Although there are more and more blood donors, scientists continue to research to find blood substitutes that can be used in an emergency and that could save many lives in the event of a catastrophe, an accident, in rural areas where ambulances are slow to arrive, or in war zones. Having blood available for transfusions in these types of situations is key to the survival of the victims, however, the precious red liquid that runs through our veins needs to be kept refrigerated after donation and its shelf life is only 42 days.
Allan Doctor, a physician-researcher at the University of Maryland School of Medicine (UMD) in the US, set out to overcome these drawbacks and in 2016 created an experimental type of artificial blood powder that he named ErythroMer and that obtained good results in its first tests with mice. Last year, the Defense Advanced Research Projects Agency (DARPA), an agency of the United States Department of Defense responsible for the development of new technologies for military use, announced a grant of 46 million dollars to a consortium led by the UMD to promote the development of a stable whole blood substitute based on ErythroMer, so it may not be long before we have a substitute for human blood. We tell you what artificial blood is and why the American army invests a fortune in its research.
- What is artificial blood like?
- Why is it so difficult to create a blood substitute?
- Other projects to create artificial blood
What is artificial blood like?
When someone starts bleeding from a cut or other minor wound, the plasma and platelets in the blood go to work to clot and close the opening, and our bodies immediately begin replacing the lost red blood cells and hemoglobin with new ones. The problem occurs when the individual suffers a severe trauma in which clotting does not work and there is difficulty replacing red blood cells at the same rate at which they are being lost.
“Each red blood cell is like a little thermostat that is constantly asking, ‘Is there enough oxygen? No? Well, let’s put some more blood in here,’” explained Allan Doctor, adding that to create an artificial blood type that is as close to human blood as possible, the product must contain clotting factors and oxygen. This artificial blood would be very useful in situations where it is difficult to obtain fresh blood, as it could be administered quickly to maintain the vital flow of oxygen to the organs until the patient was transferred to a hospital.
ErythroMer is made from recycled human hemoglobin, the protein in red blood cells that is responsible for transporting oxygen from the lungs to the rest of the body, wrapped in a membrane that mimics a tiny cell. It is a freeze-dried powder that can be used for years and is reconstituted simply by mixing it with saline, which is available anywhere. It should also be safe for any blood type, as its membrane does not include the red blood cell surface proteins that cause incompatibilities.
The latest data from animal tests with this product demonstrated effective oxygen delivery in mice that had 70% of their blood volume replaced with ErythroMer, while in rabbits that had half their blood volume removed, infusion of a fluid containing ErythroMer resuscitated the animals, just as real blood does.
Doctor is a strong proponent of hemoglobin-based oxygen carriers (HBOCs), such as ErythroMer. Despite decades of failed attempts to develop a good red blood cell substitute, ErythroMer, while still in preclinical animal testing, could be more durable and versatile than real blood and Doctor hopes to conduct an initial safety trial in healthy humans soon.
Why is it so difficult to create a blood substitute?
Mimicking blood is difficult: it is a complex mixture of molecules and cells. More than half of our blood is plasma, a yellowish liquid made up of water, proteins and salts. The rest is cellular matter, mainly platelets, essential for clotting after a cut or wound; white blood cells, which fight infection; and red blood cells, which not only give blood its red colour but also carry oxygen-providing haemoglobin.
Red blood cells, produced by the bone marrow at a rate of 2 million per second, are regenerated every 120 days. At any one time, there are 30 trillion of these cells coursing through the body’s 20,000 kilometers of blood vessels. Inside a red blood cell, there are about 260 million hemoglobin molecules. Each of these globular proteins has an iron complex called heme at its center, which captures oxygen and gives red blood cells their color.
DARPA’s Solutions to Bleeding with Bioartificial Resuscitation Products (FSHARP) program also seeks to develop synthetic platelets and freeze-dried plasma, but the primary goal is to mimic blood’s powerful oxygen carrier, and Doctor and his team in Baltimore, which includes biotech startup KaloCyte, are specifically focused on creating artificial red blood cells.
The first hemoglobin-based oxygen carriers (HBOCs) attempted to copy the polymeric structure of hemoglobin, but without a membrane. However, hemoglobin is a complicated molecule and toxic to tissues and vessels. It carries oxygen, a destructive oxidizing agent, in the wrong place. “You can’t just inject [hemoglobina] into the bloodstream,” Doctor said.
Other projects to create artificial blood
Over the past century, patients given blood substitutes made from free hemoglobin developed hypertension, high metabolic rates and rapid pulses. In the worst cases, these products caused heart attacks and kidney failure, due to a narrowing of blood vessels triggered by the free hemoglobin. But there were also successes.
The most successful non-encapsulated HBOC to date is Hemopure, developed in the 1990s and involving the extraction of hemoglobin from cow red blood cells, purification of the hemoglobin to remove pathogens, and chemically linking four proteins together as a tetramer. Hemopure was approved in South Africa in 2001 to treat perioperative anemia, but has been used primarily when standard transfusions were not an option.
However, a meta-analysis published in The Journal of the American Medical Association (JAMA) in 2008 concluded that all HBOC products were inherently toxic to the heart and that patients treated with them were 30% more likely to die compared with those receiving conventional transfusions, so testing was halted, investors panicked, and companies went bankrupt or stopped developing HBOC.
Doctor’s creation is not the only attempt to encapsulate hemoglobin in lipids to create a viable blood substitute. In Japan, a team led by chemist Hiromi Sakai of Nara Medical University has developed hemoglobin vesicles (HbVs), and a safety trial in men in 2020 showed encouraging results, with mild side effects. Other innovative approaches to replacing red blood cells are also being explored. The company Hemarina is developing a product based on hemoglobin from marine worms.
Even in Spain, at the beginning of 2023, the Spanish National Research Council (CSIC) announced its participation in SynEry, a European project whose objective is to develop by 2026 a scalable and on-demand technology to obtain an artificial substitute for blood, through the design of synthetic red blood cells.
Scientists and researchers at the Center for Blood Oxygen Transport and Hemostasis (CBOTH) at the University of Maryland School of Medicine hope to succeed where others have failed: creating an artificial blood substitute that can be freeze-dried, stored at room temperature, and used instantly in the field when donated human blood is in short supply or absent altogether. Leaders of this project are also hopeful that artificial blood will transform wound care and prevent uncontrolled bleeding, the most common cause of preventable deaths in severely injured trauma patients.
