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Oxygen Carriers

  • Anirban Sen GuptaEmail author
  • Allan Doctor
Chapter

Abstract

In blood, the primary role of RBCs is to transport oxygen via highly regulated mechanisms involving hemoglobin (Hb). Hb is a tetrameric porphyrin protein comprising of two α- and two β-polypeptide chains, each containing an iron-containing heme group capable of binding one oxygen molecule. In military as well as civilian trauma, exsanguinating hemorrhage can lead to suboptimal tissue oxygenation and subsequent morbidity and mortality. In such cases, transfusion of whole blood or RBCs can significantly improve survival. However, blood products including RBCs have limited availability and portability and present additional challenges related to type matching, pathogenic contamination risks, and short shelf-life. These issues lead to substantial logistical barriers to their pre-hospital use in austere battlefield and remote civilian conditions. While robust efforts are underway to resolve these issues, recent research breakthroughs have led to bioinspired engineering of RBC surrogates, using various cross-linked, polymeric, and encapsulated forms of Hb. These “next-generation” Hb-based oxygen carriers (HBOCs) can potentially provide therapeutic oxygenation when whole blood or RBCs are not available. Several of these HBOCs have undergone rigorous pre-clinical and clinical evaluation, but have not yet received clinical approval in the USA for human use. This chapter will comprehensively review both historical and new HBOC designs, including current state-of-the-art and novel molecules in development, along with a critical discussion of successes and challenges in this field.

Keywords

Blood Hemorrhage RBC Hemoglobin RBC surrogate Oxygen carrier 

References

  1. 1.
    Holcomb JB, McMullin NR, Pearse L, Caruso J, Wade CE, Oetjen-Gerdes L, Champion HR, Lawnick M, Farr W, Rodriguez S, et al. Causes of death in U.S. Special Operations Forces in the Global War on terrorism, 2001–2004. Ann Surg. 2007;245(6):986–91.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Blackbourne LH, Baer DG, Eastridge BJ, Kheirabadi B, Bagley S, Kragh JF Jr, Cap AP, Dubick MA, Morrison JJ, Midwinter MJ, et al. Military medical revolution: prehospital combat casualty care. J Trauma Acute Care Surg. 2012;76(6 Suppl 5):S372–7.CrossRefGoogle Scholar
  3. 3.
    Cohen MJ, Kutcher M, Redick B, Nelson M, Call M, Knudson MM, Schreiber MA, Bulger EM, Muskat P, Alarcon LH, et al. Clinical and mechanistic drivers of acute traumatic coagulopathy. J Trauma Acute Care Surg. 2013;75(1 Suppl 1):S40–7.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Dorlac WC, DeBakey ME, Holcomb JB, Fagan SP, Kwong KL, Dorlac GR, Schreiber MA, Persse DE, Moore FA, Mattox KL. Mortality from isolated civilian penetrating injury. J Trauma. 2005;59(1):217–22.PubMedCrossRefGoogle Scholar
  5. 5.
    Smith ER, Shapiro G, Sarani B. The profile of wounding in civilian public mass shooting fatalities. J Trauma Acute Care Surg. 2016;81(1):86–92.PubMedCrossRefGoogle Scholar
  6. 6.
    van Oostendorp SE, Tan ECTH, Geeraedts LMG Jr. Prehospital control of life-threatening truncal and junctional haemorrhage is the ultimate challenge in optimizing trauma care; a review of treatment options and their applicability in the civilian trauma setting. Scand J Trauma Resusc Emerg Med. 2016;24(1):110.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Holcomb JB, Tilley BC, Baraniuk S, Fox EE, Wade CE, Podbielski JM, del Junco DJ, Brasel KJ, Bulger EM, Callcut RA, et al. Transfusion of plasma, platelets, and red blood cells in a 1:1:1 vs a 1:1:2 ratio and mortality in patients with severe trauma: the PROPPR randomized clinical trial. JAMA. 2015;313(5):471–82.PubMedPubMedCentralGoogle Scholar
  8. 8.
    Holcomb JB, del Junco DJ, Fox EE, Wade CE, Cohen MJ, Schreiber MA, Alarcon LH, Bai Y, Brasel KJ, Bulger EM, et al. The prospective, observational, multicenter, major trauma transfusion (PROMMTT) study: comparative effectiveness of a time-varying treatment with competing risks. JAMA Surg. 2013;148(2):127–46.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Holcomb JB, Jenkins D, Rhee P, Johannigman J, Mahoney P, Mehta S, Cox ED, Gehrke MJ, Beilman GJ, Schreiber M, et al. Damage control resuscitation: directly addressing the early coagulopathy of trauma. J Trauma. 2007;62(2):307–10.CrossRefGoogle Scholar
  10. 10.
    Carmen R. The selection of plastic materials for blood bags. Transfus Med Rev. 1993;7(1):1–10.PubMedCrossRefGoogle Scholar
  11. 11.
    Heddle NM, Klama LN, Griffith L, Roberts R, Shukla G, Kelton JG. A prospective study to identify the risk factors associated with acute reactions to platelet and red cell transfusions. Transfusion. 1993;33(10):794–7.PubMedCrossRefGoogle Scholar
  12. 12.
    Blajchman MA. Bacterial contamination and proliferation during the storage of cellular blood products. Vox Sang. 1998;74(Suppl 2):155–9.PubMedCrossRefGoogle Scholar
  13. 13.
    Seghatchian J, de Sousa G. Pathogen-reduction systems for blood components: the current position and future trends. Transfus Apher Sci. 2006;35(3):189–96.PubMedCrossRefGoogle Scholar
  14. 14.
    Cap AP, Pidcoke HF, DePasquale M, Rappold JF, Glassberg E, Eliassen HS, Bjerkvig CK, Fosse TK, Kane S, Thompson P, et al. Blood far forward: time to get moving! J Trauma Acute Care Surg. 2015;78(6 Suppl 1):S2–6.PubMedCrossRefGoogle Scholar
  15. 15.
