Alleviating liver failure conditions using an integrated hybrid cryogel based cellular bioreactor as a bioartificial liver support
Apeksha DamaniaMohsin HassanNana ShirakigawaHiroshi MizumotoAnupam KumarShiv Kumar SarinHiroyuki IjimaMasamichi KamihiraAshok Kumar
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Abstract Conventionally, some bioartificial liver devices are used with separate plasmapheresis unit to separate out plasma from whole blood and adsorbent column to detoxify plasma before it passes through a hepatocytes-laden bioreactor. We aim to develop a hybrid bioreactor that integrates the separate modules in one compact design improving the efficacy of the cryogel based bioreactor as a bioartificial liver support. A plasma separation membrane and an activated carbon cloth are placed over a HepG2-loaded cryogel scaffold in a three-chambered bioreactor design. This bioreactor is consequently connected extracorporeally to a rat model of acute liver failure for 3 h and major biochemical parameters studied. Bilirubin and aspartate transaminase showed a percentage decrease of 20–60% in the integrated bioreactor as opposed to 5–15% in the conventional setup. Urea and ammonia levels which showed negligible change in the conventional setup increase (40%) and decrease (18%), respectively in the integrated system. Also, an overall increase of 5% in human albumin in rat plasma indicated bioreactor functionality in terms of synthetic functions. These results were corroborated by offline evaluation of patient plasma. Hence, integrating the plasmapheresis and adsorbent units with the bioreactor module in one compact design improves the efficacy of the bioartificial liver device.Keywords:
Bioartificial liver device
Plasmapheresis
Several configurations of extracorporeal bioartificial liver devices have been developed for the potential treatment of fulminant hepatic failure or as a bridge to liver transplantation. Recently, we developed a microchannel flat-plate bioreactor with an internal membrane oxygenator in which porcine hepatocytes are cultured as a monolayer on the bottom glass surface. In the present study, we investigated synthetic function of porcine hepatocytes in the bioreactor in both in vitro and in vivo flow circuit models. In vitro, albumin synthesis was stable in the bioreactor for up to 4 days of perfusion. In vivo, with the extracorporeal connection of the bioreactor to rat vasculature, porcine albumin was detectable for 24 h in the rat plasma. We also developed a simple mathematical model to predict the in vivo porcine albumin concentration in rat plasma. These results indicate that this configuration of a microchannel flat-plate bioreactor has potential as a liver support device and warrants further investigation.
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Fulminant hepatic failure
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Plasmapheresis
Acute hepatic failure
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The goal of this study was to evaluate efficacy of a new bioartificial device (ALEX) in an experimental model of acute hepatic failure in pigs combined with a albumin dyalisis system. A Molecular Adsorbent Recycling System (MARS) was connected to a Bioartificial liver (ALEX) filled of 10 billion hepatocytes. A Partial Liver Transplantation was performed. 5 pigs were not treated (G1). 7 were treated by MARS (G2); 7 with ALEX (G3); 7 with MARS and ALEX (C4). The treatments started immediately after PLT. Each treatment was of 6 hours and repeated 3 times a day for 3 days. In G1 100% Pigs died after 24 hours. In G2 1 pig died at day 1; 2 pigs died at day 3; 4 survived at day 3; In G3 2 pigs died after 24 hours, while the remaining pigs survived at day 3; In G4 100% pigs survived at day 3. All the died pigs showed a deep hypoglycemia. Ammonia was 700 m g/dl ± 300 and Total Bilirubin 15 mg/dl ± 6. The urine output was 0 at time 24. An high intracranial pressure was found in G1 and in G2 in the died pigs. In G4 all the parameters considered improved, while in G 2 only the bilirubin and Ammonia and in G3 only the prothrombin time and the intracranial pressure improved. Looking at the hepatic cells in G3 after each treatment 25% of cell viability into the bioreactor dropped. In G4 95% of viability was observed after each treatment. It is clear that by using both system it is possible to give a significant support action, able to all animals to survive to this acute liver failure model. Even the liver cells into the bioreactor, showed a significant improving in function and viability.
