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Abstract
A fluidized bed bioreactor containing encapsulated hepatocytes may be a valuable alternative to a hollow fiber bioreactor for achieving the improved mass transfer and scale-up potential necessary for clinical use. However, a conventional fluidized bed bioreactor (FBB) operating under high perfusion velocity is incapable of providing the desired performance due to the resulting damage to cell-containing microcapsules and large void volume. In this study, we developed a novel diversion-type microcapsule-suspension fluidized bed bioreactor (DMFBB). The void volume in the bioreactor and stability of alginate/chitosan microcapsules were investigated under different flow rates. Cell viability, synthesis and metabolism functions, and expression of metabolizing enzymes at transcriptional levels in an encapsulated hepatocyte line (C3A cells) were determined. The void volume was significantly less in the novel bioreactor than in the conventional FBB. In addition, the microcapsules were less damaged in the DMFBB during the fluidization process as reflected by the results for microcapsule retention rates, swelling, and breakage. Encapsulated C3A cells exhibited greater viability and CYP1A2 and CYP3A4 activity in the DMFBB than in the FBB, although the increases in albumin and urea synthesis were less prominent. The transcription levels of several CYP450-related genes and an albumin-related gene were dramatically greater in cells in the DMFBB than in those in the FBB. Taken together, our results suggest that the DMFBB is a promising alternative for the design of a bioartificial liver system based on a fluidized bed bioreactor with encapsulated hepatocytes for treating patients with acute hepatic failure or other severe liver diseases.
Highlights
A bioartificial liver (BAL) support system that employs viable hepatocytes has been shown to provide temporary and important support, serving as a bridge to liver transplantation for patients with acute hepatic failure or other liver diseases [1]
In the fluidized bed bioreactor (FBB), a portion of the microcapsules in the center of the column were pushed by the perfusion flow and forced upward along the central axis sharply, whereas the microcapsules away from the center or at the edge of the container were exposed to weak perfusion
In the diversion-type microcapsule-suspension fluidized bed bioreactor (DMFBB), because the flow force of the inlet perfusion was shunted into a diversion-type vortex by the turbine guide vanes at the bottom of the bioreactor, the fluidized bed within the DMFBB was found to rise horizontally and uniformly as a whole as the microcapsules were lifted by the increasing flow velocities
Summary
A bioartificial liver (BAL) support system that employs viable hepatocytes has been shown to provide temporary and important support, serving as a bridge to liver transplantation for patients with acute hepatic failure or other liver diseases [1]. The most widely adopted bioreactor is based on a hollow fiber membrane, in which cells are cultured on capillary spaces, and the blood or plasma flows through the hollow pores [4]. An obvious disadvantage of this type of configuration is the heterogeneous distribution of hepatocytes in extra-capillary spaces. Another deficiency of this type of bioreactor is the location of the semipermeable membrane between cells and blood or plasma, which serves as a barrier to diffusion. Aggregation of many hepatocytes potentially could occlude the pores of hollow fibers, which would hamper bidirectional mass transport and reduce the efficiency of the BAL devices [3,7]
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