Journal
EXPERIMENTAL BIOLOGY AND MEDICINE
Volume 241, Issue 1, Pages 101-114Publisher
SAGE PUBLICATIONS LTD
DOI: 10.1177/1535370215592121
Keywords
In vitro liver model; hepatotoxicity; high content analysis; microphysiology systems; microfluidics; liver disease models
Categories
Funding
- Cancer Center Support Grant from the National Institutes of Health [P30 CA047904]
- National Institutes of Health
- National Center for Advancing Translational Sciences [5UH2TR000503-02, 4UH3TR000503-03, 3UH2TR000503-02S1]
- Office Of The Director, National Institutes Of Health of the National Institutes Of Health [S10OD012269]
- [P30CA047904]
- NATIONAL CANCER INSTITUTE [P30CA047904] Funding Source: NIH RePORTER
- NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES [UH2TR000503, UH3TR000503] Funding Source: NIH RePORTER
- OFFICE OF THE DIRECTOR, NATIONAL INSTITUTES OF HEALTH [S10OD012269] Funding Source: NIH RePORTER
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This paper describes the development and characterization of a microphysiology platform for drug safety and efficacy in liver models of disease that includes a human, 3D, microfluidic, four-cell, sequentially layered, self-assembly liver model (SQL-SAL); fluorescent protein biosensors for mechanistic readouts; as well as a microphysiology system database (MPS-Db) to manage, analyze, and model data. The goal of our approach is to create the simplest design in terms of cells, matrix materials, and microfluidic device parameters that will support a physiologically relevant liver model that is robust and reproducible for at least 28 days for stand-alone liver studies and microfluidic integration with other organs-on-chips. The current SQL-SAL uses primary human hepatocytes along with human endothelial (EA.hy926), immune (U937) and stellate (LX-2) cells in physiological ratios and is viable for at least 28 days under continuous flow. Approximately, 20% of primary hepatocytes and/or stellate cells contain fluorescent protein biosensors (called sentinel cells) to measure apoptosis, reactive oxygen species (ROS) and/or cell location by high content analysis (HCA). In addition, drugs, drug metabolites, albumin, urea and lactate dehydrogenase (LDH) are monitored in the efflux media. Exposure to 180 mu M troglitazone or 210 mu M nimesulide produced acute toxicity within 2-4 days, whereas 28 mu M troglitazone produced a gradual and much delayed toxic response over 21 days, concordant with known mechanisms of toxicity, while 600 mu M caffeine had no effect. Immune-mediated toxicity was demonstrated with trovafloxacin with lipopolysaccharide (LPS), but not levofloxacin with LPS. The SQL-SAL exhibited early fibrotic activation in response to 30nM methotrexate, indicated by increased stellate cell migration, expression of alpha-smooth muscle actin and collagen, type 1, alpha 2. Data collected from the in vitro model can be integrated into a database with access to related chemical, bioactivity, preclinical and clinical information uploaded from external databases for constructing predictive models.
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