Mini review on Artificial Blood Substitutes: Future perspective of Perfluorocarbon based oxygen carriers
Main Article Content
Abstract
The primary cause of death in the battle field and in civilian trauma is haemorrhagic shock. Around 50% combat deaths occur due to haemorrhage, depending on the severity of bleeding medical supervision can be provided like in catastrophic haemorrhage individual death occurs before providing the medical care and it is not a prehospital combat medical management problem during warfare scenario, even to transport wounded personnel to causality centre often takes 45 minutes to one hours. The hazardous nature of the forward combat areas and hostile operational environment frequently prevents medical personnel from quickly reaching the wounded even if the transport distances are small. Moreover, injuries with penetrating battlefield trauma often have only a "platinum 5 minutes." It is very important for military medical personnel to understand their options for treating haemorrhage quickly and efficiently during combat. Early intervention and definitive treatment could save up to 30% of soldier’s who die of action or of wounds.
In view of this there is a requirement for the development of synthetic blood substitutes or oxygen therapeutic agents (OTA) in order to maintain the tissue oxygenation. Blood substitutes are the substances which mimic one of the physiological functions of the blood that is transportation of oxygen and carbon dioxide throughout the body. Blood substitutes or OTAs are being clinically tested as artificial oxygen carriers to improve tissue oxygenation and also to reduce allogenic blood transfusions. Two types of blood substitutes are reported so far: 1. Haemoglobin based oxygen carriers (HBOCs) and 2. Perfluorocarbon based oxygen carriers (PFOCs). PFOCs has huge advantages like universal compatibility, no requirement of cold storage, longer shelf life and no risk of infection transmission. These products have their own limitations and they have been withdrawn from international market for clinical use because of their side effects. It is a challenging task to the scientists to develop a safe, stable and biocompatible blood substitute for combat scenarios and also for civilian applications.
Keywords:
Artificial blood, Blood transfusion, Oxygen therapeutic agents (OTA), Haemoglobin based oxygen carriers (HBOCs), Perfluorocarbon based oxygen carriers (PFOCs)
Article Details
How to Cite
MAHESHWARI, D T; KUMAR, M S Yogendra; INDUSHEKAR, R.
Mini review on Artificial Blood Substitutes: Future perspective of Perfluorocarbon based oxygen carriers.
Medical Research Archives, [S.l.], v. 12, n. 6, june 2024.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/5478>. Date accessed: 21 nov. 2024.
doi: https://doi.org/10.18103/mra.v12i6.5478.
Section
Review Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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13. Amberson WR, Jennings J J, Rhode CM. Clinical experience with hemoglobin-saline solutions. J. Appl. Physiol. 1949; 1(7): 469-489.
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15. Cohn EJ. Blood: A brief survey of its chemical components and of their natural functions and clinical uses. Blood. 2015; 126: 2531.
16. Cohn SM. Blood substitutes in surgery. Surgery. 2000; 127(6): 599-602.
17. Brohi K, Gruen R L, Holcomb JB. Why Are Bleeding Trauma Patients Still Dying? Intensive Care Med. 2019;45(5):709–711. Doi:10.1007/s00134-019-05560-x
18. Cherkas D, Traumatic Hemorrhagic Shock: Advances in Fluid Management. Emerg. Med. Pract. 2011;13(11):1–20.
19. Chatrath V, Khetarpal R, Ahuja J. Fluid Management in Patients with Trauma: Restrictive versus Liberal Approach. J Anaesthesiol Clin. Pharmacol. 2015;31(3):308 –316. Doi:10.4103/0970-9185.161664.
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21. Samira Moradi, Ali Jahanian-Najafabadi, Mehryar Habibi Roudkenar. Artificial Blood Substitutes: First Steps on the Long Route to Clinical Utility. Clin Med Insights Blood Disord. 2016;27(9):33-41. doi: 10.4137/CMB D.S38461
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23. Cabrales P , Intaglietta M. Blood substitutes: evolution from non-carrying to oxygen and gas carrying fluids. ASAIO J. 2013;59(4):337.
24. Shekhar C. Blood relatives: artificial oxygen carriers between promise and concern. J. Chem. Biol. 2007;10:1091–92.
25. Matton A. P. M, Burlage L. C and van Rijn R, Normothermic machine perfusion of donor livers without the need for human blood products. Liver Transplant, 2018, 24:528–538. https:// doi. org/ 10.1002/ lt. 25005.