    Borgman MA, Spinella PC, Perkins JG, Grathwohl KW, Repine T, Beekley AC, Sebesta J, Jenkins D, Wade CE, Holcomb JB. The ratio of blood products transfused affects mortality in patients receiving massive transfusions at a combat support hospital. J Trauma. 2007;63(4):805–13.Google Scholar
  16. 16.
    Boscarino C, Tien H, Acker J, Callum J, Hansen AL, Engels P, Glassberg E, Nathens A, Beckett A. Feasibility and transport of packed red blood cells into special forces operational conditions. J Trauma Acute Care Surg. 2014;76(4):1013–9.PubMedCrossRefGoogle Scholar
  17. 17.
    Spinella PC, Dunne J, Beilman GJ, O'Connell RJ, Borgman MA, Cap AP, Rentas F. Constant challenges and evolution of US military transfusion medicine and blood operations in combat. Transfusion. 2012;52(5):1146–53.PubMedPubMedCentralGoogle Scholar
  18. 18.
    Kauvar D, Holcomb JB, Norris GC, Hess JR. Fresh whole blood transfusion: a controversial military practice. J Trauma. 2006;61(1):181–4.PubMedCrossRefGoogle Scholar
  19. 19.
    Pidcoke HF, McFaul SJ, Ramasubramanian AK, Parida BK, Mora AG, Fedyk CG, Valdez-Delgado KK, Montgomery RK, Reddoch KM, Rodriguez AC, et al. Primary hemostatic capacity of whole blood: a comprehensive analysis of pathogen reduction and refrigeration effects over time. Transfusion. 2013;53(Suppl 1):137S–49S.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Noorman F, van Dongen TTCF, Plat M-CJ, Badloe JF, Hess JR, Hoencamp R. Transfusion: −80°C frozen blood products are safe and effective in military casualty care. PLoS One. 2016;11(12):e0168401.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Acker JP, Marks DC, Sheffield WP. Quality assessment of established and emerging blood components for transfusion. J Blood Transfus. 2016;2016:4860284.PubMedPubMedCentralGoogle Scholar
  22. 22.
    Blajchman MA. Substitutes for success. Nat Med. 1999;5:17–8.PubMedCrossRefGoogle Scholar
  23. 23.
    Modery-Pawlowski CL, Tian LL, Pan V, McCrae KR, Mitragotri S, Sen Gupta A. Approaches to synthetic platelet analogs. Biomaterials. 2013;34(2):526–41.PubMedCrossRefGoogle Scholar
  24. 24.
    Sen Gupta A. Biomaterials-based strategies for blood substitutes. In: Santambrogio L, editor. Biomaterials in regenerative medicine and the immune system: Springer, Switzerland; 2015. p. 113–37.Google Scholar
  25. 25.
    Giangrande PLF. The history of blood transfusion. Br J Haematol. 2000;110(4):758–67.PubMedCrossRefGoogle Scholar
  26. 26.
    Hillyer CD, editor. Blood banking and transfusion medicine: Churchill Livingstone Elsevier, Philadelphia, USA; 2007.Google Scholar
  27. 27.
    Carson JL, Hill S, Carless P, Hébert P, Henry D. Transfusion triggers: a systematic review of the literature. Transfus Med Rev. 2002;16(3):187–99.PubMedCrossRefGoogle Scholar
  28. 28.
    Sharma S, Sharma P, Tyler LN. Transfusion of blood and blood products: indications and complications. Am Fam Physician. 2011;83(6):719–24.PubMedGoogle Scholar
  29. 29.
    Whitaker B, Rajbhandary S, Kleinman S, Harris A, Kamani N. Trends in United States blood collection and transfusion: results from the 2013 AABB blood collection, utilization, and patient blood management survey. Transfusion. 2016;56(9):2173–83.PubMedCrossRefGoogle Scholar
  30. 30.
    Goodnough LT, Brecher ME, Kanter MH, AuBuchon JP. Transfusion medicine — blood transfusion. N Engl J Med. 1999;340(6):438–47.PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Hess JR. An update on solutions for red cell storage. Vox Sang. 2006;91(1):13–9.PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Greening DW, Glenister K, Sparrow RL, Simpson RJ. International blood collection and storage: clinical use of blood products. J Proteome. 2009;73(3):386–95.CrossRefGoogle Scholar
  33. 33.
    Tien H, Nascimento B Jr, Callum J, Rizoli S. An approach to transfusion and hemorrhage in trauma: current perspectives on restrictive transfusion strategies. Can J Surg. 2007;50(3):202–9.PubMedPubMedCentralGoogle Scholar
  34. 34.
    Johansson PI, Ostrowski SR, Secher NH. Management of major blood loss: an update. Acta Anaesthesiol Scand. 2010;54(9):1039–49.PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Pohlman TH, Walsh M, Aversa J, Hutchison EM, Olsen KP, Lawrence Reed R. Damage control resuscitation. Blood Rev. 2015;29(4):251–62.CrossRefGoogle Scholar
  36. 36.
    Cannon JW, Khan MA, Raja AS, Cohen MJ, Como JJ, Cotton BA, Dubose JJ, Fox EE, Inaba K, Rodriguez CJ, et al. Damage control resuscitation in patients with severe traumatic hemorrhage: a practice management guideline from the Eastern Association for the Surgery of Trauma. J Trauma Acute Care Surg. 2017;82(3):605–17.CrossRefGoogle Scholar
  37. 37.
