Currently, there is a shortage in the number of red blood cell (RBC) units available for blood transfusions. Donated human red blood cells (currently the only source for these transfusions) do not adequately meet current demands and are unlikely to meet future demands. For example, in the United States, 14 million red blood cell units are made available for transfusions each year, and an annual deficit of 1 million units still exists. Internationally, the deficit is around 200 million units annually. In the future, these deficits may become even more severe, as the current deficit projections do not take into account the more acute need for blood in cases of mass civilian casualties, such as natural disasters, terrorist attacks and wars.
The shortage in red blood cell units and the lack of suitable substitutes results in many preventable deaths. For example, more than 530,000 women die each year during pregnancy or childbirth, with hemorrhage being the leading cause of death (accounting for up to 44% of maternal deaths in some areas of sub-Saharan Africa). Many of these deaths could be prevented with the proper supply of red blood cell units or with a proper substitute for red blood cell transfusions.
While the current deficits are in part due to a shortage in the number of blood donors, a number of other factors also contribute to the current crisis. Several of these factors relate to the pool of available donated human red blood cells being limited by existing obstacles to safe transfusion. For example, red blood cell units may carry infectious diseases and many multi-level proactive interventional programs of stringent red blood cell donor screening and expensive nucleic acid testing procedures have been implemented to protect recipients. With each new emerging disease, new diagnostic tests are performed, further limiting the available donor pool and further increasing costs. In addition, donated human red blood cells contain proteins and cytokines that may cause reactions in up to 2% of transfusions with symptoms ranging in severity from mild allergic reactions to severe shock and even death. Also, red blood cell transfusions may lead to various metabolic conditions (e.g. hyperkalemia, hypocalcemia and alkalosis), and multiple red blood cell transfusions may exert an immunosuppressive effect on the recipient, increasing risk of hospital-acquired infections.1 These potential complexities further increase costs associated with donor red blood cell transfusions.
In addition to the above-mentioned obstacles to safe transfusion, costs are also increased due to requirements for cross-matching donor and recipient red blood cell units before transfusion, as well as the short storage life (typically 15 days) and expensive storage requirements (e.g., must be kept at 2-3° C., special storage solutions are required to extend red blood cell life to 42 days, etc.) of red blood cell units.2 While there have been many recent improvements in technology, the collection and storage of donated red blood cells remains a difficult and expensive task. There is a need for a less expensive and more effective alternative to donated human red blood cell transfusions.
