L. Scott Levin, MD, FACS, FAOA
Foteini Mourkioti, PhD
A series of procedures being developed at Penn Medicine by a renowned orthopaedic surgeon and a leading musculoskeletal scientist has the potential to revolutionize hand and limb transplantation and replantation within the next decade.
Ex vivo limb perfusion keeps human tissue alive outside the body — an approach that's shown promising results in recent years with solid organ transplantation. According to recent studies, ex vivo heart and lung perfusion has resulted in "significantly better outcomes after transplantation compared to the gold standard of static cold organ preservation." The researchers who conducted the first large randomized clinical trial in liver transplantation reported, in 2018, a similar finding.
As it stands, a shortage of donor lungs results in the death of 20 percent of lung transplant candidates awaiting transplant.
Currently, ex vivo lung perfusion is only available in the United States through a clinical trial. Penn Medicine, led by thoracic surgeon Edward Cantu, MD, MSCE, is one of six sites participating in the trial.
Dr. Cantu believes that ex vivo perfusion could expand the pool of donor lungs.
L. Scott Levin, MD, FACS, FAOA, Chair of the Penn Medicine Department of Orthopaedic Surgery, Co-Director of the Penn Nerve Center, and Paul B. Magnuson Professor of Bone and Joint Surgery at the Perelman School of Medicine at the University of Pennsylvania, and Foteini Mourkioti, PhD, Co-Director of the Musculoskeletal Regeneration Program at the Penn Institute of Regenerative Medicine, believe ex vivo perfusion could impact donor hands and limbs in the same fashion.
According to one estimate, more than 130 patients around the world have received hand and arm transplants. While such operations are complex and require rigorous rehabilitation, their benefits are undeniable, says Dr. Levin, who performed the world's first pediatric bilateral hand transplant at Penn in 2011.
"Most patients who have undergone VCA [vascularized composite allotransplantation] have gotten back incredible function," Dr. Levin said in a 2018 article, The Road to More Hand Transplants. "Where they were fully disabled and dependent, they now live independently."
With ex vivo limb perfusion, donor hands and limbs could be flown cross-country, or even to the other side of the world.
Drs. Levin and Mourkioti also envision it reshaping the treatment of extremity trauma on the battlefield.
"If a soldier is wounded and the arm or leg has to be amputated, rather than discarding the amputated part, it can be escorted back to another echelon of care," Dr. Levin explains. "And those tissues could either be utilized for further reconstruction or the limb could potentially be replanted or reconstructed and reattached to the patient."
Redrawing a Critical Timeframe
Drs. Levin and Mourkioti began development of their prototype about five years ago. While theirs is not the first foray into such a concept, they do appear to have made the greatest inroads.
Two years ago, they began testing their ex vivo perfusion using porcine limbs because, Dr. Mourkioti says, they are comparable to human limbs in critical aspects.
"We used this as our proof of principle," says Dr. Mourkioti, who Dr. Levin describes as "one of the world's foremost muscle experts." "If we can preserve the extremity of the pig, it's similar to the protocol we're going to use for humans."
"Just developing the prototype, developing our machine, proving that it works, which it does, these have all been huge milestones," Dr. Levin says.
If their progress remains consistent, he expects them to complete "a series of very intricate studies, led by Dr. Mourkioti, that demonstrates that we can maintain viability of tissues, particularly muscle" within the next year. At that point, they will begin procuring donor human limbs for study.
But already, they have accomplished what no one else has. Until now, the longest perfusion time reported by any ex vivo tissue perfusion study was 24 hours. Dr. Mourkioti says they have shown the ability to "maintain the structure of the tissue for up to 72 hours."
For further context, a human limb can be maintained for up to six hours, 12 hours in unique situations, with the current technology and methodology.
"So what we've achieved so far is really huge compared to what we have right now," Dr. Mourkioti explains.
Prolonging tissue viability to this extent is the difference between salvaging a hand or limb in a wartime setting and not because it "decreases the need to rapidly revascularize the parts," Dr. Levin says. "The tissue can tolerate a longer time from amputation to replantation or transplantation."
An Advance Made Possible by Collaboration
Such a dramatic increase in the size of the window of viability also means organ procurement agencies would likely no longer be hamstrung by geography, as they are now. Dr. Levin envisions a point five to 10 years in the future when a portable, golf bag-size iteration of their device will be commonplace at hospitals and military bases. In this scenario, a donor hand could be procured in Seattle and transplanted the next day in Philadelphia.
It would be a seismic shift in the way the operation is done. And it was made possible by the collaborative culture of Penn Medicine, according to Dr. Levin.
"These kinds of advances occur because of collaboration between clinicians and scientists," he says.
"The two disciplines coming together, I think that is the power here," Dr. Mourkioti agrees. "Because it hasn't been done before. In most of the trials you see, it's either one side or the other."
Together, they have been able to traverse knowledge gaps that previously proved too vast for other researchers. They made it this far because they complement each other's expertise.
"We're capitalizing on each other's knowledge to actualize what I think is a very important concept," Dr. Levin explains.