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Lab mice
Photo by Aaron Logan

SAN DIEGO—Researchers have developed artificial red blood cells (RBCs) that appear able to emulate functions of natural red blood cells (RBCs), at least in rodents.

The artificial RBCs, known as ErythroMer, are designed to be freeze-dried, stored at ambient temperatures, and reconstituted with water when needed.

If ErythroMer proves safe and effective in humans, it could represent an alternative to blood transfusions that might be useful in situations where donated blood is difficult to obtain or store.

“There are currently no simple, practical means to bring transfusion to most trauma victims outside of hospitals,” said Allan Doctor, MD, of Washington University in Saint Louis, Missouri.

“ErythroMer would be a blood substitute that a medic can carry in his or her pack and literally take it out, add water, and inject it.”

Dr Doctor presented details on ErythroMer at the 2016 ASH Annual Meeting (abstract 1027).

Design

“Due to significant advances in synthetic chemistry and nanomedicine, we’re now able to encapsulate biologics with programmable polymers to generate nanoparticles that can emulate normal cellular physiology,” Dr Doctor noted.

With ErythroMer, he and his colleagues encapsulated human hemoglobin, methylene blue, and 2,3-DPG in an amphiphilic polymer shell. The polymer and its payload components, through microfluidization, self-assemble into toroids that are about one-fiftieth the size of human RBCs.

ErythroMer is designed to be pH-responsive, so that, in areas of high pH, 2,3-DPG is sequestered in the inner surface of the particle shell and does not bind to hemoglobin. In areas of low pH, 2,3-DPG is released from the shell and binds to hemoglobin, facilitating oxygen offloading. The role of methylene blue is to inhibit auto-oxidation of hemoglobin.

The last step in synthesis of the particle is crosslinking of the surface, which neutralizes the surface charge, stabilizes the particle, and generates a selective diffusion barrier to nitric oxide. The particle can be lyophilized for extended storage and later reconstituted.

Testing

Tests showed that ErythroMer matches the oxygen binding feature of human RBCs within 10%, a level researchers say should be sufficient to stabilize a bleeding patient until a blood transfusion can be obtained.

Experiments in mice showed that ErythroMer captures oxygen in the lungs and releases it to tissues in a pattern that is indistinguishable from that seen in a control group of mice injected with their own blood.

In rats, ErythroMer effectively resuscitated animals in shock following acute loss of 40% of their blood volume.

So far, tests suggest ErythroMer has overcome barriers that halted the development of previous blood substitutes.

However, Dr Doctor noted that ErythroMer does have its weaknesses. The particles are cleared rapidly from the bloodstream (in 3 to 7 hours), and hemoglobin sourcing presents a challenge. The researchers are now exploring the possibility of using recombinant hemoglobin genetically engineered in yeast.

The team hopes to further optimize ErythroMer’s shell, extend circulation time, confirm the efficacy of ErythroMer in a larger animal model (rabbits), evaluate the impact of the product on the coagulation and immune systems, and scale up production.

If further testing goes well, the researchers estimate that ErythroMer could be ready for use by field medics and emergency responders within 10 to 12 years.

ErythroMer development has been supported by the Children’s Discovery Institute at Washington University and St. Louis Children’s Hospital, the Skandalaris Center at Washington University, and the BioSTL Fundamentals Program.

This research was funded by the National Institute of General Medical Sciences; the National Heart, Lung, and Blood Institute; the National Institute of Child Health and Human Development, the US Department of Defense; the American Heart Association; Doris Duke Foundation; and Children’s Discovery Institute. end hematology article


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