Broad Reactivity and Influence of NO: Lessons from the Microcosm Hb 49

4.7 Some Fish Demonstrate a Fundamental “Need” for Hb-dependent NO Cycling, as in Humans 50

4.8 Reactions of NO with Hb that Preserve NO Bioactivity 52

4.9 Mammalian RBC/Hb–NO Interactions 52

4.10 A Mutant Mouse Challenges the SNO-Hb Hypothesis, but does not Overthrow it 54

4.11 Signaling by Hb-derived SNO: A Metabolically Responsive, Regulated Pathway 54

4.12 Signaling by Hb-derived SNO: Pathway Complexity Revealed by Multiple Defects in Disease States 55

4.13 Therapeutic Implications of the Hb–NO Signaling System 56

4.14 HBOCs, NO, and SNO 56

4.15 Other Gaseous Hb Ligands of Potential Therapeutic Significance 57

4.16 NO-related Enzymatic Activities of Hb: Reconciling Nitrite Reductase and SNO Synthase Functions 57

4.17 Measuring Biologically Relevant Hb–NO Adducts 58

4.18 Conclusion 58

Acknowledgments 58

References 59

5. The Role of Reactive Oxygen and Nitrogen Species in Ischemia/Reperfusion Injury 63
Ester Spagnolli and Warren M. Zapol

