Shortly after the discovery of blood circulation in 1616people tried various transfusion alternatives such as beer, milk and urine. In the 1870s and 1880s, the transfusion of milk from cows, goats and even women gain territory in the USA. Unsurprisingly, these products have fallen out of favor due to health complications.
With the advent of the World Wars, research efforts to find alternatives to blood intensified. In recent decades, however, despite unprecedented medical advances, from pig heart transplantation to 3D printing of organssynthesizing something as basic as blood has had limited success.
Blood is like a giant soup with several ingredients. The liquid component – and the most important – is plasma, which contains salts, antibodies and other major proteins. The solid – or cellular – component is a small fraction of platelets (essential for clotting), white blood cells (to fight infections) and an abundance of red blood cells (RBCs). Each RBC contains a special protein called hemoglobin which is essential for the transport of oxygen and other gases.
Research progress on specific blood components has varied. “Freeze-dried plasma is already on the market and freeze-dried platelets are in human trials,” said Allan Doctor, director of the Center for Blood Oxygen Transport and Hemostasis at the University of Maryland School of Medicine. “But biosynthetic oxygen carriers are still in advanced preclinical development due to the complexity of mimicking, rather than simply freeze-drying, human cells.”
The way hemoglobin latches on to oxygen in our lungs and releases it to our organs – while accounting for varying demands such as when we exercise or acclimatize to higher altitudes – is sophisticated. . The transport of carbon dioxide from tissues to our lungs is equally dynamic and complex.
“Hemoglobin-based oxygen carriers (HBOCs) – also known as ‘blood substitutes’ – are made from hemoglobin that has been removed from red blood cells,” said Abdu Alayash, head of the lab. of Biochemistry and Vascular Biology at the FDA’s Center for Biologics Evaluation. and Research, said in an email. “But because the hemoglobin in these transporters is no longer locked away, it can undergo chemical changes that make it extremely reactive and toxic as it circulates through the bloodstream, causing tissue damage.”
The first generation of HBOCs had significant side effects such as high blood pressure, kidney damage and heart damage. As a result, these clinical trials were halted and progress in blood substitute research slowed. But recent advances in biomedical engineering, synthetic chemistry, and stem cell biology have helped address several limitations and inspired many more creative approaches to finding viable blood substitutes.
Although donor blood is our best option, it has several limits. Each unit can be stored for up to six weeks in cool temperatures, posing logistical challenges for use in emergency situations. Blood cells also have a mosaic of proteins on its surface that trigger strong immune responses if mismatched during a transfusion and can harbor infectious pathogens.
The ideal prototype of a blood substitute aims to overcome these limitations. Being stable outside of hospitals would make it easier to use in emergency situations. Being devoid of proteins that trigger immune reactions would make it more widely transfusible. A sterile design and manufacturing pipeline would prevent the spread of blood-borne pathogens. And not being derived from human blood products would benefit people such as Jehovah’s Witnesses for whom blood transfusion is forbidden.
But while it can be difficult to meet all the criteria, researchers are making significant progress through multidisciplinary approaches.
Some groups enhance the usability of HBOC to lessen hemoglobin reactive side effects. One such product is Hemopure – derived from cow’s hemoglobin purified and stabilized with binding chemicals. Although having undergone numerous series of clinical testshis Side effects — including high blood pressure and strokes — prevented full Food and Drug Administration approval.
“The product works as a good bridge between an emergency situation and letting your body resume its natural blood production process,” said Jonathan H. Waters, director of the blood management program at the Medical Center of the University. ‘University of Pittsburgh. “But since it’s not FDA approved, we have to go through a lot of steps to access it for humanitarian purposes.”
Practicing in an area with a high density of Jehovah’s Witnesses, Hemopure often serves as a lifeline. Waters hopes regulators recognize the importance of these clinical scenarios and consider them in future approval decisions.
Advances in nanocapsule technologies have led to other products such as erythromer, a red powder composed of human hemoglobin in a complex mixture of membrane lipids. Its unique formulation, developed by Doctor, Dipanjan saucepan and colleagues, allows for several months of stability and rapid recovery not only in resource-limited areas such as war zones, but also in pre-hospital civilian trauma. Having passed the FDA requirements for new drugs before investigationit is scheduled for phase I clinical trials in 2024.
But some researchers say using cow or human hemoglobin may be the root problem because these are molecules that exist naturally inside the RBC membrane – without direct contact with the bloodstream. When isolated and exposed to blood vessels, they react with molecules they are not meant to affect, causing harmful side effects. Jacob Elmer’s group at Villanova University instead explores the hemoglobin of the earthworm commonly known as the Canadian earthworm – which naturally circulates in the bloodstream without the protection of a red blood cell.
“Earthworm hemoglobin has many favorable adaptations that make it an excellent candidate for blood replacement,” Elmer said, “and preliminary studies have shown that it can safely deliver oxygen to mice. and hamsters without the adverse effects of cow and human hemoglobin.”
Although these studies are still in their infancy, Elmer said he hopes they could lead to the development of safer and more effective oxygen carriers.
However, not everyone is invested in the transfusion of mature hemoglobins and instead exploits the flexibility of stem cells.
“Adult human cells can be transformed into versatile stem cells, which can then be streamlined into blood cells,” said Christopher Thom, a blood researcher at the University of Pennsylvania’s Perelman School of Medicine. “But there are many boundaries that we need to better understand, including why these stem cell-derived red blood cells promote the expression of fetal hemoglobin and do not readily shed their nuclei as they mature, making their oxygen transport less efficient.
Advances in this field can lead to the conversion of any cellular source into blood cells and the production of large quantities of red blood cells under simple laboratory conditions.
Despite the scientific complexities, research into synthetic blood substitutes is advancing rapidly. Several preclinical studies on HBOCs are nearing completion, and clinical trials are on the horizon. Groups studying hemoglobins and invertebrate stem cells are eager to delve into the search for unique oxygen transport mechanisms and engage in knowledge exchange.
“Once we’re able to optimize the oxygen-carrying component, putting all the pieces together to test synthetic whole blood will be the next big step,” Dr.
Beyond the science alone, some researchers are frustrated with regulatory requirements.
“The FDA has been the biggest obstacle to advancing the development of artificial oxygen carriers, despite multiple candidates,” Jonathan Jahr, professor emeritus at UCLA Anesthesiology, said in an email. “They need to go beyond asking for a product with no side effects, because all drugs have side effects, including blood!”
For the FDA, however, safety and toxicity issues warrant caution.
“The FDA recognizes that HBOCs have many potential advantages over human blood, including availability, compatibility and long-term storage,” spokeswoman Abby Capobianco said in an email. “However, they also raise a number of concerns, including toxicity. The basis of HBOC toxicity is poorly understood and industry research may be proprietary. »
Capobianco said the FDA supports “the safe clinical development of HBOCs” and works with industry and scientific groups to advance these products.
But even if the wrinkles of HBOC side effects are mitigated, can synthetic blood go from being a time-limited “bridge” technology to something more self-contained? The doctor said he had hope.
“Once we can establish the benefits in clinical settings where blood is not an option and learn how to prolong the circulation time of artificial oxygen carriers,” he said, “I expect that we can continue to use these carriers as a true alternative to natural blood.