26. Neelam S, Semwal B C, Maurya Krishna, Khatoon Ruqsana, Paswan Shravan. Artificial Blood: A tool for survival of humans. Int.Res.J.Phar. 2012; 3(5): 119-123.
27. A V More, S Y Sayyed, P G Morankar, S R Churi, S S Gawli, R A Karande, R Y Gorade. A comprehensive insight into artificial blood. Int.J.Phar. Sci and Res. 2023;14(3): 1108-1119.
28. D R Spahn , R van Brempt, G Theilmeier, J P Reibold, M Welte, H Heinzerling, K M Birck, P E Keipert, K Messmer, H Heinzerling, K M Birck, P E Keipert, K Messmer. Perflubron emulsion delays blood transfusions in orthopedic surgery. European Perflubron Emulsion Study Group. Anesthesiology.1999; 91(5): 1195-208. DOI: 10.1097/00000542-199911000-00009
29. Tinits P. Oxygen therapy and oxygen toxicity. Ann Emerg Med., 1983, 12:321–328.
30. Keipert P E. Perfluorochemical emulsions: future alternatives to transfusion. Blood Subst Princ Meth Prod Clin Trials. 1998; 2:127–156.
31. Eckstein E C, Koleski J F, Waters C M. Concentration profiles of 1 and 2.5 microns beads during blood flow. Hematocrit effects. ASAIO Trans. 1989; 35:188–190.
32. Lin Chen, Zeyong Yang, Henry Liu. Hemoglobin-Based Oxygen Carriers: Where AreWe Now in 2023? Medicina. 2023;(59): 396. https://doi.org/10.3390/ medicina59020396.
33. Vanessa R Melanson, Jeremy R Hershfield, Michael Kevin Deegan, Hyeveen Cho, Dion Perinon, Stacey L Bateman , Jason C Barnhill. Artificial Blood Development Implications for Military Medicine, J. Spec. Oper. Med., 2023 Oct 5;23(3):63-69. doi: 10.55460/OVOP-V2QC.
34. Sahu S. C, Simplaceanu V, Gong Q, Ho N. T, Glushka J. G and Prestegard J. H, Orientation of Deoxyhemoglobin at High Magnetic fields: Structural Insights from RDCs in Solution, J. Am. Chem. Soc., 2006, 128, 6290–6291. Doi:10.1021/ja060023z.
35. Yu S, Hemoglobin: Physiology and Hemoglobinopathy. In Blood Substitutes and Oxygen. Biotherapeutics. 2022; 45–51.
36. Bleeker W. K, van der Plas J, Feitsma R. I, Agterberg J, Rigter, G, de Vries-van Bowersox J. C and J R Hess, Trauma and military applications of blood substitutes. Artif cells Blood Substit Immobil Biotechnol.1994; 22 (2): 145-57.
37. Creteur J and Vincent J. L, Hemoglobin solutions. Crit. Care Med. 2003; 31(12): S698-S707.
38. Chang T. M, Red blood cell substitutes. Best Pract. Res. Clin. Haematol., 2000, 13(4), 651-667.
39. Squires J. E, Artificial blood. Science, 2002, 295(5557), 1002- 1005.
40. Baumler H, Xiong Y, Liu Z Z. Novel hemoglobin particles promising new- generation hemoglobin-based oxygen carriers. Artif Organs. 2014;38:708–714. https:// doi. org/ 10. 1111/ aor. 12331
41. Kao I, Xiong Y, Steffen A. Preclinical in vitro safety investigations of submicron sized hemoglobin based oxygen carrier HbMP-700. Artif Organs. 2018;42:549–559. https:// doi. org/ 10. 1111/aor. 13071
42. Henkel-Honke T, Oleck M. Artificial oxygen carriers: A current review. AANA J. 2007; 75(3):205-211.
43. Pape A, Habler O. Alternatives to allogeneic blood transfusions. Best Pract. Res. Clin. Anaesthesiol. 2007; 21(2): 221-239.
44. Spahn DR, Kocian R. The place of artificial oxygen carriers in reducing allogeneic blood transfusions and augmenting tissue oxygenation. Can. J. Anaesth. 2003; 50(6): S41-S47.
45. Kaneda S, Ishizuka T, Sekiguchi A, Morimoto K and Kasukawa H, Efficacy of liposome-encapsulated hemoglobin in a rat model of cerebral ischemia. Artif. Organs, 2014, 38(8), 650-655.
