Gut-liver-axis microphysiological system for studying cellular fluidic shear stress and inter-tissue interaction

Abstract

Gut-liver-axis (GLA) is a fundamental interaction between the gut and liver for maintaining human health. To clarify the physiological and pathological roles of GLA in the human body, a GLA microphysiological system (GLA-MPS) holds great potential. However, in current GLA-MPS, the importance of a physiologically relevant flow for gut and liver cells cultivation is not fully addressed. In addition, the integration of individual organ perfusion, circulation flow, and organ tissue functions in a single device has not been achieved. Here, we introduce a GLA-MPS by integrating two cell culture chambers with individually applied perfusion flows and a circulation channel with an on-chip pneumatic micropump under cell culture chambers via a porous membrane for interconnecting them. We analyzed the fluid shear stress (FSS) with computational fluid dynamics simulations and confirmed that the physiologically relevant FSS (i.e., 8 x 10-3 and 1.2 x 10-7 dyne cm-2) could be applied for the gut (Caco-2) and liver (HepG2) cells, respectively. Under physiologically relevant flow, the Caco-2 and HepG2 cells in the GLA-MPS maintained a cell survival rate of 95% and 92%, respectively; further, they enhanced the expression of functional proteins such as zonula occludens 1 (ZO-1) and albumin (ALB), respectively. Thus, the presented GLA-MPS can be adapted as an advanced in vitro model in a wide range of applications for disease modeling associated with inter-tissue interactions, such as fatty liver diseases.