An earlier version of this article stated that ErythroMer had passed the FDA’s pre-investigational new drug requirements. It has completed a pre-Investigational new drug consultation with the FDA.
Shortly after the discovery of blood circulation in 1616, people tried various transfusion alternatives such as beer, milk and urine. In the 1870s and 1880s, transfusion of cow, goat and even human milk gained traction in the United States. Unsurprisingly, these products fell out of favor because of health complications.
With the advent of world wars, research efforts to find blood alternatives intensified. In the past several decades, however, despite unprecedented medical advances, from transplanting pig hearts to 3D printing of organs, synthesizing something as fundamental as blood has had limited success.
Blood and its components
Blood is like a giant soup with multiple ingredients. The liquid — and largest — component 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 encases a special protein called hemoglobin that is essential for transporting oxygen and other gases.
Research advances in specific blood components have varied. “Freeze-dried plasma is already on the market in Europe, 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 complexities of imitating, rather than just freeze drying, human cells.”
The way hemoglobin latches onto oxygen in our lungs and releases it into our organs — while accounting for variable demands such as when we are exercising or acclimating to higher altitudes — is sophisticated. Transporting carbon dioxide from tissues back to our lungs is equally dynamic and intricate.
“Hemoglobin-based oxygen carriers (HBOCs) — also known as ‘blood substitutes’ — are manufactured using hemoglobin that has been removed from red cells,” Abdu Alayash, chief of the Laboratory 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 carriers is no longer enclosed, it can undergo chemical changes that make it extremely reactive and toxic while circulating in blood, causing damage to tissues.”
The first generation of HBOCs had substantial side effects such as elevated blood pressure, kidney injury and damage to the heart. As a result, those clinical trials were discontinued and progress in blood substitute research slowed down. 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 limitations. Each unit can be stored for up to only six weeks at cool temperatures, causing logistical challenges for use in emergency situations. Blood cells also have a mosaic of proteins on its surface that elicit 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 shelf stable outside hospitals would make it easier for use in urgent situations. Being devoid of proteins eliciting immune reactions would make it more broadly 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 prohibited.
But while satisfying every criterion may be difficult, researchers are making significant headway through multidisciplinary approaches.
Some groups are improving HBOC usability to mitigate reactive hemoglobin side effects. One such product is Hemopure — derived from purified cow hemoglobin and stabilized by binding chemicals. Despite having undergone many rounds of clinical testing, its side effects — including high blood pressure and strokes — have prevented full approval from the Food and Drug Administration.
“The product works as a good bridge between an emergency situation and letting your body resume its natural blood making process,” said Jonathan H. Waters, director of the Blood Management Program at the University of Pittsburgh Medical Center. “But because it isn’t FDA approved, we need to go through many hoops to access it for compassionate use.”
Practicing in an area with a high density of Jehovah’s Witnesses, Hemopure often serves as a lifesaving conduit. Waters hopes that regulatory agencies recognize the importance of these clinical scenarios and account for 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 blend of membrane lipids. Its unique formulation, developed by Doctor, Dipanjan Pan and colleagues, allows for several months of shelf stability and quick reconstitution in not only resource-limited areas such as war zones but also civilian pre-hospital traumas. ErythroMer has completed a pre-Investigational new drug consultation with the FDA. If it receives the new drug designation at the “planned pace,” it may be in Phase 1 clinical trials by the end of 2024, Doctor said.
But some researchers argue that using cow or human hemoglobin may be the fundamental problem since they are molecules that naturally exist sheathed inside the RBC membrane — without direct contact to the bloodstream. When isolated and exposed to blood vessels, they react with molecules they are not supposed to affect, causing harmful side effects. Jacob Elmer’s group at Villanova University is instead exploring hemoglobin from the earthworm commonly known as Canadian nightcrawler — which naturally circulates in the bloodstream without the protection of a red blood cell.
“Earthworm hemoglobin has many favorable adaptations that makes it a great blood substitute candidate,” Elmer said, “and preliminary studies have shown that they can safely deliver oxygen in mice and hamsters without the adverse effects of cow and human hemoglobin.”
While these studies are in early stages, Elmer said he hopes that they may lead to the development of safer and more effective oxygen carriers.
Not everyone, however, is invested in transfusing mature hemoglobins and are instead harnessing the flexibility of stem cells.
“Adult human cells can be turned into multipurpose stem cells, which can then be streamlined into blood cells,” said Christopher Thom, a blood researcher at University of Pennsylvania’s Perelman School of Medicine. “But there are several limitations that we need to better understand, including why these stem cell-derived RBCs favor expression of fetal hemoglobin and don’t easily lose their nuclei when they mature, which makes their oxygen transport less efficient.”
Progress in this domain may lead to converting any cell source into blood cells and produce large amounts of RBCs in simple laboratory settings.
Despite scientific complexities, research on synthetic blood substitutes is advancing rapidly. Several preclinical studies for HBOCs are rounding up, and clinical trials are on the horizon. Groups studying invertebrate hemoglobins and stem cells are eager to delve into researching unique mechanisms of oxygen transport and engage in knowledge exchange.
“Once we are able to optimize the oxygen carrying component, putting all the pieces together to trial synthetic whole blood will be the next big step,” Doctor said.
Beyond the science alone, some researchers are frustrated by regulatory requirements.
“The FDA has been the biggest impediment to advancement of developing artificial oxygen carriers, despite multiple candidates,” said Jonathan Jahr, professor emeritus at UCLA Anesthesiology, in an email. “They must get beyond demanding a product with no side effects, as all drugs have side effects, including blood!”
For the FDA, however, safety and toxicity concerns warrant caution.
“The FDA recognizes that HBOCs have many potential advantages over human blood, including availability, compatibility and long-term storage,” said spokeswoman Abby Capobianco in an email. “However, they also raise a number of concerns, including toxicity. The basis of HBOC toxicity is poorly understood and research done by industry 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 in HBOC side effects are evened out, can synthetic blood go from being a time-limited “bridging” technology to something more stand-alone? Doctor said he is hopeful.
“Once we can establish benefit in clinical settings where blood is not an option and have learned how to extend the circulation time of the artificial oxygen carriers,” he said, “I expect that we will be able to pursue use of these carriers as a true alternative to natural blood.”