Yale scientists restored cell and organ functions in pigs after death

Illustration of organ perfusion and cell recovery with OrganEx technology. A cell-sparing blood analog is delivered to vital organs one hour after death. Credit: Marin Balaich

Yale-developed technology restores cell and organ function in pigs after death, a potential breakthrough in organ transplants.

Minutes after the heart’s last beat, a cascade of biochemical events caused by a lack of blood flow, nutrients, and oxygen begins to destroy the body’s cells and organs. However, according to a group of researchers[{” 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 be done in other important transplant organs,” said Sestan.

In the new study, scientists applied a modified version of BrainEx, called OrganEx, to whole pigs. The technology consists of a perfusion device similar to heart-lung machines — which act as the heart and lungs during surgery — and an experimental fluid containing compounds that promote cellular health and reduce inflammation in the pig’s body. Anesthetized pigs underwent cardiac arrest and were treated with OrganEx one hour after death.

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

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

Normally, when the heart stops, organs swell, blood vessels collapse, and circulation stops, he says. However, blood circulation was restored and the organs of dead pigs that received OrganEx began to function at the cellular and tissue level.

“It was difficult to tell the difference between a healthy organ under a microscope and an organ treated with OrganEx technology after death,” Vrselja said.

As in the 2019 experiment, the scientists found that cellular activity was restored in some areas of the brain. But in no part of the experiment was there any organized electrical activity that would indicate consciousness.

In particular, the team was particularly surprised to observe involuntary and spontaneous muscle movements in the head and neck regions while treating treated animals under anesthesia during a six-hour experiment. These movements show that some motor functions are preserved, Sestan said.

According to the researchers, further research is needed to restore motor function in animals. They also sought ethical scrutiny from other scientists and bioethicists.

Experimental protocols for the final study were approved by the Yale 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 say. For example, it extends the life of organs in human patients and increases the availability of donor organs for transplantation. It can also help treat organs or tissues damaged by ischemia during a heart attack or stroke.

This exciting new technology has many potential applications,” said Stephen Latham, director of the Interdisciplinary Center for Bioethics at Yale. “However, we need to carefully monitor all future studies, especially those involving brain perfusion.”

Reference: David Andrijevic, Zvonimir Vrselja, Taras Lysy, Shupei Zhang, Mario Scarica, Ana Spajic, David Dellall, Stephanie L. Thorne, Robert B. “Cellular recovery after prolonged whole-body warm ischemia” by Duckrow, Shaoji Ma, Fan S. Duy, Atagun U. Isiktash, Dan Liang, Mingfeng Lee, Suel-Ki Kim, Stefano G. Daniele, Khadija Banu, Sudhir Perinchery, Madhav S. Menon, Anita Huttner, Kevin N. Sheth, Kevin T. Gobeske, Gregory T. Tietjen, Hitten P. Zaveri, Stephen R. Latham, Albert J. Sinusas and Nenad Sestan, 3 August 2022, nature.
DOI: 10.1038/s41586-022-05016-1

The study 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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