Skip to main content

Synthetic Blood Substitutes

  • Chapter
  • First Online:
Trauma Induced Coagulopathy

Abstract

In damage control resuscitation (DCR) management of traumatic hemorrhage and coagulopathy, timely transfusion of whole blood (WB) or blood components (platelets, RBCs, plasma in controlled ratios) can significantly reduce mortality. WB or component transfusion is also clinically important in managing bleeding dysfunctions and risks in surgery, myelosuppression, and congenital coagulation defects. However, donor-derived blood products suffer from many logistical challenges including shortage in supply due to limited donor availability, need for type matching, high risks of pathogenic contamination, limited portability and shelf-life, and various biological side effects. A robust volume of research is being directed to resolve these issues, including pathogen reduction technologies (PRT), low temperature storage, and bioreactor-based technologies to produce blood cells from stem cells in vitro. In parallel, significant clinical interest has developed toward bioengineering of synthetic blood substitutes that can provide blood’s functions while circumventing the above logistical challenges associated with natural blood products. Research in this field over the last few decades have primarily focused on the development of semisynthetic and synthetic RBC substitutes for enabling oxygen transport and platelet substitutes for enabling rapid hemorrhage control. This chapter provides a comprehensive review of the various “synthetic blood substitute” approaches, along with a critical discussion of successes, challenges, and current state-of-the-art and future opportunities in this field.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 139.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 179.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 249.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Holcomb JB, McMullin NR, Pearse L, Caruso J, Wade CE, Oetjen-Gerdes L, Champion HR, Lawnick M, Farr W, Rodriguez S, Butler FK. Causes of death in U.S. special operations forces in the global war on terrorism, 2001–2004. Ann Surg. 2007;245:986–91.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Eastridge BJ, Mabry RL, Seguin P, Cantrell J, Tops T, Uribe P, Mallett O, Zubko T, Oetjen-Gerdes L, Rasmussen TE, Butler FK, Kotwal RS, Holcomb JB, Wade C, Champion H, Lawnick M, Moores L, Blackbourne LH. Death on the battlefield (2001Y2011): implications for the future of combat casualty care. J Trauma Acute Care Surg. 2012;73:S431–7.

    Article  PubMed  Google Scholar 

  3. Eastridge BJ, Hardin M, Cantrell J, Oetjen-Gerdes L, Zubko T, Mallak C, Wade CE, Simmons J, Mace J, Mabry R, Bolenbaucher R, Blacknbourne LH. Died of wounds on the battlefield: causation and implications for combat casualty care. J Trauma. 2011;71:S4–8.

    PubMed  Google Scholar 

  4. Eastridge BJ, Holcomb JB, Shackelford S. Outcomes of traumatic hemorrhagic shock and epidemiology of preventable death from injury. Transfusion. 2019;59:1423–8.

    Article  PubMed  Google Scholar 

  5. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. 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;59:217–22.

    Article  CAS  PubMed  Google Scholar 

  7. Smith ER, Shapiro G, Sarani B. The profile of wounding in civilian public mass shooting fatalities. J Trauma Acute Care Surg. 2016;81:86–92.

    Article  PubMed  Google Scholar 

  8. King LS. Blood program in world war II. Medical Department, United States Army. JAMA. 1965;191(11):954. https://doi.org/10.1001/jama.1965.03080110078044.

    Article  Google Scholar 

  9. Giangrande PLF. The history of blood transfusion. Br J Haematol. 2000;110:758–67.

    Article  CAS  PubMed  Google Scholar 

  10. Hillyer CD, editor. Blood banking and transfusion medicine. Philadelphia, PA, USA: Churchill Livingstone Elsevier; 2007.

    Google Scholar 

  11. Kauvar DS, Wade CE. The epidemiology and modern management of traumatic hemorrhage: US and international perspectives. Crit Care. 2005;9:S1–9.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Blackbourne LH, Baer DG, Eastridge BJ, Kheirabadi B, Bagley S, Kragh JF Jr, Cap AP, Dubick MA, Morrison JJ, Midwinter MJ, Butler FK, Kotwal RS, Holcomb JB. Military medical revolution: prehospital combat casualty care. J Trauma Acute Care Surg. 2012;76:S372–7.

    Article  Google Scholar 

  13. Spinella PC, Cap AP. Prehospital hemostatic resuscitation to achieve zero preventable deaths after traumatic injury. Curr Opin Hematol. 2017;24:529–35.

    Article  PubMed  Google Scholar 

  14. Cohen MJ, Kutcher M, Redick B, Nelson M, Call M, Knudson MM, Schreiber MA, Bulger EM, Muskat P, Alarcon LH, Myers JG, Rahbar MH, Brasel KJ, Phelan HA, del Junco DJ, Fox EE, Wade CE, Holcomb JB, Cotton BA, Matijevic N, PROMMTT Study Group. Clinical and mechanistic drivers of acute traumatic coagulopathy. J Trauma Acute Care Surg. 2013;75:S40–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Holcomb JB, Tilley BC, Baraniuk S, Fox EE, Wade CE, Podbielski JM, del Junco DJ, Brasel KJ, Bulger EM, Callcut RA, Cohen MJ, Cotton BA, Fabian TC, Inaba K, Kerby JD, Muskat P, O’Keeffe T, Rizoli S, Robinson BR, Scalea TM, Schreiber MA, Stein DM, Weinberg JA, Callum JL, Hess JR, Matijevic N, Miller CN, Pittet JF, Hoyt DB, Pearson GD, Leroux B, van Belle G, PROPPR Study Group. 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;313:471–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Chapman MP, Moore EE, Chin TL, Ghasabyan A, Stringham J, Gonzalez E, Moore HB, Banerjee A, Silliman CC, Sauaia A. Combat: initial experience with a randomized clinical trial of plasma-based resuscitation in the field for traumatic hemorrhagic shock. Shock. 2015;44(Suppl 1):63–70.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Sperry JL, Guyette FX, Brown JB, Yazer MH, Triulzi DJ, Early-Young BJ, Adams PW, Daley BJ, Miller RS, Harbrecht BG, Claridge JA, Phelan HA, Witham WR, Putnam AT, Duane TM, Alarcon LH, Callaway CW, Zuckerbraun BS, Neal MD, Rodengart MR, Forsythe RM, Billiar TR, Yealy DM, Peitzman AB, Zenati MS, PAMPer study group. Prehospital plasma during air medical transport in trauma patients at risk of hemorrhagic shock. N Engl J Med. 2018;379:315–26.

    Article  PubMed  Google Scholar 

  18. Perkins JG, Beekley AC. Damage control resuscitation. Chapter 4. In: Editor-in-Chief: Lenhart MK, editor. Combat casualty care: lessons learned from OEF and OIF. USA: Published by Office of the Surgeon General, Department of the Army; 2012.

    Google Scholar 

  19. Holcomb JB, Jenkins D, Rhee P, Johannigman J, Mahoney P, Mehta S, Cox ED, Gehrke MJ, Bellman GJ, Schreiber M, Flaherty SF, Grathwohl KW, Spinella PC, Perkins JG, Beekley AC, McMullin NR, Park MS, Gonzalez EA, Wade CE, Dubick MA, Schwab CW, Moore FA, Champion HR, Hoyt DB, Hess JR. Damage control resuscitation: directly addressing coagulopathy of trauma. J Trauma. 2007;62:307–31.

