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HepatoMune: A Bioengineered Micro-liver Platform for the Study of Inflammatory Responses in Toxicology Investigation

Abstract: Liver inflammation involves the early release of multiple pro-inflammatory factors, reactive oxygen species and chemokines by specialized macrophages, known as Kupffer cells. This inflammatory response occurs alongside the downregulation of major liver-specific metabolizing enzymes (ie. CYP450), which can alter the liver's metabolism of foreign biologics, such as therapeutic antibodies or xenobiotics. Inflammation is further associated with improper distribution and clearance of small molecule drugs, which may result in intensified side effects, nullification of therapeutic benefits, or potential hepatotoxicity.

Hepregen has developed an in vitro model capable of propagating an inflammatory response that is predictive of clinically-relevant, immune-mediated liver toxicities (Khetani and Bhatia, 2008). The model incorporates a co-culture of Kupffer cells, primary hepatocytes, and non-parenchymal stromal cells in a miniaturized, in vitro model of the human liver, called HepatoMune. HepatoMune tri-cultured hepatocytes retain in vivo-like morphology, express liver-specific genes, metabolize compounds using active Phase I/II drug metabolism enzymes, secrete diverse liver-specific products, and exhibit transporter activity (Phase III). Additionally, Kupffer cells in HepatoMune respond to modulators, such as LPS, and are viable for 10 days. These features provide far superior performance relative to conventional in vitro hepatocyte culture models such as suspension, mono or sandwich cultures.

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