Artificial blood

Artificial blood refers to manufactured substitutes for the oxygen-carrying function of red cells. The term is misleading in a way worth stating at the outset: no product replaces blood. Blood carries oxygen and carbon dioxide, clots, transports immune cells, buffers pH, distributes hormones and regulates temperature. Every substitute developed so far addresses only oxygen transport, and is more accurately called an oxygen therapeutic. Four decades of development have produced one product approved and withdrawn in the United States, several approved in other jurisdictions or for veterinary use, a large trial record of harm, and a recent shift toward growing real red cells in culture instead.

§What a substitute has to do

Donated red cells set a demanding benchmark. They circulate for months, release oxygen in response to local acidity and carbon dioxide, do not leak their contents into tissue, and are cleared by an orderly process when worn out. A substitute must match enough of that to be useful without triggering the vascular and oxidative injury that free haemoglobin causes, and it must do so at a price and shelf life that justify displacing a donation system that already works in wealthy countries. The one property no candidate has ever attempted is the rest of blood's job: clotting, immunity and the transport of everything that is not oxygen. Whole blood, and the Organ shortage-like logistics of collecting it, remain necessary regardless.

§Haemoglobin-based oxygen carriers

The obvious approach is to use haemoglobin without the cell around it. Cell-free haemoglobin binds oxygen, needs no blood typing, can be sterilized, and can be stored at room temperature for a year or more — the properties that make it attractive for trauma care, military medicine and settings without a cold chain.

Raw haemoglobin outside a red cell behaves badly. The tetramer dissociates into dimers small enough to be filtered by the kidney, causing renal injury. It is not protected by the red cell's reducing enzymes, so it oxidizes to methaemoglobin and releases free haem and iron, which drive oxidative tissue damage. Its oxygen affinity is wrong without the 2,3-diphosphoglycerate that red cells supply. And, most consequentially, it moves freely into the space between endothelial cells and there scavenges nitric oxide, the signalling molecule that keeps arterioles dilated.

Chemistry addressed the first problems and not the last. Cross-linking the tetramer prevented dissociation; polymerization with glutaraldehyde produced larger molecules with longer circulation; conjugation to polyethylene glycol increased size and reduced extravasation. Products developed on these principles included a diaspirin cross-linked human haemoglobin, a polymerized human haemoglobin, and a polymerized bovine haemoglobin. The bovine product remains licensed in South Africa and is available in the United States under expanded access for patients with severe anaemia who cannot receive a transfusion, most often for religious reasons; a veterinary version is approved for dogs.

§Why the trials failed

The clinical record is the reason haemoglobin-based carriers are not in routine use. A trauma trial of the diaspirin cross-linked product was stopped in the 1990s for excess mortality in the treatment arm. A polymerized human haemoglobin was tested in prehospital trauma under regulations permitting enrolment without consent, which generated its own controversy, and did not establish benefit; its manufacturer wound up.

The decisive analysis was a 2008 meta-analysis by Charles Natanson and colleagues covering sixteen trials of five different products across several clinical settings. It found an increase in mortality of roughly thirty percent and a near-tripling of myocardial infarction risk associated with these agents, and the effect was consistent across products, which pointed to a class mechanism rather than a manufacturing defect.¹ The mechanism generally accepted is nitric oxide scavenging: an agent designed to deliver oxygen constricts the vessels that deliver it, raising blood pressure and reducing perfusion of the microcirculation, with the heart the most vulnerable organ.

A class effect, not a bad batch

The consistency of the harm signal across chemically distinct products is what makes the haemoglobin approach hard to rescue. Any successor has to keep haemoglobin away from endothelial nitric oxide, which in practice means putting it back inside something — a vesicle, a polymer shell, a cell.

§Perfluorocarbons

Perfluorocarbons dissolve gases physically rather than binding them chemically. They carry roughly twenty times more oxygen per volume than water, release it readily, and can be manufactured synthetically with no biological source at all. Because they are immiscible with water they must be delivered as emulsions of submicrometre droplets.

Their limitations follow from the physics. Physical dissolution is linear in oxygen partial pressure, so a patient must breathe high concentrations of oxygen for the carrier to be useful, which restricts the setting. Emulsion droplets are cleared by macrophages and stored temporarily in liver and spleen, and the emulsifiers activate complement, causing flu-like reactions and transient reductions in platelet count.

