Hemoglobin (Hb)-based oxygen (O2) carriers (HBOCs) are currently being developed as red blood cell (RBC) substitutes for use in transfusion medicine. Despite significant commercial development, recent late stage clinical results of polymerized hemoglobin (PolyHb) solutions (i.e. Hemopure? (OPK Biotech, Cambridge, MA), a glutaraldehyde polymerized bovine Hb; and PolyHeme? (Northfield Laboratories Inc., Evanston, IL), a glutaraldehyde polymerized pyridoxylated human Hb) hamper further development. Both of these commercial products elicit vasoconstriction at the microcirculatory level, and lead to the development of systemic hypertension and oxidative tissue damage. These side-effects are hypothesized to occur either by a nitric oxide (NO) scavenging or oxygen (O2) oversupply mechanism and are both exacerbated by PolyHb extravasation into the tissue space. In light of these 2 potential mechanisms, it is apparent that PolyHb size will have a profound impact on the extent of vasoconstriction, systemic hypertension and oxidative tissue toxicity. Therefore in this application, we hypothesize that PolyHb size will regulate vasoconstriction at the microcirculatory level, systemic hypertension and tissue oxidative damage. In order to test this hypothesis, we plan to synthesize several PolyHbs of varying size in the low O2 affinity state by cross-linking/polymerizing bovine Hb using the cross-linking agent glutaraldehyde. In order to test the central hypothesis of this application, we propose 3 specific aims:
Specific Aim 1 : Analyze the role of endothelial function on the development of oxidative tissue injury to PolyHbs of varying size.
Specific Aim 2 : Analyze cardiac function in the presence of PolyHbs of varying size.
Specific Aim 3 : Evaluate the ability of PolyHb to restore perfusion and oxygenation after resuscitation from hemorrhagic shock. The proposed work is both significant and innovative, since it seeks to develop safe and efficacious PolyHbs for use in transfusion medicine. In addition, state-of-the-art biophysical techniques and two unique animal models will be used to understand PolyHb physiological responses and determine the clinical potential of these novel materials.
The U.S. blood supply is at risk due to the presence of emerging infectious diseases. In order to preserve the blood supply and protect the population, this application seeks to develop novel oxygen carrying solutions consisting of polymerized hemoglobins that are safe and efficacious by screening these materials using an animal model with similar antioxidant status to humans.
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