    PubMed  Google Scholar 

  20. Fisher AD, Miles EA, Cap AP, Strandenes G, Kane SF. Tactical damage control resuscitation. Mil Med. 2015;180:869–75.

    Article  PubMed  Google Scholar 

  21. Butler FK, Holcomb JB, Schreiber MA, Kotwal RS, Jenkins DA, Champion HR, Bowling F, Cap AP, Dubose JJ, Dorlac WC, Dorlac JR, McSwain NE, Timby JW, Blackbourne LH, Stockinger ZT, Strandenes G, Weiskopf RB, Gross KE, Bailey JA. Fluid resuscitation for hemorrhagic shock in tactical combat casualty care: TCCC guidelines change 14-01– 2 June 2014. J Spec Oper Med. 2014;14:13–38.

    PubMed  Google Scholar 

  22. Warner N, Zheng J, Nix G, Fisher AD, Johnson JC, Williams JE, Northern DM, Hellums JS. Military prehospital use of Group O low titre whole blood. J Spec Oper Med. 2018;18:15–8.

    Article  PubMed  Google Scholar 

  23. Cap AP, Beckett A, Benov A, Borgman M, Chen J, Corley JB, Doughty H, Fisher A, Glassberg E, Gonzales R, Kane SF, Malloy WW, Nessen S, Perkins JG, Prat N, Quesada J, Reade M, Sailliol A, Spinella PC, Stockinger Z, Strandenes G, Taylor A, Yazer M, Bryant B, Gurney J. Whole blood transfusion. Mil Med. 2018;183(Suppl 2):44–51.

    Article  PubMed  Google Scholar 

  24. Yazer MH, Jackson B, Sperry JL, Alarcon L, Triulzi DJ, Murdock AD. Initial safety and feasibility of cold-stored uncrossmatched whole blood transfusion in civilian trauma patients. J Trauma Acute Care Surg. 2016;81:21–6.

    Article  PubMed  Google Scholar 

  25. Young PP, Borge PD Jr. Making whole blood for trauma available (again): the American Red Cross experience. Transfusion. 2019;59(S2):1439–45.

    Article  PubMed  Google Scholar 

  26. Condron M, Scanlan M, Schreiber M. Massive transfusion of low-titer cold-stored O-positive whole blood in a civilian trauma setting. Transfusion. 2019;59:927–30.

    Article  PubMed  Google Scholar 

  27. Red Cross press release. May 14, 2019. https://www.redcross.org/about-us/news-and-events/press-release/2019/red-cross-issues-critical-need-for-type-o-blood-donations.html.

  28. Roberts N, James S, Delaney M, Fitzmaurice C. The global need and availability of blood products: a modelling study. Lancet Haematol. 2019;S2352-3026(19):30200–5. https://doi.org/10.1016/S2352-3026(19)30200-5. [Epub ahead of print].

    Article  Google Scholar 

  29. 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;52:1146–53.

    Article  PubMed  Google Scholar 

  30. Lambert MP, Sullivan SK, Fuentes R, French DL, Poncz M. Challenges and promises for the development of donor-independent platelet transfusions. Blood. 2013;121:3319–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Magron A, Laugier J, Provost P, Boilard E. Pathogen reduction technologies: the pros and cons for platelet transfusion. Platelets. 2018;29(1):2–8.

    Article  CAS  PubMed  Google Scholar 

  32. Reddoch-Cardenas KM, Bynum JA, Meledeo MA, Nair PM, Wu X, Garlington DN, Ramasubramanian AK, Cap AP. Cold-stored platelets: a product with function optimized for hemorrhage control. Transfus Apher Sci. 2019;58:16–22.

    Article  CAS  PubMed  Google Scholar 

  33. Milford EM, Reade MC. Comprehensive review of platelet storage methods for use in the treatment of active hemorrhage. Transfusion. 2016;56(Suppl 2):S140–8.

    Article  PubMed  Google Scholar 

  34. Barroso J, Osborne B, Teramura G, Pellham E, Fitzpatrick M, Biehl R, Yu A, Pehta J, Slichter SJ. Safety evaluation of a lyophilized platelet-derived hemostatic product. Transfusion. 2018;58(12):2969–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Migliaccio AR, Whittsett C, Papayannopoulou T, Sadelain M. The potential of stem cells as an in vitro source of red blood cells for transfusion. Cell Stem Cell. 2012;10:115–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Avanzi MP, Mitchell WB. Ex vivo production of platelets from stem cells. Br J Haematol. 2014;165:237–47.

    Article  CAS  PubMed  Google Scholar 

  37. Thon JN, Mazutis L, Wu S, Sylman JL, Ehrlicher A, Machlus KR, Feng Q, Lu S, Lanza R, Neeves KB, Weitz DA, Italiano JE Jr. Platelet bioreactor-on-a-chip. Blood. 2014;124:1857–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Sugimoto N, Eto K. Platelet production from induced pluripotent stem cells. J Thromb Haemost. 2017;15:1717–27.

    Article  CAS  PubMed  Google Scholar 

  39. Ito Y, Nakamura S, Sugimoto N, Shigemori T, Kato Y, Ohno M, Sakuma S, Ito K, Kumon H, Hirose H, Okamoto H, Nogawa M, Iwasaki M, Kihara S, Fujio K, Matsumoto T, Higashi N, Hashimoto K, Sawaguchi A, Harimoto KI, Nakagawa M, Yamamoto T, Handa M, Watanabe N, Nishi E, Arai F, Nishimura S, Eto K. Turbulence activates platelet biogenesis to enable clinical scale ex vivo production. Cell. 2018;174:636–48.

    Article  CAS  PubMed  Google Scholar 

  40. Focosi D, Amabile G. Induced pluripotent stem cell-derived red blood cells and platelet concentrates: from bench to bedside. Cell. 2018;7:2. https://doi.org/10.3390/cells7010002.

    Article  CAS  Google Scholar 

  41. 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;22:633–48.

    Article  CAS  PubMed  Google Scholar 

  42. Umbreit J. Methemoglobin—It’s not just blue: a concise review. Am J Hematol. 2007;82(2):134–44.

    Article  CAS  PubMed  Google Scholar 

  43. 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.

    Article  CAS  PubMed  Google Scholar 

  44. Schechter AN. Hemoglobin research and the origins of molecular medicine. Blood. 2008;112:3927–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Squires JE. Artificial blood. Science. 2002;295:1002–5.

    Article  CAS  PubMed  Google Scholar 

  46. Chang TMS. Blood substitutes based on nanobiotechnology. Trends Biotechnol. 2006;24:372–7.

    Article  CAS  PubMed  Google Scholar 

  47. Stowell CP, Levin J, Spiess BD, Winslow RM. Progress in the development of RBC substitutes. Transfusion. 2001;41:287–99.

    Article  CAS  PubMed  Google Scholar 

  48. Winslow RM. Red cell substitutes. Semin Hematol. 2007;44:51–9.

    Article  CAS  PubMed  Google Scholar 

  49. 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;40:197–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Napolitano LM. Hemoglobin-based oxygen carriers: first, second or third generation? Human or bovine? Where are we now? Crit Care Clin. 2009;25:279–301.

