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

1. Introduction: Blood Is a System; Oxygen Delivery Is a Function

Blood performs multiple biological functions, including oxygen and carbon dioxide transport, hemostasis, immune defense, buffering, volume support, nutrient transport, signaling, maintenance of homeostasis, and more. An isolated oxygen-carrying molecule cannot reproduce that entire biological architecture. This distinction matters because early development of hemoglobin-based products was frequently described using "artificial blood" and "blood substitute," terminology that implicitly invited comparison with blood as a whole rather than with a specific physiological function.

Alayash, writing from the U.S. Food and Drug Administration (FDA), explicitly described "blood substitute" and "artificial blood" as misnomers because the compounds under discussion primarily provided oxygen transport and volume support while lacking many other functions of blood. He argued that hemoglobin-based oxygen carriers (HBOCs) and oxygen therapeutics were more appropriate terms [4]. That conceptual distinction deserves development: blood is a biological system; oxygen delivery is a physiological function.

In this Perspective, we propose Precision Oxygen Therapeutics as a contemporary classification for studying specific oxygen delivery as an independent measure and controlled therapeutic beneficial outcome.

Biological Hemoglobin Oxygen Carrier (BHOC) is a function-first technological designation within that treatment construct. The purpose is not to relabel the historical literature, but to create a precise new vocabulary for the characterization of investigational materials, translational research, and clinical hypothesis that will offer outcomes that a supportive of the metabolic life functions.

2. Historical Evolution: From Blood Substitution to Oxygen Therapeutics

The need for guidance transition did not begin in 2026. An archival industry report published by Stover & Associates in September 1996, A New Generation of Oxygen Therapeutics, described hemoglobin-based and perfluorocarbon oxygen carriers as a broader generation of oxygen therapeutics rather than only as red-cell substitutes [1]. The report is used here as a historical source, not as evidence that the scientific or clinical assumptions it contained were subsequently validated. Its existence is independently reflected in contemporary reviews of the field [3].

The transition is also evident in Biopure's development history. In prepared testimony before the U.S. Joint Economic Committee in 1999, Carl W. Rausch described Biopure's technology as a new class of biopharmaceuticals called "oxygen therapeutics," while noting that such products were often called blood substitutes because they could replace intravascular fluid and deliver oxygen [2]. In 2004, Alayash used oxygen therapeutics to describe modified hemoglobin systems intended to address oxygen deficits in ischemic settings [4].

Clinical experience further broadened the investigative clinical protocols. In a report of HBOC-201 clinical use after its approval for human use in South Africa, Levien observed an increasing tendency among clinicians familiar with the product to use it for a tissue-oxygenation effect rather than solely as a red-cell (hemoglobin) replacement, while emphasizing that this real world clinical observation required controlled prospective evaluation [5]. These sources show a progressive change in the dominant question: from reproducing blood units, to replacing packed red blood cells, to supporting oxygen-delivery function. Development programs also included acute normovolemic hemodilution models, in which whole blood was removed and retained for reinfusion after surgery; in those settings, low plasma hemoglobin concentrations were evaluated in relation to hemodynamic stability and oxygen availability.

Table 1. Developmental evolution of oxygen-carrier terminology. 

Developmental stage	Dominant question
Artificial blood	Can blood be reproduced?
Blood substitute	Can donor RBCs be replaced?
HBOC (all types, irrespective of source or purity)	Can hemoglobin-mediated oxygen carriage be provided without intact RBCs?
Oxygen therapeutics	Can oxygen-delivery function itself be therapeutically supported?
Precision Oxygen Therapeutics	Can oxygen delivery be measured, regulated, and supported according to physiological demand at the microvascular and tissue level? (with or without RBCs)

Table 1. Developmental evolution of oxygen-carrier terminology. 

Developmental stage	Dominant question
Artificial blood	Can blood be reproduced?
Blood substitute	Can donor RBCs be replaced?
HBOC (all types, irrespective of source or purity)	Can hemoglobin-mediated oxygen carriage be provided without intact RBCs?
Oxygen therapeutics	Can oxygen-delivery function itself be therapeutically supported?
Precision Oxygen Therapeutics	Can oxygen delivery be measured, regulated, and supported according to physiological demand at the microvascular and tissue level? (with or without RBCs)

3. Proposed Terminology and Scope

Consider the following canonical definition: Precision Oxygen Therapeutics is a translational scientific and therapeutic construct concerned with the measurement, regulation, and therapeutic support of oxygen delivery according to physiological demand, conceptually independent of whether donor blood is available or any transfusion or perfusion is otherwise feasible.

