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.

Background: Severe hemorrhage simultaneously compromises circulating volume, hemostasis, red-cell oxygen-carrying capacity, and tissue oxygen delivery. Fresh whole blood can restore several of these functions and remains the biological reference for hemorrhagic shock resuscitation when promptly available. Military medicine and emergency medical services (EMS), however, increasingly face scenarios in which these functions require support before appropriate blood products and surgical care can reach the patient. Objective: This Perspective examines the transition from unit-based blood replacement toward function-based resuscitation, with particular attention to prolonged casualty care, contested evacuation, drone-dominated warfare, strategic blood readiness, hemostatic technologies, oxygen-delivery therapeutics, and fieldable delivery systems. Evidence framework: Peer-reviewed military, trauma, transfusion, and oxygen-carrier literature was considered alongside Joint Trauma System guidance and official U.S. Department of Defense, U.S. Army, NATO, DARPA, FDA, Congressional, and Government Accountability Office documents. This is a narrative and translational Perspective, not a systematic review. Perspective: During the twentieth century, military trauma systems progressively compressed injury-to-surgical-care intervals from approximately 6-12 hours during World War II to 2-4 hours in Korea and approximately one hour during Vietnam [3]. During Afghanistan, implementation of the U.S. Department of Defense Golden Hour policy reduced median helicopter transport time in a large cohort from 90 to 43 minutes [6]. The operational assumption is now being challenged. Contemporary large-scale combat operation planning anticipates delayed or denied evacuation [10-17]. Ukrainian experience documents prolonged casualty care lasting 24 hours to multiple days, while drone saturation has displaced evacuation and surgical nodes farther from the contact line and increased the proportion of casualties arriving after prolonged intervals [10,11]. NATO has described the emerging transition from the “Golden Hour” toward a “Golden Day” in drone-contested environments [12]. U.S. requirements extend further: current Army planning discusses a 72-hour expectation, U.S. Marine Corps standards include capability beyond 96 hours for selected personnel, and USSOCOM research requirements seek far-forward solutions capable of supporting 3-5 patients for at least 5-7 days [13,16,17]. These changes redefine the engineering problem. The objective is no longer solely to move casualties rapidly toward advanced medical capability. Increasingly, therapeutic capability must move toward the casualty, remain available during prolonged holding and transport, and function with minimal infrastructure, personnel burden, weight, volume, and cold-chain dependence. Military medical research increasingly reflects this functional architecture. DARPA’s FSHARP program separated critical blood functions including oxygen delivery, hemostasis, and volume support [29]. Its 2026 RAPIID program explicitly advances “shelf-stable” oxygen carriers, platelet-derived products, and dried plasma toward clinical trials, regulatory authorization, scale manufacturing, and field deployment [31]. DARPA’s GOLDEVAC program independently explores automated prolonged resuscitation and oxygenation through a single intravascular interface extending from near the point of injury through evacuation [30]. Authors’ perspective: Next-generation far-forward oxygen therapeutics should be evaluated by both molecular oxygen-carrying performance and operational delivery architecture: shelf stability, compact form factor, minimal preparation, closed delivery, monitored administration, compatibility with clinically practical vascular access, flexibility during transport, and limited dependence on gravity-fed infusion systems. Within this framework, BHOC (Biological Hemoglobin Oxygen Carrier) is proposed as a candidate component of Precision Oxygen Therapeutics. Its intended function is oxygen transport and delivery under defined conditions, rather than replacement of the broader functions of whole blood. A proposed BHOC treatment protocol would pair a characterized biological oxygen carrier with a compact cartridge-based, controlled-delivery system. This concept requires independent physicochemical, engineering, preclinical, regulatory, and clinical validation. Conclusion: The central scientific question is changing from “How do we replace blood?” to “Which biological function is failing, how long must that function be supported, and how can it reach the point of casualty before appropriate definitive blood therapy becomes available?” This transition may define the next phase of military resuscitation, civilian EMS, and Precision Oxygen Therapeutics.

