Biohybrid Artificial Liver (BAL) Systems

Abstract

A biohybrid artificial liver (BAL) system is an artificial extracorporeal supportive device which represents an important therapeutic strategy for patients with acute liver failure. Generally, a BAL system consists of functional liver cells supported by an artificial cell culture material. In particular, it incorporates hepatocytes into a bioreactor in which the cells are immobilized, cultured, and induced to perform the hepatic functions by processing the blood or plasma of liver failure patients. The BAL system acts as a bridge for the patients until a donor organ is available for transplantation or until liver regeneration. The development of a BAL system involves many design considerations. It must provide (1) an adhesion support to the cells; (2) adequate mass transfer of oxygen, nutrients, and toxic substances from the blood or plasma of patients to the cell compartments and proteins, catabolites, and other specific compounds produced by cells from the cell compartment to the blood or plasma; (3) immunoprotection of cells; and (4) biocompatibility. BAL devices are classified by the cell source, the type of culture system for the hepatocytes, and the configuration of the bioreactor. Several BAL systems have been evaluated preclinically in in vitro experiments and in large animal models of liver failure (Morelli et al. 2010). Currently, different types of BAL devices are in various stages of clinical evaluation, and some of them are listed in Table 1 (van de Kerkhove et al. 2004). Many of these devices use hollow fiber membranes (HFMs) as supports for the cultured hepatocytes and as immunoselective barriers between the plasma of the patients and the hepatocytes used in the bioreactor. Membranes also permit the transport of nutrients and metabolites to cells and the transport of catabolites and specific metabolic products to the blood. In the membrane bioreactors, mass transfer is determined by the molecular weight cutoff (MWCO) or pore diameter of the membrane and occurs by diffusion and/or convection in response to existing transmembrane concentration or pressure gradients. Most of the bioreactors for BAL systems use membranes with MWCO ranging from 70 to 100 kDa that allow the transport of serum albumin but exclude proteins with high MW such as immunoglobulins and cells. One of the first clinical devices using HFMs was developed by Sussman and coworkers, namely, the extracorporeal liver-assist device (ELAD) in which the human hepatocytes were located outside the hollow fiber and blood flows through the lumen of the hollow fibers. This