    Napolitano LM, Kurek S, Luchette FA, Corwin HL, Barie PS, Tisherman SA, Hebert PC, Anderson GL, Bard MR, Bromberg W, et al. American College of Critical Care Medicine of the Society of Critical Care Medicine; Eastern Association for the Surgery of Trauma Practice Management Workgroup: clinical practice guideline: red blood cell transfusion in adult trauma and critical care. Crit Care Med. 2009;37(12):3124–57.PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Holcomb JB, Donathan DP, Cotton BA, Del Junco DJ, Brown G, Wenckstern TV, Podbielski JM, Camp EA, Hobbs R, Bai Y, et al. Prehospital transfusion of plasma and red blood cells in trauma patients. Prehosp Emerg Care. 2015;19(1):1–9.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Brown JB, Sperry JL, Fombona A, Billiar TR, Peitzman AB, Guyette FX. Pre-trauma center red blood cell transfusion is associated with improved early outcomes in air medical trauma patients. J Am Coll Surg. 2015;220(5):797–808.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Smith JW, Gilcher RO. Red blood cells, plasma, and other new apheresis-derived blood products: improving product quality and donor utilization. Transfus Med Rev. 1999;13(2):118–23.PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    D’Alessandro A, Kriebardis AG, Rinalducci S, Antonelou MH, Hansen KC, Papassideri IS, Zolla L. An update on red blood cell storage lesions, as gleaned through biochemistry and omics technologies. Transfusion. 2015;55(1):205–19.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Devine DV, Serrano K. The platelet storage lesion. Clin Lab Med. 2010;30(2):475–87.PubMedCrossRefPubMedCentralGoogle Scholar
  43. 43.
    Jobes D, Wolfe Y, O’Neill D, Calder J, Jones L, Sesok-Pizzini D, Zheng XL. Toward a definition of “fresh” whole blood: an in vitro characterization of coagulation properties in refrigerated whole blood for transfusion. Transfusion. 2011;51(1):43–51.PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    D’Amici GM, Mirasole C, D’Alessandro A, Yoshida T, Dumont LJ, Zolla L. Red blood cell storage in SAGM and AS3: a comparison through the membrane two-dimensional electrophoresis proteome. Blood Transfus. 2012;10(Suppl 2):s46–54.PubMedPubMedCentralGoogle Scholar
  45. 45.
    Paglia G, D'Alessandro A, Rolfsson Ó, Sigurjónsson ÓE, Bordbar A, Palsson S, Nemkov T, Hansen KC, Gudmundsson S, Palsson BO. Biomarkers defining the metabolic age of red blood cells during cold storage. Blood. 2016;128:e43–50.PubMedCrossRefPubMedCentralGoogle Scholar
  46. 46.
    Chaudhari CN. Frozen red blood cells in transfusion. Med J Armed Forces India. 2009;65(1):55–8.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Hess JR. Red cell freezing and its impact on supply chain. Transfus Med. 2004;14(1):1–8.PubMedCrossRefPubMedCentralGoogle Scholar
  48. 48.
    Solheim BG. Pathogen reduction of blood components. Transfus Apher Sci. 2008;39(1):75–82.PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    Chang R, Eastridge BJ, Holcomb JB. Remote damage control resuscitation in austere environments. Wilderness Environ Med. 2017;28(2S):S124–34.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Squires JE. Artificial blood. Science. 2002;295(5557):1002–5.PubMedCrossRefGoogle Scholar
  51. 51.
    Chang TMS. Blood substitutes based on nanobiotechnology. Trends Biotechnol. 2006;24:372–7.PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    Natanson C, Kern SJ, Lurie P, Banks SM, Wolfe SM. Cell-free hemoglobin-based blood substitutes and risk of myocardial infarction and death: a meta-analysis. JAMA. 2008;299(19):2304–12.PubMedCrossRefPubMedCentralGoogle Scholar
  53. 53.
    Klotz IM. Hemoglobin-oxygen equilibria: retrospective and phenomenological perspective. Biophys Chem. 2003;100(1–3):123–9.PubMedPubMedCentralGoogle Scholar
  54. 54.
    Goutelle S, Maurin M, Rougier F, Barbaut X, Bourguignon L, Ducher M, Maire P. The Hill equation: a review of its capabilities in pharmacological modelling. Fundam Clin Pharmacol. 2008;22(6):633–48.PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Umbreit J. Methemoglobin—It's not just blue: a concise review. Am J Hematol. 2007;82(2):134–44.PubMedCrossRefPubMedCentralGoogle Scholar
  56. 56.
    Dorman SC, Kenny CF, Miller L, Hirsch RE, Harrington JP. Role of redox potential of hemoglobin-based oxygen carriers on methemoglobin reduction by plasma components. Artif Cells Blood Substit Immobil Biotechnol. 2002;30(1):39–51.PubMedCrossRefPubMedCentralGoogle Scholar
  57. 57.
    Stowell CP, Levin J, Spiess BD, Winslow RM. Progress in the development of RBC substitutes. Transfusion. 2001;41(2):287–99.PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Winslow RM. Red cell substitutes. Semin Hematol. 2007;44(1):51–9.PubMedCrossRefPubMedCentralGoogle Scholar
  59. 59.
    Chang TMS. From artificial red blood cells, oxygen carriers, and oxygen therapeutics to artificial cells, nanomedicine, and beyond. Artif Cells Blood Substit Immobil Biotechnol. 2012;40(3):197–9.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Napolitano LM. Hemoglobin-based oxygen carriers: first, second or third generation? Human or bovine? Where are we now? Crit Care Clin. 2009;25(2):279–301.PubMedCrossRefGoogle Scholar
  61. 61.
    Piras AM, Dessy A, Chiellini F, Chiellini E, Farina C, Ramelli M, Valle ED. Polymeric nanoparticles for hemoglobin-based oxygen carriers. Biochim Biophys Acta. 2008;1784(10):1454–61.PubMedCrossRefGoogle Scholar
  62. 62.
    Buehler PW, Alayash AI. All hemoglobin-based oxygen carriers are not created equally. Biochim Biophys Acta. 2008;1784(10):1378–81.PubMedCrossRefGoogle Scholar
  63. 63.
