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Open AccessArticle

Flow-Based Three-Dimensional Co-Culture Model for Long-Term Hepatotoxicity Prediction

Department of HBP Surgery & Liver Transplantation, Department of Surgery, Korea University College of Medicine, Seoul 02841, Korea
Author to whom correspondence should be addressed.
Micromachines 2020, 11(1), 36;
Received: 22 November 2019 / Revised: 13 December 2019 / Accepted: 25 December 2019 / Published: 27 December 2019
(This article belongs to the Special Issue Optimization of Microfluidic Devices)
We developed concave microwell arrays to establish a size-controllable 3-D co-culture liver model for in vitro drug toxicity testing, to predict hepatotoxicity. The interaction of hepatocytes with hepatic stellate cells (HSCs) was investigated by co-culturing primary 3-D hepatocyte spheroids and HSCs (heterosphere), using 3-D liver-on-a-chip. The effect of HSCs was investigated during spheroid formation; they were involved in controlling the organization of spheroidal aggregates and the formation of tight cell–cell contacts. Scanning electron microscopy (SEM) images showed that co-cultured spheroids with smoother surfaces in the flow chip aggregated more tightly and rapidly, compared to mono-cultured spheroids, until 13 days. Metabolic function analysis revealed that heterospheres secreted 40% more albumin and urea than hepatospheres on day 13. Additionally, an acetaminophen (AAP) and isoniazid (INH) concentration-dependent increase in CYP3A4 expression was detected in the 3-D cultures, and an increase in Lactate dehydrogenase (LDH) release after AAP and INH treatment was observed. CYP1A2, Mrp1 and UGT1A5 mRNA expression levels in the heterospheres and hepatospheres were evaluated from days 3 to 13. To examine the potential for toxicity testing in the flow-conditioned culture of the heterospheres, we evaluated cytotoxicity using the endpoint LDH release in the heterospheres and hepatospheres. IC50 values for AAP and INH after 24 h of exposure were calculated from the dose–response curves of the compounds. Flow-conditioned heterosphere culture results suggest that it may be suitable for long-term culture and cytotoxicity testing. Thus, our co-culture system closely resembles the in vivo environment and allows long-term in vitro hepatotoxicity prediction. View Full-Text
Keywords: microfluidic; hepatic stellate cell; hepatotoxicity; spheroid; co-culture microfluidic; hepatic stellate cell; hepatotoxicity; spheroid; co-culture
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Choi, Y.Y.; Seok, J.-I.; Kim, D.-S. Flow-Based Three-Dimensional Co-Culture Model for Long-Term Hepatotoxicity Prediction. Micromachines 2020, 11, 36.

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