46. Kasper S. M, Walter M, Grüne F, Bischoff A, Erasmi H and Buzello W, Effects of a Hemoglobin-Based Oxygen Carrier (HBOC-201) on hemodynamics and oxygen transport in patients undergoing preoperative hemodilution for elective abdominal aortic surgery. Anesth. Analg., 1996, 83(5), 921-927.
47. Sakai H, Sou K, Horinouchi H, Kobayashi K and Tsuchida E. Haemoglobin-vesicles as artificial oxygen carriers: Present situation and future visions. J. Intern. Med. 2008; 263(1): 4-15.
48. Veronese F M, Pasut G. PEGylation, successful approach to drug delivery. Drug Discov. Today. 2005; 10(21): 1451-1458.
49. Agnillo F D, Chang T M. Polyhemoglobin-superoxide dismutase-catalase as a blood substitute with antioxidant properties. Nat Biotechnol.1998;16(7):667-71. Doi: 10.1038/nbt0798-667
50. Bian Y, Rong Z, Chang T. Polyhemoglobin-superoxide dismutase-catalase-carbonic anhydrase: A novel biotechnology-based blood substitute that transports both oxygen and carbon dioxide and also acts as an antioxidant. Artif. Cells Blood Substit. Immobil. Biotechnol. 2011; 39(3): 127-136.
51. Scott M G, Kucik D F, Goodnough L T, Monk T G. Blood substitutes: Evolution and future applications. Clin. Chem. 1997; 43(9): 1724-1731.
52. Jahr J S, Nesargi S B, Lewis K, Johnson C. Blood substitutes and oxygen therapeutics: An overview and current status. Am. J. Ther. 2002; 9(5): 437-443.
53. Anbari K K, Garino J P, Mackenzie C F. Hemoglobin substitutes. Eur. Spine J. 2004; 13( 1):S76-S82.
54. Takeoka S. Developmental trend of artificial blood (artificial red blood cells). Japan Med. Assoc. J. 2005; 48: 135-139.
55. Fontes P A. The evolution of oxygen carrier solutions for machine perfusion. Transplantation, 2017; 101(11): 2657-2658.
56. Hill, S.E. Oxygen therapeutics-current concepts. Can. J. Anaesth., 2001, 48(4) (Suppl.), S32-S40.
57. Kim HW, Greenburg A G. Artificial oxygen carriers as red blood cell substitutes: A selected review and current status. Artif. Organs. 2004; 28(9): 813-828.
58. Faithfull N S. Oxygen delivery from fluorocarbon emulsions—aspects of convective and diffusive transport. Biomaterials, artificial cells, and immobilization biotechnology: official journal of the International Society for Artificial Cells and Immobilization Biotechnology. 1992;20: 797–804.
59. Keipert P E, Faithfull N S, Roth D J, Bradley J D, Batra S, Jochelson P, Flaim K E. Supporting tissue oxygenation during acute surgical bleeding using a perfluorochemical-based oxygen carrier. Adv Exp Med Biol. 1996; 388:603–609.
60. Honda K, Hoshino S, Shoji M, Usuba A, Motoki R, Tsuboi M, Inoue H, Iwaya F. Clinical Use of a Blood Substitute. N Engl J Med. 1980; 303(7):391-2.
61. Mitsuno T, Ohyanagi H, Naito R. Clinical Studies of A Perfluorochemical Whole Blood Substitute (Fluosol-DA). Ann Surg. 1982;195(1):60–9.
62. Riess JG. Perfluorocarbon-based Oxygen Delivery. Artif Cells Blood Substit Biotechnol. 2006;34(6):567–80.
63. Hong F, Shastri K. A, Logue G L, Spaulding M B. Complement activation by artificial blood substitute Fluosol: In vitro and in vivo studies. Transfusion. 1991; 31(7): 642-647.