    Article  CAS  PubMed  Google Scholar 

  51. Buehler PW, Alayash AI. All hemoglobin-based oxygen carriers are not created equally. Biochim Biophys Acta. 1784;2008:1378–81.

    Google Scholar 

  52. Winslow RM. Cell-free oxygen carriers: scientific foundations, clinical development, and new directions. Biochim Biophys Acta. 1784;2008:1382–6.

    Google Scholar 

  53. Alayash AI. Setbacks in blood substitutes research and development: a biochemical perspective. Clin Lab Med. 2003;106:76–85.

    Google Scholar 

  54. Amberson WR, Jennings JJ, Rhode CM. Clinical experience with hemoglobin-saline solutions. J Appl Physiol. 1949;1:469–89.

    Article  CAS  PubMed  Google Scholar 

  55. Bunn H, Jandl J. The renal handling of hemoglobin. Trans Assoc Am Physicians. 1968;81:147–52.

    CAS  PubMed  Google Scholar 

  56. 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;16:447–57.

    Article  CAS  PubMed  Google Scholar 

  57. 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;26:697–705.

    Article  CAS  PubMed  Google Scholar 

  58. Vallelian F, Schaer CA, Deuel JW, Ingoglia G, Humar R, Buehler PW, Schaer DJ. Revisiting the putative role of heme as a trigger of inflammation. Pharmacol Res Perspect. 2018;6:e00392.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Looker D, Abbott-Brown D, Cozart P, Durfee S, Hoffman S, Mathews AJ, Miller-Roehrich J, Shoemaker S, Trimble S, Fermi G, Komiyama NH, Nagai K, Stetler GL. A human recombinant haemoglobin designed for use as a blood substitute. Nature. 1992;356:258–60.

    Article  CAS  PubMed  Google Scholar 

  60. Fronticelli C, Koehler RC, Brinigar WS. Recombinant hemoglobins as artificial oxygen carriers. Artif Cells Blood Substit Immobil Biotechnol. 2007;35:45–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Varnado CL, Mollan TL, Birukou I, Smith BJZ, Henderson DP, Olson JS. Development of recombinant hemoglobin-based oxygen carriers. Antioxid Redox Signal. 2013;18:2314–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Lamy ML, Daily EK, Brichant JF, Larbuisson RP, Demeyere RJ, Vandermeersch EA, Kehot JJ, Parsloe MR, Berridge JC, Sinclair CJ, Baron JF, Przybelski RJ. Randomized trial of diaspirin cross-linked hemoglobin solution as an alternative to blood transfusion after cardiac surgery. Anesthesiology. 2000;92:646–56.

    Article  CAS  PubMed  Google Scholar 

  63. 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.

    Article  CAS  PubMed  Google Scholar 

  64. 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;68:1158–71.

    PubMed  Google Scholar 

  65. Winslow RM. New transfusion strategies: red cell substitutes. Annu Rev Med. 1999;50:337–53.

    Article  CAS  PubMed  Google Scholar 

  66. Viele MK, Weisopf RB, Fisher D. Recombinant human hemoglobin does not affect renal function in humans: analysis of safety and pharmacokinetics. Anesthesiology. 1997;86:848–58.

    Article  CAS  PubMed  Google Scholar 

  67. 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;187:113–20.

    Article  CAS  PubMed  Google Scholar 

  68. Jahr JS, Moallempour M, Lim JC. HBOC-201, hemoglobin glutamer-250 (bovine), Hemopure (Biopure Corporation). Expert Opin Biol Ther. 2008;8:1425–33.

    Article  CAS  PubMed  Google Scholar 

  69. 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;127:79–86.

    Article  CAS  PubMed  Google Scholar 

  70. Apte SS. Blood substitutes – the polyheme trial. Mcgill J Med. 2008;11:59–65.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Alayash AI. Blood substitutes: why haven’t we been more successful? Trends Biotechnol. 2014;32:177–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Chang TMS. Future generations of red blood cell substitutes. J Intern Med. 2003;253:527–35.

    Article  CAS  PubMed  Google Scholar 

  73. 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;64:803–13.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Vandegriff KD, Winslow RM. Hemospan: design principles for a new class of oxygen therapeutic. Artif Organs. 2009;33:133–8.

    Article  PubMed  Google Scholar 

  75. Bobofchak KM, Tarasov E, Olsen KW. Effect of cross-linker length on the stability of hemoglobin. Biochim Biophys Acta. 1784;2008:1410–4.

    Google Scholar 

  76. 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. 1784;2008:1428–34.

    Google Scholar 

  77. 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;9:158–65.

    Article  CAS  PubMed  Google Scholar 

  78. Olofsson C, Ahl T, 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;105:1153–63.

    Article  CAS  PubMed  Google Scholar 

  79. Buehler PW, Alayash AI. Toxicities of hemoglobin solutions: in search of in-vitro and in-vivo model systems. Transfusion. 2004;44:1516–30.

    Article  CAS  PubMed  Google Scholar 

  80. Alayash AI. Oxygen therapeutics: can we tame haemoglobin? Nat Rev Drug Discov. 2004;3:152–9.

    Article  CAS  PubMed  Google Scholar 

  81. 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;288:22408–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. D’Agnillo F, Chang TMS. Polyhemoglobin–superoxide dismutase. Catalase as a blood substitute with antioxidant properties. Nat Biotechnol. 1998;16:667–71.

    Article  PubMed  Google Scholar 

  83. 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 Immobil Biotechnol. 2002;30:25–42.

    Article  Google Scholar 

  84. 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;38:684–90.

    Article  CAS  PubMed  Google Scholar 

  85. 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.

    Article  CAS  PubMed  Google Scholar 

  86. 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.

    Article  CAS  PubMed  Google Scholar 

  87. Abuchowski A. SANGUINATE (PEGylated Carboxyhemoglobin Bovine): mechanism of action and clinical update. Artif Organs. 2017;41(4):346–50.

    Article  PubMed  Google Scholar 

  88. 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;14:1816–25.

    Article  CAS  PubMed  Google Scholar 

  89. 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:e110541. https://doi.org/10.1371/journal.pone.0110541.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. 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 Biomater Artif Cells Artif Organs. 1988(16):1–9.

    Google Scholar 

  91. Chang TMS, Poznansky MJ. Semipermeable microcapsules containing catalase for enzyme replacement in acatalsaemic mice. Nature. 1968;218:242–5.

    Article  Google Scholar 

  92. Chang TMS. Semipermeable microcapsules. Science. 1964;146:524–5.

    Article  CAS  PubMed  Google Scholar 

  93. Djordjevich L, Miller IF. Synthetic erythrocytes from lipid encapsulated hemoglobin. Exp Hematol. 1980;8:584.

    CAS  PubMed  Google Scholar 

  94. Hunt CA, Burnette RR, MacGregor RD, Strubbe A, Lau D, Taylor N. Synthesis and evaluation of a prototypal artificial red cell. Science. 1985;230:1165–8.

    Article  CAS  PubMed  Google Scholar 

  95. 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;88:10976–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. 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;34:1534–43.

    Article  CAS  PubMed  Google Scholar 

  97. 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;38:1626–32.

    Article  CAS  PubMed  Google Scholar 

  98. Ceh B, Winterhalter M, Frederik PM, Vallner JJ, Lasic DD. Stealth® liposomes: from theory to product. Adv Drug Deliv Rev. 1997;24:165–77.

