Advances in bioartificial liver devices

Liver failure is the cause of death for over 30,000 patients each year in the United States alone.When this process occurs in healthy individuals with normal livers, it is termed acute liver failure (ALF). Loss of liver function that complicates chronic liver disease is termed acute-on-chronic liver failure. Liver transplantation is curative for ALF and acute-onchronic liver failure.1-6 Over the years, survival after transplantation has improved with advances in both patient management and surgical techniques, but the procedure is not always available in a timely fashion,7-9 prompting new surgical approaches such as split-liver transplantation, procurement from living donors, and auxiliary liver transplantation.10 The problem of organ shortage is compounded by difficulty in predicting the outcome of liver failure. The King’s College prognostic criteria have been adopted by most centers,11 although they fail to identify patients at low risk of dying.12 Alternatives to whole organ transplantation for liver dysfunction are under active investigation. Figure 1 schematically depicts the 4main cellular approaches that are currently being investigated: isolated cell transplantation,13-17 tissue engineering of implantable constructs,18-27 transgenic xenotransplantation,28-31 and extracorporeal bioartificial liver devices (BAL). Extracorporeal support for patients suffering from liver failure has been attempted for over 40 years. Temporary systems have been developed to attempt to expedite recovery from acute decompensation, facilitate regeneration in ALF, or serve as a bridge to liver transplantation. Various nonbiological approaches have met with limited success, presumably because of the role of the synthetic and metabolic functions of the liver that are inadequately replaced in these systems. Hemodialysis, hemoperfusion over charcoal or resins or immobilized enzymes, plasmapheresis, and plasma exchange have all been explored. Conversely, purely biological approaches have shown encouraging results in some cases but have been difficult to implement in the clinical setting. In addition to orthotopic liver transplantation, these include whole organ perfusion, perfusion of liver slices, and cross hemodialysis.32 Bioartificial devices typically incorporate isolated cells into bioreactors to simultaneously promote cell survival and function as well as provide for a level of transport seen in vivo. Several previous reviews have addressed the field of BAL development.33,34 We will highlight recent advances in liver biology and bioengineering that have impacted the field. The important issues include choice of cellular components, stabilization of hepatocyte phenotype, bioreactor design, regulation and safety, and clinical trials.