Technology developed by Yale restores cell and organ function in pigs after death

Within minutes of the heart’s final beat, a cascade of biochemical events triggered by a lack of blood flow, oxygen and nutrients begins to destroy the body’s cells and organs. But a team of Yale scientists has found that massive, permanent cell failure doesn’t have to happen so quickly.

Using a new technology developed by the team that delivers a specially designed cell-protecting fluid to organs and tissues, the researchers restored blood circulation and other cellular functions in the pigs a full hour after they died, report in the August 3 edition of the magazine. Nature.

The authors said the findings may help expand the health of human organs during surgery and expand the availability of donor organs.

Not all cells die immediately, there’s a longer series of events,” said David Andrijevic, a research associate in neuroscience at Yale School of Medicine and co-senior author of the study. “It’s a process in which you can intervene, stop and restore some cellular function.”

Illustration of organ perfusion and cell recovery with OrganEx technology. The cell-saving blood analog is delivered to vital organs within an hour of death. (Credits: Marin Balaic)

The research builds on an earlier project led by Yale that restored circulation and certain cellular functions in the brain of a dead pig using technology called BrainEx. Published in 2019, that study and the new one were led by the laboratory of Yale’s Nenad Sestan, the Harvey and Kate Cushing Professor of Neuroscience and Professor of Comparative Medicine, Genetics and Psychiatry.

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

In the new study, which involved lead author Sestan and colleagues Andrijevic, Zvonimir Vrselja, Taras Lysyy and Shupei Zhang, all of Yale, the researchers applied a modified version of BrainEx called OrganEx to the whole pig. The technology consists of a perfusion 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 in the whole body of the pig. Cardiac arrest was induced in anesthetized pigs, which were treated with OrganEx one hour after death.

Six hours after treatment with OrganEx, the scientists found that certain key cellular functions were active in many areas of the pigs’ bodies, including the heart, liver and kidneys, and that some organ function 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 surprised us,” Sestan said.

Normally, when the heart stops beating, the organs begin to swell, collapsing blood vessels and blocking circulation, he said. However, circulation was restored and the organs of deceased pigs treated with OrganEx appeared functional at the cell and tissue level.

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

As in the 2019 experiment, the researchers also found that cellular activity was restored in some areas of the brain, although no organized electrical activity indicative of 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 they assessed the treated animals, which remained anesthetized throughout the six-hour experiment. These movements indicate the preservation of some motor functions, Sestan said.

The researchers stressed that further studies are needed to understand the apparently restored motor functions in animals and that rigorous ethical review by other scientists and bioethicists is required.

Experimental protocols for the latter study were approved by the Yale Institutional Animal Care and Use Committee and guided by an external ethics and advisory committee.

The OrganEx technology could have several potential applications, the authors said. For example, it could extend the life of organs in human patients and expand the availability of donor organs for transplantation. It can also help treat organs or tissues damaged by ischemia during heart attacks or strokes.

There are numerous potential applications for this exciting new technology,” said Stephen Latham, director of Yale’s Interdisciplinary Center for Bioethics. “However, we must maintain careful vigilance for all future studies, especially those involving perfusion of the brain”.

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.

The study was conducted at the Yale Translational Research Imaging Center, which is led by co-author Dr. Albert Sinusas, professor of medicine, radiology and biomedical engineering. The Nature paper provides a full list of authors.

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