    Google Scholar 

  99. Immordino ML, Dosio F, Cattel L. Stealth liposomes: review of the basic science, rationale, and clinical applications, existing and potential. Int J Nanomedicine. 2006;1:297–315.

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Sakai H, Sou K, Horinouchi H, Kobayashi K, Tsuchida E. Review of hemoglobin-vesicles as artificial oxygen carriers. Artif Organs. 2009;33:139–45.

    Article  PubMed  Google Scholar 

  101. Agashe H, Awasthi V. Current perspectives in liposome-encapsulated hemoglobin as oxygen carrier. Adv Planar Lipid Bilayers Liposomes. 2009;9:1–28.

    Article  CAS  Google Scholar 

  102. 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 Pharmacol Exp Ther. 1999;288:665–70.

    Google Scholar 

  103. Sakai H, Sou K, Horinouchi H, Kobayashi K, Tsuchida E. Hemoglobin-vesicle, a cellular artificial oxygen carrier that fulfils the physiological roles of the red blood cell structure. Adv Exp Med Biol. 2010;662:433–8.

    Article  CAS  PubMed  Google Scholar 

  104. 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;20:1419–40.

    Article  CAS  PubMed  Google Scholar 

  105. Taguchi K, Urata Y, Anraku M, Watanabe H, Kadowaki D, Sakai H, Horinouchi H, Kobayashi K, Tsuchida E, Maruyama T, Otagiri M. 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;37:2197–203.

    Article  CAS  PubMed  Google Scholar 

  106. 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;33:146–52.

    Article  CAS  PubMed  Google Scholar 

  107. Sakai H. Present situation of the development of cellular-type hemoglobin-based oxygen carrier (hemoglobin-vesicles). Curr Drug Discov Technol. 2012;9:188–93.

    Article  CAS  PubMed  Google Scholar 

  108. Yadav VR, Nag O, Awasthi V. Biological evaluation of Liposome-encapsulated hemoglobin surface-modified with a novel PEGylated nonphospholipid amphiphile. Artif Organs. 2014;38:625–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Yu WP, Chang TMS. Submicron polymer membrane hemoglobin nanocapsules as potential blood substitutes: preparation and characterization. Artif Cells Blood Substit Immobil Biotechnol. 1996;24:169–84.

    Article  CAS  PubMed  Google Scholar 

  111. Chang TMS, Yu WP. Nanoencapsulation of hemoglobin and RBC enzymes based on nanotechnology and biodegradable polymer. In: Chang TMS, editor. Blood substitutes: principles, methods, products and clinical trials, vol. 2. Basel: Karger; 1998. p. 216–31.

    Google Scholar 

  112. Piras AM, Dessy A, Chiellini F, Chiellini E, Farina C, Ramelli M, Valle ED. Polymeric nanoparticles for hemoglobin-based oxygen carriers. Biochim Biophys Acta. 1784;2008:1454–61.

    Google Scholar 

  113. Chang TMS. Blood replacement with nanobiotechnologically engineered hemoglobin and hemoglobin nanocapsules. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2010;2:418–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Rameez S, Alosta H, Palmer AF. Biocompatible and biodegradable polymersome encapsulated hemoglobin: a potential oxygen carrier. Bioconjug Chem. 2008;19:1025–32.

    Article  CAS  PubMed  Google Scholar 

  115. 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;20:1881–91.

    Article  CAS  PubMed  Google Scholar 

  116. Arifin DR, Palmer AF. Polymersome encapsulated hemoglobin: a novel type of oxygen carrier. Biomacromolecules. 2005;6:2172–81.

    Article  CAS  PubMed  Google Scholar 

  117. 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;26:5279–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Duan L, Yan X, Wang A, Jia Y, Li J. Highly loaded hemoglobin spheres as promising artificial oxygen carriers. ACS Nano. 2012;6:6897–904.

    Article  CAS  PubMed  Google Scholar 

  119. 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;7:7454–61.

    Article  CAS  PubMed  Google Scholar 

  120. 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;13:893–902.

    Article  CAS  PubMed  Google Scholar 

  121. 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;16:906–13.

    Article  CAS  PubMed  Google Scholar 

  122. 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;22:1446–53.

    Article  CAS  Google Scholar 

  123. 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;117:19751–8.

    CAS  Google Scholar 

  124. 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:A1027.

    Article  Google Scholar 

  125. Kheir JN, Scharp LA, Borden MA, Swanson EJ, Loxley A, Reese JH, Black KJ, Velazquez LA, Thomson LM, Walsh BK, Mullen KE, Graham DA, Lawlor MW, Brugnara C, Bell DC, McGowan FX Jr. Oxygen gas–filled microparticles provide intravenous oxygen delivery. Sci Transl Med. 2012;4:140ra188.

    Article  CAS  Google Scholar 

  126. 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;2:1131–41.

    Article  CAS  PubMed  Google Scholar 

  127. 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;37:41–4.

    Article  PubMed  CAS  Google Scholar 

  128. Goldsmith HL, Marlow J. Flow behaviour of erythrocytes. I. Rotation and deformation in dilute suspensions. Proc R Soc Lond B. 1972;182:351–84.

    Article  Google Scholar 

  129. 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;217:364–70.

    Article  CAS  PubMed  Google Scholar 

  130. 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;106:21495–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Haghgooie R, Toner M, Doyle PS. Squishy non-spherical hydrogel microparticles. Macromol Rapid Commun. 2010;31:128–34.

    CAS  PubMed  Google Scholar 

  132. Merkel TJ, Jones SW, Herlihy KP, Kersey FR, Shields AR, Napier M, Luft JC, Wu H, Zamboni WC, Wang AZ, Bear JE, DeSimone JM. Using mechanobiological mimicry of red blood cells to extend circulation times of hydrogel microparticles. Proc Natl Acad Sci U S A. 2011;108:586–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Li S, Nickels J, Palmer AF. Liposome-encapsulated actin-hemoglobin (LEAcHb) artificial blood substitutes. Biomaterials. 2005;26:3759–69.

    Article  CAS  PubMed  Google Scholar 

  134. 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;377:199–206.

    Article  CAS  PubMed  Google Scholar 

  135. Krafft MP, Riess JG. Perfluorocarbons: life sciences and biomedical uses. J Polym Sci Part A: Polym Chem. 2007;45:1185–98.

    Article  CAS  Google Scholar 

  136. Riess JG, Krafft MP. Fluorinated materials for in vivo oxygen transport (blood substitutes), diagnosis and drug delivery. Biomaterials. 1998;19:1529–39.

    Article  CAS  PubMed  Google Scholar 

  137. Schutt EG, Klein DH, Mattrey RM, Riess JG. Injectable microbubbles as contrast agents for diagnostic ultrasound imaging: the key role of perfluorochemicals. Angew Chem Int Ed Engl. 2003;42:3218–35.

    Article  CAS  PubMed  Google Scholar 

  138. Cosgrove D. Ultrasound contrast agents: an overview. Eur J Radiol. 2006;60:324–30.

    Article  PubMed  Google Scholar 

  139. Spiess BD. Basic mechanisms of gas transport and past research using perfluorocarbons. Diving Hyperb Med. 2010;40:23–8.