5.1 Introduction 63

5.2 Redox System and Free Radicals in Biological Systems 64

5.3 Pathophysiology of Ischemia/Reperfusion Injury 65

5.3.1 Cell Death 65

5.3.2 The Inflammatory Response 67

5.4 Protection Against I/R Injury 67

5.4.1 Ischemic Pre- and Post-conditioning 67

5.4.2 Pharmacological Conditioning 68

5.4.2.1 The Protective Role of ROS and Antioxidants 68

5.4.2.2 The Protective Role of NO 69

5.4.2.3 NO-based Therapies for I/R Injury 70

5.5 Conclusion 72

Acknowledgments 72

References 72

Part II. Medical Needs for Oxygen Supply 79

6. Acute Traumatic Hemorrhage and Anemia 81
Lena M. Napolitano

6.1 Introduction 81

6.2 Blood Transfusion in Trauma 83

6.2.1 Massive Transfusion 83

6.2.2 Massive Transfusion and Coagulopathy 83

6.2.3 Hypotensive or Delayed Resuscitation 84

6.2.4 Hemostatic Resuscitation 84

6.2.5 Massive Transfusion Protocols 86

6.2.6 Transfusion after Hemorrhage Control 86

6.2.7 Efficacy of RBC Transfusion in Trauma and Associated Risks 86

6.3 Oxygen Therapeutics in Trauma 88

6.3.1 Diaspirin Crosslinked Hb 90

6.3.2 Hemopure 90

6.3.3 PolyHeme 91

6.3.4 MP4OX 93

6.3.5 Recombinant Human Hb 95

6.3.6 Adverse Effects of HBOCs 95

6.3.7 HBOCs in Trauma: A Way Forward? 96

6.4 Conclusion 97

References 97

7. Diagnosis and Treatment of Haemorrhages in ‘Nonsurgical’ Patients 107
Umberto Rossi and Rosa Chianese

7.1 Introduction 107

7.1.1 Aetiopathogenetic Classification 107

7.1.2 Multifactorial Pathogenesis 108

7.1.3 Haemorrhagic Syndromes from Antithrombotic Treatment or Prophylaxis 108

7.2 Clinical Assessment 111

7.2.1 Medical History 111

7.2.2 Physical Examination 112

7.3 Laboratory Tests 113

7.3.1 Screening Tests 113

7.3.2 Second-level Laboratory Tests 113

7.3.3 Other Tests 114

7.4 Haemorrhagic Syndromes Clinically Indicative of Systemic Defects with Normal Screening Tests 117

7.5 Blood and Blood Components in the Treatment of Haemorrhagic Syndromes 118

Further Reading 118

8. Management of Perioperative Bleeding 121
Sibylle A. Kozek-Langenecker

8.1 Introduction 121

8.2 Pathomechanisms of Coagulopathy in Massive Bleeding 121

8.3 Perioperative Coagulation Monitoring 122

8.4 Limitations of Routine Coagulation Tests in the Perioperative Setting 123

8.5 Thromboelastography (TEG) and Rotational Thromboelastometry (ROTEM) 124

8.6 Procoagulant Interventions 124

8.7 Algorithm for Coagulation Management 126

References 127

9. Oxygenation in the Preterm Neonate 131
Vidheya Venkatesh, Priya Muthukumar, Anna Curley and Simon Stanworth

9.1 Introduction 131

9.2 Physiology of Oxygen Transport in Fetal and Postnatal Life 132

9.2.1 Oxygenation of the Fetus 132

9.2.2 Measuring Oxygenation in the Neonate 133

9.3 Oxygen Therapy in the Postnatal Period 133

9.3.1 Oxidative Stresses in the Newborn Period 134

9.3.2 Clinical Sequelae of Hyperoxia 134

9.3.2.1 Retinopathy of Prematurity 134

9.3.2.2 Oxygen and Chronic Lung Disease 135

9.3.2.3 Oxygen and Periventricular Leukomalacia 136

9.4 Oxygen and Resuscitation of the Newborn Infant 136

9.5 Transfusion in the Newborn 137

9.6 ROP and Transfusions 137

9.7 Conclusion 137

References 138

10. Ischemia 145
Hooman Mirzakhani and Ala Nozari

10.1 Introduction 145

10.2 Pathophysiology 145

10.2.1 Energy Failure 145

10.2.2 Cell Membrane Damage 146

10.2.3 Increased Cytosolic Calcium 146

10.2.4 Inflammation 148

10.2.5 The No-reflow Phenomenon 149

10.2.6 Free Radicals and Reactive Oxygen Species 149

10.2.7 Excitotoxicity 150

10.3 Therapeutic Potentials 150

10.3.1 Preconditioning 150

10.3.2 Antioxidants 151

10.3.3 Anti-inflammation Therapy 151

10.3.4 Therapeutic Hypothermia 151

10.3.5 Hydrogen Sulfide 152

10.3.6 Hyperoxia and Hyperbaric Oxygen 152

10.3.7 Hemoglobin-based Oxygen Carriers 152

10.4 Conclusion 153

References 153

11. Normobaric and Hyperbaric Oxygen Therapy for Ischemic Stroke and Other Neurological Conditions 159
Ari Moskowitz, Yu-Feng Yvonne Chan and Aneesh B. Singhal

