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

Journal Article · · Bioengineering
 [1];  [1];  [1];  [1];  [1];  [2];  [2];  [3];  [3];  [4];  [1]
  1. Charité – Universitätsmedizin Berlin (Germany). Berlin-Brandenburg Center for Regenerative Therapies (BCRT)
  2. Leipzig Univ. (Germany). Dept. of Hepatobiliary Surgery and Visceral Transplantation
  3. Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
  4. StemCell Systems GmbH, Berlin (Germany)
+ Show Author Affiliations
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.
Research Organization:
Charité – Universitätsmedizin Berlin (Germany); Leipzig Univ. (Germany); Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Sponsoring Organization:
Defense Threat Reduction Agency (DTRA) (United States); Federal Ministry of Education and Research (BMBF) (Germany); USDOE
Grant/Contract Number:
AC52-06NA25396
OSTI ID:
1479987
Report Number(s):
LA-UR--18-21816
Journal Information:
Bioengineering, Journal Name: Bioengineering Journal Issue: 1 Vol. 5; ISSN 2306-5354
Publisher:
MDPICopyright Statement
Country of Publication:
United States
Language:
English

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Cited By (4)

Metabolism of remimazolam in primary human hepatocytes during continuous long-term infusion in a 3-D bioreactor system text January 2019
Conceptual Design of Micro-Bioreactors and Organ-on-Chips for Studies of Cell Cultures journal July 2018
Advances in Micro-Bioreactor Design for Organ Cell Studies journal August 2018
Human-Derived Organ-on-a-Chip for Personalized Drug Development journal April 2019

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Related Subjects

42 ENGINEERING
60 APPLIED LIFE SCIENCES
acetaminophen
hepatotoxicity
in vitro perfusion
microscale 3D liver bioreactor
primary human liver cells