    Winslow RM. Cell-free oxygen carriers: scientific foundations, clinical development, and new directions. Biochim Biophys Acta. 2008;1784(10):1382–6.PubMedCrossRefGoogle Scholar
  64. 64.
    Alayash AI. Setbacks in blood substitutes research and development: a biochemical perspective. Clin Lab Med. 2010;30(2):381–9.PubMedCrossRefGoogle Scholar
  65. 65.
    Amberson WR, Jennings JJ, Rhode CM. Clinical experience with hemoglobin-saline solutions. J Appl Physiol. 1949;1(7):469–89.PubMedCrossRefGoogle Scholar
  66. 66.
    Bunn H, Jandl J. The renal handling of hemoglobin. Trans Assoc Am Phys. 1968;81:147–52.PubMedGoogle Scholar
  67. 67.
    Buehler PW, D’Agnillo F, Schaer DJ. Hemoglobin-based oxygen carriers: from mechanisms of toxicity and clearance to rational drug design. Trends Mol Med. 2010;16(10):447–57.PubMedCrossRefGoogle Scholar
  68. 68.
    Kim-Shapiro DB, Schechter AN, Gladwin MT. Unraveling the reactions of nitric oxide, nitrite, and hemoglobin in physiology and therapeutics. Arterioscler Thromb Vasc Biol. 2006;26(4):697–705.PubMedCrossRefGoogle Scholar
  69. 69.
    Looker D, Abbott-Brown D, Cozart P, Durfee S, Hoffman S, Mathews AJ, Miller-Roehrich J, Shoemaker S, Trimble S, Fermi G, et al. A human recombinant haemoglobin designed for use as a blood substitute. Nature. 1992;356(6366):258–60.PubMedCrossRefGoogle Scholar
  70. 70.
    Fronticelli C, Koehler RC, Brinigar WS. Recombinant hemoglobins as artificial oxygen carriers. Artif Cells Blood Substit Immobil Biotechnol. 2007;35(1):45–52.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Varnado CL, Mollan TL, Birukou I, Smith BJZ, Henderson DP, Olson JS. Development of recombinant hemoglobin-based oxygen carriers. Antioxid Redox Signal. 2013;18(17):2314–28.PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Lamy ML, Daily EK, Brichant JF, Larbuisson RP, Demeyere RJ, Vandermeersch EA, Kehot JJ, Parsloe MR, Berridge JC, Sinclair CJ, et al. Randomized trial of Diaspirin cross-linked hemoglobin solution as an alternative to blood transfusion after cardiac surgery. Anesthesiology. 2000;92:646–56.PubMedCrossRefGoogle Scholar
  73. 73.
    Saxena R, Wijnhoud A, Carton H, Hacke W, Kaste M, Przybelski R, Stern KN, Koudstaal PJ. Controlled safety study of a hemoglobin-based oxygen carrier, DCLHb, in acute ischemic stroke. Stroke. 1999;30:993–6.PubMedCrossRefGoogle Scholar
  74. 74.
    Sloan EP, Koenigsberg MD, Philbin NB, Gao W. DCLHb Traumatic Hemorrhagic Shock Study Group. European HOST investigators. Diaspirin cross-linked hemoglobin infusion did not influence base deficit and lactic acid levels in two clinical trials of traumatic hemorrhagic shock patient resuscitation. J Trauma. 2010;68(5):1158–71.PubMedCrossRefGoogle Scholar
  75. 75.
    Winslow RM. New transfusion strategies: red cell substitutes. Annu Rev Med. 1999;50:337–53.PubMedCrossRefGoogle Scholar
  76. 76.
    Viele MK, Weisopf RB, Fisher D. Recombinant human hemoglobin does not affect renal function in humans: analysis of safety and pharmacokinetics. Anesthesiology. 1997;86(4):848–58.PubMedCrossRefGoogle Scholar
  77. 77.
    Gould SA, Moore EE, Hoyt DB, Burch JM, Haenel JB, Garcia J, DeWoskin R, Moss GS. The first randomized trial of human polymerized hemoglobin as a blood substitute in acute trauma and emergent surgery. J Am Coll Surg. 1998;187(2):113–20.PubMedCrossRefGoogle Scholar
  78. 78.
    Jahr JS, Moallempour M, Lim JC. HBOC-201, hemoglobin glutamer-250 (bovine), Hemopure (Biopure Corporation). Expert Opin Biol Ther. 2008;8(9):1425–33.PubMedCrossRefGoogle Scholar
  79. 79.
    Cheng DC, Mazer CD, Martineau R, Ralph-Edwards A, Karski J, Robblee J, Finegan B, Hall RI, Latimer R, Vuylsteke A. A phase II dose-response study of hemoglobin raffimer (Hemolink) in elective coronary artery bypass surgery. J Thorac Cardiovasc Surg. 2004;127(1):79–86.PubMedCrossRefGoogle Scholar
  80. 80.
    Alayash AI. Blood substitutes: why haven’t we been more successful? Trends Biotechnol. 2014;32(4):177–85.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Chang TMS. Future generations of red blood cell substitutes. J Intern Med. 2003;253(5):527–35.PubMedCrossRefGoogle Scholar
  82. 82.
    Chen J-Y, Scerbo M, Kramer G. A review of blood substitutes: examining the history, clinical trial results, and ethics of hemoglobin-based oxygen carriers. Clinics. 2009;64(8):803–13.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Vandegriff KD, Winslow RM. Hemospan: design principles for a new class of oxygen therapeutic. Artif Organs. 2009;33(2):133–8.PubMedCrossRefGoogle Scholar
  84. 84.
    Bobofchak KM, Tarasov E, Olsen KW. Effect of cross-linker length on the stability of hemoglobin. Biochim Biophys Acta. 2008;1784(10):1410–4.PubMedCrossRefGoogle Scholar
  85. 85.
