Precision Oxygen Therapeutics: From Blood Substitutes to the Biological Hemoglobin Oxygen Carrier (BHOC) Framework for Controlled Microvascular and Tissue-Level Oxygen Delivery

The development of hemoglobin-based oxygen carriers (HBOC) has historically been guided by the need for autologous blood stores and for the reduction of blood transfusion for kidney dialysis patients. It was to be a temporary blood replacement or a "blood substitute". That terminology is physiologically and contextually incomplete: blood (as an organ system) is a complex biological system, whereas oxygen transport and delivery are specific functions that can be investigated, measured, and therapeutically supported. By 1990 the autologous blood programs were determined to be ineffective for supporting oxygen delivery and the FDA approved erythropoietin drastically reduced the need and risk exposure for blood transfusions in the dialysis patient population. By the mid-1990s, the field of HBOC blood replacements/substitutes was already moving toward recognition of the systems-physiological immediate need for oxygen delivery, a requirement for metabolic support. The unmet medical need for controlled, “immediate” oxygen delivery was created as an outgrowth further identified due to many applied physiological discoveries that were associated and related to ischemia and ischemic reperfusion. Thus, the opportunity for "oxygen therapeutics" was born. The subsequent physiological and clinical experience has reinforced the importance understanding the actions of hemoglobin types and states, purity, and stability, while also clearly demonstrating that broad measures such as “hemoglobin concentration or level” and arterial oxygen saturation are imprecise and inadequate indicators of time sensitive metabolic support. Blood flow, microvascular distribution, oxygen affinity and unloading, vascular signaling, diffusion, metabolic demand, and temperature are increasingly recognized as critical determinants for adequate perfusion and reproducible positive clinical outcomes. From the voluminous preclinical and clinical work, we strongly believe that Precision Oxygen Therapeutics must be defined in an appropriate and translational guidance concerned with the real-time measurement, regulation measures, and metabolic support of oxygen delivery according to physiological and systemic biological demand. Within this structure, we define a Biological Hemoglobin Oxygen Carrier (BHOC) as a biologically derived or biologically engineered hemoglobin-mediated oxygen-delivery material or therapeutic whose molecular composition and formulation, oxygen-binding and unloading characteristics, pharmacology, vascular interactions, redox behavior, and manufacturing attributes can be quantitatively characterized and reproducibly controlled within a structured GMP framework. BHOC is not proposed as a replacement for the historically established classification HBOC or the more general term oxygen carrier (OC). With the expanding volume of continuously recorded physiological data, Precision Oxygen Therapeutics may now be considered an additional biological tool within the evolving field of transfusion medicine. The guidance shifts the scientific question from whether a practice "replaces blood" to how an intervention can support oxygen-delivery function at the appropriate physiological location, intensity, and duration while maintaining acceptable vascular and systemic safety and integrity. This Perspective suggests relevant terminology, positions its development in historical context, and outlines a testable research agenda for microvascular and tissue-level oxygen delivery.