'Piggy-backing' extends human lung survival and healing

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A Vanderbilt and Columbia universities team extended the current six-hour window for human lungs outside the body to 24, as well as triggered damaged lung recovery, by connecting five human lungs to a pig, sharing the animal’s liver, kidney, and other functions.

For people who need a lung transplant, the wait is often prolonged by the frustrating fact that most donor organs have to be discarded: Only 20% of donated lungs meet medical criteria for transplantation, translating into far fewer organs than people on waiting lists. Now, a team of researchers has shown they might be able to salvage more of these lungs by borrowing a pig’s circulatory system.

Delicate lungs recovered from donors are typically connected to perfusion machines that keep oxygen and nutrients flowing to maintain viability, but that works for only about six hours, not long enough for often-injured lung tissue to recover before the organ fails.

Matthew Bacchetta of Vanderbilt University and Gordana Vunjak-Novakovic of Columbia University led a team that extended the current six-hour window for lungs outside the body to 24 hours.

As they reported, they did it by connecting each of five human lungs declined as too damaged for transplantation to a pig, sharing the animal’s liver, kidney, and other functions.

In one case, that cross-species cross-circulation allowed a human lung that failed after its six hours of standard perfusion to heal enough to meet transplant requirements and theoretically help a lung patient, though no transplant was done.

Robert Bartlett, a surgeon known for developing another machine to keep organs viable – extracorporeal membrane oxygenation, a type of heart-lung machine called ECMO – called the work a “very important paper.” He sees a future in which transplantation wouldn’t always be an emergency whose time constraints limit the number of suitable organs. Now retired from clinical practice, he runs a lab at the University of Michigan exploring ways to expand the supply of organs for transplantation, and he was not involved in the new research.

“If there were a way to maintain organs in a healthy state outside the body for a day or several days, then many things would change in transplantation,” Bartlett said. “You could have perfect matching. You could treat organs injured outside the body until they’re working well. So that’s what Bacchetta and his crew are working on. And they’re doing a marvellous job.”

Bacchetta and Vunjak-Novakovic, who is a professor of biomedical engineering and medicine at Columbia, previously rehabilitated damaged pig lungs by hooking them up to the circulatory system of another pig. For the current experiments, they connected pigs and human lungs with common problems found after donation: swelling from excess fluid, traumatic injury, damage from inhaled gastric fluids. All the organs had gone through six hours of perfusion before being declined for transplant. For the experiments, immune suppression drugs were infused into the pigs to prevent rejection of the human lung.

While connected to the pigs, the organs’ cells and function were monitored. After 24 hours, the lungs had improved and would likely continue to get better, the researchers said.

Bacchetta, who is an associate professor of surgery at Vanderbilt, compared the lungs’ recovery to what happens after spraining an ankle. Inflammation and healing take time, he said, more than can be supplied by six hours on a perfusion machine – which he said has significantly improved lung transplantation in the decade since it was introduced. The pig performs as a natural bioreactor to allow repair of the donated lungs.

“All of a sudden, (the lungs are) attached to a functioning liver, a functioning gut. We don’t have to worry about glucose regulation because there’s a pancreas. All of these metabolites that are formed are now cleared,” he said. “We used a fairly standard immunosuppressive regimen and took these rejected lungs and showed that we could actually sustain them and make them better.”

“If there were a way to maintain organs in a healthy state outside the body for a day or several days, then many things would change in transplantation,” Bartlett said. “You could have perfect matching. You could treat organs injured outside the body until they’re working well. So that’s what Bacchetta and his crew are working on. And they’re doing a marvellous job.”

Bacchetta and Vunjak-Novakovic, who is a professor of biomedical engineering and medicine at Columbia, previously rehabilitated damaged pig lungs by hooking them up to the circulatory system of another pig. For the current experiments, they connected pigs and human lungs with common problems found after donation: swelling from excess fluid, traumatic injury, damage from inhaled gastric fluids. All the organs had gone through six hours of perfusion before being declined for transplant. For the experiments, immune suppression drugs were infused into the pigs to prevent rejection of the human lung.

While connected to the pigs, the organs’ cells and function were monitored. After 24 hours, the lungs had improved and would likely continue to get better, the researchers said.

Bacchetta, who is an associate professor of surgery at Vanderbilt, compared the lungs’ recovery to what happens after spraining an ankle. Inflammation and healing take time, he said, more than can be supplied by six hours on a perfusion machine – which he said has significantly improved lung transplantation in the decade since it was introduced. The pig performs as a natural bioreactor to allow repair of the donated lungs.