    Caretti A, Fantacci M, Caccia D, Perrella M, Lowe KC, Samaja M. Modulation of the NO/cGMP pathway reduces the vasoconstriction induced by acellular and PEGylated haemoglobin. Biochim Biophys Acta. 2008;1784(10):1428–34.PubMedCrossRefGoogle Scholar
  86. 86.
    Jahr JS, Akha AS, Holtby RJ. Crosslinked, polymerized, and PEG-conjugated hemoglobin-based oxygen carriers: clinical safety and efficacy of recent and current products. Curr Drug Discov Technol. 2012;9(3):158–65.PubMedCrossRefGoogle Scholar
  87. 87.
    Olofsson CAT, Johansson T, Larsson S, Nellgård P, Ponzer S, Fagrell B, Przybelski R, Keipert P, Winslow N, Winslow RM. A multicenter clinical study of the safety and activity of maleimide-polyethylene glycol-modified Hemoglobin (Hemospan) in patients undergoing major orthopedic surgery. Anesthesiology. 2006;105(6):1153–63.PubMedCrossRefGoogle Scholar
  88. 88.
    Buehler PW, Alayash AI. Toxicities of hemoglobin solutions: in search of in-vitro and in-vivo model systems. Transfusion. 2004;44(10):1516–30.PubMedCrossRefGoogle Scholar
  89. 89.
    Alayash AI. Oxygen therapeutics: can we tame haemoglobin? Nat Rev Drug Discov. 2004;3:152–9.PubMedCrossRefGoogle Scholar
  90. 90.
    Roche CJ, Cassera MB, Dantsker D, Hirsch RE, Friedman JM. Generating S-Nitrosothiols from hemoglobin. Mechanisms, conformational dependence and physiological relevance. J Biol Chem. 2013;288(31):22408–25.PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    D’Agnillo F, Chang TMS. Polyhemoglobin–superoxide dismutase-catalase as a blood substitute with antioxidant properties. Nat Biotechnol. 1998;16(7):667–71.PubMedCrossRefGoogle Scholar
  92. 92.
    Powanda D, Chang TMS. Cross-linked polyhemoglobin–superoxide dismutase–catalase supplies oxygen without causing blood brain barrier disruption or brain edema in a rat model of transient global brain ischemia–reperfusion. Artif Cells Blood Substit Immob Biotechnol. 2002;30(1):25–42.Google Scholar
  93. 93.
    Ogata Y, Goto H, Kimura T, Fukui H. Development of neo red cells (NRC) with the enzymatic reduction system of methemoglobin. Artif Cells Blood Substit Immobil Biotechnol. 1997;25(4):417–27.PubMedCrossRefGoogle Scholar
  94. 94.
    Simoni J, Simoni G, Moeller JF, Feola M, Wesson DE. Artificial oxygen carrier with pharmacologic actions of adenosine-5′-triphosphate, adenosine, and reduced glutathione formulated to treat an array of medical conditions. Artif Organs. 2014;38(8):684–90.PubMedCrossRefGoogle Scholar
  95. 95.
    Simoni J, Simoni G, Wesson DE, Feola M. ATP-adenosine-glutathione cross-linked hemoglobin as clinically useful oxygen carrier. Curr Drug Discov Technol. 2012;9(3):173–87.PubMedCrossRefGoogle Scholar
  96. 96.
    Wollocko H, Anvery S, Wollocko J, Harrington JM, Harrington JP. Zero-link polymerized hemoglobin (OxyVita®Hb) stabilizes the heme environment: potential for lowering vascular oxidative stress. Artif Cells Nanomed Biotechnol. 2017;45(4):701–9.PubMedCrossRefGoogle Scholar
  97. 97.
    Ma L, Thompson FM, Wang D, Hsia CJC. Polynitroxylated PEGylated Hemoglobin (PNPH): a nanomedicine for critical care and transfusion, chapter 16. In: Kim HW, Greenberg AG, editors. Hemoglobin-based oxygen carriers as red cell substitutes and oxygen therapeutics. Berlin: Springer-Verlag; 2013. p. 299–313.CrossRefGoogle Scholar
  98. 98.
    Chang TMS. Hemoglobin corpuscles’ report of a research project for Honours Physiology, Medical Library, McGill University 1957. Reprinted as part of ‘30 anniversary in Artificial Red Blood Cells Research’. J Biomat Artif Cells Artif Organs. 1988;16:1–9.CrossRefGoogle Scholar
  99. 99.
    Chang TMS, Poznansky MJ. Semipermeable microcapsules containing catalase for enzyme replacement in acatalsaemic mice. Nature. 1968;218(5138):242–5.CrossRefGoogle Scholar
  100. 100.
    Chang TMS. Semipermeable microcapsules. Science. 1964;146(3643):524–5.PubMedCrossRefGoogle Scholar
  101. 101.
    Djordjevich L, Miller IF. Synthetic erythrocytes from lipid encapsulated hemoglobin. Exp Hematol. 1980;8(5):584.PubMedGoogle Scholar
  102. 102.
    Hunt CA, Burnette RR, MacGregor RD, Strubbe A, Lau D, Taylor N. Synthesis and evaluation of a prototypal artificial red cell. Science. 1985;230(4730):1165–8.PubMedCrossRefGoogle Scholar
  103. 103.
    Rudolph AS, Klipper RW, Goins B, Phillips WT. In vivo biodistribution of a radiolabeled blood substitute: 99mTc-labeled liposome-encapsulated hemoglobin in an anesthetized rabbit. Proc Natl Acad Sci U S A. 1991;88(23):10976–80.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Sakai H, Sou K, Horinouchi H, Kobayashi K, Tsuchida E. Review of hemoglobin-vesicles as artificial oxygen carriers. Artif Organs. 2009;33(2):139–45.PubMedCrossRefGoogle Scholar
  105. 105.
