New developments and future trends of artificial blood

Introduction

Artificial blood, better referred to as oxygen therapeutic agents (OTAs), research represents nearly a century of innovation aimed at producing safe, effective, and universally available alternative intravenous oxygen delivery agents without the adverse events of donor-derived blood (1). The need arises from persistent challenges in traditional transfusion medicine, including limited supply, short shelf life, infectious risk, immunologic incompatibility, and large numbers of adverse outcomes resulting from transfusion. From early experiments in the 1930s with hemoglobin-based (simply stroma free) oxygen carriers (HBOCs) to recent breakthroughs in stem-cell-derived red blood cells (RBCs) and nanoscale platforms, this field has evolved significantly (2). HBOCs initially offered promise by using cell-free or modified hemoglobin to deliver oxygen. However, nitric oxide (NO) scavenging, oversupply of oxygen to tissues, and capillary closure resulted in oxidative stress, leading to vasoconstriction, hypertension, and organ injury, ultimately halting many clinical programs (3).

Parallel work on perfluorocarbon (PFC) emulsions showed chemically inert carriers that dissolve oxygen and are to be contrasted to the chemical binding of oxygen required by HBOCs (4). Those persons studying HBOCs ascribed that PFCs needed high inspired oxygen to be effective (5). That is only partially true and is a result of a hemoglobin focused thinking and not truly understanding how PFCs function in the environment of RBCs and tissue oxygen demand. Their ability to enhance tissue oxygen delivery with low and no flow in the microvasculature has been studied, but not appreciated and advanced for the medical breakthrough that it represents (6).

Today several companies are testing PFCs as ways to salvage brain tissue in acute stroke and traumatic brain injury as well as a therapy for acute cardiac arrest (a very low flow situation). Transient flu-like reactions in early preparations have been overcome and understood such that present day PFCs no longer are restricted from this reaction. It is however a stigma that hangs over the pharmaceutical class. Hematopoietic stem cell (HSC) technology introduced the potential for ex vivo cultured RBCs from hematopoietic or induced pluripotent stem cells (iPSCs), providing a renewable source of compatible blood, especially for rare phenotypes. Initiatives such as the UK RESTORE trial have shown proof- of-concept with mini-transfusions of lab-grown RBCs in human volunteers (7,8). In recent years, innovations like ErythroMer—a lipid-encapsulated hemoglobin nanoparticle—have marked a new era, offering lyophilization for battlefield and emergency deployment (9). Parallel research in platelet substitutes, including liposomal mimetics, polymeric microparticles, and freeze-dried formulations such as Thrombosomes, addresses donor platelet shortages and hemostatic emergencies (10). Despite these advances, artificial blood faces critical hurdles in safety, cost, scalability, and regulatory approval. Current efforts focus on improving enucleation in cultured RBCs, mitigating vasoactivity in HBOCs, and streamlining manufacturing. As nanomedicine, stem cell biology, biomaterials engineering, and computational modelling converge, the vision of transfusion-independent oxygen therapeutics is inching closer to clinical reality. This manuscript reviews current technologies, clinical trials, safety considerations, economic and regulatory challenges, and future directions. Recent literature has thoroughly traced the history of artificial blood and the translational boundaries that must be considered in the creation of hemoglobin solutions (11). However, many earlier studies of artificially synthesized blood describe the history in chronologically comprehensive fashion rather than expounding an analysis with translational applicability or future integration strategies (1). By contrast, the current literature distinguishes itself in interpreting recent clinical trial findings and incorporating innovative technologies in the nano- and stem-cell disciplines with a comparative analysis of translation barriers in different platforms. Particular emphasis is placed on identifying why specific approaches failed, where technological inflection points have occurred, and how hybrid or modular systems may overcome longstanding physiological and regulatory barriers. This forward-looking framework aims to clarify the realistic clinical trajectory of artificial blood in the coming decade.

