Hepatic tissue engineering: from transplantation to customized cell‐based liver directed therapies from the laboratory

•  Introduction •  Development of cell isolation and primary culture for hepatocytes •  Three–dimensional culture using matrices •  Development of bioreactor systems for liver cells •  First clinical application of bioreactors with liver cells •  Development of matrix‐based hepatocyte transplantation •  Outlook: future perspective for the development of successful tissue engineering approaches for transplantationAbstract Today, liver transplantation is still the only curative treatment for liver failure due to end‐stage liver diseases. Donor organ shortage, high cost and the need of immunosuppressive medications are still the major limitations in the field of liver transplantation. Thus, alternative innovative cell‐based liver directed therapies, for example, liver tissue engineering, are under investigation with the aim that in future an artificial liver tissue could be created and be used for the replacement of the liver function in patients. Using cells instead of organs in this setting should permit ( i ) expansion of cells in an in vitro phase, ( ii ) genetic or immunological manipulation of cells for transplantation, ( iii ) tissue typing and cryopreservation in a cell bank and ( iv ) the ex vivo genetic modification of patient's own cells prior to re‐implantation. Function and differentiation of liver cells are influenced by the three‐dimensional organ architecture. The use of polymeric matrices permits the three‐dimensional formation of a neo tissue and specific stimulation by adequate modification of the matrix surface, which might be essential for appropriate differentiation of transplanted cells. In addition, culturing hepatocytes on three‐dimensional matrices permits culture in a flow bioreactor system with increased function and survival of the cultured cells. Based on bioreactor technology, bioartificial liver devices (BAL) are developed for extracorporeal liver support. Although BALs improved clinical and metabolic conditions, increased patient survival rates have not been proven yet. For intracorporeal liver replacement, a concept that combines tissue engineering using three‐dimensional, highly porous matrices with cell transplantation could be useful. In such a concept, whole liver mass transplantation, long‐term engraftment and function as well as correction of a metabolic defect in animal models could be achieved with a principally reversible procedure. Future studies have to investigate which environmental conditions and transplantation system would be most suitable for the development of artificial functional liver tissue including blood supply for a potential use in a clinical setting.