    Pape A, Kertscho H, Meier J, Horn O, Laout M, Steche M, Lossen M, Theissen A, Zwissler B, Habler O. Improved short-term survival with polyethylene glycol modified hemoglobin liposomes in critical normovolemic anemia. Intensive Care Med. 2008;34(8):1534–43.PubMedCrossRefGoogle Scholar
  106. 106.
    Kawaguchi AT, Fukumoto D, Haida M, Ogata Y, Yamano M, Tsukada H. Liposome-encapsulated hemoglobin reduces the size of cerebral infarction in the rat: evaluation with photochemically induced thrombosis of the middle cerebral artery. Stroke. 2007;38(5):1626–32.PubMedCrossRefGoogle Scholar
  107. 107.
    Agashe H, Awasthi V. Current perspectives in liposome-encapsulated hemoglobin as oxygen carrier. Adv Plan Lipid Bilayers Liposomes. 2009;9:1–28.CrossRefGoogle Scholar
  108. 108.
    Ceh B, Winterhalter M, Frederik PM, Vallner JJ, Lasic DD. Stealth® liposomes: from theory to product. Adv Drug Delivery Rev. 1997;24(2–3):165–77.Google Scholar
  109. 109.
    Immordino ML, Dosio F, Cattel L. Stealth liposomes: review of the basic science, rationale, and clinical applications, existing and potential. Int J Nanomedicine. 2006;1(3):297–315.PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Philips WT, Klpper RW, Awasthi VD, Rudolph AS, Cliff R, Kwasiborski V, Goines VA. Polyethylene glycol modified liposome-encapsulated hemoglobin: a long circulating red cell substitute. J Pharm Exp Ther. 1999;288(2):665–70.Google Scholar
  111. 111.
    Sakai H, Sou K, Horinouchi H, Kobayashi K, Tsuchida E. Hemoglobin-vesicle, a cellular artificial oxygen carrier that fulfills the physiological roles of the red blood cell structure. Adv Exp Med Biol. 2010;662:433–8.PubMedCrossRefGoogle Scholar
  112. 112.
    Tsuchida E, Sou K, Nakagawa A, Sakai H, Komatsu T, Kobayashi K. Artificial oxygen carriers, hemoglobin vesicles and albumin-hemes, based on bioconjugate chemistry. Bioconjug Chem. 2009;20(8):1419–40.PubMedCrossRefGoogle Scholar
  113. 113.
    Taguchi K, Urata Y, Anraku M, Watanabe H, Kadowaki D, Sakai H, Horinouchi H, Kobayashi K, Tsuchida E, Maruyama T, et al. Hemoglobin vesicles, Polyethylene Glycol (PEG)ylated liposomes developed as a Red Blood Cell Substitute, do not induce the accelerated blood clearance phenomenon in mice. Drug Metab Dispos. 2009;37(11):2197–203.PubMedCrossRefGoogle Scholar
  114. 114.
    Kaneda S, Ishizuka T, Goto H, Kimura T, Inaba K, Kasukawa H. Liposome-encapsulated Hemoglobin, TRM-645: current status of the development and important issues for clinical application. Artif Organs. 2009;33(2):146–52.PubMedCrossRefGoogle Scholar
  115. 115.
    Tao Z, Ghoroghchian PP. Microparticle, nanoparticle, and stem cell-based oxygen carriers as advanced blood substitutes. Trends Biotechnol. 2014;32(9):466–73.PubMedCrossRefGoogle Scholar
  116. 116.
    Sakai H. Present situation of the development of cellular-type hemoglobin-based oxygen carrier (hemoglobin-vesicles). Curr Drug Discov Technol. 2012;9(3):188–93.PubMedCrossRefGoogle Scholar
  117. 117.
    Yadav VR, Nag O, Awasthi V. Biological evaluation of Liposome-encapsulated Hemoglobin surface-modified with a novel PEGylated nonphospholipid amphiphile. Artif Organs. 2014;38(8):625–33.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Yadav VR, Rao G, Houson H, Hedrick A, Awasthi S, Roberts PR, Awasthi V. Nanovesicular liposome-encapsulated hemoglobin (LEH) prevents multi-organ injuries in a rat model of hemorrhagic shock. Eur J Pharm Sci. 2016;93:97–106.PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Kheir JN, Scharp LA, Borden MA, Swanson EJ, Loxley A, Reese JH, Black KJ, Velazquez LA, Thomson LM, Walsh BK, et al. Oxygen gas–filled microparticles provide intravenous oxygen delivery. Sci Transl Med. 2012;4(140):140–88.CrossRefGoogle Scholar
  120. 120.
    Kheir JN, Polizzotti BD, Thomson LM, O’Connell DW, Black KJ, Lee RW, Wilking JN, Graham AC, Bell DC, McGowan FX. Bulk manufacture of concentrated oxygen gas-filled microparticles for intravenous oxygen delivery. Adv Healthc Mater. 2013;2(8):1131–41.PubMedCrossRefGoogle Scholar
  121. 121.
    Yu WP, Chang TMS. Submicron polymer membrane hemoglobin nanocapsules as potential blood substitutes: preparation and characterization. Artif Cells Blood Substit Immobil Biotechnol. 1996;24(3):169–84.PubMedCrossRefGoogle Scholar
  122. 122.
    Chang TMS, Yu WP. Nanoencapsulation of hemoglobin and RBC enzymes based on nanotechnology and biodegradable polymer. In: TMS C, editor. Blood substitutes: principles, methods, products and clinical trials, vol. 2. Basel: Karger; 1998. p. 216–31.Google Scholar
  123. 123.
    Chang TMS. Blood replacement with nanobiotechnologically engineered hemoglobin and hemoglobin nanocapsules. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2010;2(4):418–30.PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Rameez S, Alosta H, Palmer AF. Biocompatible and biodegradable polymersome encapsulated hemoglobin: a potential oxygen carrier. Bioconjug Chem. 2008;19(5):1025–32.PubMedCrossRefGoogle Scholar
  125. 125.
