For Trauma Use — Dried Blood Powder, Just Add Water

Zosia Chustecka

December 03, 2016

SAN DIEGO — It may be a decade yet before it becomes a reality, but there was a buzz here today about artificial blood cells that could be used for trauma patients.

The lead indication is use in the battlefield, where a paramedic would mix a bag of red powder with a bag of sterile water to make artificial blood that could be immediately given to any individual, without the need to check blood type.

It could make a difference between life and death.

It is estimated that 25% of in-field deaths of US military personnel are preventable, and hemorrhagic shock is the cause of death in 90% of these cases, where individuals die not from damage to major organs but because they basically bleed to death before they can be brought to a hospital, commented Allan Doctor, MD, professor of pediatrics, biochemistry, and molecular biophysics at Washington University in St Louis, Missouri.

Another potential use is for trauma victims, again to prevent death from blood loss. The product could be carried by ambulances and rescue helicopters, and it could sit on the shelf for years, without the need for refrigeration, until it is needed, unlike donated blood, which requires special storage conditions and ages, and can eventually no longer be used.

The National Academy of Medicine estimates that, in the United States alone, there are approximately 17,000 preventable trauma deaths per year because of untreated hemorrhagic shock in the prehospital phase of resuscitation.

These potential uses were described here at the American Society of Hematology 58th Annual Meeting. Dr Doctor will report on the development of the new artificial blood substitute, known as ErythroMer, at a session on December 5 (abstract 1027), but gave a brief preview at today's press briefing.

"This is a conceptual and significant technical advance, as this is a system that can take up oxygen and then deliver it to tissues, which solves a lot," commented press briefing moderator Armand Keating, MD, professor of medicine and biomedical engineering and director of the Cell Therapy Program at the University Health Network in Toronto, Ontario.

He said the timeframe of 8 to 10 years before the first in-human studies that Dr Doctor outlined for the product "sounds like a realistic timeframe."

"There is lot of work that still needs to be done," commented Dr Keating. "For example, What's the circulation time? How long are those microparticles going to last? They are one-fiftieth the size of red blood cells, so what are the implications of that? Will they have the capacity to extravasate into tissues? Would they pass through the kidney?" he said.

Donut-Shaped Nanoparticles

The ErythroMer donut-shaped artificial cells were developed in partnership with Dipanjan Pan, PhD, at the University of Illinois at Urbana-Champaign.

"The product is a nanoparticle, about one-fiftieth the size of a red blood cell, and it has a synthetic polymer artificial membrane that is encoded with wet-ware that manipulates the oxygen affinity of the particle to imitate that of a red blood cell," Dr Doctor explained. "It catches the oxygen and then it releases it into the tissue."

"In a red blood cell, this is done by a complex set of enzymes," he said. "We have a small molecule that alters the hemoglobin oxygen affinity."

Availability of this small molecule in the particle cavity is controlled by the inner surface of the particle shell in response to changes in blood pH, and this enhances oxygen acquisition in the lungs and then releases oxygen in tissues that have the greatest need, particularly in tissues where there is lactic acid. "It acts like an electromagnet, grabbing oxygen from one place and releasing it in another," Dr Doctor commented.

"This is a feature that was never available before," he said, describing the innovation as a "design breakthrough."

Previous attempts at developing hemoglobin-based oxygen carriers (HBOCs) have failed, the researchers comment in their abstract, because of design flaws that did not preserve physiologic interactions of hemoglobin with oxygen (they capture oxygen in lungs, but do not release oxygen effectively to tissue) and also with nitric oxide (they trap nitric oxide, causing vasoconstriction). The design of ErythroMer surmounts these weaknesses by encapsulating hemoglobin, controlling oxygen capture/release with a novel 2,3-DPG shuttle, and attenuating nitric oxide uptake through shell properties.

"So now we are able to package the blood carrying protein hemoglobin with a small molecule that alters its behavior," Dr Doctor said.

Thus far, the hemoglobin used in the development of this product has been obtained from donated blood that has passed its use-by date, but to avoid the risk of viral contamination, work is underway to enable possible future production with recombinant hemoglobin genetically engineered in yeast (developed in partnership with the Chalmers University of Technology in Gothenburg, Sweden).

There are also plans to scale up production. So far the product has been made at Washington University in Saint Louis and University of Illinois at Urbana Champaign, but there are plans to scale up production under the newly created company KaloCyte, a biotech start up founded by Drs Doctor and Pan in January 2016.

Proof-of-Concept in Mice

The proof-of concept study in genetically engineered mice was conducted in partnership with Greg Hare, MD, PhD, at the University of Toronto, Ontario. Using bioluminescence, researchers showed that ErythroMer takes up oxygen in the lungs and delivers it to tissues in a pattern indistinguishable from that seen in a control group of mice injected with their own blood.

In another set of studies conducted in rats, ErythroMer effectively resuscitated animals in shock following acute loss of 40% of their blood volume, the team reports.

The team also reports that ErythroMer matches the oxygen-binding feature of human red bloods cells within 10% and say this should be sufficient to stabilize a bleeding patient until a blood transfusion can be arranged.

"The ErythroMer prototype has passed rigorous initial ex vivo and in vivo 'proof-of-concept' testing and bench testing," the researchers conclude. "In models of major bleeding/anemia, ErythroMer reconstitutes normal hemodynamics and oxygen delivery, observed at the system, tissue, and cellular level."

The next steps are tests in larger animals, ongoing safety assessment, optimizing pharmacokinetics, and ultimately in-human trials. If all goes well, researchers hope that ErythroMer could be available for use by field medics and early 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, Skandalaris Center at Washington University, and BioSTL Fundamentals Program. Dr Doctor reports equity ownership in KaloCyte.

American Society of Hematology 58th Annual Meeting. Abstract 1024. Presented December 5, 2016.

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