Biopure Corporation’s emergency and military program was not initially conceived to develop another transfusion product. Over more than a decade, its development focused on a distinct operational challenge: how can oxygen-carrying support be made available early enough for severely bleeding casualties when conventional donor red blood cells cannot be obtained, arrive too late, are difficult to transport, or cannot be properly maintained near the point of injury? Surviving government, congressional, scientific, and corporate records trace a clear progression. It begins with military blood-logistics concerns in the late 1990s, followed by an explicit U.S. congressional requirement for room-temperature-stable hemoglobin oxygen carriers shortly before September 11, 2001. After the attacks, the work expanded into emergency-readiness deliberations and U.S. Army trauma research funding, culminating in a formal U.S. Navy clinical-development program named Restore Effective SUrvival in Shock - RESUS. These records matter because they reveal a shift away from blood-replacement logistics toward understanding the physiology and practical delivery of oxygen during hemorrhagic shock. By the program’s later stages, the research scope extended beyond oxygen-carrying capacity alone to include vasoactivity, nitric-oxide biology, formulation engineering, and multifunctional resuscitation.

Background. The Naval Medical Research Center and Biopure Corporation developed the proposed Restore Effective SUrvival in Shock (RESUS) trauma trial of HBOC-201. A military research agreement, a planned field contingency, an investigational new drug application and permission to start a trial represent different steps. This review examines what the public record establishes about each step. Methods. We reviewed selected public records from 2003 to 2008: the RESUS agreement and amendment, a Department of Defense budget justification, an FDA advisory meeting notice and contemporaneous Biopure filings with the US Securities and Exchange Commission. We classified each action by actor, date and documented status. This is a focused historical review, not a systematic search or an evaluation of clinical efficacy. Results. The agreement assigned Navy and company roles and later included a conditional defense contingency provision for a possible request for 1,500 units. That provision did not itself authorize clinical use or establish delivery. NMRC submitted a RESUS investigational new drug application in June 2005, and FDA placed the proposed trial on clinical hold in July. An FDA advisory committee discussed the proposal in December 2006. Biopure reported an 11 to 8 vote, with one abstention, against proceeding with the design then proposed; the revised Phase 2 protocol remained on hold in 2007. A separate DoD budget line and subsequent preclinical supply arrangements document research activity, not battlefield deployment. Conclusion. The records trace RESUS from military research planning through IND submission, clinical hold, advisory review, revised protocol and preclinical product work. They do not establish that the proposed RESUS human trial began, that the contingency supply clause was executed, or that HBOC-201 received US authorization for operational military use.

The scientific work of Professor William W. Muir addresses a fundamental problem in oxygen therapeutics: increasing oxygen transport capacity does not necessarily mean that oxygen reaches the tissues where it is needed. Over several decades, Muir investigated cardiovascular physiology, respiratory gas exchange, hemorrhagic shock, microvascular perfusion, hemoglobin-based oxygen carriers (HBOCs), and tissue oxygenation. His scientific involvement with Biopure, collaboration with Carl W. Rausch, and subsequent reported advisory activities in veterinary product development form an important part of this history. This article traces the development of these ideas and their experimental evaluation, leading to a proposed next step: Precision Oxygen Therapeutics based on Biological Hemoglobin Oxygen Carrier (BHOC), with oxygen delivery treated as a distinct therapeutic function rather than an attempt to replace blood.

Kidney transplantation offers a route beyond long-term dialysis, yet access depends on a sequence of clinical, organizational, and biological decisions. This analytical essay combines a patient coauthor's lived experience with a narrative synthesis of published studies, registry reports, and public policy documents. It examines dialysis-market concentration, referral and waitlisting, organ-offer transparency, kidney nonuse, and the limits imposed by ischemic injury. Observational associations between facility ownership and transplant access are distinguished from evidence of intentional conduct. Established evidence for hypothermic machine perfusion is separated from investigational oxygen-carrier applications, including Biological Hemoglobin Oxygen Carriers (BHOC), for which product-specific benefit must be demonstrated. A patient-centered quality framework links referral timelines, allocation decisions, organ support, graft outcomes, and patient-reported experience. The central proposal is to assess economic reform and biomedical innovation together rather than as competing explanations for limited transplantation. This is not a systematic review, original clinical study, or demonstration of BHOC efficacy; it proposes an evidence-generation and quality-improvement agenda.