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One of the most important challenges in bioartificial liver designed for patients suffering from acute liver failure is oxygenation of cells within the bioreactor. The aim of this study was to evaluate the impact of oxygenation of bioartificial liver using perfluorocarbon (PFC) emulsion on the metabolic activity of hepatic cells in vitro. Mineral fibers coated with collagen type I were used as scaffolds for hepatic cells. Significantly higher total protein synthesis by hepatic C3A cells cultured in the bioreactor for 24 hours, in the group treated with medium supplemented with PFC emulsion, was observed in comparison with medium without PFC. Albumin production increased in the group treated with PFC after 1 hour of perfusion and was continuously, statistically, significantly higher during perfusion then the control group. In conclusion, the use of oxygen carriers, such as the PFC emulsion, can significantly improve synthetic performance of the bioreactor. Mineral fibers coated with extracellular proteins may serve as support for hepatic cells in the bioreactor.
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Abstract Conventionally, some bioartificial liver devices are used with separate plasmapheresis unit to separate out plasma from whole blood and adsorbent column to detoxify plasma before it passes through a hepatocytes-laden bioreactor. We aim to develop a hybrid bioreactor that integrates the separate modules in one compact design improving the efficacy of the cryogel based bioreactor as a bioartificial liver support. A plasma separation membrane and an activated carbon cloth are placed over a HepG2-loaded cryogel scaffold in a three-chambered bioreactor design. This bioreactor is consequently connected extracorporeally to a rat model of acute liver failure for 3 h and major biochemical parameters studied. Bilirubin and aspartate transaminase showed a percentage decrease of 20–60% in the integrated bioreactor as opposed to 5–15% in the conventional setup. Urea and ammonia levels which showed negligible change in the conventional setup increase (40%) and decrease (18%), respectively in the integrated system. Also, an overall increase of 5% in human albumin in rat plasma indicated bioreactor functionality in terms of synthetic functions. These results were corroborated by offline evaluation of patient plasma. Hence, integrating the plasmapheresis and adsorbent units with the bioreactor module in one compact design improves the efficacy of the bioartificial liver device.
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Acute liver failure (ALF) plasma has cytotoxic effects on the cell-loaded bioreactor in bioartificial liver support systems due to the presence of innumerable hepatotoxic compounds that adversely affect the morphology and functionality of the cells. We have designed a hybrid bioreactor that integrates a hepatic cell-loaded cryogel disc and an activated carbon cloth in one compact unit, with potential application as a bioartificial liver support. In this article, we assess the performance of this integrated hybrid cryogel-based bioreactor in a perfusion-based culture system and analyze its functionality and longevity in the presence of intermittent exposure to ALF plasma. The bioreactor maintained functionality in terms of glucose consumption and albumin synthesis for up to 40 days under perfusion. Additionally, intermittent perfusion of plasma from rodent models of ALF resulted in a decrease in viability and functionality only after the second spike of plasma, with the bioreactor maintaining its functionality even after the first spike. Similar results were obtained with patient plasma indicating the potential to reuse the bioreactor for multiple sessions of liver dialysis. Collectively, these results suggest the potential of the integrated cryogel-based bioreactor to be used at most twice before being disposed of. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 259-269, 2018.
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Bioartificial liver system are being developed as extracorporeal availability liver support therapy for patients with acute liver failure. In the system, bioreactor takes part in an important role. Up to new, many types bioreactors have been designed and studied. They are flat plate, hollow fiber, perfused beds or scaffolds, and beds with encapsulated or suspended cells bioreactor. In the article, the action, function, and criteria of bioreactor are introduced and 4 main types bioreactor's study development is reviewed.
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A wide range of toxic substances accumulates in the circulation of patients with liver failure, including more lipid-soluble substances, which bind to plasma proteins. Serum albumin is the most important binding protein for ligands such as bilirubin and bile acids, which are potentially toxic and can cause apoptosis in astrocytes and hepatocytes respectively in vitro. Resin haemoperfusion was originally investigated to remove these compounds, as well as inflammatory cytokines. Current effective methods for removal of protein-bound compounds in patients with liver failure include high volume plasmapheresis and different forms of albumin dialysis. Bioartificial liver support systems need adsorbent and/or dialysis modules to replace the lack of excretory function.
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