A list of publications referenced in this disclosure follows, each of which is incorporated by reference for the cited portions of their respective disclosures:    1. L. M. Napolitano, Crit. Care Clin, 25: 279-301 (2009).    2. W. J. Williams, E. Beutler, A. J. Erslev, R. W. Rundles, Hematology. McGraw-Hill Book Company, New York (1977).    3. T. Standl, Transfus. Med. Hemother., 21: 262-268 (2004).    4. A. I. Alayash, Nature, 3: 152-159 (2004).    5. T. M. S. Chang, Crit. Care Med., 32: 612-613 (2004).    6. B. T. Kjellstrom, J. Intern. Med., 253: 495-497 (2003).    7. Y. O. Schumacher, M. Ashenden, Sports Med., 34: 141-150 (2004).    8. K. C. Lowe, E. Ferguson, J. Intern. Med., 253: 498-507 (2003).    9. H. G. Klein, Oncology, 16: 147-151 (2002).    10. S. E. Hill, Can. J. Anesth., 48: S32-S40 (2001).    11. R. M. Winslow, J. Intern. Med., 253: 508-517 (2003).    12. E. Niiler, Nature Biotechnol., 20: 962-963 (2002).    13. E. Maevsky, G. Ivanitsky, L. Bogdanova, O. Axenova, N. Karmen, E. Zhiburt, R. Senina, S. Pushkin, I. Maslennikov, A. Orlov I. Marinicheva, Art. Cells, Blood Subs., and Biotech., 33: 37-46 (2005).    14. P. E. Keipert, Adv. Exp. Med. Biol., 540: 207-213 (2003).    15. C. P. Stowell, Curr. Opin. Hematol., 9: 537-543 (2002).    16. J. G. Riess, Chem. Rev., 101: 2797-2919 (2001).    17. A. S. Rudolph, A. Sulpizio, P. Hieble, V. MacDonald, M. Chavez, G. Feuerstein, J. Applied Phys., 82: 1826-1835 (1997).    18. E. Moore, J. Am. Coll. Surgeons, 196: 1-17 (2003).    19. T. M. S. Chang, Trends Biotechnol., 17: 61-67 (1999).    20. H. Sakai, K. Tomiyama, K. Sou, S. Takeoka, E. Tsuchida, Bioconjugate Chem., 11: 425-432 (2000).    21. W. T. Phillips, R. W. Klipper, V. D. Awasthi, A. S. Rudolph, R. Cliff, V. Kwasiborski, B. A. Goins, J. Pharmacol. Exp. Ther., 288: 665-670 (1999).    22. R. O. Wright, B. Magnani, M. W. Shannon, A. D. Woolf, Ann. of Emergency Med., 28: 499-503 (1996).    23. Y. Teramura, H. Kanazawa, H. Sakai, S. Takeoka, E. Tsuchida, Bioconjugate Chem., 14: 11711176 (2003).    24. S. Takeoka, H. Sakai, T. Kose, Y. Mano, Y. Seino, H. Nishide, E. Tsuchida, Bioconjugate Chem., 8: 539-544 (1997).    25. R. M. Winslow, Drug Delivery Rev. 40: 131-142 (2000).    26. R. M. Winslow, Annu. Rev. Med. 50: 337-353 (1999).    27. T. M. S. Chang, Crit. Care Med. 32: 612-613 (2004).    28. T. M. S. Chang, Curr. Opin. Invest. Drugs, 3: 1187-1190 (2002).    29. H. Sakai, S. Takeoka, S. I. Park, T. Kose, H. Nishide, Y. Izumi, A. Yoshizu, K. Kobayashi, E. Tsuchida, Bioconjugate Chem., 8: 23-30 (1997).    30. M. C. Farmer, B. P. Gaber, Methods Enzymol. 149: 184-200 (1987).    31. A. S. Rudolph, R. W. Klipper, B. A. Goins, W. T. Phillips, Proc. Natl. Acad. Sci. U.S.A. 88: 097610980 (1991).    32. D. Bhadra; S. Bhadra; P. Jain; N. K. Jain, Pharmazie, 57:5-29 (2002).    33. H. Sakai; A. G. Tsai; S. I. Park, S. Takeoka, H. Nishide, E. Tsuchida; M. Intaglietta, J. Biomed. Mater. Res. 40: 66-78 (1997).    34. K. Nakai, A. Usuba, T. Ohta, M. Kuwabara, Y. Nakazato, R. Motoki, T. A. Takahashi, Artif. Organs 22: 320-325 (1998).    