It takes only minutes after ischemia (insufficient blood supply) for cellular processes such as intracellular acidosis and swelling to develop, triggering injury to membranes and organelles. The end result is cell death. But, what if those processes could be slowed, stopped, or even reversed?
Now, researchers describe a technology—OrganEx—which preserved tissue integrity, decreased cell death, and restored selected molecular and cellular processes across multiple vital organs in pigs. The technology, which delivers a specially designed cell-protective fluid to organs and tissues, restored blood circulation, and other cellular functions in pigs a full hour after their deaths.
The findings may help extend the health of human organs during surgery and expand the availability of donor organs, the authors noted.
This work is published in Nature, in the article, “Cellular Recovery After Prolonged Warm Ischemia of the Whole Body.”
“All cells do not die immediately, there is a more protracted series of events,” said David Andrijevic, MD, associate research scientist in neuroscience at Yale School of Medicine. “It is a process in which you can intervene, stop, and restore some cellular function.”
The research builds upon a prior Yale-led project, published in 2019, that restored circulation and certain cellular functions in the brain of a dead pig with a technology named BrainEx.
“If we were able to restore certain cellular functions in the dead brain, an organ known to be most susceptible to ischemia, we hypothesized that something similar could also be achieved in other vital transplantable organs,” said Nenad Sestan, MD, PhD, professor of neurobiology at the Yale School of Medicine.
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 fluid containing compounds that can promote cellular health and suppress inflammation throughout the pig’s body. Cardiac arrest was induced in anesthetized pigs, which were treated with OrganEx an 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 in the heart, liver, and kidneys—and that some organ function had been restored. For instance, 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, organs begin to swell, collapsing blood vessels and blocking circulation, he said. Yet circulation was restored and organs in the deceased pigs that received OrganEx treatment appeared functional at the level of cells and tissue.
“Under the microscope, it was difficult to tell the difference between a healthy organ and one which had been treated with OrganEx technology after death,” Vrselja said.
In addition, single-nucleus transcriptomic analysis revealed organ- and cell-type-specific gene expression patterns that are reflective of specific molecular and cellular repair processes.
Similar to earlier experiments, the researchers also found that cellular activity in some areas of the brain had been restored, though no organized electrical activity that would indicate consciousness was detected during any part of the experiment.
The team was especially surprised to observe involuntary and spontaneous muscular movements in the head and neck areas when they evaluated the treated animals, which remained anesthetized through the entire six-hour experiment. These movements indicate the preservation of some motor functions, Sestan said.
The researchers wrote that their study “comprises a comprehensive resource of cell-type-specific changes during defined ischaemic intervals and perfusion interventions spanning multiple organs, and it reveals an underappreciated potential for cellular recovery after prolonged whole-body warm ischemia in a large mammal.”
They stressed that additional studies are necessary to understand the apparently restored motor functions in the animals, and that rigorous ethical review from other scientists and bioethicists is required.
The OrganEx technology could eventually have several potential applications, the authors said. For instance, it could extend the life of organs in human patients and expand the availability of donor organs for transplant. It might also be able to help treat organs or tissue damaged by ischemia during heart attacks or strokes.
“There are numerous potential applications of this exciting new technology,” said Stephen Latham, director of the Yale Interdisciplinary Center for Bioethics. “However, we need to maintain careful oversight of all future studies, particularly any that include perfusion of the brain.”