    Sheng Y, Yuan Y, Liu C, Tao X, Shan X, Xu F. In vitro macrophage uptake and in vivo biodistribution of PLA-PEG nanoparticles loaded with hemoglobin as blood substitutes: effect of PEG content. J Mater Sci Mater Med. 2009;20(9):1881–91.PubMedCrossRefGoogle Scholar
  126. 126.
    Arifin DR, Palmer AF. Polymersome encapsulated hemoglobin: a novel type of oxygen carrier. Biomacromolecules. 2005;6(4):2172–81.PubMedCrossRefGoogle Scholar
  127. 127.
    Rameez S, Bamba I, Palmer AF. Large scale production of vesicles by hollow fiber extrusion: a novel method for generating polymersome encapsulated hemoglobin dispersions. Langmuir. 2010;26(7):5279–85.PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Misra H, Lickliter J, Kazo F, Abuchowski A. PEGylated Carboxyhemoglobin bovine (SANGUINATE): results of a phase I clinical trial. Artif Organs. 2014;38(8):702–7.PubMedCrossRefGoogle Scholar
  129. 129.
    Ananthakrishnan R, Li Q, O’Shea KM, Quadri N, Wang L, Abuchowski A, Schmidt AM, Ramasamy R. Carbon monoxide form of PEGylated hemoglobin protects myocardium against ischemia/reperfusion injury in diabetic and normal mice. Artif Cells Nanomed Biotechnol. 2013;41(6):428–36.PubMedCrossRefGoogle Scholar
  130. 130.
    Abuchowski A. SANGUINATE (PEGylated Carboxyhemoglobin bovine): mechanism of action and clinical update. Artif Organs. 2017;41(4):346–50.PubMedCrossRefGoogle Scholar
  131. 131.
    Wu L. Carbon monoxide: endogenous production, physiological functions, and pharmacological applications. Pharmacol Rev. 2005;57(4):585–630.PubMedCrossRefGoogle Scholar
  132. 132.
    Tomita D, Kimura T, Hosaka H, Daijima Y, Haruki R, Ludwig K, Böttcher C, Komatsu T. Covalent core-shell architecture of hemoglobin and human serum albumin as an artificial O2 carrier. Biomacromolecules. 2013;14(6):1816–25.PubMedCrossRefGoogle Scholar
  133. 133.
    Hosaka H, Haruki R, Yamada K, Böttcher C, Komatsu T. Hemoglobin-albumin cluster incorporating a Pt nanoparticle: artificial O2 carrier with antioxidant activities. PLoS One. 2014;9(10):e110541.PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Duan L, Yan X, Wang A, Jia Y, Li J. Highly loaded hemoglobin spheres as promising artificial oxygen carriers. ACS Nano. 2012;6(8):6897–904.PubMedCrossRefGoogle Scholar
  135. 135.
    Xiong Y, Liu ZZ, Georgieva R, Smuda K, Steffen A, Sendeski M, Voigt A, Patzak A, Bäumler H. Nonvasoconstrictive hemoglobin particles as oxygen carriers. ACS Nano. 2013;7(9):7454–61.PubMedCrossRefPubMedCentralGoogle Scholar
  136. 136.
    Li B, Li T, Chen G, Li X, Yan L, Xie Z, Jing X, Huang Y. Regulation of conjugated hemoglobin on micelles through copolymer chain sequences and the protein’s isoelectric aggregation. Macromol Biosci. 2013;13(7):893–902.PubMedCrossRefPubMedCentralGoogle Scholar
  137. 137.
    Qi Y, Li T, Wang Y, Wei X, Li B, Chen X, Xie Z, Jing X, Huang Y. Synthesis of hemoglobin-conjugated polymer micelles by thiol Michael-addition reactions. Macromol Biosci. 2016;16(6):906–13.PubMedCrossRefPubMedCentralGoogle Scholar
  138. 138.
    Jia Y, Cui Y, Fei J, Du M, Dai L, Li J, Yang Y. Construction and evaluation of hemoglobin-based capsules as blood substitutes. Adv Funct Mater. 2012;22(7):1446–53.CrossRefGoogle Scholar
  139. 139.
    Chen B, Jia Y, Zhao J, Li H, Dong W, Li J. Assembled hemoglobin and catalase nanotubes for the treatment of oxidative stress. J Phys Chem C. 2013;117(38):19751–8.CrossRefGoogle Scholar
  140. 140.
    Le Gall T, Polard V, Rousselot M, Lotte A, Raouane M, Lehn P, Opolon P, Leize E, Deutsch E, Zal F, et al. In vivo biodistribution and oxygenation potential of a new generation of oxygen carrier. J Biotechnol. 2014;187:1–9.PubMedCrossRefPubMedCentralGoogle Scholar
  141. 141.
    Tsai AG, Intaglietta M, Sakai H, Delpy E, La Rochelle CD, Rousselot M, Zal F. Microcirculation and NO-CO studies of a natural extracellular hemoglobin developed for an oxygen therapeutic carrier. Curr Drug Discov Technol. 2012;9(3):166–72.PubMedCrossRefPubMedCentralGoogle Scholar
  142. 142.
    Wang X, Gao W, Peng W, Xie J, Li Y. Biorheological properties of reconstructed erythrocytes and its function of carrying-releasing oxygen. Artif Cells Blood Substit Immobil Biotechnol. 2009;37(1):41–4.PubMedCrossRefGoogle Scholar
  143. 143.
    Goldsmith HL, Marlow J. Flow behaviour of erythrocytes. I. Rotation and deformation in dilute suspensions. Proc R Soc Lond B. 1972;182(1068):351–84.CrossRefGoogle Scholar
  144. 144.
    Charoenphol P, Mocherla S, Bouis D, Namdee K, Pinsky DJ, Eniola-Adefeso O. Targeting therapeutics to the vascular wall in atherosclerosis--carrier size matters. Atherosclerosis. 2011;217(2):364–70.PubMedCrossRefGoogle Scholar
  145. 145.
