Zero-link hemoglobin (OxyVita®): Impact of molecular design characteristics on pre-clinical studies

Abstract

Zero-link Hb (OxyVita®, OXYVITA, Inc., New Windsor, New York), a new generation hemoglobin-based-oxygen-carrier (HBOC), is produced using a modified zero-linked polymerization mechanism that employs chemical activators to incorporate inter-dimerically cross-linked bovine hemoglobin tetramers into super-polymeric macromolecules (Average M. wt. = 17 MDa) for oxygen delivery when whole blood or packed red cells are not available. This molecular design pathway was developed to address several basic biochemical and physiological concerns associated with earlier generations of HBOCs. Observations made during pre-clinical (various animal models) and clinical studies provided evidence these earlier generation acellular HBOCs gave evidence of reduced retention times within the circulatory system, extravasation across endothelial tissue membranes due to their small molecular size leading to arterial and veinous vasoconstriction that was coupled with rapid increases in mean arterial pressure (MAP) upon infusion. Zero-link Hb's increased molecular size and structural stability was developed in direct response to these serious concerns that accompanied the evolution of HBOC development within the past several decades. The distinct nature of the zero-linked synthetic route eliminates the need for chemical linkers within the product, eliminates side reaction concerns: such as reversibility and decomposition due to weak and non-specific chemical bonding, changes in temperature and/or pressure within the circulatory system, and residual toxicity. The incorporation of these molecular design characteristics within OxyVita Hb have been responsible for significant findings as determined by the pre-clinical studies that have been carried out by many independent investigators between 2002 to 2012. This chapter will present: (1) a short overview of previous generation HBOCs; (2) the experimental development of OxyVita Hb (liquid and powder forms); (3) the physiochemical properties and functional behavior of OxyVita Hb; and (4) the implications of the molecular design properties for pre-clinical studies that involved issues of extravasation and vasoconstriction, increases in MAP, regulation of oxygen delivery, and effects on coagulatory functions.