Chemically modified and recombinant hemoglobin blood substitutes

Several intramolecularly cross-linked hemoglobins having properties useful as blood substitutes have been developed. At least one of these, HbXL99 alpha, is amenable to large-scale production. This hemoglobin, and perhaps other cross-linked derivatives as well, is sufficiently heat stable to achieve complete viral inactivation. This makes it possible to use human blood as a starting material. Preliminary studies on the use of HbXL99 alpha to perfuse the heart during coronary angioplasty appear promising (Rossen et al. 1987). For large-volume blood replacement, a derivative having a longer intravascular retention time would be desirable. The development of more selective cross-linking agents for the polymerization of hemoglobin would be useful for this purpose. The expression of human hemoglobin in E. coli (Nagai and Thogersen 1984, 1987; Hoffman et al. 1989) and in transgenic mice (Behringer et al. 1989; Ryan et al. 1990) has been achieved. The E. coli system should prove useful for the design of hemoglobin mutants having specifically tailored properties for use as blood substitutes. Adequate supplies of donated blood will likely be available for at least the next decade for the production of chemically modified hemoglobin derivatives. If the supply of human blood later becomes limiting, large-scale production of human hemoglobin should be feasible in transgenic pigs or cows. The economics of this process could be enhanced by producing other blood proteins of commercial value, e.g., human albumin and factor VIII, in the same animal.