    PubMed  Google Scholar 

  140. Riess JG. Perfluorocarbon-based oxygen delivery. Artif Cells Blood Substit Immobil Biotechnol. 2006;34:567–80.

    Article  CAS  PubMed  Google Scholar 

  141. Freire MG, Gomes L, Santos LM, Marrucho IM, Coutinho JA. Water solubility in linear fluoroalkanes used in blood substitute formulations. J Phys Chem B. 2006;110:22923–9.

    Article  CAS  PubMed  Google Scholar 

  142. Gould SA, Rosen AL, Sehgal LR, Sehgal HL, Langdale LA, Krause LM, Rice CL, Chamberlin WH, Moss GS. Fluosol-DA as a red-cell substitute in acute anemia. N Engl J Med. 1986;314:1653–6.

    Article  CAS  PubMed  Google Scholar 

  143. Spahn DR. Blood substitutes artificial oxygen carriers: perfluorocarbon emulsions. Crit Care. 1999;3:R93–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Castro CI, Briceno JC. Perfluorocarbon-based oxygen carriers: review of products and trials. Artif Organs. 2010;34:622–34.

    PubMed  Google Scholar 

  145. Torres Filho IP, Pedro JRP, Narayanan SV, Nguyen NM, Roseff SD, Spiess BD. Perfluorocarbon emulsion improves oxygen transport of normal and sickle cell human blood in vitro. J Biomed Mater Res Part A. 2014;102A:2105–15.

    Article  CAS  Google Scholar 

  146. Keipert PE. Perfluorochemical emulsions: future alternatives to transfusion. Blood Subst Princ Meth Prod Clin Trials. 1998;2:127–56.

    CAS  Google Scholar 

  147. Spiess BD. Perfluorocarbon emulsions: one approach to intravenous artificial respiratory gas transport. Int Anesthesiol Clin. 1995;33:103–13.

    Article  CAS  PubMed  Google Scholar 

  148. Spahn DR, van Brempt R, Theilmeier G, Reibold JP, Welte M, Heinzerling H, Birck KM, Keipert PE, Messmer K. Perflubron emulsion delays blood transfusions in orthopedic surgery. European Perflubron Emulsion Study Group. Anesthesiology. 1999;91:1195–208.

    Article  CAS  PubMed  Google Scholar 

  149. Flaim SF. Perflubron-based emulsion: efficacy as temporary oxygen carrier. In: Winslow RM, Vandegriff KD, Intaglietta M, editors. Advances in blood substitutes. Boston: Birkhäuser; 1997. p. 91–132.

    Chapter  Google Scholar 

  150. Riess JG, Keipert PE. Update on perfluorocarbon-based oxygen delivery systems. In: Tsuchida E, editor. Blood substitutes: present and future perspectives. Lausanne: Elsevier Science SA; 1998. p. 91–102.

    Chapter  Google Scholar 

  151. Keipert PE. Oxygent™, a perfluorochemical-based oxygen therapeutic for surgical patients. In: Winslow RM, editor. Blood substitutes. London: Elsevier; 2006. p. 313–23.

    Google Scholar 

  152. Keipert PE, Faithfull NS, Bradley JD, Hazard DY, Hogan J, Levisetti MS, Peters RM. Oxygen delivery augmentation by low-dose perfluorochemical emulsion during profound normovolemic hemodilution. Adv Exp Med Biol. 1994;345:197–204.

    Article  CAS  PubMed  Google Scholar 

  153. Stern SA, Dronen SC, McGoron AJ, Wang X, Chaffins K, Millard R, Keipert PE, Faithfull NS. Effect of supplemental perfluorocarbon administration on hypotensive resuscitation of severe uncontrolled hemorrhage. Am J Emerg Med. 1995;13:269–75.

    Article  CAS  PubMed  Google Scholar 

  154. Manning JE, Batson DN, Payne FB, Adam N, Murphy CA, Perretta SG, Norfleet EA. Selective aortic arch perfusion during cardiac arrest: enhanced resuscitation using oxygenated perflubron emulsion, with and without aortic arch epinephrine. Ann Emerg Med. 1997;29:580–7.

    Article  CAS  PubMed  Google Scholar 

  155. Wahr JA, Trouwborst A, Spence RK, Henny CP, Cernaianu AC, Graziano GP, Tremper KK, Flaim KE, Keipert PE, Faithfull NS, Clymer JJ. A pilot study of the effects of a perflubron emulsion, AF 0104, on mixed venous oxygen tension in anesthetized surgical patients. Anesth Analg. 1996;82:103–7.

    CAS  PubMed  Google Scholar 

  156. Daugherty WP, Levasseur JE, Sun D, Spiess BD, Bullock MR. Perfluorocarbon emulsion improves cerebral oxygenation and mitochondrial function after fluid percussion brain injury in rats. Neurosurgery. 2004;54:1223–30.

    Article  PubMed  Google Scholar 

  157. Zhou Z, Sun D, Levasseur JE, Merenda A, Hamm RJ, Zhu J, Spiess BD, Bullock MR. Perfluorocarbon emulsions improve cognitive recovery after lateral fluid percussion brain injury in rats. Neurosurgery. 2008;63:799–806.

    Article  PubMed  Google Scholar 

  158. Yacoub A, Hajec MC, Stanger R, Wan W, Young H, Mathern BE. Neuroprotective effects of perfluorocarbon (Oxycyte) after contusive spinal cord injury. J Neurotrauma. 2014;31:256–67.

    Article  PubMed  PubMed Central  Google Scholar 

  159. Henkel-Hanke T, Oleck M. Artificial oxygen carriers: a current review. AANA J. 2007;75:205–11.

    Google Scholar 

  160. Maevsky E, Ivanitsky G, Bogdanova L, Axenova O, Karmen N, Zhiburt E, Senina R, Pushkin S, Maslennikov I. Clinical results of Perftoran application: present and future. Artif Cells Blood Substit Immobil Biotechnol. 2005;33:37–46.

    Article  CAS  PubMed  Google Scholar 

  161. Collman JP, Brauman JI, Rose E, Suslick KS. Cooperativity in O2 binding to iron porphyrins. Proc Natl Acad Sci U S A. 1978;75:1052–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Kano K, Kitagishi H. HemoCD as an artificial oxygen carrier: oxygen binding and autoxidation. Artif Organs. 2009;33:177–82.

    Article  CAS  PubMed  Google Scholar 

  163. Collman JP, Boulatov R, Sunderland CJ, Fu L. Functional analogues of cytochrome c oxidase, myoglobin, and hemoglobin. Chem Rev. 2004;104:561–88.

    Article  CAS  PubMed  Google Scholar 

  164. Kakizaki T, Kobayashi K, Komatsu T, Nishide H, Tsuchida E. Lipidheme-microsphere (LH-M). A new type of totally synthetic oxygen carrier and its oxygen carrying ability. Artif Cells Blood Substit Immobil Biotechnol. 1994;22:933–8.

    Article  CAS  PubMed  Google Scholar 

  165. Yuasa M, Aiba K, Ogata Y, Nishide H, Tsuchida E. Structure of the liposome composed of lipid-heme and phospholipids. Biochim Biophys Acta. 1986;860:558–65.

