Patient-Specific iPSCs-Based Liver-On-A-Chip

Abstract

Successful advent of future medicine (e.g., personalized, preventive, predictive, participating medicine) will be strongly bonded to the availability of human-physiology-describing models. The combination of advanced researches in induced personalized stem cells (iPSCs) and the state-of-the-art microengineering is considered to create in-vitro models of organ functions in a near future; the first can generate patient-specific human cell lines, and the latter enables physiologically relevant microenvironments for recapitulating organ-level functions. Here we present a patient-specific iPSC-derived hepatocytes in an integrated microphysiological analysis platform (iMAP). The iMAP for iPSC-derived hepatocyte model is designed to culture the hepatocytes using endothelial-like physical barriers, which separate cell culture chambers and perfusion channels with Peclet number <<1. The physiological architecture supports enhanced hepatic functions of the iPSCs-derived hepatocytes, especially protein synthesis and drug metabolism. Compared to a conventional sandwich culture method, the liver-on-a-chip supports three-dimensional sinusoidal organization, enhanced junction protein and continuously refreshed media around the hepatic tissue to express higher albumin secretion and specifically enhanced drug metabolism (e.g., phenacetin is more metabolized to acetaminophen and N-acetyl-p-benzoquinone imine). Also, iPSCs-derived hepatocytes, by being matured from hepatoblast in the liver-on-a-chip platform, can increase the structural integrity due to avoiding dissociation of polarized hepatocytes and organogenesis-like tissue development in the microenvironment. The iMAP for iPSC-derived hepatocyte model will be tested for patient-specific pharmacokinetics/pharmacodynamics by involving various patient-derived iPSCs, and also other organ models will be integrated to estimate organ-organ interactions, which will provide various human-physiology-describing in-vitro models.