2. Clifford C Cloonan. Treating traumatic bleeding in a combat setting. Mil Med. 2004; 169(2):8-10. Doi: 10.7205/milmed.169.12s.8
3. Jon C Bowersox, John R Hess. Trauma and Military Applications of Blood Substitutes. Artificial Cells, Blood Substitutes, and Biotechnology. 1994;22(2):145-157. doi.org/ 10.3109/10731199409117410
4. Suman Sarkar. Artificial blood. Indian J Crit Care Med., 2008;12(3): 140-144. doi: 10.4103 /0972-5229.43685
5. Spahn DR. Artificial oxygen carriers: a new future? Crit Care Lond Engl. 2018; 22:46. https:// doi. org/ 10. 1186/ s13054- 018- 1949-5
6. La Muraglia GM, O’Hara PJ, Baker WH, Naslund TC, Norris EJ, Li J, Vandermeersch E. The reduction of the allogenic transfusion requirement in aortic surgery with a hemoglobinbased solution. J. Vasc. Surg. 2000; 31(2): 299-308. DOI: 10.1016/s0741-5214(00)90161-7
7. Kresie L. Artificial blood: An update on current red cell and platelet substitutes. Proc. Bayl. Univ. Med. Cent. 2001; 14(2): 158-161. doi: 10.1080/08998280.2001.11927754
8. Nitin B Charbe , Francisco Castillo, Murtaza M Tambuwala , Parteek Prasher , Dinesh Kumar Chellappan, Aurora Carreño, Saurabh Satija , Sachin Kumar Singh , Monica Gulati , Kamal Dua , José Vicente González-Aramundiz, Flavia C Zacconi. A new era in oxygen therapeutics? From perfluorocarbon systems to haemoglobin-based oxygen carriers. Blood Rev. 2022; 54:100927, doi:10.1016/j.blre.2022.100927
9. Daniel Farrar, Mike Grocott. Intravenous artificial oxygen carriers. Hosp. Med. 2003;64 (6):352-356. DOI: 10.12968/hosp.2003.64.6.352
10. Riess JG. Oxygen carriers (“blood substitutes”) raison d’etre, chemistry and some physiology. Chem. Rev. 2001;101(9): 2797- 2920. doi: 10.1021/cr970143c
11. Haldar R, Gupta D, Chitranshi S, Singh MK, Sachan S. Artificial blood: A fu-turistic dimension of modern-day transfusion sciences. Cardiovascular & He-matological Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry-Cardiovascular & Hematological Agents. 2019; 17(1): 11-16.
12. Mitchell P, Weiskopf R, Zapol WM. NIH/FDA/DOD interagency working group on oxygen therapeutics. Hemoglobin-Based Oxygen Carriers as Red Cell Substitutes and Oxygen Therapeutics. 2013; 141-147.
13. Amberson WR, Jennings J J, Rhode CM. Clinical experience with hemoglobin-saline solutions. J. Appl. Physiol. 1949; 1(7): 469-489.
14. Cherian VT. Physiological Functions of Blood. In Blood Substitutes and Oxygen Biotherapeutics; Springer. 2022; 33–43.
15. Cohn EJ. Blood: A brief survey of its chemical components and of their natural functions and clinical uses. Blood. 2015; 126: 2531.
16. Cohn SM. Blood substitutes in surgery. Surgery. 2000; 127(6): 599-602.
17. Brohi K, Gruen R L, Holcomb JB. Why Are Bleeding Trauma Patients Still Dying? Intensive Care Med. 2019;45(5):709–711. Doi:10.1007/s00134-019-05560-x
18. Cherkas D, Traumatic Hemorrhagic Shock: Advances in Fluid Management. Emerg. Med. Pract. 2011;13(11):1–20.
19. Chatrath V, Khetarpal R, Ahuja J. Fluid Management in Patients with Trauma: Restrictive versus Liberal Approach. J Anaesthesiol Clin. Pharmacol. 2015;31(3):308 –316. Doi:10.4103/0970-9185.161664.
20. Fahad Khan, Kunwar Singh and Mark T. Friedman. Artificial Blood: The History and Current Perspectives of Blood Substitutes. Discoveries 2020, 8(1); e104. DOI:10.15190/ d.2020.
21. Samira Moradi, Ali Jahanian-Najafabadi, Mehryar Habibi Roudkenar. Artificial Blood Substitutes: First Steps on the Long Route to Clinical Utility. Clin Med Insights Blood Disord. 2016;27(9):33-41. doi: 10.4137/CMB D.S38461
22. Mullon J, Giacoppe G, Clagett C, McCune D, Dillard T. Transfusions of polymerized bovine hemoglobin in a patient with severe autoimmune hemolytic anemia. N. Engl. J. Med. 2000; 342(22): 1638-1643.