11.1 Introduction 159

11.2 Rationale of Oxygen Therapy in AIS 160

11.3 Hyperbaric Oxygen Therapy 162

11.4 Normobaric Oxygen Therapy 164

11.5 The Status of Supplemental Oxygen Delivery 165

11.6 Comparison of HBO and NBO in AIS 165

11.7 Safety Concerns 168

11.8 HBO and NBO in Other Conditions 169

11.9 Conclusion 169

References 170

12. Transfusion Therapy in β Thalassemia and Sickle Cell Disease 179
Carlo Brugnara and Lucia De Franceschi

12.1 Introduction 179

12.2 β Thalassemia and Transfusion 179

12.3 Sickle Cell Disease and Transfusion 182

12.4 Iron Chelation Tools 185

12.5 Conclusion 186

References 186

Part III. “Old” and New Strategies for Oxygen Supply 193

13. Transfusion: Political, Administrative and Logistic Issues 195
John R. Hess and Giuliano Grazzini

Disclaimer 195

13.1 Introduction 195

13.2 Blood Safety 196

13.3 Blood Availability 198

13.4 Cost and Fairness 200

13.5 Transfusion Medicine 201

References 202

14. Conscientious Objection in Patient Blood Management 205
Kenneth E. Nollet and Hitoshi Ohto

14.1 Introduction 205

14.2 Conscientious Objection 205

14.3 Patient Blood Management 206

14.4 Jehovah’s Witnesses 207

14.5 Will the Real Objection Please Stand Up? 208

14.6 Conscientious Objection in Relation to Oxygen Therapeutics and Other Innovations 208

Acknowledgements 209

References 210

15. Red-cell Transfusion in Clinical Practice 213
Harvey G. Klein

15.1 Introduction 213

15.2 Red-cell Use 214

15.3 The Red-cell-transfusion Trigger 215

15.4 Risks of Red-cell Transfusion 216

15.5 Conclusion 218

Disclaimer 218

References 218

16. Causes and Consequences of Red Cell Incompatibility 221
Chisa Yamada and Robertson Davenport

16.1 Introduction 221

16.2 Red Cell Antigens 221

16.2.1 ABO and the H System 221

16.2.2 The Lewis System and Structurally Related Antigens 222

16.2.3 The Rh System 222

16.2.4 Other Blood Group Systems 222

16.3 Red Cell Antibodies 223

16.3.1 Naturally Occurring Antibodies and Immune Antibodies 223

16.3.2 Autoantibodies 224

16.3.3 Drug Induced Antibodies 224

16.4 Compatibility Testing 224

16.4.1 ABO and Rh D Typing 224

16.4.2 Antibody Screening and Identification 224

16.4.3 Selection of Appropriate Blood 225

16.4.4 Crossmatch Testing 225

16.5 Hemolytic Transfusion Reactions 225

16.5.1 Pathophysiology 226

16.5.2 Prevention 228

References 228

17. Biochemistry of Storage of Red Blood Cells 231
Ryan Stapley, Dario A. Vitturi and Rakesh P. Patel

17.1 Introduction 231

17.2 Pathologic Consequences of Transfusion with Aged RBCs 232

17.3 Changes in Oxygen Affinity During RBC Storage 232

17.4 Role of Oxidative Damage During RBC Storage 233

17.5 Changes in the Physical Properties of RBCs During Storage 234

17.6 RBCs as Modulators of Vascular Flow 234

17.6.1 ATP Release Hypothesis 234

17.6.2 SNO-hemoglobin Hypothesis 235

17.6.3 Nitrite Reductase/Anhydrase Hypothesis 236

17.7 RBC-dependent Modulation of Inflammation 237

17.8 Conclusion 237

Acknowledgements 238

References 238

18. Proteomic Investigations of Stored Red Blood Cells 243
Lello Zolla and Angelo D’Alessandro

18.1 Introduction 243

18.2 RBC Ageing and Metabolism in vivo 244

18.3 RBC Storage Lesions Through Proteomics 248

18.4 Conclusion 252

References 252

19. Red Blood Cells from Stem Cells 257
Anna Rita Migliaccio, Carolyn Whitsett and Giovanni Migliaccio

19.1 Introduction 257

19.2 Stem-cell Sources for ex vivo Generation of Erythroid Cells as a Transfusion Product 258

19.3 Conditions that Favor ex vivo Erythroid Cell Expansion 260

19.4 A Clinical-grade Production Process for ex vivo Generation of Red-cell Transfusion Products 261

19.4.1 The Nature of the Production Process 261

19.4.2 Cellular Composition of the Product 263

19.4.3 Functional Status of Product 264

19.4.4 Safety Considerations 265

19.5 Time Line of the Clinical Application of ex vivo-generated Erythroid Cells 266

19.5.1 Drug Discovery 266

19.5.2 Drug Delivery 267

19.5.3 Ex vivo-expanded EBs for Alloimmunized Patients 268

References 268

20. The Universal Red Blood Cell 273
Luca Ronda and Serena Faggiano

20.1 Introduction 273

20.1.1 ABO Antigens 274

20.1.2 The Rh System 274

20.2 Enzymatic Removal of A and B Antigens 275

20.2.1 Conversion of B RBCs to Group O 275

20.2.2 Conversion of A RBCs to Group O 277

20.3 RBC Camouflage Through PEGylation 277

20.3.1 Functionalized Methoxy PEG 278

20.3.2 Cyanuric Chloride PEG 279

20.3.3 Extension Arm-facilitated RBC PEGylation 279

20.3.4 Increasing the Degree of RBC PEGylation 280

20.4 Conclusion 280

References 280

21. Allosteric Effectors of Hemoglobin: Past, Present and Future 285
Martin K. Safo and Stefano Bruno

21.1 Introduction 285

21.2 Natural and Synthetic Allosteric Effectors 288

21.2.1 Organic Phosphates 288

21.2.2 Synthetic Aromatic Propionate Right-shifters 289

21.2.3 Aromatic Aldehyde Left-shifters 290

21.3 Molecular Mechanism of Action of Allosteric Effectors 293

21.3.1 Oxygen Binding Curve and Hb Structural Changes 293

21.3.2 How Allosteric Effectors can Bind to the Same Site and Have Opposite Allosteric Properties 294

21.3.3 Decreasing Subunit Mobility and Changes in Allosteric Properties: Molecular Ratchets 294

21.4 The First Visualization of an Important Pharmacological Theory via Hb Allosteric Effector Binding 295

21.5 The Clinical Importance of Hemoglobin Allosteric Effectors 295

References 296

22. Hemoglobin-based Oxygen Carriers: History, Limits, Brief Summary of the State of the Art, Including Clinical Trials 301
Jonathan S. Jahr, Arezou Sadighi, Linzy Doherty, Alvin Li and Hae Won Kim