Current available technologies

Current artificial blood technologies remain primarily investigational, spanning four core domains: HBOCs, PFC emulsions, stem-cell-derived/cultured RBCs, and platelet substitutes. HBOCs, such as Hemopure (HBOC-201; HbO₂ Therapeutics, Souderton, PA, USA), use polymerized bovine hemoglobin and offer oxygen delivery without crossmatching; however, vasoconstriction, hypertension, and myocardial risks limit their adoption to expanded-access programs in the U.S. and clinical use in South Africa and Russia (12,13). PFC emulsions dissolve oxygen in a linear fashion, exemplified by Perftoran/Perftec (Scientific-Production Company Perftoran, Pushchino, Russia), ABL-101 (Aurum Biosciences, Glasgow, Scotland) is an offshoot of Oxycyte (previously tested by Oxygen Biotherapeutics, Durham, NC, USA); Oxygent, tested by Alliance Pharmaceuticals is no longer in clinical testing but its patents and over 100 clinical trial data could be picked up by a pharmaceutical company (14,15). Dodecafluorpentane (NuVox, Tucson, AZ, USA) is in human phase II and III trials for a number of indications. It is an ultrashort acting PFC that dramatically enhances oxygen delivery to tissues (16).

The PFCs offer advantages in that they are chemically stable, have long-term storage, are able to be supplied in vial or IV bag formats with universal applicability and not biologic infectivity (17). They are effective with normal RBCs of slightly higher inspired oxygen concentrations. The old and outdated view that they needed 100% oxygen is not true. Understanding tissue PFC loading and elimination from liver and whole body is complex. To date, regulatory agencies carefully are watching potential chemical side effects and organ dysfunctions. Stem-cell-derived RBCs, including those trialed in the RESTORE study, promise pathogen-free, universal blood production but are constrained by high cost, low expansion yield, incomplete enucleation, and slow regulatory progression (7,8). Platelet substitutes, like SynthoPlate™ and freeze-dried Thrombosomes, aim to replicate adhesion and aggregation functions for trauma, oncology, and thrombocytopenia settings, with early clinical trials showing encouraging results (18,19). Despite decades of research, no artificial product fully replicates the multifunctional role of natural blood, including immune defense and nutrient transport. Current developments target niche applications in military, emergency, and rare-disease contexts. Moving forward, improvements in nanotechnology, stem cell bioprocessing, and biocompatibility engineering remain critical for broader clinical translation.

Recent clinical developments and trial outcomes

Innovations and clinical trials aimed at developing artificial blood began in the 1930s and have continued to advance up to the present day. Figure 1 highlights key milestones and achievements in this evolving field. These ongoing efforts reflect the persistent pursuit of safe and effective artificial blood products, with each era contributing valuable insights and technological progress toward their realization.

Figure 1 Recent clinical and technological milestones in artificial blood development. AI, artificial intelligence; FDA, Food and Drug Administration; Hb, hemoglobin; HBOC, hemoglobin-based oxygen carrier; RBC, red blood cell.

RBCs

HBOCs

Modern development of artificial RBCs started from the 1930s when the first HBOC created with cow blood was used in a cat (2). In the 1950s, the United States (U.S.) Navy carried out initial human tests using stroma-free hemoglobin solutions (2). Followed by in the 1960s, the U.S. Army conducted experiments with diaspirin crosslinked hemoglobin to lower renal clearance (2). However, these studies met issues including kidney toxicity, increased blood pressure and myocardial infarctions due to acute coronary spasm (2). To address challenges in developing HBOCs, strategies over the years have included pyridoxilation to modify oxygen affinity, crosslinking for higher molecular weight and longer circulation, PEGylation, and carboxylation (1). Work continues with new methods to make human and animal based hemoglobins non-toxic to endothelial cells and renal cells as well as decreasing vascular spasm.