Within this framework, a Biological Hemoglobin Oxygen Carrier (BHOC) is defined as a biologically derived or biologically engineered hemoglobin-mediated oxygen-delivery material or therapeutic whose composition, molecular characteristics, oxygen-binding and exchange control, pharmacology, physiology, redox behavior, and manufacturing attributes can be quantitatively characterized and reproducibly controlled.

The relationship among terms may be deliberately asymmetric. Presently, HBOC in historical references, remains an established scientific and bibliographic term for the historical and some contemporary literature on hemoglobin-based oxygen carriers. BHOC is not proposed as a replacement label for all HBOCs, nor should historical products be retroactively relabeled. Rather, BHOC denotes a function-first application in which biological origin or engineering, oxygen-delivery behavior, vascular interaction, and product-specific quality attributes are treated as an integrated characterization problem. Precision Oxygen Therapeutics is broader still: it is a research and therapeutic guidance, and in principle can include oxygen-delivery technologies beyond hemoglobin-based systems.

This scope distinction is important for both scientific clarity and literature retrieval. Historical evidence should continue to be indexed and searched using HBOC, hemoglobin-based blood substitute, oxygen therapeutic, and specific product names. BHOC and Precision Oxygen Therapeutics are proposed as forward-looking terms that organize future work around measurable oxygen-delivery function rather than around the metaphor of replacing blood.

Table 2. Canonical terminology proposed in this Perspective.

Term	Canonical definition / scope
Precision Oxygen Therapeutics	A translational scientific and therapeutic framework concerned with the measurement, regulation, and therapeutic support of oxygen delivery according to physiological demand, conceptually independent of whether donor blood is available or transfusion is otherwise feasible.
Biological Hemoglobin Oxygen Carrier (BHOC)	A biologically derived or biologically engineered hemoglobin-mediated oxygen-delivery material or therapeutic whose composition, molecular characteristics, oxygen-binding and unloading behavior, pharmacology, physiological interactions, redox behavior, and manufacturing attributes can be quantitatively characterized and reproducibly controlled.
Precision oxygen delivery	Controlled support of oxygen availability according to physiological demand, with particular attention to microvascular distribution, tissue-level availability, unloading, blood flow, vascular signaling, and systemic response. The term describes a development objective and requires indication-specific validation.

Table 2. Canonical terminology proposed in this Perspective.

Term	Canonical definition / scope
Precision Oxygen Therapeutics	A translational scientific and therapeutic framework concerned with the measurement, regulation, and therapeutic support of oxygen delivery according to physiological demand, conceptually independent of whether donor blood is available or transfusion is otherwise feasible.
Biological Hemoglobin Oxygen Carrier (BHOC)	A biologically derived or biologically engineered hemoglobin-mediated oxygen-delivery material or therapeutic whose composition, molecular characteristics, oxygen-binding and unloading behavior, pharmacology, physiological interactions, redox behavior, and manufacturing attributes can be quantitatively characterized and reproducibly controlled.
Precision oxygen delivery	Controlled support of oxygen availability according to physiological demand, with particular attention to microvascular distribution, tissue-level availability, unloading, blood flow, vascular signaling, and systemic response. The term describes a development objective and requires indication-specific validation.

4. The Intervention Is the Precise Oxygen-Delivery Pathway, Not Oxygen Content and Availability Alone

Global oxygen “delivery” is commonly expressed as the product of cardiac output and arterial oxygen content (DO₂ = cardiac output × CaO₂). This relationship is fundamental, but it does not ensure homogeneous regional oxygen metabolic support. Adequate cardiac output, arterial saturation, blood pressure, or circulating hemoglobin can coexist with impaired microvascular perfusion, heterogeneous capillary flow, altered oxygen unloading, diffusion limitation, endothelial dysfunction, or impaired cellular utilization [6].

A useful systems representation is: oxygen loading → carriage → circulation → microvascular distribution → unloading → diffusion → tissue support → cellular utilization. Failure at any step can reduce effective oxygenation. The red blood cell illustrates this integration: hemoglobin oxygen affinity and unloading are affected by oxygen tension, carbon dioxide, pH, temperature, and 2,3-DPG, while red-cell deformability, transit, and vascular signaling influence where oxygen is distributed. Contemporary RBC physiology describes interacting allosteric and vaso-regulatory components of oxygen transport [7].