23. Cabrales P , Intaglietta M. Blood substitutes: evolution from non-carrying to oxygen and gas carrying fluids. ASAIO J. 2013;59(4):337.
24. Shekhar C. Blood relatives: artificial oxygen carriers between promise and concern. J. Chem. Biol. 2007;10:1091–92.
25. Matton A. P. M, Burlage L. C and van Rijn R, Normothermic machine perfusion of donor livers without the need for human blood products. Liver Transplant, 2018, 24:528–538. https:// doi. org/ 10.1002/ lt. 25005.
26. Neelam S, Semwal B C, Maurya Krishna, Khatoon Ruqsana, Paswan Shravan. Artificial Blood: A tool for survival of humans. Int.Res.J.Phar. 2012; 3(5): 119-123.
27. A V More, S Y Sayyed, P G Morankar, S R Churi, S S Gawli, R A Karande, R Y Gorade. A comprehensive insight into artificial blood. Int.J.Phar. Sci and Res. 2023;14(3): 1108-1119.
28. D R Spahn , R van Brempt, G Theilmeier, J P Reibold, M Welte, H Heinzerling, K M Birck, P E Keipert, K Messmer, H Heinzerling, K M Birck, P E Keipert, K Messmer. Perflubron emulsion delays blood transfusions in orthopedic surgery. European Perflubron Emulsion Study Group. Anesthesiology.1999; 91(5): 1195-208. DOI: 10.1097/00000542-199911000-00009
29. Tinits P. Oxygen therapy and oxygen toxicity. Ann Emerg Med., 1983, 12:321–328.
30. Keipert P E. Perfluorochemical emulsions: future alternatives to transfusion. Blood Subst Princ Meth Prod Clin Trials. 1998; 2:127–156.
31. Eckstein E C, Koleski J F, Waters C M. Concentration profiles of 1 and 2.5 microns beads during blood flow. Hematocrit effects. ASAIO Trans. 1989; 35:188–190.
32. Lin Chen, Zeyong Yang, Henry Liu. Hemoglobin-Based Oxygen Carriers: Where AreWe Now in 2023? Medicina. 2023;(59): 396. https://doi.org/10.3390/ medicina59020396.
33. Vanessa R Melanson, Jeremy R Hershfield, Michael Kevin Deegan, Hyeveen Cho, Dion Perinon, Stacey L Bateman , Jason C Barnhill. Artificial Blood Development Implications for Military Medicine, J. Spec. Oper. Med., 2023 Oct 5;23(3):63-69. doi: 10.55460/OVOP-V2QC.
34. Sahu S. C, Simplaceanu V, Gong Q, Ho N. T, Glushka J. G and Prestegard J. H, Orientation of Deoxyhemoglobin at High Magnetic fields: Structural Insights from RDCs in Solution, J. Am. Chem. Soc., 2006, 128, 6290–6291. Doi:10.1021/ja060023z.
35. Yu S, Hemoglobin: Physiology and Hemoglobinopathy. In Blood Substitutes and Oxygen. Biotherapeutics. 2022; 45–51.
36. Bleeker W. K, van der Plas J, Feitsma R. I, Agterberg J, Rigter, G, de Vries-van Bowersox J. C and J R Hess, Trauma and military applications of blood substitutes. Artif cells Blood Substit Immobil Biotechnol.1994; 22 (2): 145-57.
37. Creteur J and Vincent J. L, Hemoglobin solutions. Crit. Care Med. 2003; 31(12): S698-S707.
38. Chang T. M, Red blood cell substitutes. Best Pract. Res. Clin. Haematol., 2000, 13(4), 651-667.
39. Squires J. E, Artificial blood. Science, 2002, 295(5557), 1002- 1005.
40. Baumler H, Xiong Y, Liu Z Z. Novel hemoglobin particles promising new- generation hemoglobin-based oxygen carriers. Artif Organs. 2014;38:708–714. https:// doi. org/ 10. 1111/ aor. 12331
41. Kao I, Xiong Y, Steffen A. Preclinical in vitro safety investigations of submicron sized hemoglobin based oxygen carrier HbMP-700. Artif Organs. 2018;42:549–559. https:// doi. org/ 10. 1111/aor. 13071
42. Henkel-Honke T, Oleck M. Artificial oxygen carriers: A current review. AANA J. 2007; 75(3):205-211.
43. Pape A, Habler O. Alternatives to allogeneic blood transfusions. Best Pract. Res. Clin. Anaesthesiol. 2007; 21(2): 221-239.
