A clinical-scale BioArtificial Liver, developed for GMP, improved clinical parameters of liver function in porcine liver failure

Abstract

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 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.

Advances in the slow freezing cryopreservation of microencapsulated cells

“…MSCs. [83,88,118,119]. Since in FLF the treatment need is immediate, and thus, the banking of these cell-products for the "on demand" access of patients has been extensively studied for two decades mostly with the use of slow freezing cryopreservation ( Table 5).…”

“…A similar study using cryopreserved microencapsulated porcine hepatocytes in FLF induced mice was also performed [123]. The Liver Group, from University College of London (UCL), is developing a bioartificial liver (7x10 10 cells biomass) for the treatment of FLF [83,88,125], studying for that aim, the slow freezing cryopreservation of alginate microencapsulated liver HepG2 spheroids [12,63,64,74,79,126,127]. To reduce contamination risks in the process, they compared a CRF without the use of liquid coolants with another CRF that use liquid nitrogen for slow cooling cryopreservation [126].…”

“…In addition, clinicians training with microencapsulated cells result an important factor to avoid handling errors that can take down the effectiveness of the cell therapy product. Considering all these quality control steps, currently a clinical scale bioartificial liver has been developed for GMP [83], showing its potential in vivo and demonstrating that a big part of the path has been done for the treatment of FLF patients.…”

Injectable hydrogels based on glycyrrhizin, alginate, and calcium for three‐dimensional cell culture in liver tissue engineering

“…The BAL device has demonstrated improved outcomes in animal models of acute liver failure . Recently, phase I and II clinical trials have also confirmed that BAL exhibited significant improvement on prognostic clinical liver‐related parameters, suggesting the safety of BAL for human hepatocytes . However, there are many challenges on BAL systems, such as hepatocyte viability and the regulation of liver specific function, which lead to more limit of BAL systems for clinical treatment.…”

“…5,6 Recently, phase I and II clinical trials have also confirmed that BAL exhibited significant improvement on prognostic clinical liver-related parameters, suggesting the safety of BAL for human hepatocytes. 7,8 However, there are many challenges on BAL systems, such as hepatocyte viability and the regulation of liver specific function, which lead to more limit of BAL systems for clinical treatment. Scaffold material is one of the major factors for the BAL system, which can supply a similar microenvironment for cells growth.…”