For an oxygen therapeutic, therefore, maximum oxygen content is not necessarily the optimal design objective. The more relevant problem is to determine how much available oxygen is carried, where and when it is released, how rapidly it is released, and what vascular response accompanies that release. This is the distinction between oxygen carriage and precision oxygen delivery and support.

5. Vascular Tone and Nitric-Oxide Biology Are Part of Oxygen-Delivery Pharmacology

One of the central challenges identified in HBOC development has been vasoactivity. Unstabilized cell-free hemoglobin can scavenge nitric oxide more readily than erythrocyte-contained hemoglobin because normal red-cell compartmentalization limits the interaction between hemoglobin and the vascular wall. Experimental work has linked plasma hemoglobin to altered vascular reactivity, vasoconstriction, and increased vascular resistance [8].

These effects are clinically important and should not be minimized. A 2008 meta-analysis of multiple earlier cell-free hemoglobin products reported increased risks of myocardial infarction and death across heterogeneous surgical, stroke, and trauma trials [9]. The investigational products, molecular architectures, indications, dosing strategies, and trial designs were heterogeneous; nevertheless, the analysis identified a safety signal that remains central to the field's regulatory history. This heterogeneity also supports product-specific evaluation rather than assuming uniform biological behavior across all hemoglobin-based oxygen carriers.

At the same time, the physiology of vasoactivity is not exhausted by the equation "hemoglobin + nitric-oxide scavenging = failure." Winslow described a second mechanism in which facilitated oxygen delivery by cell-free hemoglobin may produce precapillary oxygen oversupply and a regulatory vasoconstrictive response [10,11]. The magnitude and clinical relevance of vasoactivity may vary with molecular architecture, oxygen affinity, dose, organ, and physiological context. These mechanisms are not mutually exclusive. Their relevance is that vascular tone should be treated as part of oxygen-delivery pharmacology rather than as an isolated side effect detached from oxygen flux.

Intact RBCs also participate in oxygen-dependent vascular signaling. Work by Pawloski, Hess, and Stamler described export of NO-related bioactivity from red cells [12], while Crawford and colleagues demonstrated nitrite/NO-related mechanisms contributing to hypoxic vasodilation [13]. Reviews of erythrocyte vascular biology emphasize the interaction among oxygen affinity, oxygen unloading, nitric-oxide chemistry, ATP signaling, membrane biology, and blood flow [7,14]. These mechanisms remain an active scientific field and should not be automatically extrapolated from intact RBCs to a cell-free BHOCs. The translational question is therefore investigative material-specific: what is the net relationship among oxygen release, nitric-oxide biology, vascular tone, regional blood flow, and tissue oxygenation?

6. From a Fixed-Dose Oxygen Carrier to a Feedback-Oriented Physiological Intervention

The word precision should guide a development objective, not a marketing adjective. Precision Oxygen Therapeutics should ultimately be evaluated as a feedback-oriented system in which physiological demand and evidence of oxygen-delivery deficit inform intervention, and the measured response informs continuation, adjustment, or discontinuation.

The conceptual sequence is: physiological demand → identification of oxygen-delivery deficit → selection of intervention → oxygen-carrying support → microvascular distribution and unloading → measurement of physiological response → adjustment or discontinuation. The therapeutic objective is not maximal oxygenation availability. It is adequate oxygen delivery without physiologically inappropriate under-delivery or oxidative stress.

A major limitation is that no single routinely available variable constitutes a universal real-time tissue oxygenation endpoint. Candidate research tools include regional near-infrared spectroscopy, transcutaneous oxygen measurements, lactate kinetics, venous oxygen variables, microcirculatory imaging, organ-specific functional endpoints, and emerging measurements of cellular or mitochondrial oxygenation. The relevant control variables are likely to be indication-specific rather than universal [6]. Accordingly, the framework requires parallel development of monitoring strategies and oxygen-delivery and support therapeutics.

7. Conceptual Independence from Donor-Blood Availability

Alternative oxygen carriers have historically been positioned for situations in which donor blood is unavailable, incompatible, refused, or operationally inaccessible. Those remain important scenarios. Precision Oxygen Therapeutics, however, separates two variables that are often conflated: the availability of donor blood and the adequacy of oxygen delivery.

