Synthetic oxygen carriers as substitutes of red blood cells for blood transfusion.

The search for an efficacious blood substitute has remained a persistent challenge for more than a century. Despite extensive efforts to develop synthetic oxygen carriers, no broadly approved alternative to human blood has yet been realized. In this review, we first provide an overview of the historical development and repeated failures of artificial blood substitutes, while highlighting the continuing clinical demand for transfusion alternatives. We then discuss recent setbacks in blood substitute development, particularly adverse events observed in human trials. Current research efforts with goals to improve biocompatibility are further examined, with a particular focus on oxygen-carrying micro-/nano-particles, emerging fabrication technologies, and unmet clinical needs. Hemoglobin-based cellular and acellular oxygen carriers, as well as novel non-hemoglobin-based systems, are reviewed in detail with emphasis on technical innovations and biological advances. Finally, future development in the field was briefly envisioned to shed light on the rational design and versatile applications of safe and efficient oxygen carriers.