“All of a sudden, (the lungs are) attached to a functioning liver, a functioning gut. We don’t have to worry about glucose regulation because there’s a pancreas. All of these metabolites that are formed are now cleared,” he said. “We used a fairly standard immunosuppressive regimen and took these rejected lungs and showed that we could actually sustain them and make them better.”

To translate these findings into the clinic will take a deeper understanding of how “magic molecules” recondition these organs, Bartlett said. It’s something in the blood plasma exchanged between the animal and the organs, he said, not white blood cells or elements of the blood. “Once we know why it works, we’ll really be able to isolate those molecules and achieve the same thing. From work in our laboratory and others, we think that this will be possible within a couple of years.”

Christian Bermudez, a surgeon and director of thoracic transplantation at the University of Pennsylvania, said he was intrigued by the concept of using pigs as bioreactors. “It makes sense. There are some issues from the immunologic standpoint that need to be further assessed or some infection problems that also need to be addressed, but I don’t see them as insurmountable for a temporary solution like this.”

Pigs as bioreactors – called xenogeneic cross-circulation – would represent a different way for humans to benefit from the animals. Scientists have pushed the frontiers of xenotransplantation by genetically engineering pigs to lack certain viruses that would harm people should pig organs be transplanted into them. The biotech company eGenesis is testing CRISPR’d pig organs in nonhuman primates in China.

Beyond transplantation, Bacchetta sees cross-circulation to keep organs viable as a boon for basic scientists studying stem cells or drugs to regenerate organs. He also thinks this technique could be applied to other injuries.

“I served in the US Army in Iraq and Afghanistan so I’m familiar with the need for salvaging tissue and limbs,” he said. “I think not just professionally, but personally, I have a goal and a desire to find a way to help soldiers who have suffered major tissue loss.”

For now, he is focused on improving outcomes for lung patients, including the possibility of connecting donated lungs to patients while they wait for a transplant, following the bioreactor model for organs to repair themselves outside the body, even if attached to very sick people.

“In these patients, their liver works, their gut works, their heart works. But their lungs don’t work. So how about if I attach some lungs that are damaged? It’s reversible damage. Let their body work essentially as a bioreactor and allow those lungs to heal.”
Bartlett thinks that approach is feasible. “I think the Bacchetta group will hopefully do that, and do it soon.”

There’s precedent, Bermudez noted, dating to the first open-heart surgery using cross-circulation in 1954. In that operation, C Walton Lillehei repaired a 13-month-old boy’s heart defect while the child was attached to his father’s circulatory system, temporarily taking over the heart’s job of pumping and oxygenation.

Bacchetta is focused on pushing higher the proportion of suitable donations in order to reduce the mismatch between the number of donated lungs and the number of patients in danger of dying on the waiting list. The shortage has been exacerbated by the coronavirus pandemic, which caused donations of all organ types to plunge. There were 54 lung transplants performed from 28 June through 4 July, according to the latest weekly figures from the United Network for Organ Sharing, but there were 1,075 people on the waiting list on 11 July.

“Increasing that donation number from 20% to 40% would have an immediate and profound impact,” he said. “And it would also allow us to rethink our criteria for people we may have not thought eligible for transplantation because we know what a scarce resource it is.”

Abstract
Patients awaiting lung transplantation face high wait-list mortality, as injury precludes the use of most donor lungs. Although ex vivo lung perfusion (EVLP) is able to recover marginal quality donor lungs, extension of normothermic support beyond 6 h has been challenging. Here we demonstrate that acutely injured human lungs declined for transplantation, including a lung that failed to recover on EVLP, can be recovered by cross-circulation of whole blood between explanted human lungs and a Yorkshire swine. This xenogeneic platform provided explanted human lungs a supportive, physiologic milieu and systemic regulation that resulted in functional and histological recovery after 24 h of normothermic support. Our findings suggest that cross-circulation can serve as a complementary approach to clinical EVLP to recover injured donor lungs that could not otherwise be utilized for transplantation, as well as a translational research platform for immunomodulation and advanced organ bioengineering.

Authors
Ahmed E Hozain, John D O’Neill, Meghan R Pinezich, Yuliya Tipograf, Rachel Donocoff, Katherine M Cunningham, Andrew Tumen, Kenmond Fung, Rei Ukita, Michael T Simpson, Jonathan A Reimer, Edward C Ruiz, Dawn Queen, John W Stokes, Nancy L Cardwell, Jennifer Talackine, Jinho Kim, Hans-Willem Snoeck, Ya-Wen Chen, Alexander Romanov, Charles C Marboe, Adam D Griesemer, Brandon A Guenthart, Matthew Bacchetta, Gordana Vunjak-Novakovic

 

STAT News report

 

Nature Medicine abstract

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