Stem-cell-derived RBCs

Based on the previous design’s outcomes, newer efforts have focused on ex vivo manufacturing of RBCs through HSCs or iPSCs (20). The concept of utilizing iPSCs to produce RBCs originated from an initial report in 2006, which was followed by a proof-of- concept study in which in vitro autologous RBCs derived from stem cells were, for the first time, transfused into a human subject (21,22). A major advantage of iPSCs over HSCs or embryonic stem cells is that they can be produced from any cell type, both immature and mature cells, thus, avoiding ethical concerns arising from use of human embryos (21). Subsequent designs to develop cultured RBCs through iPSCs occurred in the United Kingdom (UK), with a £5 million Strategic Award granted to a consortium led by the Scottish National Blood Service (SNBTS) with objective to begin the first human trials by late 2016 (23). However, successful RBC generation from iPSCs is limited by high cost, low expansion rates, lack of adult hemoglobin expression, and insufficient enucleation (i.e., nucleus-free RBCs), and the 2016 UK trial did not occur as planned owing to such limitations (20,21). In the meantime, Park et al. demonstrated the feasibility of producing iPSC-differentiated RBCs for clinical transfusion in patients without other options using refined methods compatible with Good Manufacturing Practice (GMP) (21). These investigators were able to successfully manufacture RBCs from iPSCs generated from peripheral blood mononuclear cells from two patients with rare blood types [Jr(a-) and D-] (21). Subsequently, the 2022 Phase 1 Recovery and Survival of Stem Cell Originated Red Cells (RESTORE) Trial, a UK collaborative initiative by the NHS Blood and Transplant, University of Bristol, National Institute for Health and Care Research Cambridge Clinical Facility in association with other organizations, performed mini-transfusions of laboratory-developed RBCs to human volunteers (7). In 2023, notable positive feedback came from trial recipients, although comprehensive results remain unpublished.

Nanoscale synthetic RBC analogues

In the subsequent phase, researchers developed ErythroMer a nanoscale, bio-synthetic artificial lipid-based nanoparticles with proof of concept published in 2016 (24). ErythroMer offers advantages such as lyophilization for room-temperature storage, an estimated one-year shelf life, and ease of transport—features that are particularly beneficial in emergency and military settings (24,25). With a half-life of 18–20 hours, ErythroMer is positioned as a bridging therapy and holds promise for treating acute bleeding, autoimmune hemolytic anemia, and providing alternatives for individuals declining traditional transfusions due to religious beliefs (25). The concept of ErythroMer is to reduce the toxic nature of free hemoglobin by encapsulating hemoglobin in an artificial membrane (26). The original development of this product was funded by a $2.7 million grant from the National Institutes of Health’s National Heart, Lung, and Blood Institute, aimed at advancing synthetic blood technology. In 2023, it received an additional $46 million from the federal Defense Advanced Research Projects Agency (DARPA). Nonetheless, the product’s future remains contingent upon successful clinical trials.

Enucleation rates in RBC manufacturing are increasing, enhancing similarity to natural RBCs—crucial for better deformability and reduced immune response. Initial methods saw rates below 25–30%, but the 2019 hydrochlorofluorocarbons (HCFC) method achieved up to 60% (7). In addition, amplification of progenitors or erythroid precursors from HSCs or iPSCs has increased, with some systems able to generate thousands of RBCs per iPSC (27). In a recent 2025 study, the investigators were able to generate approximately 4.6×10³ RBCs per iPSC (25). Though this is still well below the dose needed for full therapeutic application (i.e., 10¹¹–10¹² per unit) (21,28). Research on expanding HSCs ex vivo more robustly through better culture conditions and use of small molecule agonists (e.g., UM171) is also progressing well (28). Although these are upstream of final RBC production, as they provide starting material, they are essential for making cultured or synthetic RBCs realistic. Finally, the production of the synthetic RBC analogue, ErythroMer, represents a significant advancement in production of a stable product that could be available for onsite emergency use or in the battlefield (24,26). Challenges that remain to be addressed include amplification, enucleation, and variability in functional maturation among iPSC lines; in vivo survival (half-life); cost and manufacturing logistics; as well as regulatory and clinical trial advancement.