    Article  CAS  Google Scholar 

  166. Karasugi K, Kitagishi H, Kano K. Modification of a dioxygen carrier, hemoCD, with PEGylated dendrons for extension of circulation time in the bloodstream. Bioconjug Chem. 2012;23:2365–76.

    Article  CAS  PubMed  Google Scholar 

  167. Baglia RA, Zaragoza JPT, Goldberg DP. Biomimetic reactivity of oxygen-derived manganese and iron porphyrinoid complexes. Chem Rev. 2017;117:13320–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Hoffman M, Monroe DM III. A cell-based model of hemostasis. Thromb Haemost. 2001;85:958–65.

    Article  CAS  PubMed  Google Scholar 

  169. Versteeg HH, Heemskerk JWM, Levi M, Reitsma PH. New fundamentals in hemostasis. Physiol Rev. 2013;93:327–58.

    Article  CAS  PubMed  Google Scholar 

  170. Bergmeier W, Stefanini L. Platelets at the vascular interface. Res Pract Thromb Haemost. 2018;2:27–33.

    Article  PubMed  Google Scholar 

  171. Flaumenhaft R. Molecular basis of platelet granule secretion. Arterioscler Thromb Vasc Biol. 2003;23:1152–60.

    Article  CAS  PubMed  Google Scholar 

  172. Whiteheart SW. Platelet granules: surprise packages. Blood. 2011;118:1190–1.

    Article  CAS  PubMed  Google Scholar 

  173. Hiejnen H, van der Sluijs P. Platelet secretory behavior: as diverse as the granules ... or not? J Thromb Haemost. 2015;13:2141–51.

    Article  CAS  Google Scholar 

  174. Smith SA, Morrissey JH. Polyphosphate: a new player in hemostasis. Curr Opin Hematol. 2014;21:388–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Etchill EW, Myers SP, Raval JS, Hassoune A, Sen Gupta A, Neal MD. Platelet transfusion in crtical care and surgery: evidence-based review of contemporary practice and future directions. Shock. 2017;47:537–49.

    Article  PubMed  Google Scholar 

  176. Humbrecht C, Kientz D, Gachet C. Platelet transfusions: current challenges. Transfus Clin Biol. 2018;25:151–64.

    Article  CAS  PubMed  Google Scholar 

  177. Janetzko K, Hinz K, Marschner S, Goodrich R, Klüter H. Pathogen reduction technology (Mirasol ®) treated single-donor platelets resuspended in a mixture of autologous plasma and PAS. Vox Sang. 2009;97:234–9.

    Google Scholar 

  178. Marks DC, Faddy HM, Johnson L. Pathogen reduction technologies. ISBT Sci Ser. 2014;9:44–50.

    Article  Google Scholar 

  179. Ketter PM, Kamucheka R, Arulanandam B, Akers K, Cap AP. Platelet enhancement of bacterial growth during room temperature storage: mitigation through refrigeration. Transfusion. 2019;59:1479–89.

    Article  PubMed  Google Scholar 

  180. Cap AP. Platelet storage: a license to chill. Transfusion. 2016;56:13–6.

    Article  PubMed  Google Scholar 

  181. Apelseth TO, Cap AP, Spinella PC, Hervig T, Strandenes G. Cold stored platelets in treatment of bleeding. ISBT Sci Ser. 2017;12:17–21.

    Article  Google Scholar 

  182. Stubbs JR, Tran SA, Emery RL, Hammel SA, Haugen AL, Zielinski MD, Zietlow SP, Jenkins D. Cold platelets for trauma-associated bleeding: regulatory approval, accreditation approval and practice implementation- just the “tip of the iceberg”. Transfusion. 2017;57:2836–44.

    Article  CAS  PubMed  Google Scholar 

  183. Hoffmeister KM, Felbinger TW, Falet H, Denis CV, Bergmeier W, Mayadas TN, von Andrian UH, Wagner DD, Stossel TP, Hartwig JH. The clearance mechanism of chilled blood platelets. Cell. 2003;112:87–97.

    Article  CAS  PubMed  Google Scholar 

  184. Josefsson EC, Hartwig JH, Hoffmeister KM. Platelet storage temperature – how low can we go? Transfus Med Hemother. 2007;34:253–61.

    Article  Google Scholar 

  185. Getz TM. Physiology of cold-stored platelets. Transfus Apher Sci. 2019;58:12–5.

    Article  PubMed  Google Scholar 

  186. Fitzpatrick GM, Cliff R, Tandon N. Thrombosomes: a platelet-derived hemostatic agent for control of noncompressible hemorrhage. Transfusion. 2013;53:S100S–S106.

    Article  Google Scholar 

  187. Johnson L, Tan S, Wood B, Davis A, Marks DC. Refrigeration and cryopreservation of platelets differentially affect platelet metabolism and function: a comparison with conventional platelet storage conditions. Transfusion. 2016;56:1807–18.

    Article  CAS  PubMed  Google Scholar 

  188. Blajchman MA. Substitutes for success. Nat Med. 1999;5:17–8.

    Article  CAS  PubMed  Google Scholar 

  189. Blajchman MA. Substitutes and alternatives to platelet transfusions in thrombocytopenic patients. J Thromb Haemost. 2003;1:1637–41.

    Article  CAS  PubMed  Google Scholar 

  190. Lee D, Blajchman MA. Novel treatment modalities: new platelet preparations and substitutes. Br J Haematol. 2001;114:496–505.

    Article  CAS  PubMed  Google Scholar 

  191. Modery-Pawlowski CL, Tian LL, Pan V, McCrae KR, Mitragotri S, Sen Gupta A. Approaches to synthetic platelet analogs. Biomaterials. 2013;34:526–41.

    Article  CAS  PubMed  Google Scholar 

  192. Girish A, Sekhon U, Sen GA. Bioinspired artificial platelets for transfusion applications in traumatic hemorrhage. Transfusion. 2020;60(2):229–31. https://doi.org/10.1111/trf.15543.

    Article  PubMed  Google Scholar 

  193. Wagner DD. Cell biology of von Willebrand Factor. Annu Rev Cell Biol. 1990;6:217–46.

    Article  CAS  PubMed  Google Scholar 

  194. Ruggeri ZM. Platelet adhesion under flow. Microcirculation. 2009;16:58–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Ruggeri ZM, Mendolicchio GL. Adhesion mechanisms in platelet function. Circ Res. 2007;100:1673–85.

    Article  CAS  PubMed  Google Scholar 

  196. Rybak ME, Renzulli LA. A liposome based platelet substitute, the plateletsome, with hemostatic efficacy. Biomater Artif Cell Immobil Biotechnol. 1993;21:101–18.

    CAS  Google Scholar 

  197. Takeoka S, Teramura Y, Okamura Y, Tsuchida E, Handa M, Ikeda Y. Rolling properties of rGPIbalpha-conjugated phospholipid vesicles with different membrane flexibilities on vWf surface under flow conditions. Biochem Biophys Res Commun. 2002;296:765–70.

    Article  CAS  PubMed  Google Scholar 

  198. Nishiya T, Kainoh M, Murata M, Handa M, Ikeda Y. Reconstitution of adhesive properties of human platelets in liposomes carrying both recombinant glycoproteins Ia/IIa and Ib alpha under flow conditions: specific synergy of receptor-ligand interactions. Blood. 2002;100:136–42.

