Crosslinked, polymerized, and PEG-conjugated hemoglobin-based oxygen carriers: clinical safety and efficacy of recent and current products.

Blood substitutes, especially hemoglobin based oxygen carriers (HBOC) have been widely studied and reviewed over the past 30 years. The development of HBOCs was highlighted by crosslinking to minimize adverse effects. However, even early attempts at single crosslinking using alpha-alpha crosslinks or diaspirin crosslinking failed clinical trials due to renal morbidity and increased mortality. In fact, preclinical trials may have predicted failure of this first generation product, DCLHb (diaspirin-crosslinked Hb) (HemAssist ®, Baxter). In the 1980's, three small biopharmaceutical companies developed "second generation" HBOCs, the first being Hemosol with their raffinose crosslinked HBOC, hemoglobin- raffimer. The other two development programs modified the HBOC using glutaraldehyde polymerization, in an attempt to further alleviate the toxicities of the "first" generation HBOCs. This paper will review the definitive clinical trials of the two polymerized HBOCs, Biopure's hemoglobin glutamer-250 (bovine) and Northfield's polymerized human Hb, pegylated HBOC and Sangart's peg-conjugated HBOC, with an introductory brief review of Hemosol's hemoglobinraffimer. The paper will then introduce the newest polymerized hemoglobin, zero-linked hemoglobin polymer, which has not yet undergone clinical trials but has undergone some preclinical work that will be discussed in a section on this product. As a new generation HBOC, zero-linked hemoglobin polymer may begin to address the issues presented by the first two generations of HBOCs, and may hold promise as a universally applicable HBOC.