Abstract
Liver failure is an increasing problem. Donor-organ shortage results in patients dying before receiving a transplant. Since the liver can regenerate, alternative therapies providing temporary liver-support are sought. A bioartificial-liver would temporarily substitute function in liver failure buying time for liver regeneration/organ-procurement. Our aim: to develop a prototype bioartificial-liver-machine (BAL) comprising a human liver-derived cell-line, cultured to phenotypic competence and deliverable in a clinical setting to sites distant from its preparation. The objective of this study was to determine whether its use would improve functional parameters of liver failure in pigs with acute liver failure, to provide proof-of-principle. HepG2cells encapsulated in alginate-beads, proliferated in a fluidised-bed-bioreactor providing a biomass of 4–6×1010cells, were transported from preparation-laboratory to point-of-use operating theatre (6000miles) under perfluorodecalin at ambient temperature. Irreversible ischaemic liver failure was induced in anaesthetised pigs, after portal-systemic-shunt, by hepatic-artery-ligation. Biochemical parameters, intracranial pressure, and functional-clotting were measured in animals connected in an extracorporeal bioartificial-liver circuit. Efficacy was demonstrated comparing outcomes between animals connected to a circuit containing alginate-encapsulated cells (Cell-bead BAL), and those connected to circuit containing alginate capsules without cells (Empty-bead BAL). Cells of the biomass met regulatory standards for sterility and provenance. All animals developed progressive liver-failure after ischaemia induction. Efficacy of BAL was demonstrated since animals connected to a functional biomass (+ cells) had significantly smaller rises in intracranial pressure, lower ammonia levels, more bilirubin conjugation, improved acidosis and clotting restoration compared to animals connected to the circuit without cells. In the +cell group, human proteins accumulated in pigs' plasma. Delivery of biomass using a short-term cold-chain enabled transport and use without loss of function over 3days. Thus, a fluidised-bed bioreactor containing alginate-encapsulated HepG2cell-spheroids improved important parameters of acute liver failure in pigs. The system can readily be up-scaled and transported to point-of-use justifying development at clinical scale.
Highlights
Both acute and acute-on-chronic liver failure are well recognised
We demonstrated improvements in several key clinical parameters of acute liver failure, including intracranial pressure (ICP), blood clotting function, bilirubin conjugation, acidosis and protein synthesis, not found when animals were treated with the BAL without cells
We have investigated the role of a liver cell line cultured in a 3-dimensional format housed in a fluidised bed bioreactor to provide temporaray liver support in a near clinical model
Summary
Both acute and acute-on-chronic liver failure are well recognised. Liver failure resulting from viral hepatitis, obesity, alcohol abuse, and drug-induced injury presents major clinical problems. Whilst organ transplantation is potentially curative, there is a huge gap between organ availability and supply. Since the liver has the ability to repair and regenerate given time, alternative therapies are sought. Bioartificial livers, aim to provide temporary synthetic and detoxificatory function buying time either for liver repair and regeneration, or acting as a bridge to transplantation [1]. Artificial liver support devices, for example, those based on albumin dialysis did not significantly improve survival in recent clinical trials [2,3], likely reflecting the complex functional repertoire of the liver that only a device containing a biological component can provide
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