Issues in Bioartificial Liver Support Therapy for Acute Liver Failure

Abstract

Acute liver failure (ALF) is a medically intransigent problem. Survival, however, is etiology dependent and ranges from ∼25% for drug-induced ALF, hepatitis B, and cryptogenic cases to ∼60% for acetaminophen overdose, hepatitis A, and ischemia [73]. Liver transplantation (LTx), with 1-year survival rates of 60–80%, remains the therapy of choice for ALF patients [43, 77]. Because liver tissue has the ability to regenerate and heal [75], restoration of essential liver functions by means of auxiliary methods may improve the prognosis of many ALF patients, alleviating the need for LTx [8, 10, 73]. Recognition of the regenerative capacity of the liver has led to the development of innovative treatments for ALF that include split-LTx, extracorporeal nonbiological detoxification by artificial liver (AL) support, extracorporeal bioartificial liver (BAL) support (cell-based systems), and in vivo tissue or cell transplantation [37]. BAL bioreactor design faces several challenges that must collectively be satisfied in order to create a clinically viable system: (1) adequate cell seeding/cell density; (2) adequate transport of oxygen, nutrients, and toxins to the cells; (3) adequate transport of metabolic products from the cells; and (4) maintenance of sufficient hepatocyte-specific function over the time needed to meet a desired therapeutic goal. Therapeutic goals for systems designed to support patients with liver failure will become better defined as more systems are placed into clinical evaluation. This in turn will define the therapeutic, harmacokinetic dose, i.e., Da, that functional support systems must have to achieve clinical acceptance. Given that, the clinical efficacy of both AL (detoxification) and BAL (cell-based metabolic support) will be verified in the next 10 years. However, the clinical timing and indication will be different for the two systems: detoxification approaches will be employed earlier in the disease progression and, most likely, for AoCLF while BAL support will be used to support ALF patients and will be used when the disease continues to progress despite best medical therapy and detoxification. Research will focus on hepatic cell source in order to address ready availability, activity and function, and relatively low cost. Identification of human stem cell-derived hepatic cells to address immunologic concerns and species differences in metabolism as well as understanding and controlling the proliferation and differentiation of liver progenitor cells to functional hepatocytes will be important topics. Strategies proposed to improve mass transport in bioreactors and liver support systems are reviewed. Future BAL designs will rely heavily on pharmacological and engineering (mathematical) modeling of the entire patient/bioreactor perfusion system rather than just the bioreactor alone.