    Doshi N, Zahr AS, Bhaskar S, Lahann J, Mitragotri S. Red blood cell-mimicking synthetic biomaterial particles. Proc Natl Acad Sci U S A. 2009;106(51):21495–9.PubMedPubMedCentralCrossRefGoogle Scholar
  146. 146.
    Haghgooie R, Toner M, Doyle PS. Squishy non-spherical hydrogel microparticles. Macromol Rapid Commun. 2010;31(2):128–34.PubMedGoogle Scholar
  147. 147.
    Merkel TJ, Jones SW, Herlihy KP, Kersey FR, Shields AR, Napier M, Luft JC, Wu H, Zamboni WC, Wang AZ, et al. Using mechanobiological mimicry of red blood cells to extend circulation times of hydrogel microparticles. Proc Natl Acad Sci U S A. 2011;108(2):586–91.PubMedPubMedCentralCrossRefGoogle Scholar
  148. 148.
    Li S, Nickels J, Palmer AF. Liposome-encapsulated actin-hemoglobin (LEAcHb) artificial blood substitutes. Biomaterials. 2005;26(17):3759–69.PubMedCrossRefGoogle Scholar
  149. 149.
    Xu F, Yuan Y, Shan X, Liu C, Tao X, Sheng Y, Zhou H. Long-circulation of hemoglobin-loaded polymeric nanoparticles as oxygen carriers with modulated surface charges. Int J Pharm. 2009;377(1–2):199–206.PubMedCrossRefGoogle Scholar
  150. 150.
    Pan D, Rogers S, Misra S, Vulugundam G, Gazdzinski L, Tsui A, Mistry N, Said A, Spinella P, Hare G, Lanza G, Doctor A. ErythroMer (EM): nanoscale bio-synthetic artificial red cell proof of concept and in vivo efficacy results. Blood. 2016;128(22):A1027.Google Scholar
  151. 151.
    Weiskopf RB, Beliaev AM, Shander A, Guinn NR, Cap AP, Ness PM, Silverman TA. Addressing the unmet need of life-threatening anemia with hemoglobin-based oxygen carriers. Transfusion. 2017;57(1):207–14.PubMedCrossRefGoogle Scholar
  152. 152.
    Muir WW, Wellman ML. Hemoglobin solutions and tissue oxygenation. J Vet Intern Med. 2003;17(2):127–35.PubMedCrossRefGoogle Scholar
  153. 153.
    Sakai H, Masada Y, Takeoka S, Tsuchida E. Characteristics of bovine hemoglobin as a potential source of hemoglobin-vesicles for an artificial oxygen carrier. J Biochem. 2002;131(4):611–7.PubMedCrossRefPubMedCentralGoogle Scholar
  154. 154.
    Chan LW, White NJ, Pun SH. Synthetic strategies for engineering intravenous hemostat. Bioconjug Chem. 2015;26(7):1224–36.PubMedPubMedCentralCrossRefGoogle Scholar
  155. 155.
    Lashoff-Sullivan M, Shoffstall A, Lavik E. Intravenous hemostats: challenges in translation to patients. Nanoscale. 2013;5(22):10719–28.CrossRefGoogle Scholar
  156. 156.
    Booth C, Highley D. Crystalloids, colloids, blood, blood products and blood substitutes. Anaesth Intensive Care Med. 2010;11(2):50–5.CrossRefGoogle Scholar
  157. 157.
    McCahon R, Hardman J. Pharmacology of plasma expanders. Anaesth Intensive Care Med. 2007;8(2):79–81.CrossRefGoogle Scholar
  158. 158.
    Hickman DA, Pawlowski CL, Sekhon UDS, Marks J, Sen Gupta A. Biomaterials an advanced technologies for hemostatic management of bleeding. Adv Mater. 2018;30(4)  https://doi.org/10.1002/adma.201700859.CrossRefGoogle Scholar
  159. 159.
    Douay L, Andreu G. Ex vivo production of human red blood cells from hematopoietic stem cells: what is the future in transfusion? Transfus Med Rev. 2007;21(2):91–100.PubMedCrossRefPubMedCentralGoogle Scholar
  160. 160.
    Rousseau GF, Giarratana MC, Douay L. Large-scale production of red blood cells from stem cells: what are the technical challenges ahead? Biotechnol J. 2014;9(1):28–38.PubMedCrossRefPubMedCentralGoogle Scholar
  161. 161.
    Avanzi MP, Mitchell WB. Ex vivo production of platelets from stem cells. Br J Haematol. 2014;165(2):237–47.PubMedCrossRefPubMedCentralGoogle Scholar
  162. 162.
    Nakamura S, Takayama N, Hirata S, Seo H, Endo H, Ochi K, Fujita K, Koike T, Harimoto K, Dohda T, et al. Expandable megakaryocyte cell lines enable clinically applicable generation of platelets from human induced pluripotent stem cells. Cell Stem Cell. 2014;14(4):535–48.PubMedCrossRefPubMedCentralGoogle Scholar
  163. 163.
    Thon JN, Mazutis L, Wu S, Sylman JL, Ehrlicher A, Machlus KR, Feng Q, Lu S, Lanza R, Neeves KB, et al. Platelet bioreactor-on-a-chip. Blood. 2014;124(12):1857–67.PubMedPubMedCentralCrossRefGoogle Scholar
  164. 164.
    Spitalnik SL, Triulzi D, Devine DV, Dzik WH, Eder AF, Gernsheimer T, Josephson CD, Kor DJ, Luban NL, Roubinian NH, et al. State of the science in Transfusion Medicine Working Groups. Transfusion. 2015;55(9):2282–90.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.Department of Biomedical EngineeringCase Western Reserve UniversityClevelandUSA
  2. 2.Departments of Pediatrics, Biochemistry and BioengineeringUniversity of Maryland School of MedicineBaltimoreUSA

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