35. M. Antonietti, S. Forster, Adv. Mater. 15: 1323-1333 (2003).    36. W. T. Phillips, R. W. Klipper, V. D. Awasthi; A. S. Rudolph; R. Cliff, V. Kwasiborski, B. A. Goins, J. Pharmacol. Exp. Ther. 288: 665-670 (1999).    37. S. M. Moghimi, J. Szebeni, J. Prog. Lipid Res. 42: 463-478 (2003).    38. B. M. Discher, Y. Y. Won, D. S. Ege, J. C. Lee, F. S. Bates, D. E. Discher, D. A. Hammer, Science 284: 1143-1146 (1999).    39. P. P. Ghoroghchian, G. Li; D. H. Levine, K. P. Davis, F. S. Bates, D. A. Hammer, M. J. Therien, Macromolecules 39(5): 1673-1675 (2006).    40. J. M. Lee, H. Bermudez, B. M. Discher, M. A. Sheehan, Y. Y. Won, F. S. Bates, D. E. Discher, Biotechnol. and Bioengg. 73(2): 135-145 (2001).    41. G. P. Robbins, M. Jimbo, J. Swift, M. J. Therien, D. A. Hammer, I. J. Dmochowski, J. Am. Chem. Soc. 131 (11): 3872-3874 (2009).    42. S. M. Moghimi, A. C. Hunter, J. C. Murray, Pharmacol. Rev. 53:283-318 (2001).    43. H. Otsuka, Y. Nagasaki, K. Kataoka, Adv. Drug Delivery Rev. 55: 403-419 (2003).    44. C. Allen, J. N. Han, Y. S. Yu, D. Maysinger, A. Eisenberg, A. J. Controlled Release 63: 275-286 (2000).    45. V. R. Sinha, K. Bansal, R. Kaushik; R. Kumria, A. Trehan, Int. J. Pharm. 278: 1-23 (2004).    46. Y. Y. Won, A. K. Brannon, H. T. Davis, F. S. Bates, J. Phys. Chem. B 106: 3354-3364 (2002).    47. H. Bermudez, A. K. Brannan, D. A. Hammer, F. S. Bates, D. E. Discher, Macromolecules 35: 8203-8208 (2002).    48. P. J. Photos, L. Bacakova, B. Discher, F. S. Bates, D. E. Discher, J. Contr. Release 90: 323-334 (2003).    49. D. E. Discher, A. Eisenberg, Science 297: 967-973 (2002).    50. D. R. Arifin, A. F. Palmer, Biotechnol. Prog. 19: 1798-1811 (2003).    51. D. R. Arifin, A. F. Palmer, Biomacromolecules 6 (4): 2172-2181 (2005).    52. S. Rameez, H. Alosta, A. F. Palmer, Bioconjugate Chem. 19:1025-1032 (2008).    53. J. Zupancich, F. S. Bates, M. A. Hillmyer, Macromolecules 39:4286-4288 (2006).    54. H. Jansson, J. Swenson, J. Chem. Phys 128: 245104: 1-7 (2008).    55. H. Sakai, A. Sato, K. Masuda, S. Takeoka, E. Tsuchida, J. Biol. Chem. 283 (3): 1508-1517 (2008).    56. K. Nakai, T. Ohta, I. Sakuma, K. Akama, Y. Kobayashi, S. Tokuyama, A. Kitabatake, Y. Nakazato, T. A. Takahashi, S. Sekiguchi, J. Cardiovasc. Pharmacol. 28: 115-123 (1996).    57. H. Sakai, K. Hamada, S. Takeoka, H. Nishide, E. Tsuchida, Polymer Adv. Technol. 7: 639-644 (1996).    58. S. Kaneda, T. Ishizuka, H. Goto, T. Kimura, K. Inaba, H. Kasukawa, Artificial Organs 33(2):146-152 (2009).    59. H. Sakai, A. Sato, P. Sobolewski, S. Takeoka, J. A. Frangos, K. Kobayashi, M. Intaglietta, E. Tsuchida, Biochim. et Biophys. Acta 1784: 1441-1447 (2008).    60. S. Usami, H. H. Chen, Y. Zhao, S. Shien, R. Skalak, Ann. Biomed. Eng., 21, 77-83 (1993).    61. D. K. Brunk, D. A. Hammer, Biophys J. 72: 2820-2833 (1997).    62. O. S. Finikova, A. Y. Lebedev, A. Aprelev, T. Troxler, F. Gao, C. Garnacho, S. Muro, R. M. Hochstrasser, S. A. Vinogradov, Chemphyschem. 9(12):1673-1679 (2008).    63. S. Sakadzi, S. Yuan, E. Dilekoz, S. Ruvinskaya, S. A., Vinogradov, C. Ayata, D. A. Boas, Appl Opt. 48(10): D169-77 (2009).