Platelet concentrates

Platelet substitutes

Platelet substitutes aim to provide hemostatic support without donor products by replicating key platelet functions such as adherence, activation, aggregation, and procoagulant surface delivery. Ideal substitutes are safe, affordable, sterile, easy to store, and suitable for use in both hospitals and challenging field environments (29,30). Initial efforts produced infusible platelet membranes (IPMs) microparticles from fragmented, lyophilized outdated platelets, preserving key glycoproteins like GPIb and GPIIb/IIIa for limited hemostatic function. Phase 1 and 2 trials showed short-lived and unpredictable safety and bleeding correction, while alloimmunization and complement activation restricted broader use. Despite this, studies confirmed that platelet membrane components can promote functional clot formation if other factors are in place (29). These agents carry the risk of uncontrolled pro-thrombotic activation.

Liposome-based platelet mimetics

Recent advances in biomaterials have produced liposome-based platelet mimetics. These liposomes, made from phospholipid bilayers, can display adhesion peptide motifs like collagen-, von Willebrand factor (vWF)- , and fibrinogen-mimetic [Arg-Gly-Asp (RGD)] sites. SynthoPlate™, the most advanced version, combines multiple ligands to replicate platelet plug formation. Preclinical trauma and thrombocytopenia models show that SynthoPlate shortens bleeding time and reduces blood loss without causing thrombosis, and its particles can be lyophilized for long-term storage and emergency use (18). In addition to liposomal systems, researchers have developed polymeric and hydrogel microparticles that emulate the size, deformability, and mechanical properties of circulating platelets. These “platelet-like particles”, primarily fabricated from the biodegradable polymer poly (lactic-co-glycolic acid) (PLGA), are conjugated with adhesion peptides to facilitate targeted interaction with damaged vessel walls and incorporation into fibrin networks. Owing to their viscoelastic attributes, these particles migrate toward the vessel margin under flow conditions, mirroring the behavior of native platelets and supporting clot formation. Preclinical studies have demonstrated that these materials reduce hemorrhage volume and promote robust clotting (31). Furthermore, their ability to be stored at room temperature for extended periods enhances their practical appeal. However, comprehensive evaluation of immune compatibility, clearance kinetics, and scalable manufacturing is necessary before clinical adoption.

Stem-cell-derived platelets

Advances in stem cell and tissue engineering allow ex vivo creation of platelet-like particles (PLPs) from megakaryocytes or iPSCs. These anucleate particles possess major platelet receptors but limited hemostatic function. Early Japanese clinical trials with iPSC-derived platelets confirm their safety, though they remain few and minimally functional. Bioengineered hybrid particles, formed by coating synthetic nanoparticles with cultured cell membranes, combine biological targeting and structural stability, resulting in better circulation and improved hemostatic effects in preclinical studies (31,32). Albumin and fibrinogen microparticles represent a class of platelet substitutes designed to facilitate the bridging of activated platelets. These microparticles are engineered by depositing an albumin microsphere coating that is pre-coated with fibrinogen or peptides containing RGD sequences. Such design enables association with activated platelet GPIIb/IIIa receptors, thereby promoting aggregation while avoiding spontaneous activation. Initial clinical trials have confirmed both the safety and enhanced hemostatic efficacy of Thrombosphere (Hemosphere, Irvine, CA, USA) and Synthocytes (Andaris Group, UK). Although these products do not fully replicate all platelet functions, they provide a controlled method for augmenting aggregation in patients experiencing bleeding (29).