22.1 Introduction 301

22.2 American Society of Anesthesiologists Guidelines and Risks of Blood Transfusion 302

22.3 Limitations of Blood Transfusion 302

22.4 History 302

22.5 Development 303

22.6 Definitive Clinical Trials 304

22.6.1 Diaspirin Crosslinked Hemoglobin (DCLHb, HemeAssist, Baxter Laboratories, Deerfield, IL) 304

22.6.2 Hemoglobin Raffimer (HR, Hemolink, Hemosol Inc., Ontario, Canada) 306

22.6.3 Human Polymerized Hemoglobin (PolyHeme, Northfield Laboratories, Evanston, IL) 307 22.6.4 Hemoglobin Glutamer-250 (Bovine) (HBOC-201, Hemopure, Biopure Corp., Cambridge, MA) 308

22.6.5 Maleimide-polyethylene Glycol-modified Hemoglobin (MP4, Hemospan, Sangart Inc., San Diego, CA) 309

22.7 Current Status and Future Directions of HBOCs 311

References 314

23. Oxygen Delivery by Natural and Artificial Oxygen Carriers 317
Enrico Bucci

23.1 Introduction 317

23.2 The Role of Oxygen Carriers 317

23.3 The Role of Natural Cell-bound Oxygen Carriers 318

23.4 Matching the Rate of Oxygen Delivery with the Rate of Oxygen Consumption 320

23.4.1 The Imbalance 320

23.4.2 The Rate of Oxygen Release from the Red Cells 320

23.4.3 Matching the Delivery/Consumption Rates 321

23.4.4 The Hematocrit is a Critical Parameter 321

23.5 The Role of Artificial Cell-free Oxygen Carriers 321

23.5.1 Facilitated Diffusion 321

23.5.2 Toxicity 322

23.6 Other Parameters 322

23.7 Clinical Use? 323

Acknowledgments 324

References 324

24. Crosslinked and Polymerized Hemoglobins as Potential Blood Substitutes 327
Kenneth W. Olsen and Eugene Tarasov

24.1 Introduction 327

24.2 Crosslinking the Hb Tetramer 328

24.3 Hb Polymers 332

24.4 Conclusion 337

References 338

25. Engineering the Molecular Shape of PEG-Hemoglobin Adducts for Supraperfusion 345
Seetharama A. Acharya, Marcos Intaglietta, Amy G. Tsai, Kulal Ananda and Fantao Meng

25.1 Introduction 345

25.2 Enzon DecaPEGylated Bovine Hb is Nonhypertensive 346

25.3 EAF HexaPEGylated Hb (EAF P5K6-Hb) is Nonhypertensive 347

25.4 Molecular and Solution Properties of EAF HexaPEGylated Human Hb (EAF-P5K6-Hb) 347

25.5 High O2 Affinity of EAF HexaPEGylated Hb and Tissue Oxygenation in Extreme Hemodilution 349

25.6 Influence of Total PEG Mass Conjugated to Hb on O2 Affinity and Tissue Oxygenation by PEG-Hbs 350

25.7 Influence of PEGylation Chemistry on Structural, Functional, and Solution Properties of HexaPEGylated Hb 351

25.8 Reductive PEGylation-induced Weakening of Interdimeric Interactions of Tetrameric Hbs 352

25.9 PEGylation-promoted Dissociation of Hb Tetramer is Attenuated by the Extension Arms of EAF PEGylated Hbs 353

25.10 Does Urethane-linkage-mediated PEGylation of Hb Promote its Dissociation? 354

25.11 Hemospan: Prototype of EAF HexaPEGylated Hb Designed at Einstein 354

25.12 EAF HexaPEGylated Hb Compared to other Blood Substitutes of Earlier Designs 355

25.13 Reversible Protection of Cys-93(β) during EAF PEGylation of Hb and Crosslinked Hbs: A Structural Requirement to Generate Medium- and Low-O2-affinity PEG-Hbs 355

25.14 Engineering Extension Arms between the Protein Core and PEG Shell Attenuates PEGylation-promoted Tetramer Dissociation 356

25.15 Attenuation of Direct HexaPEGylation-promoted Dissociation of Hb Tetramers by Increasing the Tetramer Stability Through Chemical Modification 359