    Article  CAS  PubMed  Google Scholar 

  199. Nishiya T, Kainoh M, Murata M, Handa M, Ikeda Y. Platelet interactions with liposomes carrying recombinant platelet membrane glycoproteins or fibrinogen: approach to platelet substitutes. Artif Cells Blood Substit Immobil Biotechnol. 2001;29:453–64.

    Article  CAS  PubMed  Google Scholar 

  200. del Carpio MC, Campbell W, Constantinescu I, Gyongyossy-Issa MI, C. Rational design of antithrombotic peptides to target the von Willebrand Factor (vWf) – GPIb integrin interaction. J Mol Model. 2008;14:1191–202.

    Article  CAS  Google Scholar 

  201. Gyongyossy-Issa MIC, Kizhakkedathu J, Constantinescu I, Campbell W, del Carpio Munoz CA. Synthetic platelets. US Patent Application Publication US 2008/0213369 A1, 2008.

    Google Scholar 

  202. Ravikumar M, Modery CL, Wong TL, Sen GA. Mimicking adhesive functionalities of blood platelets using ligand-decorated liposomes. Bioconjug Chem. 2012;23:1266–75.

    Article  CAS  PubMed  Google Scholar 

  203. Haji-Valizadeh H, Modery-Pawlowski CL, Sen GA. A factor VIII-derived peptide enables von Willebrand factor (VWF)-binding of artificial platelet nanoconstructs without interfering with VWF-adhesion of natural platelets. Nanoscale. 2014;6:4765–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Li Z, Delaney MK, O’Brien KA, Du X. Signaling during platelet adhesion and activation. Arterioscler Thromb Vasc Biol. 2010;30:2341–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Shattil SJ, Kashiwagi H, Pampori N. Integrin signaling: the platelet paradigm. Blood. 1998;91:2645–57.

    Article  CAS  PubMed  Google Scholar 

  206. Pytela R, Piersbacher MD, Ginsberg MH, Plow EF, Ruoslahti E. Platelet membrane glycoprotein IIb/IIIa: member of a family of Arg-Gly-Asp-specific adhesion receptors. Science. 1986;231:1559–62.

    Article  CAS  PubMed  Google Scholar 

  207. Plow EF, D’Souza SE, Ginsberg MH. Ligand binding to GPIIb-IIIa: a status report. Semin Thromb Hemost. 1992;18:324–32.

    Article  CAS  PubMed  Google Scholar 

  208. Coller BS. Interaction of normal, thrombasthenic and Bernard-Soulier platelets with immobilized fibrinogen: defective platelet-fibrinogen interaction in thrombasthenia. Blood. 1980;55:169–78.

    Article  CAS  PubMed  Google Scholar 

  209. Agam G, Livne A. Passive participation of fixed platelets in aggregation facilitated by covalently bound fibrinogen. Blood. 1983;61:186–91.

    Article  CAS  PubMed  Google Scholar 

  210. Agam G, Livne AA. Erythrocytes with covalently-bound fibrinogen as a cellular replacement for the treatment of thrombocytopenia. Eur J Clin Invest. 1992;22:105–12.

    Article  CAS  PubMed  Google Scholar 

  211. Coller BS, Springer KT, Beer JH, Mohandas N, Scudder LE, Norton KJ, West SM. Thromboerythrocytes. In vitro studies of a potential autologous, semi-artificial alternative to platelet transfusions. J Clin Invest. 1992;89:546–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Yen RCK, Ho TWC, Blajchman MA. A new haemostatic agent: Thrombospheres shorten the bleeding time in thrombocytopenic rabbits. Thromb Haemost. 1995;73:986.

    Google Scholar 

  213. Levi M, Friederich PW, Middleton S, de Groot PG, Wu YP, Harris R, Biemond BJ, Heijnen HF, Levin J, ten Cate JW. Fibrinogen-coated albumin microcapsules reduce bleeding in severely thrombocytopenic rabbits. Nat Med. 1999;5:107–11.

    Article  CAS  PubMed  Google Scholar 

  214. Davies AR, Judge HM, May JA, Glenn JR, Heptinstall S. Interactions of platelets with Synthocytes, a novel platelet substitute. Platelets. 2002;13:197–205.

    CAS  PubMed  Google Scholar 

  215. Verhoef C, Singla N, Moneta G, Muir W, Rijken A, Lockstadt H, de Wilt JH, O-Yurvati A, Zuckerman LA, Frohna P, Porte RJ. Fibrocaps for surgical hemostasis: two randomized, controlled phase II trials. J Surg Res. 2015;194:679–87.

    Article  PubMed  Google Scholar 

  216. Bertram JP, Williams CA, Robinson R, Segal SS, Flynn NT, Lavik EB. Intravenous hemostat: nanotechnology to halt bleeding. Sci Transl Med. 2009;1:11–22.

    Article  CAS  Google Scholar 

  217. Gkikas M, Peponis T, Mear T, Hong C, Avery RK, Roussakis E, Yoo H-J, Parakh A, Patino M, Sahani DV, Watkins MT, Oklu R, Evans CL, Albadawi H, Velmahos G, Olsen BD. Systemically administered hemostatic nanoparticles for identification and treatment of internal bleeding. ACS Biomater Sci Eng. 2019;5:2563–76.

    Article  CAS  PubMed  Google Scholar 

  218. Ruoslahti E. RGD and other recognition sequences for integrins. Annu Rev Cell Dev Biol. 1996;12:697–715.

    Article  CAS  PubMed  Google Scholar 

  219. Du X, Plow EF, Frelinger AL III, O’Toole TE, Loftus JC, Ginsberg MH. Ligands activate integrin αIIbβ3 (Platelet GPIIb-IIIa). Cell. 1991;65:409–16.

    Article  CAS  PubMed  Google Scholar 

  220. Bassler N, Loeffler C, Mangin P, Yuan Y, Schwartz M, Hagemeyer CE, Eisenhardt SU, Ahrens I, Bode C, Jackson SP, Peter K. A mechanistic model for paradoxical platelet activation by ligand-mimetic αIIbβ3 (GPIIb/IIIa) antagonists. Arterioscler Thomb Vasc Biol. 2007;27:e9–e15.

    Article  CAS  Google Scholar 

  221. Lashof-Sullivan MM, Shoffstall A, Atkins KT, Keane N, Bir C, VandeVord P, Lavik EB. Intravenously administered nanoparticles increase survival following blast trauma. Proc Natl Acad Sci U S A. 2014;111:10293–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Okamura Y, Takeoka S, Teramura Y, Maruyama H, Tsuchida E, Handa M, Ikeda Y. Hemostatic effects of fibrinogen gamma-chain dodecapeptide-conjugated polymerized albumin particles in vitro and in vivo. Transfusion. 2005;45:1221–8.

    Article  CAS  PubMed  Google Scholar 

  223. Okamura Y, Fujie T, Nogawa M, Maruyama H, Handa M, Ikeda Y, Takeoka S. Haemostatic effects of polymerized albumin particles carrying fibrinogen γ-chain dodecapeptide as platelet substitutes in severely thrombocytopenic rabbits. Transfus Med. 2008;18:158–66.

    Article  CAS  PubMed  Google Scholar 

  224. Okamura Y, Maekawa I, Teramura Y, Maruyama H, Handa M, Ikeda Y, Takeoka S. Hemostatic effects of phospholipid vesicles carrying fibrinogen γ chain dodecapeptide in vitro and in vivo. Bioconjug Chem. 2005;16:1589–96.

