In vitro nonalcoholic fatty liver disease model with cyclo-olefin-polymer-based microphysiological systems

Abstract

Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver conditions, and its treatment involves curing the patients without liver transplantation. Understanding the mechanism of NAFLD initiation and progression would enable the development of new diagnostic tools and drugs; however, until now, the underlying mechanisms of this condition remain largely unknown owing to the lack of experimental settings that can simplify the complicated NAFLD process in vitro. Microphysiological systems (MPSs) have long been used to recapture human pathophysiological conditions in vitro for applications in drug discovery. However, polydimethylsiloxane (PDMS) is used in most of these MPSs as the structural material; it absorbs hydrophobic molecules, such as free fatty acids (FFAs), which are the key components that initiate NAFLD. Therefore, the current PDMS-based MPSs cannot be directly applied to in vitro NAFLD modeling. In this work, we present an in vitro NAFLD model with an MPS made of cyclo-olefin polymer (COP), namely COP-MPS, to prevent absorption of FFAs. We demonstrated the induction of NAFLD-like phenotype in HepaRG hepatocyte-like cells cultured in the COP-MPS by treatment with FFAs. The FFAs induced lipid accumulation in the HepaRG cells, resulting in inactivation of the apoptotic cells. We believe that the proposed COP-MPS can contribute toward the investigation of NAFLD mechanisms and identification of new drugs to prevent the progression of liver disease and thus avoid liver transplantation.