Researchers receive $2.7 million NIH grant to develop the next generation of synthetic blood

Blood loss is the leading cause of death in trauma patients between the ages of 1 and 46 years, largely because they cannot access safe blood sources quickly enough. A possible solution? Freeze-dried synthetic blood.

A multi-institutional team led by Dipanjan Pan, the Dorothy Foehr Huck & J. Lloyd Chair Professor in Nanomedicine at Penn State, recently received a five-year, $2.7 million grant from the National Institutes of Health's National Heart, Lung, and Blood Institute to develop the next generation of synthetic blood.

"Mother nature is hard to mimic, but we're getting closer," said Pan, who is also a professor of materials science and engineering and of nuclear engineering. "Our goal is to design and optimize a blood substitute prototype, called Nano-RBC, that is based on a deformable nanoparticle. It is similar in shape to red blood cells and incorporates high-per-particle payloads of hemoglobin, the protein in red blood cells responsible for carrying oxygen."

He explained that the odds of survival increase dramatically when a person can receive a transfusion before losing too much blood, but that's often not possible in rural or war-torn areas without the specialized processing and storage facilities donated blood requires.

"There is a need for an artificial oxygen carrier to substitute for banked blood in settings where stored blood is unavailable or undesirable," Pan said. "Artificial blood is described as the 'Holy Grail' of trauma medicine. Researchers have been battling to develop it for 150 years, with many failures along the way."

More recent efforts included agents that could not release oxygen in damaged tissue or overloaded the body with hemoglobin, which can raise iron in animals, including humans, to toxic levels when not managed.

We are taking inspiration from these earlier failures and developing a next-generation functional system that attempts to mimic red blood cell physiological functions."

Dipanjan Pan, the Dorothy Foehr Huck & J. Lloyd Chair Professor in Nanomedicine at Penn State

Pan and his team previously developed ErythroMer, an artificial blood product that emulates the physiological properties of red blood cells, like their ability to bind and release oxygen. That work, conducted over a decade and currently in advanced stages of animal studies, was funded by more than $14 million in grants from the NIH, the Department of Defense and other agencies. The project - which has been featured in Science, the New Yorker and Popular Science, among other media outlets - is also part of a larger $46 million multi-institutional consortium, funded by the Defense Advanced Research Projects Agency.

ErythroMer was co-invented by Pan and Allan Doctor, professor of pediatrics and director of the Center for Blood Oxygen Transport and Hemostasis at the University of Maryland School of Medicine (UMSOM). Together with Philip Spinella, a military transfusion medicine expert at the University of Pittsburgh, Pan and Doctor co-founded a company called KaloCyte, Inc. to develop the agent, which consists of lipid-based nanoparticles. Such nanoparticles are made of lipids, or fats, and can carry and protect various deliverables, including oxygen.

"While Erythromer emulated the functional and physiological properties of the red blood cells, our current project is taking this research forward to the next level by mimicking the morphological characteristics of red blood cells - their physical shape and how they move," Pan said. The advanced version of the blood substitute product would have the same donut curve and thin, flat center of biological red blood cells, but would be one-tenth of the size. "At that nanometric level, the surface to volume ratio is extremely high, meaning that for a given volume, our agent has a significantly larger surface area due to its tiny size, allowing for unique properties, biological interaction with surrounding tissues and the ability to load high concentrations of hemoglobin. In other words, fewer of our particles could deliver the same amount of hemoglobin - and the oxygen they carry - biological red blood cells could carry."

One particularly appealing property that the researchers plan to keep from ErythoMer for Nano-RBC, Pan said, is that the particles can be lyophilized, or freeze-dried and stored at room temperature.

"The product can then be resuspended in salt water before administering to patients," Pan said, noting that the team demonstrated the approach's feasibility with ErythroMer.

With the newly funded project, the researchers aim to further develop new materials that act and look like red blood cells and test their functionality in animal models. Collaborators include Doctor, who will work to elucidate the mechanisms underpinning on oxygen release properties; Paul Buehler, professor of pediatrics and of pathology at UMSOM who will examine biodistribution; and Narayana Aluru, Cockrell Family Regents Chair in Engineering #9 at the University of Texas at Austin who will focus on computational analyzes in design and testing of potential products.

"The ultimate goal is to develop safe, dried oxygen therapeutics envisioned for use when stored red blood cells are unavailable, undesirable or in short supply," Pan said. "The inventiveness of materials researchers in health and medicine is limitless, and we're demonstrating that in this ambitious and highly collaborative project."