Hemoglobin-Based Oxygen Carriers: Where Are We Now in 2023?

Abstract

The pursuit for blood a substitute has spanned over a century, but a majority of the efforts have been disappointing. As of today, there is no widely accepted product used as an alternative to human blood in clinical settings with severe anemic condition(s). Blood substitutes are currently also termed oxygen therapeutics. There are two major categories of oxygen therapeutics, hemoglobin-based and perfluorocarbon-based products. In this article, we reviewed the most developed but failed products and products still in active clinical research in the category of hemoglobin-based oxygen carriers. Among all of the discussed hemoglobin-based oxygen therapeutics, HemAssist, PolyHeme, Hemolink, Hemospan, and Hemoximer were discontinued. Hemopure is in clinical use in South Africa and Russia. Oxyglobin, the sister product of Hemopure, has been approved for veterinary use in the European Union and the United States. HemO2life has recently been approved for organ preservation in organ transplantation in the European Union. OxyVita and Sanguinate are still undergoing active clinical studies. The field of oxygen therapeutics seems to be entering a phase of rapid growth in the coming 10–20 years.

Research Progress in Oxygen Carrier Design and Application

“…Based on this, attempts have been made to use reagents such as 2-iminothiolane to introduce thiols at the terminal amino residues and surface lysines to achieve MAL-PEG conjugation at noncysteine residues. A series of products based on this PEGylation approach have been successfully developed for preclinical animal studies, such as Hemospan (discontinued 24 ), Euro-PEG-Hb, 25 and Sanguinate. 26,27 However, this approach presents two great challenges: (1) Different protein sites react with different efficiencies, and the degree of PEGylation at these residues varies, resulting in very high heterogeneity of the final product; (2) The introduced thiol-reactive sites are often at the α/β dimer interface, resulting in a higher oxygen affinity compared to native Hb, which in turn limits oxygen release.…”

“…Based on this, attempts have been made to use reagents such as 2-iminothiolane to introduce thiols at the terminal amino residues and surface lysines to achieve MAL-PEG conjugation at noncysteine residues. A series of products based on this PEGylation approach have been successfully developed for preclinical animal studies, such as Hemospan (discontinued), Euro-PEG-Hb, and Sanguinate. , …”

OMX: A Novel Oxygen Delivery Biotherapeutic Improves Outcomes in an Ovine Model of Controlled Hemorrhagic Shock

“…While no PFOC has yet gained Food and Drug Administration approval to date due to adverse events and clinical challenges, third-generation products are in preclinical development (9,(12)(13)(14)(15)(16)(17). HBOCs, on the other hand, contain human-or animal-derived Hb or recombinant Hb, frequently chemically modified through polymerization, cross-linking, conjugation, or encapsulation to overcome free Hb-induced toxicity, reduce nitric oxide (NO) scavenging, and increase half-life (18). Second-generation products were limited by inadequate O 2 delivery and associated oxidative stress along with NO scavenging, resulting in tissue injury, increases in vascular resistance, and suboptimal microcirculatory blood flow (3,9,(19)(20)(21), However, one product, HemopureⓇ (HBOC-201), was approved over 20 years ago for the treatment of anemia in South Africa and remains in use (22), and eligible patients with severe life-threatening anemia have access to HBOC-201 under the FDA's expanded compassionate use access program (13).…”

“…Second-generation products were limited by inadequate O 2 delivery and associated oxidative stress along with NO scavenging, resulting in tissue injury, increases in vascular resistance, and suboptimal microcirculatory blood flow (3,9,(19)(20)(21), However, one product, HemopureⓇ (HBOC-201), was approved over 20 years ago for the treatment of anemia in South Africa and remains in use (22), and eligible patients with severe life-threatening anemia have access to HBOC-201 under the FDA's expanded compassionate use access program (13). In addition, there are a number of third-generation HBOCs in development, which are modified to address issues seen with the earlier candidates and are reviewed extensively elsewhere (9,11,13,18).…”

Renal glomerular and tubular responses to glutaraldehyde- polymerized human hemoglobin

“…HBOCs have also shown promise as oxygen-carrying perfusates in organ preservation settings (3,4). Most HBOCs are manufactured from expired human or animal blood starting with the extraction and purification of Hb from RBCs, followed by 10.3389/fmed.2023.1158359 various protein modification strategies designed to stabilize the acellular Hb in circulation and/or maintain its oxygen transport properties (2,5,6). Despite significant progress over many years, unresolved safety issues continue to impede the development and licensure of these therapeutics in the United States.…”