Pivotal preclinical trial of the spheroid reservoir bioartificial liver

Abstract

Background & Aims The neuroprotective effect of the spheroid reservoir bioartificial liver (SRBAL) was evaluated in a porcine model of drug-overdose acute liver failure (ALF). Methods Healthy pigs were randomized into three groups (standard therapy (ST) alone, ST + No-cell device, ST + SRBAL device) before placement of an implantable intracranial pressure (ICP) monitor and a tunneled central venous catheter. One week later, pigs received bolus infusion of the hepatotoxin D-galactosamine and were followed for up to 90 hours. Results At 48 hours, all animals had developed encephalopathy and biochemical changes confirming ALF; extracorporeal treatment was initiated and pigs were observed up to 90 hours after drug infusion. Pigs treated with the SRBAL, loaded with porcine hepatocyte spheroids, had improved survival (83%, n=6) compared to ST alone (0%, n=6, p=0.003) and No-cell device therapy (17%, n=6, p=0.02). Ammonia detoxification, peak levels of serum ammonia and peak ICP, and pig survival were influenced by hepatocyte cell dose, membrane pore size and duration of SRBAL treatment. Hepatocyte spheroids remained highly functional with no decline in mean oxygen consumption from initiation to completion of treatment. Conclusions The SRBAL improved survival in an allogeneic model of drug-overdose ALF. Survival correlated with ammonia detoxification and ICP lowering indicating that hepatocyte spheroids prevented the cerebral manifestations of ALF (brain swelling, herniation, death). Further investigation of SRBAL therapy in a clinical setting is warranted.

Current Evidence for Extracorporeal Liver Support Systems in Acute Liver Failure and Acute-on-Chronic Liver Failure

“…29,30 Further research into other functional cell sources (genetically modified liver cell lines, humanized pig cells, and hepatocyte spheroids) is ongoing. 45,46 Future studies will likely have to weigh the added levels of complexity and expense compared with purely detoxifying systems, such as HVP.…”

Recent Advances in Decellularization and Recellularization for Tissue-Engineered Liver Grafts

“…Barriers to the use of xenogenic cells exist, including severe immune rejection and the potential of xenozoonosis. Efforts have been made to characterize the immune reaction triggered by porcine hepatocytes in in vitro tissue-engineered liver systems or in immunosuppressed nonhuman primate models [Hering et al, 2006;Nagata et al, 2007;Glorioso et al, 2015], suggesting a xenogenic source of hepatic cells may be a future option for the creation of transplantable liver grafts.…”

Reply to: “Pivotal preclinical trial of the spheroid reservoir bioartificial liver”

“…Especially recovery studies requiring continuous care of animals over multiple days in succession. As a result, treatment time and membrane porosity were combined to limit our study to three treatment groups (SRBAL device, no cell device, no device) and two device configurations (400 kD membrane porosity, 6 h duration vs. 65 kD membrane porosity, 24 h duration) as detailed in our manuscript [1].…”

“…In the meantime, we refer the readers to our Supplementary material 1 [1]. We are not aware of any cultured cell line capable of lowering the medium concentration of ammonia from 800 lg/dl to 100 lg/dl in one hour as we report in Supplementary Fig.…”