44. Spahn DR, Kocian R. The place of artificial oxygen carriers in reducing allogeneic blood transfusions and augmenting tissue oxygenation. Can. J. Anaesth. 2003; 50(6): S41-S47.
45. Kaneda S, Ishizuka T, Sekiguchi A, Morimoto K and Kasukawa H, Efficacy of liposome-encapsulated hemoglobin in a rat model of cerebral ischemia. Artif. Organs, 2014, 38(8), 650-655.
46. Kasper S. M, Walter M, Grüne F, Bischoff A, Erasmi H and Buzello W, Effects of a Hemoglobin-Based Oxygen Carrier (HBOC-201) on hemodynamics and oxygen transport in patients undergoing preoperative hemodilution for elective abdominal aortic surgery. Anesth. Analg., 1996, 83(5), 921-927.
47. Sakai H, Sou K, Horinouchi H, Kobayashi K and Tsuchida E. Haemoglobin-vesicles as artificial oxygen carriers: Present situation and future visions. J. Intern. Med. 2008; 263(1): 4-15.
48. Veronese F M, Pasut G. PEGylation, successful approach to drug delivery. Drug Discov. Today. 2005; 10(21): 1451-1458.
49. Agnillo F D, Chang T M. Polyhemoglobin-superoxide dismutase-catalase as a blood substitute with antioxidant properties. Nat Biotechnol.1998;16(7):667-71. Doi: 10.1038/nbt0798-667
50. Bian Y, Rong Z, Chang T. Polyhemoglobin-superoxide dismutase-catalase-carbonic anhydrase: A novel biotechnology-based blood substitute that transports both oxygen and carbon dioxide and also acts as an antioxidant. Artif. Cells Blood Substit. Immobil. Biotechnol. 2011; 39(3): 127-136.
51. Scott M G, Kucik D F, Goodnough L T, Monk T G. Blood substitutes: Evolution and future applications. Clin. Chem. 1997; 43(9): 1724-1731.
52. Jahr J S, Nesargi S B, Lewis K, Johnson C. Blood substitutes and oxygen therapeutics: An overview and current status. Am. J. Ther. 2002; 9(5): 437-443.
53. Anbari K K, Garino J P, Mackenzie C F. Hemoglobin substitutes. Eur. Spine J. 2004; 13( 1):S76-S82.
54. Takeoka S. Developmental trend of artificial blood (artificial red blood cells). Japan Med. Assoc. J. 2005; 48: 135-139.
55. Fontes P A. The evolution of oxygen carrier solutions for machine perfusion. Transplantation, 2017; 101(11): 2657-2658.
56. Hill, S.E. Oxygen therapeutics-current concepts. Can. J. Anaesth., 2001, 48(4) (Suppl.), S32-S40.
57. Kim HW, Greenburg A G. Artificial oxygen carriers as red blood cell substitutes: A selected review and current status. Artif. Organs. 2004; 28(9): 813-828.
58. Faithfull N S. Oxygen delivery from fluorocarbon emulsions—aspects of convective and diffusive transport. Biomaterials, artificial cells, and immobilization biotechnology: official journal of the International Society for Artificial Cells and Immobilization Biotechnology. 1992;20: 797–804.
59. Keipert P E, Faithfull N S, Roth D J, Bradley J D, Batra S, Jochelson P, Flaim K E. Supporting tissue oxygenation during acute surgical bleeding using a perfluorochemical-based oxygen carrier. Adv Exp Med Biol. 1996; 388:603–609.
60. Honda K, Hoshino S, Shoji M, Usuba A, Motoki R, Tsuboi M, Inoue H, Iwaya F. Clinical Use of a Blood Substitute. N Engl J Med. 1980; 303(7):391-2.
61. Mitsuno T, Ohyanagi H, Naito R. Clinical Studies of A Perfluorochemical Whole Blood Substitute (Fluosol-DA). Ann Surg. 1982;195(1):60–9.
62. Riess JG. Perfluorocarbon-based Oxygen Delivery. Artif Cells Blood Substit Biotechnol. 2006;34(6):567–80.
63. Hong F, Shastri K. A, Logue G L, Spaulding M B. Complement activation by artificial blood substitute Fluosol: In vitro and in vivo studies. Transfusion. 1991; 31(7): 642-647.