Artificial oxygen carriers: lessons from hemoglobin-based oxygen carrier clinical trials and current development efforts

The clinical benefit of blood transfusion is undeniable, and yet reliance on donated blood products has several shortcomings. These include risks of supply shortages due to reliance on volunteer donors, short storage life, and potential infectious disease transmission. Immune response complications to donated blood cannot be completely avoided, even despite significant advances in testing. Many of these limitations are exacerbated in low-income countries. For decades, cell-free hemoglobin-based blood substitutes have been developed and tested as potential substitutes for red blood cell transfusions. Early studies found that purified, native Hb exhibited significant safety risks, such as hypertension from excessive vasoconstriction and evidence of multiple organ toxicities. These effects are likely in part due to the reactive heme center, that will scavenge nitric oxide, generate reactive oxygen species, and may drive sterile inflammation. Numerous strategies have been explored to further modify hemoglobin in the hope of creating a safe and well-tolerated blood substitute. Despite some promising results in preliminary studies, large-scale clinical trials have continued to show elevated rates of adverse events and/or a failure to meet specified clinical endpoints. As a result, no hemoglobin-based oxygen carrier (HBOC) has obtained US FDA approval for clinical use. This review focuses on the history of hemoglobin-based oxygen carrier development, the lessons that have been learned from prior failures of HBOC programs, and the status of ongoing artificial oxygen carrier development efforts.