A first-generation emulsion was approved in the United States in 1989 for use during balloon angioplasty and withdrawn a few years later after minimal clinical uptake.² A second-generation perflubron emulsion reached late-stage trials in cardiac surgery, where an excess of neurological events led to the programme being halted. Interest persists for specific niches, including oxygenation during organ preservation and as ultrasound contrast agents, rather than as a general transfusion substitute.

§Encapsulated haemoglobin and cultured red cells

The current field splits along the line the meta-analysis drew.

One branch puts haemoglobin back inside a container. Liposome-encapsulated haemoglobin vesicles, developed principally in Japan using haemoglobin purified from expired donor blood, are in early-phase human testing; the encapsulation is intended to prevent extravasation and nitric oxide scavenging while retaining long shelf life. Polymer-nanoparticle carriers with pH-sensitive oxygen release are in preclinical development under military funding, on the argument that the decisive use case is prehospital haemorrhage where no blood bank exists. These belong to the same family of engineered carriers described in Targeted drug delivery and Lipid nanoparticles. They are also the closest existing objects to the artificial red cell proposed in Respirocytes, and the comparison is instructive: the proposed device assumes pressurised diamondoid vessels and onboard control systems of a kind that Medical nanorobots as a field has not built, while the real vesicles are liposomes filled with purified human protein and perform a fraction of the imagined function.

The other branch grows real red cells. Human haematopoietic stem cells from donated blood, or immortalized erythroid progenitor lines of the kind established at Bristol, can be differentiated in culture into enucleated red cells.³ The RESTORE trial in the United Kingdom, run by NHS Blood and Transplant with university partners, performed the first in-human transfusion of laboratory-grown red cells in 2022, giving volunteers small volumes of tagged cultured cells alongside standard donor cells to compare survival in circulation. Cultured cells are all newly made, whereas a donated unit contains cells of every age, so a cultured transfusion may last longer and require less frequent transfusion — the trial's actual hypothesis, and one that matters most for patients with thalassaemia or sickle cell disease who are transfused for life and accumulate alloantibodies. See Casgevy for the curative alternative in those diseases.

The obstacle is arithmetic. A single unit of blood contains about two trillion red cells. Culturing that many, reproducibly, at a cost within reach of a health service, is a manufacturing problem several orders of magnitude beyond current bioreactor capacity, and cultured units are presently many times more expensive than donated ones. It is the same scale-up wall that constrains Tissue engineering generally, without the additional requirement of building a structure. Deriving red cells from Induced pluripotent stem cells would remove the dependence on donor progenitors entirely, and has been demonstrated at laboratory scale with poor enucleation efficiency. The near-term application is therefore not general transfusion but small volumes of rare blood groups that are difficult to source from donors.

A parallel line of work attacks supply rather than substitution, using enzymes discovered in gut bacteria to strip the A and B antigens from donor red cells and convert them to universal group O.⁴ Efficiency has improved and the approach would ease matching rather than replace donation.

§Where a substitute would actually be used

The case for oxygen therapeutics rests less on replacing routine transfusion, which works well in developed health systems, than on situations where banked blood is unavailable: prehospital and battlefield haemorrhage, disaster response, regions without reliable cold chains, patients who refuse transfusion, and patients whose alloantibodies make compatible units hard to find. Long-duration spaceflight adds another, since blood cannot be stockpiled for years and marrow function is altered in microgravity, a problem noted in Space medicine; proposals to lower metabolic demand instead, discussed in Human hibernation and torpor, attack the same constraint from the other side.

Oxygen carriers also have a role outside transfusion. Perfusing a donor organ with an oxygen-carrying solution during machine preservation extends viability, which links this technology to the supply strategies in Lab-grown organs and to the mechanical circuits of the Artificial heart, where blood is likewise pumped across engineered surfaces.

Meanwhile the alternatives have improved. Whole blood has returned to prehospital trauma care, tranexamic acid reduces bleeding deaths, and restrictive transfusion thresholds reduced demand without harming outcomes. Any new product must beat these, and against the historical background of a class of agents that increased mortality, regulators are unlikely to accept anything short of a well-powered trial with a hard endpoint.

§See also

• Artificial heart
• Organ shortage
• Lab-grown organs
• Casgevy
• Targeted drug delivery
• Space medicine
• Tissue engineering
• Respirocytes

§References