A patient may have donor blood available yet still have regional or microcirculatory oxygen-delivery failure. Conversely, anemia does not automatically imply that an additional oxygen carrier (as indicated by RBC hemoglobin level determination) is required when compensatory physiology is adequate. The research trigger for precision oxygen support should therefore be investigated as a demonstrable oxygen-delivery deficit relative to physiological demand, not merely as the absence of blood hematocrit or hemoglobin level.

This is not a recommendation to bypass transfusion when transfusion is indicated, nor does it establish clinical benefit for a BHOC when donor blood is available. It is a clinical observation of signs and symptoms of anemia-generating distinction. Hemorrhage, anemia, ischemia, low-flow states, impaired microcirculation, and other conditions will require separate evidence, dosing strategies, endpoints, and risk-benefit assessments. Precision Oxygen Therapeutics is intended as a complementary and an early immediate intervention to reduce ischemic insult, while safely preparing transfusion medicine guidance, this is not an alternative doctrine.

8. Implications for Product Development and Regulatory Science

Terminology influences the questions asked during product development. A product framed as a "blood substitute" is naturally evaluated in relation to replacement of red-cell transfusion. A product developed as an oxygen therapeutic raises additional mechanistic questions: Does it improve oxygen delivery? In which population? At what dose and duration? At what tissue or organ level? With what vascular, oxidative, renal, hepatic, and cardiac consequences of limiting ischemic insult?

FDA- and NIH-associated scientific discussions of HBOCs have repeatedly emphasized mechanistic safety, clinical efficacy, cardiovascular effects, and the heterogeneity of individual investigative materials. [15,16] This history supports an investigative-specific rather than class-generic approach. Molecular size distribution, oxygen affinity, redox behavior, extravasation, methemoglobin formation, viscosity, oncotic characteristics, pharmacokinetics, impurities, and manufacturing critical quality attributes can all influence biological behavior.

Within the proposed guidance, development should therefore be treatment-specific, indication-specific, dose-specific, and physiology-specific. Appropriate clinical endpoints remain essential; mechanistic oxygen-delivery metabolic endpoints should complement, not replace, mortality, morbidity, adverse events, organ performance outcomes, and appropriate established transfusion endpoints. The purpose of the guidance suggestion is to improve the biological interpretation of those outcomes and to make cross-product (biosimilar) generalization more disciplined and relevant.

9. Bridge Function, Biological Time, and Endogenous Recovery

An oxygen carrier used in an emergency may have value not only through immediate oxygen transport and delivery but also through the creation of biological time: time to control hemorrhage, treat the underlying disease, restore circulation or perfusion, perform definitive corrective intervention, or allow and support endogenous erythropoietic recovery. Expanded-access experience with HBOC-201 has explicitly used recovery of native hemoglobin and evidence of reticulocytosis among criteria for stopping further dosing [17]. Clinical experience also illustrates the potential role of bridge or intermittent administration strategies and the importance of understanding product-specific pharmacology and adverse effects [20].

A related question, not yet real world evaluated in a clinical trial, relates to heme-iron recycling. Most iron used for erythropoiesis is recovered through macrophage recycling of heme iron from senescent erythrocytes rather than supplied by daily intestinal absorption [18,19]. This raises a testable BHOC-specific hypothesis: can iron derived from metabolism of an administered biological hemoglobin oxygen carrier enter endogenous heme/iron recycling pathways and contribute meaningfully to subsequent erythropoiesis?

No directly measured evidence establishes such a benefit. Studies would need to define BHOC catabolism, heme handling, haptoglobin and hemopexin interactions, macrophage uptake, ferroportin-mediated iron export, transferrin incorporation, marrow utilization, reticulocyte kinetics, and potential toxicity from free heme, oxidative stress, or excess iron. The concept should therefore remain an exploratory research question rather than a therapeutic claim.

10. Research Agenda and Evaluable Hypotheses

A useful guidance outlined program should generate falsifiable questions. Precision Oxygen Therapeutics generates at least five. First, tissue- or organ-level oxygen-delivery response may provide clinically relevant information not captured by hemoglobin concentration or systemic saturation alone. Second, the optimal oxygen carrier may be the product that achieves the most appropriate relationship among oxygen loading, microvascular distribution, unloading, vascular response, and metabolic demand rather than the product with the highest oxygen-carrying capacity. Third, HBOC-associated vasoactivity may vary materially with molecular architecture, oxygen affinity, dose, nitric-oxide interactions, extravasation, and patient physiology and should therefore be characterized quantitatively rather than assumed to be uniform across a class. Fourth, selected oxygen carriers may function as temporary physiological bridges in defined settings even when donor blood is technically available, but only if prospective evidence demonstrates a clinically meaningful oxygen-delivery deficit and a favorable risk-benefit profile. Fifth, metabolism of biological hemoglobin oxygen carriers may interact with endogenous heme and iron recycling, but the magnitude and clinical significance of that interaction remain unknown.

