In mammals, blood carries oxygen and nutrients to the body's organs and cells. But if blood flow stops, these cells will quickly die and organs are injured.
This death can be slowed in organs and tissues removed from the body, buying time for organ transplantation. However, preserving entire organ systems minutes after the heart stops pumping can be a challenge.
Existing methods include what's known as an extracorporeal membrane oxygenation system (ECMO), which pumps blood into a machine that removes carbon dioxide from it, while adding oxygen. While it serves the purpose of balancing gases, every minute of delay allows the damage to build.
To address the problem, a new system has been shown to restore some organ, cellular, and molecular function in dead pigs, and to preserve their tissues, even when the treatment is only initiated one hour after cardiac arrest.
The researchers adapted an existing technology called BrainEx, which has been shown to restore some function in isolated pig brains hours after death.
Their new system, called OrganEx, is intended for whole-body use in large mammals.
OrganEx has two components: a machine, and a fluid.
The machine is connected to the circulatory system. It creates a pulse similar to a heartbeat and oxygenates the fluid, similar to an ECMO. Where it stands apart is in the way it adds drugs to aid circulation and prevent clotting.
The machine also includes a number of sensors for important features of circulation like metabolism, hemoglobin, pressure, and flow.
It pumps synthetic fluid, mixed with the animal's own blood at a 1:1 ratio, through the dead animal's whole body. This fluid, unlike blood, is not made up of cells, although it is designed to protect cells from harm, and carry oxygen and drugs throughout the body.
(David Andrijevic, Zvonimir Vrselja, Taras Lysyy, Shupei Zhang; Sestan Laboratory; Yale School of Medicine)
Above: Representative images of electrocardiogram tracings in the heart (top), immunostainings for albumin in the liver (middle), and actin in the kidney (bottom). The images on the left side represent the organs subjected to a control perfusion, while the images on the right represent the organs subjected to perfusion with the OrganEx technology.
The system was tested in pigs one hour after cardiac arrest, as well as control groups in which organ functions were tested immediately after cessation of blood flow, as well as one hour and seven hours later. Kept at body temperature, tissues continued to process fuel and generate waste at a controlled rate.
One hundred pigs (Susscrofa domesticus) were used overall, including those used to develop the system prior to the published experiments.
The researchers found OrganEx can preserve the integrity of tissue, reduce cell death, and revive certain molecular and cellular processes across vital organs like the heart, brain, liver, and kidneys.
OrganEx out-performed ECMO across the board. Organs treated by the new system were less affected by hemorrhage or tissue swelling, and the researchers observed gene expression patterns specific to repair processes within certain organs and cell types.
The team also checked the architecture of cells in the brain, which usually suffer damage from ischemia.
Brain cell numbers had diminished in all treatment groups, except for OrganEx, where, in some sections of the brain, minimal damage had occurred, and in the prefrontal cortex, cells had been recovered to similar levels as the group that had not been exposed to warm ischemia.
A major test of the experiment's success was the recovery of organ function.
Brain function was measured using continuous EEG. The scientists were adamant to distinguish between the brain functions they detected and electrical activity which would indicate some level of 'life' (as brain death is the main definition of death in clinical settings).
While brain death persisted in the OrganEx group, the bodies showed some head and neck movement after contrast injection – used to help show more detail in imaging – into the carotid artery in the neck, which delivers blood to the brain and head. This movement did not occur in living sedated animals, or in the ECMO group.
"Thoughtful evaluation is needed to elucidate why head and neck movements occurred after contrast injection only in the OrganEx group," the researchers write.
They are unsure why this occurred, but say it shows motor function output had been preserved, at least in the "spinal cervical cord or its roots."
In the heart, some spontaneous activity was detected via ECG and some contractions in the left ventricle cells were seen in the OrganEx group that were not seen in the ECMO group.
Other organs, such as the liver and kidneys, also showed some key signs of recovery in their functionality.
While tests of this system in humans are still far off, the researchers believe OrganEx has huge potential for human organ transplants. They hope it will improve the time an organ intended for transplant can be preserved, which, for instance, could allow organs to be transported further distances, to recipients in need.
"The findings highlight a previously unappreciated capacity of the mammalian body to partially recover after an interruption to blood flow, which could increase organ availability for transplantation," the researchers write.
However, the team says that further studies are needed "to fully understand the potential of OrganEx to aid cellular recovery after death or interrupted blood circulation".
The research was published in Nature.