Doctor of Philosophy, The Ohio State University, 2011, Chemical and Biomolecular Engineering

Blood transfusion can be compromised by a number of physiological and practical issues such as the risk of contracting infectious diseases, initiation of harmful immunological responses, the red blood cell (RBC) storage lesion and the shrinking availability of RBCs. Thus, there is a need to develop safe and efficacious O2 carriers for use in transfusion medicine as RBC substitutes in order to maintain proper tissue and organ oxygenation. Hemoglobin (Hb) is the most prevalent protein inside the RBC and is the natural carrier of O2 in vivo. Therefore, Hb-based O2 carriers (HBOCs) are considered as good candidates for RBC substitutes. Currently, HBOCs can be manufactured by conjugation of molecules to the surface of Hb, encapsulation of Hb inside particles, site-directed mutagenesis of Hb and cross-linking/polymerizing Hb. Among these approaches, polymerization of human or bovine Hb with the difunctional cross-linking reagent glutaraldehyde represents a simple strategy to synthesize HBOCs. In fact, the two commercial polymerized Hb (PolyHb) products Hemopure® (glutaraldehyde polymerized bovine Hb, OPK Biotech, Cambridge, MA) and PolyHeme® (pyridoxalated glutaraldehyde polymerized human Hb, Northfield Laboratories Inc., Evanston, IL), which have failed Phase III clinical trials, are based on this approach. These commercial PolyHb solutions face serious safety issues including the induction of vasoconstriction in the microcirculation and the development of systemic hypertension. These side-effects are due to the existence of the Hb tetramer or αβ dimer in the blood, which subsequently extravasate through the blood vessel wall and scavenge the vasodilator nitric oxide (NO) or trigger an autoregulatory response of the blood vessel to reduce the oversupply of O2 to surrounding tissues. Therefore, the goal of this research is to synthesize a new generation of HBOCs with fewer side-effects, longer circulation lifetime in the blood and better oxygenation potential. In this (open full item for complete abstract)

Committee: Andre Palmer Dr. (Advisor); Shang-Tian Yang Dr. (Committee Member); Jeffrey Chalmers Dr. (Committee Member); Robert Gustafson Dr. (Committee Member) Subjects: Chemical Engineering