These propositions are hypotheses, not therapeutic conclusions. The next step is not broader terminology; it is disciplined experimental validation using product-specific chemistry, translational physiology, indication-specific models, and prospective clinical endpoints.

11. Limitations of the Proposed Guidance.

Precision Oxygen Therapeutics is proposed here as a translational framework; it is not an established clinical specialty, regulatory category, validated treatment protocol, or clinical consensus. There is no universally accepted bedside measure of tissue oxygen-delivery adequacy. Tissue oxygen requirements differ among organs, disease states, temperatures, and metabolic conditions. Microvascular and cellular measurements remain technically challenging and are not uniformly validated as treatment targets.

The historical HBOC field also contains controversial safety signals, including cardiovascular, vasoactive, oxidative stress, renal compromise, and methemoglobin-related concerns. Mechanisms established for erythrocyte-contained hemoglobin cannot be assumed to apply to cell-free hemoglobin, and findings from one molecular architecture should not be generalized automatically to another. The term BHOC itself does not create evidence of safety or efficacy; it creates a proposed characterization guidance that must be populated by data and proper protocol.

Finally, the historical sources used to trace the development of the term oxygen therapeutics include an archival industry report and prepared congressional testimony. These sources are appropriate for documenting terminology and conceptual history but are not substitutes for peer-reviewed evidence of clinical effect. These limitations define the research and development agenda and the evidentiary boundaries of the present Perspective.

12. Conclusion

The history of hemoglobin-based oxygen carriers (HBOCs) reflects a progressive change in their applications and in the germane scientific question: from whether safe and effective “blood “can be reproduced, including through cell-based approaches such as those explored by Rubius Therapeutics, to whether red-cell oxygen carriage can be supplied by alternative means, and to whether oxygen delivery itself can be precisely controlled and therapeutically supported. We believe there is a critical need for Precision Oxygen Therapeutics as the advanced developmental and applied step in that evolution: a framework centered on measuring, regulating, and supporting oxygen delivery to provide metabolic support according to physiological demand.

Within this context, we present the following definition of a Biological Hemoglobin Oxygen Carrier (BHOC): a quantitatively characterizable hemoglobin-mediated oxygen-delivery material or therapeutic whose oxygen-binding behavior, pharmacology, vascular interactions, redox properties, and manufacturing attributes are evaluated as an integrated system. BHOC does not replace HBOC as the established historical term; it provides a forward-looking functional framework for new product-specific development.

The relevant scientific endpoint is therefore not whether an intervention "replaces blood." It is whether an oxygen-delivery technology can provide appropriate physiological support and a favorable benefit-risk outcome at the appropriate location and duration, with acceptable microvascular and systemic safety. Blood is a biological system. Oxygen delivery is a regulated physiological function. Precision Oxygen Therapeutics proposes that this function should be investigated as a therapeutic target in its own right. The appropriate regulatory classification of any individual technology should be determined product by product and indication by indication.

Figure 1. From blood substitution to Precision Oxygen Therapeutics. Figure legend. The upper pathway summarizes the historical evolution of terminology. The lower pathway represents oxygen delivery as a physiological continuum from pulmonary loading to tissue/cellular availability. Physiological demand and measured response provide the conceptual feedback signal for future precision oxygen-delivery strategies. The diagram is conceptual and does not imply that all historical HBOCs meet the proposed BHOC definition or that feedback-controlled dosing has been clinically validated.

Figure 1. From blood substitution to Precision Oxygen Therapeutics. Figure legend. The upper pathway summarizes the historical evolution of terminology. The lower pathway represents oxygen delivery as a physiological continuum from pulmonary loading to tissue/cellular availability. Physiological demand and measured response provide the conceptual feedback signal for future precision oxygen-delivery strategies. The diagram is conceptual and does not imply that all historical HBOCs meet the proposed BHOC definition or that feedback-controlled dosing has been clinically validated.