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Press release
Monday, September 9, 2019
An NIH-funded research project is developing a new method to preserve human livers for transplantation.
Scientists have significantly extended the shelf life of human livers for transplantation by modifying an earlier protocol to extend the viability of rat livers. Previously, human livers were only viable for an average of nine hours, but the new preservation method maintains liver tissue up to 27 hours, giving transplant physicians and patients a much longer delay. .
The research is funded by the National Institute of Biomedical Imaging and Bioengineering (NIBIB) and by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), both of which are part of National Institutes of Health.
Like a glass container broken by frozen water, when the cells freeze, they often suffer irreparable damage. Since human cells are particularly sensitive, donor liver is kept above zero at 4 degrees Celsius. As a result, doctors can usually only preserve the liver for nine hours before the chances of success of a transplant decrease significantly. This short time makes it more difficult, sometimes impossible, to transfer organs to compatible patients located further.
"Giving viable organs to compatible recipients within the window of viability can often be the most challenging aspect of organ transplantation," said Seila Selimovic, Ph.D., director of the Tissue Program. by NIBIB. "By giving more time to doctors and patients, this research could one day affect thousands of patients waiting for a liver transplant."
Martin Yarmush, Ph.D., director of the Center for Medical Engineering, Korkut Uygun, Ph.D., associate professor of surgery, and their staff at Massachusetts General Hospital (MGH) in Boston, had developed new techniques that extended the shelf life of liver tissue of rat liver to temperatures below zero without damage. To do this, they added a modified glucose compound, 3-OMG and PEG-35kD – an ingredient of antifreeze – to the protective solution they use to cool the livers. The PEG compound lowers the temperature at which cells freeze and 3-OMG acts as a coolant. Thanks to these additions, they could cool the rat livers to -6 degrees Celsius without freezing them – a process called supercooling.
However, although the techniques have worked with rat livers in previous studies, they have failed when applied to human livers, which are 200 times larger. The difference in size significantly increased the risk of spontaneous formation of ice crystals (heterogeneous nucleation of ice), rendering the organ unusable for transplantation. In an article published in Nature Biotechnology on September 9, Reinier de Vries, MD, surgical researcher, Shannon Tessier, Ph.D., surgical instructor at the MGH Hospital and at Harvard Medical School in Boston and Uygun , as well as their collaborators. at MGH details three new steps in the protocol to prevent ice nucleation and preserve human livers for up to 27 hours.
"With supercooling, increasing the volume makes it harder and harder to prevent ice formation at subzero temperatures," de Vries said. "Previously, many experts said:" It's great in small rats, but it will not work in human organs, "and we've been able to multiply it by 200, from liver to human liver, by combining technologies. "
The first step was to limit the contact of the storage liquid with the air. Once cooled, the livers are immersed in the supercooling protective solution. The researchers found that the risk of ice crystal formation increased significantly in areas where the solution was in contact with the air. To eliminate this risk, scientists removed air from the storage solution bag before supercooling, eliminating the risk of spontaneous nucleation of ice on the surface of the organ.
Next, the researchers added two additional ingredients to the protection solution to help protect the hepatocytes. The first additive, trehalose, helps protect the cell and stabilize cell membranes. The second, glycerol, enhances the protective properties of the 3-OMG glucose compound added in the previous experiments. Both additives have been used in the cryogenic storage of cells in the laboratory but have not been used in the preservation of organs intended for transplantation.
Finally, they developed a new method for administering the preservation solution to the liver. The traditional method of administering the protective solution used in previous studies is to manually rinse the preservation solution through the tissue. However, the new protective solution is thicker than traditional solutions and can damage the cells lining the inside of the blood vessels. In addition, the higher viscosity means that the solution is often not evenly distributed throughout the organ, which increases the risk of ice overgrowth and freezing of the liver. To combat this problem, the researchers used machine infusion – a way to deliver oxygen and nutrients to the capillaries of biological tissues to the outside of the body – at 4 degrees Celsius with the solution traditional protection. They then slowly lowered the temperature while increasing the concentration of the new protective additives. The staggered approach allowed the liver tissue time to adjust and the solution could spread more evenly throughout the organ.
Although researchers have not yet implanted preserved liver using this new method on a human subject, traditional standards for assessing liver viability indicate that this process does not occur. will not negatively affect the organ.
"This new method of liver preservation exemplifies NIH's goal of fostering the discovery and translation of innovative ideas," said Averell H. Sherker, MD, director of the NIDDK program for liver disease. "Through further research, organs will be able to travel longer distances and benefit the most seriously ill patients requiring a liver transplant."
This work was funded by NIH's National Institute of Biomedical Imaging and Bioengineering and the National Institute of Diabetes, Digestive and Kidney Diseases with numbers R21EB023031, R01DK096075, R01DK107875, R01DK114506.
NIBIB's mission is to improve health by leading development and accelerating the application of biomedical technologies. The Institute is committed to integrating physical and engineering sciences into the life sciences to advance fundamental research and medical care. NIBIB supports research and development of emerging technologies in its internal laboratories and through grants, collaborations and training. More information is available on the NIBIB website: https://www.nibib.nih.gov.
NIDDK, an NIH component, conducts and supports research on diabetes and other endocrine and metabolic diseases; digestive diseases, nutrition and obesity; and renal, urological and hematological diseases. Covering the entire spectrum of medicine and afflicting people of all ages and ethnicities, these diseases encompass some of the most common, serious and disabling conditions affecting Americans. For more information on the NIDDK and its programs, see https://www.niddk.nih.gov.
About the National Institutes of Health (NIH):
The NIH, the country's medical research agency, has 27 institutes and centers and is part of the US Department of Health and Human Services. NIH is the lead federal agency that leads and supports basic, clinical and translational medical research. She studies causes, treatments and cures for common and rare diseases. For more information on NIH and its programs, visit www.nih.gov.
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