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Open AccessArticle

Microscale 3D Liver Bioreactor for In Vitro Hepatotoxicity Testing under Perfusion Conditions

1
Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité–Universitätsmedizin Berlin, 13353 Berlin, Germany
2
Department of Hepatobiliary Surgery and Visceral Transplantation, University of Leipzig, 04103 Leipzig, Germany
3
Los Alamos National Laboratory, Los Alamos, NM 87545, USA
4
StemCell Systems GmbH, Berlin 12101, Germany
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Bioengineering 2018, 5(1), 24; https://doi.org/10.3390/bioengineering5010024
Received: 12 February 2018 / Revised: 7 March 2018 / Accepted: 12 March 2018 / Published: 15 March 2018
(This article belongs to the Special Issue Advances in Micro-Bioreactor Design for Organ Cell Studies)
The accurate prediction of hepatotoxicity demands validated human in vitro models that can close the gap between preclinical animal studies and clinical trials. In this study we investigated the response of primary human liver cells to toxic drug exposure in a perfused microscale 3D liver bioreactor. The cellularized bioreactors were treated with 5, 10, or 30 mM acetaminophen (APAP) used as a reference substance. Lactate production significantly decreased upon treatment with 30 mM APAP (p < 0.05) and ammonia release significantly increased in bioreactors treated with 10 or 30 mM APAP (p < 0.0001), indicating APAP-induced dose-dependent toxicity. The release of prostaglandin E2 showed a significant increase at 30 mM APAP (p < 0.05), suggesting an inflammatory reaction towards enhanced cellular stress. The expression of genes involved in drug metabolism, antioxidant reactions, urea synthesis, and apoptosis was differentially influenced by APAP exposure. Histological examinations revealed that primary human liver cells in untreated control bioreactors were reorganized in tissue-like cell aggregates. These aggregates were partly disintegrated upon APAP treatment, lacking expression of hepatocyte-specific proteins and transporters. In conclusion, our results validate the suitability of the microscale 3D liver bioreactor to detect hepatotoxic effects of drugs in vitro under perfusion conditions. View Full-Text
Keywords: microscale 3D liver bioreactor; in vitro perfusion; primary human liver cells; hepatotoxicity; acetaminophen microscale 3D liver bioreactor; in vitro perfusion; primary human liver cells; hepatotoxicity; acetaminophen
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Freyer, N.; Greuel, S.; Knöspel, F.; Gerstmann, F.; Storch, L.; Damm, G.; Seehofer, D.; Foster Harris, J.; Iyer, R.; Schubert, F.; Zeilinger, K. Microscale 3D Liver Bioreactor for In Vitro Hepatotoxicity Testing under Perfusion Conditions. Bioengineering 2018, 5, 24.

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  • Supplementary File 1:

    ZIP-Document (ZIP, 44214 KB)

  • Externally hosted supplementary file 1
    Doi: 10.5281/zenodo.1169306
    Link: http://doi.org/10.5281/zenodo.1169306
    Description: Underlying data for the paper "Microscale 3D Liver Bioreactor for In Vitro Hepatotoxicity Testing under Perfusion Conditions" published in the journal Bioengineering.
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