The AMC-BAL based on pig liver cells has been tested extensively in vitro (Flendrig 1997 & 1998) and in vivo both in small animals and in larger animals with acute liver failure (ALF) caused by liver ischemia (LIS) or removal of the liver (anhepatic). A schematic drawing of the extracorporeal circuit based on plasmapheresis is shown in Figure 2.
Figure 2: Schematic representation of the bioartificial liver support system. Plasma was obtained from the recipient by a centrifugal plasma-separator. To prevent cellular immunological problems, two plasma filters were included. When blocked, these filters can easily be replaced during the extra-corporal artificial liver procedure. Different filter types (various material properties and cut-off) can be applied without changing the bioreactor design.
The survival time in these models of irreversible ALF was significantly prolonged in animals treated with the CELL-BAL in comparison to control animals only treated by intensive care or an EMPTY-BAL (see Table 1). In addition, improvement of several biochemical parameters (for instance plasma ammonia and bilirubin) was observed.
Table 1: Animal experiments on AMC-BAL treatment based on pig liver cells
|Survival time (h)|
|Animal model of ALF||Liver mass
(gram) (%of liver)
|Empty BAL||Cell BAL||Reference|
|rats; total LIS||4 g (≈ 40%)||-death||5.4 ± 1.7||11 ± 2.2||Flendrig 1999|
|rats; total LIS||140 g (≈ 20%)||24||38.9 ± 2.7||51 ± 3.4||Flendrig 1999|
|pigs; anhepatic||110 g (≈16%)||24||43 ± 14||65 ± 15||Sosef 2002|
Driven by xenotransplantation-related risks, the pig liver cells have been replaced by human liver cell line HepaRG as the biocomponent of the AMC-BAL. Recently proof of principle of the HepaRG based AMC-BAL has been obtained in rats with ALF (Nibourg 2012).
Survival time was significantly prolonged and clinical and biochemical parameters were improved (Fig 3).
Figure 3: Effects of treatment of ALF rats with AMC-BALs with HepaRG cells or no biocomponent
N.B. HE4: level of coma reaching loss of righting reflex