Yale scientists restore cell and organ function in pigs after they die

Organ Perfusion and Cellular Recovery with OrganEx Technology

Illustration of organ perfusion and cell retrieval with OrganEx technology. The cell-efficient blood analog is delivered to vital organs one hour after death. Credit: Marin Balaic

Yale-developed technology restores function to cells and organs in pigs after they die, a potential breakthrough in organ transplantation.

Just minutes after the last heartbeat, a cascade of biochemical events triggered by a lack of blood flow, nutrients, and oxygen begin to destroy cells and organs in the body. However, a team of researchers from[{” attribute=””>Yale University has discovered that massive and permanent cellular failure doesn’t have to happen so quickly.

Using a new technology the scientists developed that delivers a specially designed cell-protective fluid to organs and tissues, the team restored blood circulation and other cellular functions in pigs a full hour after their deaths. They report their findings in the August 3 edition of the journal Nature.

Their results may help extend the health of human organs during surgery and expand the availability of donor organs, the authors said.

All cells do not die immediately, there is a more protracted series of events,” said David Andrijevic, associate research scientist in neuroscience at Yale School of Medicine and co-lead author of the study. “It is a process in which you can intervene, stop, and restore some cellular function.”

The research builds upon an earlier Yale-led project that restored circulation and certain cellular functions in the brain of a dead pig with technology dubbed BrainEx. Published in 2019, that study and the new one were led by the lab of Yale’s Nenad Sestan, the Harvey and Kate Cushing Professor of Neuroscience and professor of comparative medicine, genetics, and psychiatry. The new study involved senior author Sestan and colleagues Andrijevic, Zvonimir Vrselja, Taras Lysyy, and Shupei Zhang, all from Yale.

If we were able to restore certain cellular functions in the dead brain, an organ known to be most susceptible to ischemia [inadequate blood supply]we hypothesized that something similar could also be achieved in other transplantable vital organs,” Sestan said.

In the new study, scientists applied a modified version of BrainEx called OrganEx to whole pigs. The technology consists of an infusion device similar to heart-lung machines – which do the work of the heart and lungs during surgery – and an experimental liquid containing compounds that can promote cellular health and suppress inflammation throughout the body. pork. Cardiac arrest has been induced in anesthetized pigs, which were treated with OrganEx one hour after death.

Six hours after treatment with OrganEx, the researchers found that certain key cellular functions were active in many areas of the pigs’ bodies, including the heart, liver and kidneys. In addition, some organ functions had been restored. For example, they found evidence of electrical activity in the heart, which retained the ability to contract.

We were also able to restore circulation throughout the body, which amazed us,” Sestan said.

Normally, when the heart stops beating, the organs begin to swell, collapsing blood vessels and blocking circulation, he said. Still, circulation was restored, and organs from deceased pigs that received the OrganEx treatment appeared functional at the cellular and tissue level.

Under the microscope, it was difficult to tell the difference between a healthy organ and one that had been treated with OrganEx technology after death,” Vrselja said.

Similar to the 2019 experiment, the scientists also found that cell activity in certain areas of the brain was restored. However, no organized electrical activity that would indicate consciousness was detected during any part of the experiment.

The team was particularly surprised to observe involuntary and spontaneous muscle movements in the head and neck areas when evaluating the treated animals, which remained anesthetized for the duration of the six-hour experiment. These movements indicate the preservation of certain motor functions, Sestan said.

Further studies are needed to understand the apparently restored motor functions in animals, the researchers stressed. They also called for rigorous ethical review by other scientists and bioethicists.

The experimental protocols for the latest study were approved by Yale’s Institutional Animal Care and Use Committee and guided by an external advisory and ethics committee.

The OrganEx technology could eventually have several potential applications, the researchers said. For example, it could extend the lifespan of organs in human patients and increase the availability of donor organs for transplantation. It may also be able to help treat ischemia-damaged organs or tissues in heart attacks or strokes.

There are many potential applications for this exciting new technology,” said Stephen Latham, director of the Yale Interdisciplinary Center for Bioethics. “However, we must maintain careful monitoring of all future studies, especially those that include brain perfusion.”

Reference: “Cellular Recovery After Prolonged Whole-Body Warm Ischemia” by David Andrijevic, Zvonimir Vrselja, Taras Lysyy, Shupei Zhang, Mario Skarica, Ana Spajic, David Dellal, Stephanie L. Thorn, Robert B. Duckrow, Shaojie Ma, Phan Q. Duy, Atagun U. Isiktas, Dan Liang, Mingfeng Li, Suel-Kee Kim, Stefano G. Daniele, Khadija Banu, Sudhir Perincheri, Madhav C. Menon, Anita Huttner, Kevin N. Sheth, Kevin T. Gobeske, Gregory T. Tietjen, Hitten P. Zaveri, Stephen R. Latham, Albert J. Sinusas, and Nenad Sestan, August 3, 2022, Nature.
DOI: 10.1038/s41586-022-05016-1

The research was funded by the US Department of Health and Human Services, the National Institutes of Health, and the National Institute of Mental Health.

This work was supported by NIH BRAIN Initiative grants MH117064, MH117064-01S1, R21DK128662, T32GM136651, F30HD106694, and Schmidt Futures.

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