Development of a Hybrid Liver Support System

Abstract

Hybrid liver systems are being developed as temporary extracorporeal liver support therapy. The overview given here emphasizes the development of both hepatocyte culture models for bioreactors and of systems for clinical therapy. In vitro studies demonstrate long term external metabolic function in isolated primary hepatocytes within bioreactors. These systems are capable of supporting essential liver functions. Animal experiments verify the possibility of upscaling bioreactors for clinical treatment. However, since there is no reliable animal model for investigating the treatment of acute liver failure, the promising results obtained from these studies have limited relevance to human beings. The small number of clinical studies performed thus far are not sufficient to enable any conclusions concerning improvements in the therapy of acute liver failure. Although important progress has been made in the development of these systems, multiple hepatocyte culture models and bioreactor constructions are being discussed in the literature, indicating competition in this field of medical research. For the use of hepatocytes and sinusoidal endothelial cells in coculture, a bioreactor has been designed. The construction is based on capillaries for hepatocyte aggregate immobilization. Four separate capillary membrane systems, each permitting a different function, are woven in order to create a three‐dimensional network. Cells are perfused via independent capillary membrane compartments. Decentralized oxygen supply and carbon dioxide removal with low gradients is possible. The parallel use of identical units enables easy upscaling. Initial studies on the use of discarded organs that are unsuitable for transplantation as a source for primary human liver cells seem to be promising.1

Present and Future Developments in Hepatic Tissue Engineering for Liver Support Systems

“…In contrast, flat membrane plates covered with a cryoprotective solution are completely cryopreservable (unpublished observation). All techniques discussed in this article have advantages in the large scale bioreactors for liver support systems due to their easy upscaling (Gerlach et al 1993;Flendrig et al 1997;De Bartolo and Bader 2001;Sauer et al 2001). Systems using hepatic spheroids and encapsulated hepatocytes can easily be scaled to the cell mass needed to sustain the patient's life but may be associated with the possible dead volume and limitations of the mass transfer.…”

“…Fulminant hepatic failure is a consequence of the loss of normal liver function and often occurs as a result of autoimmune and viral hepatitis, hepatocellular cancer, exposure to toxins such as alcohol and drugs, or trauma (Gimson 1996). The concept of a bioartificial liver support system is based on the assumption that only hepatocytes perform a wide range of liver-specific functions, and it uses primary hepatocytes or a hepatoma cell line due to their expression of highly differentiated functions (Sauer et al 2001). For the development of such a liver support system, special attention has been paid to providing the architectural basis for the reconstruction of a proper cellular microenvironment that ensures the highest and prolonged functional activity of the hepatocytes.…”

Current development of bioreactors for extracorporeal bioartificial liver (Review)

“…The Academic Medical Center ͑AMC͒ EBAL system loads a nonwoven hydrophilic polyester matrix in the extrafiber region in the bioreactor for hepatocytes' attachment while the inner-lumen of hollow fibers are used for oxygen supply. 114 Sauer et al 115 developed a modular extracorporeal liver support ͑MELS͒ with a more complex interwoven hollow fiber cartridge. Three different bundles of hollow fibers are interwoven to form a threedimensional framework so that each bundle can perform separate functions such as plasma inflow, plasma outflow, and oxygen supply.…”

“…Modular extracorporeal liver support ͑MELS͒, developed by the team led by Sauer IM, 115,156,157 has an integrative system including the bioreactor unit, the CellModule charged with primary hepatocytes ͑from porcine or human͒, and the detoxication unit, the DetoxModule based on albumin dialysis. In the bioreactor, there is a 3D interwoven fiber matrix by two groups of hydrophilic material and one group of hydrophobic material.…”

Liver Cell Culture Devices

“…The MELS was the only system that fused with oxygenated medium in a radial fashion (72,73). had been used in clinical studies with primary porcine hepatocytes as well as primary human hepatocytes deNaruse et al used a collagen-coated nonwoven polyester matrix in which preformed hepatocyte aggregates rived from discarded donor livers (90)(91)(92). In a phase I study with primary human hepatocytes, eight patients were entrapped (75).…”