Is the Biological Artificial Liver Clinically Applicable? A Historic Review of Biological Artificial Liver Support Systems

Abstract

Hemoperfusion, hemodiafiltration, plasma exchange, and extracorporeal liver perfusion have already been adopted to treat patients with acute and chronic hepatic failure. However, the survival rate of patients with acute hepatic failure remains at approximately 30% and has not improved as expected. Current advances in biotechnology have opened the way for the development of a biological artificial liver, which is called the hybrid artificial liver because it consists of both biological and artificial materials. Isolated hepatocytes have been investigated for use in various types of hybrid artificial liver. In addition, the role of biomatrices, microcarriers, and the microencapsulation technique has been studied with respect to long-term maintenance of hepatocellular function and development of high-density culture systems for hepatocytes. Before clinical application of hybrid artificial liver support systems becomes possible, many problems have to be resolved, including large-scale preparation and long-term preservation of biomaterials, high-density and stable immobilization of biomaterials on artificial materials, control of immunological hazards, biocompatibility, safe transportation and sterilization of biomaterials, and the high cost. We review the history of biological artificial livers and discuss their future role.

Cultivation of immortalized human hepatocytes HepZ on macroporous CultiSpher G microcarriers

“…With progression of microcarrier invasion the consumption rate declined to a level between 820 and 1010 nmol/(10 6 cells и day), indicating a lowered oxygenation of the cells in the cores of the microcarriers. Primary rat hepatocytes consume 6,820-7,680 nmol/(10 6 cells и day) in hollow fiber bioreactors (Nyberg et al, 1993;Shatford et al, 1992), and human hepatocyte consumption was found to be approximately 5,800 nmol/(10 6 cells и day) in vivo (Kasai et al, 1994). Compared to primary cells in vivo HepZ cells used 66-86% less oxygen.…”

“…Due to the shortage of donor organs, 10-30% of the patients awaiting a liver die from liver disease before grafts become available (Kasai et al, 1994). Survival rate would be improved if a liver support system were available to bridge the patients until orthotopic liver transplantation.…”

Multiporous Cellulose Microcarrier for the Development of a Hybrid Artificial Liver Using Isolated Hepatocytes

“…Cellulose multiporous MCs (Asahi Chemical Co., Tokyo, Japan) with a 100-m pore size and 500-m diameter were used. Their density was slightly higher than that of water (1.024 g/cm 3 ) and thus they provide a suitable extracellular matrix for suspension culture. MCs suspended in phosphate-buffered saline (PBS) were incubated at 121°C for 20 min to achieve sterilization and to remove air and then were coated with 0.003% type I-C collagen (Nitta Gelatin, Tokyo, Japan) during 12 h of incubation at 4°C.…”

“…Extracellular matrices have been investigated for their availability to maintain hepatocellular function for a long time [3]. Cellulose multiporous microcarriers (MCs) are capable of immobilizing isolated cells in their micropores and thus may be a suitable extracellular matrix for maintenance of cellular function.…”

“…Since the introduction of collagenase digestion method, the metabolic activity of isolated hepatocytes have been examined in various types of hybrid artificial liver support systems [3]. We previously tried to develop a hybrid artificial liver support system using isolated dog hepatocytes in a fluid bed reactor, but the viability of the hepatocytes declined markedly over 6 h of perfusion [4].…”