Platelet membrane-coated nanoparticles

Platelet substitutes are now included in the broader area of platelet-inspired nanomedicine, which reflects increasing recognition of platelets’ diverse roles, such as in immunity, inflammation, and wound repair. Platelet membrane-coated nanoparticles can locate vascular injuries or tumor microenvironments, evade immune clearance, and deliver drugs like anti-inflammatory or chemotherapeutic agents. This development combines aspects of transfusion medicine, nanotechnology, and drug delivery, and may provide applications beyond hemostatic replacement (33-36). Expired platelets represent an underutilized resource for regenerative medicine and cell therapy applications. Although platelet concentrates reach the end of their transfusion lifespan within 5–7 days, they retain viable growth factors with preserved bioactivity. Current research demonstrates their potential in wound healing, particularly through the use of platelet gels or releasates that promote angiogenesis and soft tissue repair. Moreover, expired platelet lysates have been effectively employed as substitutes for fetal bovine serum during ex vivo expansion of mesenchymal stem cells, without introducing xenogeneic complications. Additionally, expired platelets may serve as raw material for producing virally inactivated platelet lysates, growth-factor fractions, and IPMs designed to mimic hemostatic functions. Collectively, these strategies utilize materials that would otherwise become biological waste, offering significant therapeutic value as GMP-grade biomaterials. This approach not only supports sustainability objectives but also broadens the conceptual scope of platelet utilization beyond traditional transfusion practices (36).

Comparative clinical outcomes and translational bottlenecks

Although a number of technologies have been available, there have been common translational hurdles associated with artificial blood products. HBOCs, though showing clinical success, failed due to difficulties related to systemic vasoactivity and oxidative cytotoxicity, establishing the basic drawback of unencapsulated hemoglobin. PFC blood substitutes avoided the cytotoxicity related to hemoglobin but were confronted with the concerns of biological misinterpretation, regulatory ambiguity, and clinical endpoints that underestimated the microcirculatory advantages. HSC-derived RBCs have excellent biological compatibility; nonetheless, a number of hurdles related to scaling up and incomplete functional development limit translation. Platelet substitutes have shown promising hemostatic support but are not capable of assuming the entire role related to immune and reparative functions of platelets. Within this arena, biocompatibility, scalability, economic viability, and proven acceptance by government and health officials remain key bottlenecks. New encapsulation technologies, hybrid technologies, and modulated whole-blood substitutes appear to provide a promising research direction to overcome bottlenecks.

Safety and efficacy assessment

Safety remains a critical barrier in the implementation of artificial blood. Any artificial blood substitutes must have a known and tolerable side effect profile at least as good as human banked blood. That alone is not fully appreciated or embraced at this time. Toxic adverse events of the free hemoglobin, oxidative stress, endothelial toxicity (hemoglobin kills endothelial cells through oxidative destruction), NO scavenging or foreign materials on the body must be appreciated, traced and changed. Efficacy must be demonstrated in situations where regular blood components cannot be used, with a balance of the risk and benefit. A steep hill to climb will be how efficacy must be demonstrated in situations where regular blood components cannot be used while balancing the risk and benefit. Contemporary third and fourth generation PFCs have good tolerability but are plagued with a long-standing misunderstanding of their physiological niche (37). Once again, they do not need high FiO₂ to be effective, and they work mostly by enhancing diffusivity of oxygen from internal sources. If one only computes oxygen delivery by the standard hemoglobin-based oxygen content equation they will show lack of efficacy. But when utilized in tissues with low plasma flow or where RBCs are limited in perfusion due to microcirculatory dysfunction (edema, arterial stenosis or heart and circulatory failure) they are profoundly effective. It is necessary to understand how they might work with HBOCs and other technologies in synergy.

Any artificial blood products must be evaluated for their safety. Even though early HBOCs showed promising results by delivering oxygen, they raised serious safety alarms. Meta-analysis on haemoglobin-based blood substitutes, covered 16 trials involving five different products with 3,711 patients, showed a significant increase in the risk of death and myocardial infarctions in the patients (38). These results led the Food and Drug Administration (FDA) to suspend all the trials involving HBOC in the U.S. (39). The free hemoglobin from HBOC will scavenge the NO which leads to vasoconstriction and injury due to oxidative stress. The symptoms associated with vasoconstriction include renal toxicity, gastrointestinal symptoms, chest pain, abdominal pain, and coronary and cerebral vasospasm (7). The HBOC can deliver oxygen to the tissues, but the toxicity might outweigh the benefits except in special circumstances (39,40). Similarly, the common adverse events of PFCs included delayed febrile reaction and flu-like symptoms, which are attributed to the normal phagocytic activity of reticuloendothelial system (RES), which was again dependent on the particle size of the emulsion (40). The PEGylated HBOCs have shown adverse events like hypertension, myocardial infarction, high mortality, acute renal failure, and transient ischemic attack, and the trials were stopped at phase 3 (41). HSC cultured RBCs and hemoglobin vesicles (HbVs) are in clinical testing and seem to offer safety but still need further research on maturation of red cells and alloimmunization (42). More data from larger clinical trials and an improved oxygen delivery without major vasoconstriction events. Future work will need to be on a larger randomized clinical trial and monitoring with strict FDA monitoring. An overview of the artificial blood technologies and their risk-benefit profiles are provided in Table 1.

Cost analysis and economic considerations

With the advancement and automation in healthcare, the cost of processing blood is increasing. Allogeneic blood today costs approximately $250–$300 USD to acquire from a blood supplier (43,44). The total hospital costs are 3.8–5 times as much, and many reimbursements agencies do not fund blood usage in bundled care such as heart surgery and orthopedics (43,44). No one reimburses the hospital for its total costs. Furthermore, the adverse event costs of allogeneic blood are huge, largely underappreciated and have both human tolls and public health costs. Artificial blood faces a great cost hurdle due to the high research and development cost and the huge time frame to develop it. One donor unit of blood is estimated to be around $200 to $550 USD (45). The cost in traditional blood processing starts even before the donation, recruitment, testing, collecting, processing, transporting and storing (46). Even though demand is there in the market, each step at cell culture, purification, encapsulation, crosslinking, and emulsification in PFCs is adding to the cost. The artificial blood products market is staying at $4.5 billion USD in 2024 and is expected to grow at a compound annual growth rate of 9.8% through 2033, even with the current limitations. HBOC has the highest market share of 50%, whereas the market of PFCs is projected to grow at the fastest rate due to the high oxygen-carrying capacity and low complications (47). These projections are a reflection of the great potential in the artificial blood and substitutes market, with an increased demand driven by blood shortages even in developed nations, aging populations, expanding healthcare infrastructure and access.

The cost of some HBOCs, which have a shelf life of 36 months, is 6 times higher than that of regular RBCs, with significantly higher side effects (48). A study in the U.S. showed the cost of recombinant hemoglobin was $11 USD per gram. But when considering the production and equipment cost, it can go up to $200 USD per gram. Then we need to factor in the total dose, the cost shoots up and becomes financially unviable (49). In order for artificial blood to become mainstream and economically viable, either the production cost must come down, or the hemoglobin efficiency must increase significantly without many adverse events. Limited scalability and the manufacturing economics prevent the widespread adoption of artificial blood in major parts of the world.

Regulatory status and challenges

Currently, no artificial blood substitute has received universal approval or is commercially available for general use in humans anywhere in the world, including the US. While several products primarily HBOCs and PFCs have been developed, their use is extremely limited and typically restricted to specific countries (such as South Africa and Russia), compassionate use in the U.S., or veterinary medicine (49). Most artificial blood substitutes have failed to gain widespread approval due to serious safety and toxicity concerns. Global research continues, focusing on oxygen carriers, stem cell-derived RBCs, and whole blood equivalents like ErythroMer to address blood supply shortages and reduce risks related to donor blood.

In the US, artificial blood products—more accurately referred to as OTAs—are strictly regulated by the FDA as biologic drugs. At present, there are no FDA-approved OTAs for general clinical use, primarily due to unresolved safety and efficacy issues. These products must comply with demanding standards under the Public Health Service Act and the Federal Food, Drug, and Cosmetic Act. Developers face significant challenges: ensuring safety, replicating the complex functions of natural blood, managing high production costs and logistical hurdles, and navigating commercialization barriers. After decades of research, no oxygen-carrying blood substitute has met the FDA’s requirements for general use.

The first-generation PFC product, Fluosol-DA 20% (Green Cross Corp, Osaka, Japan) developed in Japan, was briefly approved by the FDA in 1989 for use during certain cardiac procedures but was eventually withdrawn due to lack of sales (50). It was supplied frozen and needed an hour or longer to be re-sonicated to get it into emulsion. Recent efforts focus on HBOCs and artificial RBCs, yet these have struggled to meet safety and efficacy standards required for widespread approval. Some investigational products have achieved “Orphan Drug” status from the FDA, which is intended to facilitate the development of treatments for rare conditions (1). For patients with severe, life-threatening anemia without other treatment options, the FDA may grant expanded access for the experimental use of unapproved blood substitutes. Despite these pathways, the main challenge remains proving both safety and efficacy.

Ethical, social, and professional considerations

Artificial blood, being a new technology, is associated with significant real-world implications concerning its applications. One of the challenges associated with artificial blood is patient acceptance. Notably, patient acceptance is especially significant in relation to trust, safety, and religious issues for synthetic or genetically-engineered tissue, including stem cell-based blood (51,52). While some patients may consider artificial blood as a means of avoiding donor transfer, others may display reluctance in response to gene-engineered or laboratory-created components. From a clinical perspective, adoption would depend on proven safety, reliability of efficacy, and well-defined clinical indications. Clinicians are likely to support artificial blood initially in high-risk or resource-limited settings where conventional transfusion is unavailable or contraindicated. Also, there are ethical issues in regard to equity, since there would be a high production costs that would be incurred with bioprocessing. Other ethical issues that would be expected to arise would relate to the sourcing of stem cells and avoiding any issues that could be perceived to be exploitative. The major scientific, manufacturing, regulatory, and ethical bottlenecks that have historically limited the clinical adoption of artificial blood, along with emerging convergence points, are summarized schematically in Figure 2.

Figure 2 Panoramic roadmap of translational challenges and convergence points in artificial blood development. AI, artificial intelligence; cRBC, cord red blood cells; GMP, Good Manufacturing Practice; Hb, hemoglobin; NO, nitric oxide.

Future trends in artificial blood

Future trends in artificial blood are defined by two major strategic shifts: the move toward comprehensive modular replacements for whole blood, and the industrial scaling of cell-based therapies. Recognizing that no single agent can replicate the full functionality of native blood, research is heavily invested in developing hybrid, multicomponent systems (53). These “whole blood surrogates” aim to provide the three core functions of blood—oxygenation, hemostasis, and hemodynamics—in a single, stable, and universal product (53). A prime example is the collaboration integrating ErythroMer, a lyophilized (freeze-dried) nanoscale oxygen carrier, with a synthetic hemostatic agent, SynthoPlate™, along with freeze-dried plasma components. The resulting products are stable at room temperature for an estimated shelf life of at least a year, positioning them as essential “Bridging therapies” for acute trauma and battlefield scenarios.

For cultured HSC RBCs, derived from iPSCs, the challenge is transitioning from biological proof-of-concept to industrial scale-up (54). While the feasibility of human transfusion has been demonstrated, current manufacturing processes are financially prohibitive, costing thousands of U.S. dollars per unit. The path to commercial viability is now focused on breakthroughs in bioprocess engineering.

The key future developments include developing modified iPSC lines, such as Kitjak2 cells, that can continually self-renew and proliferate for up to 70 cell-doubling cycles in cost-effective, cytokine-free media (55). This greatly reduces the high input cost barriers of traditional culture protocols (51). Additionally, focus remains on improving enucleation efficiency—the process by which the nucleus is shed to form a functional erythrocyte—to ensure quality and long-term in vivo survival (51).

Advances in HBOCs prioritize nanotechnology for safety. Encapsulated HBOCs, such as HbVs, physically shield the hemoglobin inside a lipid shell (56). This encapsulation creates a diffusion barrier that retards NO scavenging, effectively eliminating the severe vasoconstriction that caused the failure of earlier acellular products (5). Encapsulated carriers are also designed with biomimetic features, such as pH-responsive oxygen affinity, to optimize delivery to hypoxic tissues.

Finally, computational modeling and artificial intelligence (AI) are being leveraged to accelerate the design of these complex molecules. AI is used to predict and optimize the stability, half-life, and oxygen affinity of HBOCs, allowing fine-tuning to minimize risks like oxidative degradation and NO scavenging before costly and time-consuming preclinical trials. This multidisciplinary integration is expected to accelerate the translation of specialized artificial blood components into clinical reality. The search for an effective and universally applicable artificial blood substitute has remained a formidable challenge. Over the past decade, the research in the field of artificial blood has rapidly advanced from conceptual prototypes to clinically translatable oxygen carriers.

Future progress in artificial blood development will depend on integrating stem cell biology, materials engineering, and computational modelling of oxygen kinetics. Key priorities include:

• Scaling manufacturing: achieving cost-effective, large-scale production of HSC cultured RBCs and synthetic oxygen carriers through optimized bioreactors and continuous culture systems.
• Enhancing biocompatibility: reducing vasoactivity and oxidative stress through encapsulation, antioxidant coatings, and hemoglobin engineering.
• Regulatory harmonization: establishing unified global standards for GMP and long-term safety evaluation, focusing on renal and cardiovascular outcomes.
• Hybrid and modular systems: exploring hybrid carriers combining biological and synthetic mechanisms, for example HbVs within PFC nano emulsions.
• AI-driven design: employing AI to predict structure-function relationships and optimize oxygen affinity, stability, and in-vivo kinetics.
• Ethical and economic considerations: ensuring equitable access and transparency in stem-cell sourcing, gene editing, and cost allocation.

Although neither HSC cultured RBCs, HBOCs nor PFCs have yet achieved routine transfusion replacement, their niche approvals and ongoing clinical studies demonstrate renewed momentum. Progress in large scale bioprocessing, nano encapsulation, and oxygen delivery modelling may finally translate these long-standing concepts into viable clinical tools for transfusion independent oxygen therapeutics.

Strengths and limitations of the review

This review integrates clinical trial data, translation studies, and emerging technology for various artificial blood modalities to provide a comprehensive and look-ahead perspective. However, challenges emerge due to reliance on early clinical trial data for various technologies and the rapidly progressing nature of this field, making some conclusions potentially time specific. Moreover, while this comparison highlights key roadblocks, definitive clinical success for various methods is still unattained.

Conclusions

In conclusion, artificial blood research has made notable progress over the past decade, advancing HBOCs, PFC emulsions, stem-cell-derived RBCs, platelet substitutes, and nanoscale analogues. These technologies aim to address limitations of donor blood, such as supply shortages, short shelf life, and infectious risks, but each faces unique challenges in safety, scalability, and cost. Despite improvements like reduced toxicity and longer shelf life in newer formulations widespread clinical use is limited by regulatory, economic, and manufacturing barriers. Current efforts focus on scaling up lab-grown RBC production, improving biocompatibility, and using innovations in nanotechnology and AI. While artificial blood cannot yet replace donor transfusions for routine care, promising clinical trials and niche approvals suggest specialized applications are likely in the near future, particularly in military, emergency, and rare disease settings. Continued interdisciplinary collaboration and attention to ethical and economic considerations will be key to achieving the goal of transfusion-independent oxygen therapeutics.

Acknowledgments

We thank J. Peter R. Pelletier, MD, Clinical Professor at University of Florida and Director of Transfusion Services, for his initial contributions to the manuscript and guidance in developing its concept.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Blood for the series “Artificial Blood”. The article has undergone external peer review.

Peer Review File: Available at https://aob.amegroups.com/article/view/10.21037/aob-2025-1-51/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://aob.amegroups.com/article/view/10.21037/aob-2025-1-51/coif). The series “Artificial Blood” was commissioned by the editorial office without any funding or sponsorship. M.T.F. served as the unpaid Guest Editor of the series, and serves as an unpaid editorial board member of Annals of Blood from November 2024 to October 2026. B.S. reports patents of Use of PFCs for TBI and Use of PFCs for Cardiac Arrest. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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