Efficacy of Fluidized Bed Bioartificial Liver in Treating Fulminant Hepatic Failure in Pigs: A Metabolomics Study

Abstract

Bioartificial livers may act as a promising therapy for fulminant hepatic failure (FHF) with better accessibility and less injury compared to orthotopic liver transplantation. This study aims to evaluate the efficacy and safety of a fluidized bed bioartificial liver (FBBAL) and to explore its therapeutic mechanisms based on metabolomics. FHF was induced by D-galactosamine. Eighteen hours later, pigs were treated with an FBBAL containing encapsulated primary porcine hepatocytes (B group), with a sham FBBAL (containing cell-free capsules, S group) or with only intensive care (C group) for 6 h. Serum samples were assayed using ultra-performance liquid chromatography-mass spectrometry. The difference in survival time (51.6 ± 7.9 h vs. 49.3 ± 6.6 h) and serum metabolome was negligible between the S and C groups, whereas FBBAL treatment significantly prolonged survival time (70.4 ± 11.5h, P < 0.01) and perturbed the serum metabolome, resulting in a marked decrease in phosphatidylcholines, lysophosphatidylcholines, sphingomyelinase, and fatty acids and an increase in conjugated bile acids. The FBBAL exhibits some liver functions and may exert its therapeutic effect by altering the serum metabolome of FHF pigs. Moreover, alginate–chitosan capsules have less influence on serum metabolites. Nevertheless, the alterations were not universally beneficial, revealing that much should be done to improve the FBBAL.

Establishment of a pattern recognition metabolomics model for the diagnosis of hepatocellular carcinoma

“…Our findings are in line with previous studies that demonstrated diminished levels of serum phospholipid metabolites in patients with liver diseases (including HCC, liver cirrhosis, hepatitis, and liver failure)[ 7 , 9 ]. Indeed, through an untargeted metabolomics approach, we found significantly reduced amounts of phospholipid metabolites in patients with HCC.…”

“…There were no statistical differences in age and sex among the patients with HCC, patients with cirrhosis, and healthy controls. Also, the constituent ratio of etiology of liver injury (pathogenesis) was comparable between the HCC and cirrhosis groups, all of which confirm the reliability of the UPLC-MS assay and optimal homogeneity of baseline characteristics[ 9 ].…”

“…The emergence of metabolomics has provided a powerful tool for discovering novel biomarkers and revealing metabolic pathways of cancer and liver diseases[ 8 , 9 ]. A metabolomics approach to screen individual metabolites or their combinations for the diagnosis of HCC[ 10 ] identified a series of potential biomarkers including phenylalanyl-tryptophan, glycocholate, concanavanine succinic acid, bile acid, long chain fatty acid, and so on for future clinical application[ 5 , 7 , 11 ].…”

Novel D-galactosamine-induced cynomolgus monkey model of acute liver failure

“…Currently, D-gal is usually administered through the external jugular vein or the abdominal cavity[ 23 - 25 , 27 ]. The abdominal cavity injection is simple and convenient, but resulting models are unstable, while administration through the external jugular vein and portal vein usually requires a long anesthesia time and surgical venous intubation, so the method is more complicated.…”

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

“…Further, in a study using porcine hepatocytes in a fluidised bed bioreactor in pigs with liver failure, whilst survival time in a D-galactosamine model was increased, there were marked perturbations in the serum metabolome, e.g. reductions in some phospholipids in particular phosphatidyl and lysophosphatidyl cholines as well as fatty acids 24 , molecules intimately associated with the stress response. It is also known that primary porcine hepatocytes are prone to loss of function and apoptosis in vitro 25 .…”