25.16 Influence of the Extension Arm on the HexaPEGylation-enhanced Thermal Stability of Hb 359

25.17 PEGylation of Hb Induces a Hydrostatic Molecular Drag to the PEG-Hb Conjugate 360

25.18 EAF HexaPEGylated Hb is a Superperfusion Agent 360

25.19 EAF PEG-Hb-induced Vasodilation 361

25.20 In vivo Vasodilation by EAF PEG-Hb through its Enhanced Nitrite Reductase Activity 361

25.21 EAF PEG-Hbs as Mechanotransducers of e-NOS Activity 363

25.22 The Pattern of PEGylation of Intramolecularly Crosslinked Hbs Influences the Viscosity of the PEG-Hb Solution 364

25.23 Conclusion 364

Acknowledgments 366

References 367

26. Hb Octamers by Introduction of Surface Cysteines 371
V´eronique Baudin-Creuza, Chien Ho and Michael C. Marden

26.1 Introduction 371

26.2 Genetic Engineering of Proteins with Cysteines 373

26.2.1 Protein Expression 373

26.2.2 Oligomer Size 374

26.2.3 Disulfide Bond Formation 375

26.2.4 Functional Properties of the Octamers 376

26.2.5 Octamer Properties 378

26.2.6 Octamer Constraint 378

26.3 Conclusion 378

References 378

27. Hemoglobin Vesicles as a Cellular-type Hemoglobin-based Oxygen Carrier 381
Hiromi Sakai, Hirohisa Horinouchi, Eishun Tsuchida and Koichi Kobayashi

27.1 Introduction 381

27.2 The Concept of Hb Encapsulation in Liposomes 382

27.3 Hb Encapsulation Retards Gas Reactions 383

27.4 HBOCs as a Carrier of not only O2 but also CO 385

27.5 Conclusion 387

Acknowledgments 387

References 387

28. Animal Models and Oxidative Biomarkers to Evaluate Preclinical Safety of Extracellular Hemoglobins 391
Paul W. Buehler and Felice D’Agnillo

Disclaimer 391

28.1 Introduction 391

28.2 HBOC Safety and Efficacy 392

28.2.1 Proposed Mechanisms of Toxicity 392

28.2.1.1 Hypertension 392

28.2.1.2 Oxidative Stress 392

28.2.2 Safety Pharmacology and Toxicology Studies 393

28.2.3 In vivo Models of Efficacy “Proof of Concept” 395

28.2.3.1 Tissue Blood Flow and Oxygenation 395

28.2.3.2 Traumatic Hemorrhage 396

28.2.3.3 Local Ischemia 397

28.2.3.4 Sickle Cell Disease 397

28.2.4 Experimental Approaches to Assessing Preclinical Safety of HBOCs 398

28.2.4.1 Species Antioxidant Status (Natural Evolution) 398

28.2.4.2 Chemically Induced Antioxidant Depletion 398

28.2.4.3 Endothelial Dysfunction 399

28.2.4.4 Sepsis and Endotoxemia 400

28.3 Experimental Oxidative Biomarkers and Extracellular Hb Exposure 400

28.3.1 Heme Iron Oxidation 400

28.3.2 Amino-acid Oxidation 401

28.3.3 Heme Catabolism and Iron Sequestration 401

28.4 Markers of in vivo Oxidative Stress and Tissue Damage 403

28.4.1 4-hydroxy-2-nonenal (4-HNE) Protein Adducts 403

28.4.2 8-hydroxy-2-deoxyguanosine (8-OHdG) 403

28.5 Conclusion 404

References 405

29. Academia–Industry Collaboration in Blood Substitute Development: Issues, Case Histories and a Proposal 413
Hae Won Kim, Andrea Mozzarelli, Hiromi Sakai and Jonathan S. Jahr

29.1 Introduction 413

29.2 Generic Issues in Academia–Industry Collaboration 414

29.3 Academia–Industry Collaboration in HBOC Development 415

29.4 Proposal for a New Academia–Industry Collaboration Model in HBOC Development: an HBOC Research Consortium (a Conceptual Model) 417

29.4.1 Mission 417

29.4.2 Guiding Principles 417

29.4.3 Key Objectives 417

29.4.4 Structure 418

29.4.5 Operation 419

29.5 Discussion 420

29.6 Conclusions 421

Appendix: Successful Academia–Industry Collaboration Cases in HBOC Development 422

Case A: Waseda–Keio–Industry Research Collaboration 422

Case B: EuroBloodSubstitutes Consortium 424

References 426

Index 429

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