title: Hepatic organoids for microfluidic drug screening.
abstract: We introduce the microfluidic organoids for drug screening (MODS) platform, a digital microfluidic system that is capable of generating arrays of individually addressable, free-floating, three-dimensional hydrogel-based microtissues (or 'organoids'). Here, we focused on liver organoids, driven by the need for early-stage screening methods for hepatotoxicity that enable a "fail early, fail cheaply" strategy in drug discovery. We demonstrate that arrays of hepatic organoids can be formed from co-cultures of HepG2 and NIH-3T3 cells embedded in hydrogel matrices. The organoids exhibit fibroblast-dependent contractile behaviour, and their albumin secretion profiles and cytochrome P450 3A4 activities are better mimics of in vivo liver tissue than comparable two-dimensional cell culture systems. As proof of principle for screening, MODS was used to generate and analyze the effects of a dilution series of acetaminophen on apoptosis and necrosis. With further development, we propose that the MODS platform may be a cost-effective tool in a "fail early, fail cheaply" paradigm of drug development.
authors.affiliation: Institute of Biomaterials and Biomedical Engineering, University of Toronto, 164 College St., Toronto, ON M5S 3G9, Canada. aaron.wheeler@utoronto.ca.
authors.forename: Sam H
authors.initials: SH
authors.lastname: Au
authors.forename: M Dean
authors.initials: MD
authors.lastname: Chamberlain
authors.forename: Shruthi
authors.initials: S
authors.lastname: Mahesh
authors.forename: Michael V
authors.initials: MV
authors.lastname: Sefton
authors.forename: Aaron R
authors.initials: AR
authors.lastname: Wheeler
mesh_terms: D000818:Animals; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000737:chemistry* / Q000187:drug effects; D051379:Mice; D046210:Microfluidic Analytical Techniques / Q000295:instrumentation*; D041681:NIH 3T3 Cells; D004364:Pharmaceutical Preparations / Q000032:analysis*
chemical_list: D004364:Pharmaceutical Preparations