Liver failure, whether arising directly from acute liver failure or from decompensated chronic liver disease is an increasing problem worldwide and results in many deaths. In the UK only 10% of individuals requiring a liver transplant...
moreLiver failure, whether arising directly from acute liver failure or from decompensated chronic liver disease is an increasing problem worldwide and results in many deaths. In the UK only 10% of individuals requiring a liver transplant receive one. Thus the need for alternative treatments is paramount. A BioArtificial Liver machine could temporarily replace the functions of the liver, buying time for the patient's liver to repair and regenerate. We have designed, implemented and tested a clinical-scale BioArtificial Liver machine containing a biomass derived from a hepatoblastoma cell-line cultured as three dimensional organoids, using a fluidised bed bioreactor, together with single-use bioprocessing equipment, with complete control of nutrient provision with feedback BioXpert recipe processes, and yielding good phenotypic liver functions. The methodology has been designed to meet specifications for GMP production, required for manufacture of advanced therapy medicinal products (ATMPs). In a porcine model of severe liver failure, damage was assured in all animals by surgical ischaemia in pigs with human sized livers (1.2–1.6 kg liver weights). The BioArtificial liver (UCLBAL) improved important prognostic clinical liver-related parameters, eg, a significant improvement in coagulation, reduction in vasopressor requirements, improvement in blood pH and in parameters of intracranial pressure (ICP) and oxygenation. Acute liver failure (ALF) is frequently a catastrophic event as the clinical course is often complicated by multi-organ failure with cerebral oedema being the terminal event. Acute liver failure can occur at any age, is commonly idiosyncratic with no specific therapy and patients present to hospital critically ill. Approximately 15% will recover spontaneously; the remainder fulfil the Kings College transplant criteria and 85% of those are listed on an urgent transplant waiting list. Currently in UK more than 20% of patients die on the waiting list. Liver disease is the only major disease in the UK on the increase, whilst donor organ availability is almost static, thus there is a large unmet medical need for an alternative treatment. Since the liver has the capacity to repair and regenerate given time, a solution is to provide temporary liver function to " buy time " either for complete recovery or to find a suitable donor organ. We have developed a bio-artificial liver machine based on a biomass comprised of human-liver derived cells 1–4 combined with adsorptive removal of DNA and endotoxin, to be used in an extracor-poreal circuit, treating the whole plasma fraction of the patient over several hours. The human liver is 1.2–1.6 kg containing 1–2 × 10 11 hepatocytes; experimental and clinical evidence demonstrates that patients can survive even if they have only ~30% of liver function 5. The aim of this study was to develop methodology appropriate to GMP production for a cell therapy to be delivered on the clinical scale, delivering ~70 billion cells and to test it in a severe, non-reversible model of acute liver failure in pigs with liver weights equivalent to those in humans.
