CLEVELAND (WJW) — Collaboration happening now between Case Western Reserve University and other American universities seeks a “world-first” innovation for which medical researchers have been questing for decades: artificial whole blood.

The work seeks to combine three independently created components that mimic the functions of real blood into something that can be freeze-dried and easily stored as powder for a long time, then transported — for instance, in an ambulance or in a field medic’s toolkit — and reconstituted on demand using saline.

The four-year project is made possible by $46.4 million in new federal funding from the Defense Advanced Research Projects Agency, or DARPA.

If all goes well, it could start helping civilians within the next decade: being used in surgical blood transfusions; relieving nationwide blood shortages; or helping lower mortality rates for trauma victims at the scenes of their injuries, said Anirban Sen Gupta, the Leonard Case J. professor of engineering at the Case School of Engineering.

“That’s why this is so exciting — this could be the culmination of a century of efforts by human beings to create a substitute for whole blood,” Sen Gupta is quoted in a news release. “This is a historic effort and one that scientists in our field have been talking about for a long time. We needed something visionary like this DARPA endeavor to really make it come together.”

Why is it important?

When a warfighter is injured in combat and is losing blood, the sooner they can get a blood transfusion, the more likely they are to survive, Sen Gupta said. But right now, there’s no good framework for supplying blood in emergencies outside of major hospitals or blood banks.

“Often times, blood transfusions are not available at the point of injury or in combat situations,” he said. “Similar situations can happen in car accidents, disasters, mass casualties. … Even if it’s available, it can be hours to get access to it. In these scenarios, time becomes the enemy.”

And blood is not available without donors. Far fewer people donated blood during the COVID-19 pandemic, leading to nationwide shortages. The product under development by the DARPA team would create a blood surrogate that doesn’t rely on donors, Sen Gupta said.

“The additional challenge is even if blood is available … where [is it] available for transfusion? It’s usually in big hospitals or hospitals that have good blood banks. Small and mid-sized hospitals that are not well-resourced may lack the ability to provide life-saving blood transfusions,” he added.

If the team is successful, the artificial blood could be helping military servicemembers and civilians alike in another seven to eight years, Sen Gupta said.

(Case Western Reserve University)

How does it work?

The artificial blood surrogate being developed by the DARPA-funded team has three components, each made independently of each other:

  • Artificial platelets — the organisms that cluster at the site of an injury to stop bleeding — called SynthoPlate, developed at Case Western and licensed to Sen Gupta’s Cleveland-based laboratory Haima Therapeutics
  • Surrogates for red blood cells — which transport oxygen around the human body — developed by professors at University of Maryland and University of Pittsburgh
  • Plasma — the liquid containing all the blood’s components — from Teleflex, a Pennsylvania-based medical technology company

For the first time ever, those three components are now able to be freeze-dried for long-term storage and transportation, Sen Gupta said.

Over the next four years, the teams will work to determine whether those components can be combined effectively using saline to make an artificial whole blood ready for transfusion, and whether that product can be manufactured on a large scale. They’ll then follow through with testing and trials.

“This is a complex ask that requires a big investment, and the DARPA endeavor has brought that investment,” Sen Gupta said. “The groups have been collaborating prior to this already. We’ve been collaborating with relatively small funds from a variety of sources. That has been moving the needle in bits and pieces for some time.”

The finished product won’t be entirely synthetic, Sen Gupta said. The plasma that researchers are now able to freeze-dry comes from donors, and the hemoglobin for the red blood cells comes from either donated red blood cells that have expired, or from bovines. The platelets developed by Sen Gupta’s lab, however, are entirely artificial, he said.

Since the components themselves are merely mimicking real blood, they aren’t exclusive to any particular blood type. Technically, that means they should be universally applicable — no matter what blood type a patient has — and testing performed on human blood in test tubes and on live animals hasn’t shown any complications, Sen Gupta said.

“This is one big logistical advantage of the product,” he wrote in an email.

Safety and ethical concerns

Over the course of its four-year development, the artificial blood product is expected to perform more and more like real blood each year, reaching 90% performance by the fourth year, Sen Gupta said. Simultaneously, the team will be ramping up production of the components to see if the combined product can scale and doing testing to ensure it’s 100% safe.

Once they get there, DARPA requires the team to apply for an investigational new drug application with the U.S. Food and Drug Administration, which is required before testing and clinical trials can begin on humans. Trials will continue for another few years, first focusing on safety, trying it out on otherwise healthy people; then efficacy, delivering it to patients who need blood.

If the trials are successful, the product will be approved for a certain scenario that requires a blood transfusion — surgery, for instance. After that, Sen Gupta said more approvals could later extend to trauma victims or hemophiliacs, whose condition keeps their blood from clotting properly.

Case Western ethics professor Shannon French will review the ethical implications of the DARPA endeavor, Sen Gupta said.

French is there to ensure there’s no unethical research on live beings and consider how this invention affects certain sub-groups, like Jehovah’s Witnesses, who abstain from blood and refuse blood transfusions. There’s also ethical questions around consent for transfusions when patients are unconscious.

Ethics overseers will also consider how it could be distributed or accessed globally, since blood shortages are a global problem, Sen Gupta said.

Shown here are some members of a team developing an artificial blood surrogate. From left to right: Harihara Baskaran, professor and chair of chemical engineering at Case Western Reserve University; Umut Gurkan, professor of mechanical and aerospace engineering at Case Western Reserve University; Allan Doctor, professor of pediatrics and director of the Center for Blood Oxygen Transport and Hemostasis at the University of Maryland School of Medicine and team leader of the DARPA project; and Anirban Sen Gupta, the Leonard Case Jr. professor of engineering at the Case School of Engineering. (Case Western Reserve University)

What are the scientific challenges?

Scientists started seeking an artificial blood surrogate in the 1980s during the AIDS pandemic, when there was widespread fear of infection from donated blood, said Sen Gupta. Even prior to that, the first attempt at making an artificial red blood cell happened in Canada in the 1950s.

At that time, scientists’ designs were “elegant” but also “somewhat rudimentary,” said Sen Gupta.

“Mimicking biology is a very difficult thing,” Sen Gupta said. “The way blood works is the result of millions of years of evolution, and capturing that with a few years of laboratory research is really an audacious attempt to do — which we still do, right?”

Those early designs couldn’t account for the cyclical nature of the human circulatory system, he said. Red blood cells in the lungs are different in that they’re able to take on more oxygen than red blood cells elsewhere in the body, which they then pass to those other red blood cells.

So in the 1990s and early 2000s, researchers began focusing on instead making individual components of whole blood like the red blood cells, platelets and plasma, Sen Gupta said. The red blood cells developed at University of Maryland are now able to actually transport the oxygen from the lungs.

“That makes it closer to how a real red blood cell functions,” he said.

Likewise, early versions of artificial platelets — the part of the blood that forms clots and stops bleeding — were unable to sense exactly where they were needed, and would instead cluster together indiscriminately, possibly causing other problems, said Sen Gupta. The synthetic platelets developed at Case Western have solved that issue, he said.

“This is really first in the world. This is really a tremendous effort across multiple universities and industry partners. We are just grateful that we are part of it in Cleveland,” said Sen Gupta.