Development of non-extravasating hemoglobin-based oxygen carriers

The availability of a variety of cell-free oxygen carriers (DBBF-BvHb, DECA, ZL-HbBv) and of diverse animal models (kidney function and lymph content, cranial windows, microsphere technology) produces a wealth of information which may help to solve the problems posed in the development of cell-free hemoglobin-based oxygen carriers. This chapter illustrates a systematic approach to the problem of optimal oxygen affinity and molecular size that was undertaken to include a study with "tetrameric" and polymerized hemoglobins with different properties and sizes. The different molecules were characterized and then tested in a variety of animal models. The research group concluded that prevention of extravasation is of paramount importance, postulateing that in the interstitial space hemoglobin could very efficiently scavenge NO, a natural vasorelaxant, resulting in hypertension. They also concluded that cell-free hemoglobin, regardless of P50, is highly efficient at delivery of oxygen to vessel walls because of its participation in facilitated diffusion, and can produce vasoconstriction independently of NO scavenging. However, they postulated that this is a separate mechanism that does not produce hypertension. A very interesting product of this research is "zero-linked" hemoglobin, so called because it results from direct polymerization of surface amino acids rather than the use of crosslinking agents. This product has a very large molecular volume and high oxygen affinity. It is a very useful model compound to explore important physical properties and their effect on biological reactivity.