Orthotopic liver transplantation is the only available treatment for severe liver failure, but it is currently limited by organ shortage. One technical challenge that has thus far limited the development of a tissue-engineered liver graft is oxygen and nutrient transport. Here we demonstrate a novel approach to generate transplantable liver grafts using decellularized liver matrix. The decellularization process preserves the structural and functional characteristics of the native microvascular network, allowing efficient recellularization of the liver matrix with adult hepatocytes and subsequent perfusion for in vitro culture. The recellularized graft supports liver-specific function including albumin secretion, urea synthesis and cytochrome P450 expression at comparable levels to normal liver in vitro. The recellularized liver grafts can be transplanted into rats, supporting hepatocyte survival and function with minimal ischemic damage. These results provide a proof of principle for the generation of a transplantable liver graft as a potential treatment for liver disease.
Initial poor function and primary nonfunction are important problems in clinical transplantation. The incidence of primary nonfunction is about 6% and that of initial poor function is about 15%. Grafts with initial poor function have a higher graft failure rate in the first 3 mo after transplantation. Severe steatosis and cold preservation in University of Wisconsin solution for over 30 hr will alone cause primary nonfunction. However, primary nonfunction is probably most often caused by the presence of multiple relative risk factors. The major donor-relative risk factors are moderate steatosis, cold preservation over 12 hr and donor age over 50 yr, whereas retransplantation, high (United Network of Organ Sharing class 4) medical status and kidney failure are recipient relative risk factors. The most important perioperative risk factor is warm ischemia time. Rates of primary nonfunction and initial poor function might be reduced by avoidance of combinations of risk factors. Several tests have been developed to predict primary nonfunction and initial poor function, but none is yet clinically efficient.
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