HEPATOCYTES--TRANSPLANTATION, EXTRACORPOREAL SUPPORT

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Although various therapeutic modalities have been described for treating liver insufficiency, with the exception of organ transplantation, none have proven to be clinically useful. Liver transplantation is not widely used because of the high cost, technical difficulty, need for sophisticated technology and support teams and difficulty in obtaining cadaver donor organs. Several investigators attempted to develop the technique of hepatocyte transplantation. Results with this method have been largely disappointing due to inability to show long-term survival and retention of specific hepatocype function of donor cells. However, successful hepatocyte transplantation would be useful because it would allow living related donor use, use of a single donor for multiple recipients, would be simple and cost-effective and cells could be stored for later use. We have developed a technique which allows hepatocyte attachment on collagen-coated microspheres which results in prolonged hepatocyte viability and function both in vivo and in vitro. We hypothesize that this technique can be used to (1.) Develop a new method of intra-peritoneal hepatocyte transplantation which will allow prolonged viability and function of transplanted cells (2.) To construct an extracorporeal liver assist system for metabolic support until the host liver regenerates and (3.) To develop a new method of storage of hepatocytes for long periods of time. A series of comprehensive in vivo and in vitro experimental studies will be carried out to test our hypotheses. Freshly prepared or stored microcarrier-attached hepatocytes will be transplanted into Gunn rats which lack UDPglucuronosyltransferase activity for bilirubin, analbuminemic rats, and rats with liver insufficiency (90% partial hepatectomy, encephalopathy, ischemic and chemical liver injury) to correct deficits, improve liver function and enhance survival. Similarly, microcarrier-attached hepatocytes will be perfused in vitro and tested for specific liver functions; the ability of this support system to improve animal survival in experimental models of liver insufficiency will be tested. The overall objective of our studies is to determine the efficacy of the microcarrier-attached cells in hepatocyte transplantation and in developing an extracorporeal liver support system.