    Article  CAS  PubMed  Google Scholar 

  225. Ravikumar M, Modery CL, Wong TL, Sen GA. Peptide-decorated liposomes promote arrest and aggregation of activated platelets under flow on vascular injury relevant protein surfaces in vitro. Biomacromolecules. 2012;13:1495–502.

    Article  CAS  PubMed  Google Scholar 

  226. Okamura Y, Katsuno S, Suzuki H, Maruyama H, Handa M, Ikeda Y, Takeoka S. Release abilities of adenosine diphosphate from phospholipid vesicles with different membrane properties and their hemostatic effects as a platelet substitute. J Control Release. 2010;148:373–9.

    Article  CAS  PubMed  Google Scholar 

  227. Girish A, Hickman DA, Banerjee A, Luc N, Ma Y, Miyazawa K, Sekhon UDS, Sun M, Huang S, Sen Gupta A. Trauma-targeted delivery of tranexamic acid improves hemostasis and survival in rat liver hemorrhage model. J Thromb Haemost. 2019;17:1632–44.

    Article  CAS  PubMed  Google Scholar 

  228. Ni H, Freedman J. Platelets in hemostasis and thrombosis: role of integrins and their ligands. Transfus Apher Sci. 2003;28:257–64.

    Article  PubMed  Google Scholar 

  229. Okamura Y, Handa M, Suzuki H, Ikeda Y, Takeoka S. New strategy of platelet substitutes for enhancing platelet aggregation at high shear rates: cooperative effects of a mixed system of fibrinogen gamma-chain dodecapeptide- or glycoprotein Ib alpha-conjugated latex beads under flow conditions. J Artif Organs. 2006;9:251–8.

    Article  CAS  PubMed  Google Scholar 

  230. Shukla M, Sekhon UD, Betapudi V, Li W, Hickman DA, Pawlowski CL, Dyer MR, Neal MD, McCrae KR, Sen GA. In vitro characterization of SynthoPlate™ (synthetic platelet) technology and its in vivo evaluation in severely thrombocytopenic mice. J Thromb Haemost. 2017;15:375–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  231. Dyer MR, Hickman D, Luc N, Haldeman S, Loughran P, Pawlowski C, Sen Gupta A, Neal MD. Intravenous administration of synthetic platelets (SynthoPlate) in a mouse liver injury model of uncontrolled hemorrhage improves hemostasis. J Trauma Acute Care Surg. 2018;84:917–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. Hickman DA, Pawlowski CL, Shevitz A, Luc NF, Kim A, Girish A, Marks J, Ganjoo S, Huang S, Niedoba E, Sekhon UDS, Sun M, Dyer M, Neal MD, Kashyap VS, Sen GA. Intravenous synthetic platelet (SynthoPlate) nanoconstructs reduce bleeding and improve ‘golden hour’ survival in a porcine model of traumatic arterial hemorrhage. Sci Rep. 2018;8(1):3118.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  233. Anselmo AC, Modery-Pawlowski CL, Menegatti S, Kumar S, Vogus DR, Tian LL, Chen M, Squires TM, Sen Gupta A, Mitragotri S. Platelet-like nanoparticles: mimicking shape, flexibility and surface biology of platelets to target vascular injuries. ACS Nano. 2014;8:11243–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  234. Sarkar S. Artificial blood. Indian J Crit Care Med. 2008;12:140–1444.

    Article  PubMed  PubMed Central  Google Scholar 

  235. Booth C, Highley D. Crystalloids, colloids, blood, blood products and blood substitutes. Anaesth Intens Care Med. 2010;11:50–5.

    Article  Google Scholar 

  236. McCahon R, Hardman J. Pharmacology of plasma expanders. Anaesth Intens Care Med. 2007;8:79–81.

    Article  Google Scholar 

  237. Chatrath V, Khetarpal R, Ahuja J. Fluid management in patients with trauma: restrictive versus liberal approach. J Anaesthesiol Clin Pharmacol. 2015;31:308–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  238. Ishikura H, Kitamura T. Trauma-induced coagulopathy and critical bleeding: the role of plasma and platelet transfusion. J Intensive Care. 2017;5:2. https://doi.org/10.1186/s40560-016-0203-y.

    Article  PubMed  PubMed Central  Google Scholar 

  239. Hagisawa K, Kinoshita M, Takikawa M, Takeoka S, Saitoh D, Seki S, Sakai H. Combination therapy using fibrinogen γ-chain peptide-coated, ADP-encapsulated liposomes and hemoglobin vesicles for trauma-induced massive hemorrhage in thrombocytopenic rabbits. Transfusion. 2019;59:2186–96.

    Article  CAS  Google Scholar 

  240. Molinaro R, Corbo C, Martinez JO, Taraballi F, Evangelopoulos M, Minardi S, Yazdi IK, Zhao P, De Rosa E, Sherman MB, De Vita A, Toledano Furman NE, Wang X, Parodi A, Tasciotti E. Biomimetic proteolipid vesicles for targeting inflamed tissues. Nat Mater. 2016;15:1037–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  241. Hammer DA, Robbins GP, Haun JB, Lin JJ, Qi W, Smith LA, Ghoroghchian PP, Therien MJ, Bates FS. Leuko-polymersomes. Faraday Discuss. 2008;139:129–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  242. Parodi A, Quattrocchi N, van de Ven AL, Chiappini C, Evangelopoulos M, Martinez JO, Brown BS, Khaled SZ, Yazdi IK, Enzo MV, Isenhart L, Ferrari M, Tasciotti E. Synthetic nanoparticles functionalized with biomimetic leukocyte membranes possess cell-like functions. Nat Nanotechnol. 2013;8:61–8.

    Article  CAS  PubMed  Google Scholar 

  243. Committee on Military Trauma Care’s Learning Health System and Its Translation to the Civilian Sector, Board on Health Sciences Policy, Board on the Health of Select Populations, Health and Medicine Division, National Academies of Sciences, Engineering, and Medicine. In: Berwick D, Downey A, Cornett E, editors. A national trauma care system: integrating military and civilian trauma systems to achieve zero preventable deaths after injury. Washington, DC: National Academies of Sciences, Engineering, and Medicine; 2016. https://doi.org/10.17226/23511.

    Chapter  Google Scholar 

Download references

Acknowledgment

ASG is supported by the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health under award numbers R01 HL121212 and R01 HL129179. The content and perspectives expressed in this publication are solely the responsibility of the author and do not necessarily represent the official views of the National Institutes of Health.

Disclosure

ASG is a co-author on patents US 9107845 and US 9636383 in the area of synthetic platelets. ASG is a co-founder of and Chief Scientific Advisor to Haima Therapeutics, a biotech start-up company focused on the research and development of synthetic platelets.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Anirban Sen Gupta .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2021 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Gupta, A.S. (2021). Synthetic Blood Substitutes. In: Moore, H.B., Neal, M.D., Moore, E.E. (eds) Trauma Induced Coagulopathy. Springer, Cham. https://doi.org/10.1007/978-3-030-53606-0_43

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-53606-0_43

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-53605-3

  • Online ISBN: 978-3-030-53606-0

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics