Traditional blood transfusion is a life-saving therapy but depends entirely on human donors and a cold chain. Globally more than 118 million blood donations are collected each year – with 40% from high-income countries serving just 16% of the population. This imbalance means many regions face dangerous shortages. Artificial blood – broadly, any substitute that carries oxygen and vital components like red blood cells do – is being developed to address supply gaps, reduce infection risk, and make transfusions “universal” (no blood-type matching needed).
Types of Blood Substitutes
Artificial blood approaches generally fall into three categories:
- Hemoglobin-based carriers (HBOCs): These use haemoglobin (from humans, animals or engineered sources) stripped of its red-cell packaging. The haemoglobin may be chemically modified or enclosed in particles or albumin. HBOCs can transport oxygen, but free haemoglobin in plasma is toxic: it scavenges nitric oxide (causing vasoconstriction) and can oxidise to harmful radicals. Recent designs aim to “tame” this chemistry (for example by PEGylation or mutating haemoglobin to reduce NO binding).
- Perfluorocarbon carriers (PFCs): These are inert fluorine-based liquids that dissolve oxygen directly. Several PFC emulsions (like the 1980s Fluosol) were tested and some marketed, but all showed side-effects (lung or liver stress) and failed FDA approval. Newer PFC products are under development: for example, Perftoran (a Russian/U.S.-rebranded PFC mix used in 35,000 patients with mild effects) is now being rebranded as FluorO2, and PHER‑O2 is in translational research. Latest PFCs may be coated with proteins (albumin, etc.) to improve safety.
- Cultured red blood cells: These are real red cells grown in vitro from stem or progenitor cells (e.g. cord-blood, induced pluripotent stem cells or immortalised lines) under conditions that mimic bone marrow. Such lab-made cells carry oxygen naturally and avoid immune or infection issues of donor blood. They offer promise for rare blood types, but production is complex. For example, the UK’s “RESTORE” trial is infusing tiny volumes (10 mL) of stem-cell-derived erythrocytes into volunteers to compare their survival time to normal blood. This will help assess whether manufactured cells behave like donor cells in humans.
Breakthroughs and Trials
Recent advances are bringing artificial blood closer to reality:
- Japan’s universal blood trials: At Nara Medical University, Professor Hiromi Sakai is testing hemoglobin vesicles – tiny lipid-coated Hb bubbles made from expired human blood. In March 2025, Nara began a Phase I trial giving 100–400 mL doses to healthy volunteers. These vesicles lack blood-type antigens and can be stored ~2 years at room temperature. Preliminary reports suggest only mild side-effects (minor fever or rash) that resolved quickly. If safe and effective, this “purple” artificial blood could ease shortages and emergencies.
- Albumin-encapsulated Hb: Professor Teruyuki Komatsu (Chuo University) has designed a nanoparticle with a core of polymerised haemoglobin and an outer shell of human serum albumin, plus catalase enzyme to prevent Hb oxidation. At ~30 nm, these particles evade immune clearance. In a rat study of 50% blood loss, an infusion of this SFHbNP restored blood pressure and circulation fully, with no organ damage The formulation was well tolerated in vitro and in animals. This suggests albumin-coated HBOCs can safely mimic RBCs in haemorrhage therapy.
- Engineered fetal haemoglobin: Researchers have inserted specific mutations into fetal Hb (γ-subunit) to create a safer HBOC. The mutant showed much lower nitric oxide scavenging and lipid oxidation. In a rat reperfusion-injury model, the PEGylated Hb lowered oxidative stress and significantly improved survival compared to controls. This “tamed” Hb is a leading candidate for future HBOCs with far fewer side-effects.
- Stem-cell red cells: The UK’s RESTORE trial (NHS Blood & Transplant/NIHR) is pioneering transfusions with lab-grown cells. Donor-derived CD34+ cells were cultured 20 days to mostly enucleated reticulocytes, then infused twice (4 months apart). The study will track how long these cells circulate vs normal cells using isotope tracers. Early results are pending, but success would validate manufactured RBCs for rare types. Larger-scale RBC pharming efforts (using iPSCs or immortal lines) are also scaling up, aiming to produce “blood pharming” solutions to perennial shortages.
- Perfluorocarbon renaissance: PFC oxygen carriers are seeing renewed interest. Besides Perftoran/FluorO2 and PHER‑O2 noted above, novel PFCs bound to albumin or polymers promise better oxygen capacity with fewer side-effects. PFCs are chemically simpler than proteins, so can be made in large quantities; the goal is to overcome past issues like long in-body half-life and lung retention.
- US trauma blood programs: In 2023 the US Defense Advanced Research Projects Agency (DARPA) funded a $46M project to make a freeze-dried “whole blood” kit. It includes KaloCyte’s ErythroMer (a dry encapsulated Hb RBC substitute), synthetic platelets, and freeze-dried plasma. The aim is a portable, room-temp-stable pack medics can use on battlefields or accidents. This high-profile program underscores military interest in artificial blood solutions.
Challenges Ahead
Despite excitement, hurdles remain:
- Toxicity and side-effects: Free or modified haemoglobin can constrict vessels and generate reactive oxygen, as detailed above. Past HBOCs also caused kidney stress or inflammation in trials. Similarly, PFCs can embolise or trigger immune reactions. Any new carrier must prove it is as safe as donor blood under stress.
- Oxygen-delivery efficiency: Matching natural RBCs’ oxygen offloading is difficult. Large doses of carriers may be needed for full effect. For PFC emulsions especially, high volumes are required, which previously limited efficacy. Ensuring artificial cells release oxygen effectively in capillaries is a key engineering challenge.
- Scale-up and cost: Culturing sufficient red cells or extracting/engineering haemoglobin at scale is expensive. For example, lab-grown RBC transfusion today is limited to millilitre quantities. Producing tonnes of artificial blood for hospitals at reasonable price will require new biomanufacturing breakthroughs. Similarly, companies must secure ingredient supply (e.g. recombinant Hb) and support from investors.
- Regulatory barriers: To date no HBOC or PFC product has full FDA/EMA approval for transfusion. Regulators will demand rigorous demonstration of safety and comparability to human blood. Long-term studies and large clinical trials are still needed. For instance, Sakai’s human trials in Japan are safety-focused, with wider efficacy studies next if no problems arise.
- Shelf life and storage: One big advantage of artificial blood is long shelf life (some can be stored months or years at ambient temperature). But stability must be maintained. Degradation or aggregation over time could pose risks. Developers must show that oxygen carriers remain functional after storage and are free of pyrogens or breakdown products.
Applications and Outlook
Potential uses for artificial blood include:
- Emergency and trauma care: In accidents, disasters or battlefield wounds, rapid transfusion is critical. Artificial blood could be pre-stocked in ambulances or field kits, requiring no blood-typing. Japan’s initiative explicitly cites disaster response as a driver. A freeze-dried transfusion pack, for example, would empower first-responders to start transfusions en route or on-site.
- Surgery and chronic transfusions: Elective surgeries and patients with chronic anaemia (e.g. thalassemia) could benefit from artificial donors, reducing reliance on scarce volunteer blood. Lab-made RBCs might also supply rare blood groups or be antigen-negated for sensitised patients.
- Military medicine: Portability and universal compatibility make artificial blood attractive to armed forces. The DARPA project shows how the military is betting on it to save service members before they reach a hospital.
- Global supply and stockpiling: Finally, any blood substitute that can be stockpiled without refrigeration (and without risk of disease transmission) would help low-income regions. A universally compatible, long-lasting haemoglobin carrier could reduce preventable deaths from blood shortages worldwide.
In summary, decades of research have brought multiple candidate blood substitutes to the brink of clinical use. Recent trials in Japan, breakthroughs in design (PEGylated haemoglobin, albumin shells) and renewed PFC research reflect a maturing field. The goals are clear: a safe, effective oxygen carrier available on demand. If achieved, it could revolutionise transfusion medicine – saving millions more lives in emergencies, surgeries and beyond.
Sources
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Perfluorocarbon-based artificial oxygen carriers for red blood cell substitutes: considerations and direction of technology | Journal of Pharmaceutical Investigation
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