supercooled rat liver
June 30, 2014

Supercooling Process Could Extend Preservation Period Of Transplant Organs

redOrbit Staff & Wire Reports - Your Universe Online

A new technique which uses supercooling to preserve human transplant organs could drastically increase their viable preservation duration, according to new research appearing in the June 29 edition of the journal Nature Medicine.

In the study, senior authors Dr. Martin Yarmush and Dr. Korkut Uygun of the Massachusetts General Hospital Center for Engineering in Medicine (MGH-CEM) and their colleagues explain that they used a technique based on “subzero nonfreezing preservation and extracorporeal machine perfusion” which allowed them to transplant rat livers which had been preserved for up to four days – three times the traditional viable preservation period.

“To our knowledge, this is the longest preservation time with subsequent successful transplantation achieved to date,” Dr. Uygun, an assistant professor in surgery at Harvard Medical School, explained in a statement Sunday. “If we can do this with human organs, we could share organs globally, helping to alleviate the worldwide organ shortage.”

The first step in the process is the use of machine perfusion, a method of delivering nutrients and oxygen to the capillaries in biological tissues while they are outside of the body, to supercool the liver tissue of the rodents. This allows the organs to be preserved at subzero temperatures without the cells being irreversibly damaged.

Dr. Yarmush, Dr. Uygun and their fellow researchers did this by adding a non-toxic compound of modified glucose, 3-O-methyl-D-glucose (3-OMG), to the solution being delivered to the liver. This substance cannot be metabolized by cells, so it accumulates in liver cells (hepatocytes) and helps protect them from the cold.

They went on to further modify the solution by adding polyethylene glycol (PEG-35kD) to protect cell membranes by lowering the freezing point of the solution. According to the researchers, whose work was supported by the National Institute of Biomedical Imaging and Bioengineering (NIBIB) and the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK), ethylene glycol is the active ingredient in anti-freeze.

Next, the livers were slowly cooled below the freezing point and all the way down to 21 degrees Fahrenheit, but without inducing freezing. As a result, the organ was supercooled for preservation, and spent several days in storage. Afterwards, the researchers turned again to machine perfusion to re-raise the organs’ temperatures, while also delivering oxygen and other nutrients that helped prepare the livers for transplantation.

“Using this new technique, the researchers were able to store the supercooled rat livers for three days (72 hours) and four days (96 hours) at 21 degrees Fahrenheit,” said the NIBIB, a division of the National Institutes of Health (NIH). “All the rats who had supercooled livers stored for three days survived three months, but none of the rats who had transplants using current methods did.”

More than half (58 percent) of animals receiving livers that had been stored for 96 hours survived. In addition, when the researchers examined each step in the process to ensure that each was essential, they found that eliminating supplemental components PEG-35kD and 3-OMG resulted in all of the rats dying off in less than one week. Likewise, opting not to use machine perfusion or supercooling resulted in death within one hour of transplantation.

“It is exciting to see such an achievement in small animals, by recombining and optimizing existing technology,” said NIBIB Tissue Engineering and Regenerative Medicine program director Dr. Rosemarie Hunziker, who noted that the next step will be to conduct similar research using larger animals. “The main point here is that using all of these approaches at once was what led to success. Halfway measures did not do.”

“Such a tour de force reflects this team's very deep understanding of the complex processes at work here, and how they relate simultaneously to each other,” she added. “The longer we are able to store donated organs, the better the chance the patient will find the best match possible, with both doctors and patients fully prepared for surgery. This is a critically important step in advancing the practice of organ storage for transplantation.”

While the study authors emphasize that the process must undergo extensive testing before it can be applied for use in human patients, they add that it is the first method to report a successful survival rate following the storage of the livers for three days. The possibility that livers could be stored for up to four days before use could ultimately make it possible for hospitals and medical communities to use organs currently deemed unsuitable for transplant.

Image 2 (below): The liver is perfused with a solution in this pump system before and after supercooling preservation. The blue color is caused by antifreeze that surrounds the components of the system to regulate the temperature. Credit: Source: Wally Reeves, Korkut Uygun, Maish Yarmush, Harvard University


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