Review of a flat membrane bioreactor as a bioartificial liver

Recent developments in tissue engineering permit to use isolated hepatocytes in a bioreactor for the creation of a bioartificial liver which supports patients suffering from acute liver failure. In this study, the authors discuss the development of a flat membrane bioreactor using pig hepatocytes for the replacement of liver functions. The flat membrane bioreactor permits a high-density hepatocyte culture under sufficient oxygenation conditions, comparable to an in vivo microenvironment. In this bioreactor, built according to the in vivo organisation of the liver, pig hepatocytes are cultured with non-parenchymal cells within an extracellular matrix between oxygen-permeable flat-sheet membranes as individual plates. The performance of the "scale-up bioreactor" was tested in vitro for 18 days in static and flux conditions. Pig hepatocytes in the bioreactor were maintained in three-dimensional co-culture with non-parenchymal cells and are reorganised in a way similar to the liver cell plates in vivo: cells remained polarised in vitro clearly demonstrating biliary zones surrounding individual hepatocytes. The biochemical performance of the bioreactor was assessed by estimating its ability to remove two of the major toxins associated with hepatic encephalopathy: benzodiazepines and ammonia. The rates of ammonia elimination and drug biotransformation were maintained at constant high levels for almost two weeks. This "scaled-up bioreactor" provides conditions favourable for the formation of contiguous cell sheets, which allow to maintain constant liver specific functions.