Synergistic Modulation of a Tunable Microenvironment to Fabricate a Liver Fibrosis Chip for Drug Testing.

Abstract

Liver fibrosis is a progressive physiological change that occurs after liver injury and seriously endangers human health. The lack of reliable and physiologically relevant pathological models of liver fibrosis leads to a longer drug development period and sizeable economic investment. The fabrication of a biomimetic liver-on-a-chip is significant for liver disease treatment and drug development. Here, a sandwich chip with a microwell array structure in its bottom layer was fabricated to simulate the Disse space structure of hepatic sinusoids in vitro. By synergistic modulation of the cross-linking degree of gelatin-methacryloyl (GelMA) hydrogels and the induction of transforming growth factor-beta (TGF-β), the early and late stages of liver fibrosis were designed in the chip. Owing to its three-dimensional-mixed-culture strategy, it was possible to construct a liver sinusoid model in vitro to allow for faithful physiological emulation. The model was further subjected to drug treatment, and it presented a significant difference in treatment response in early and late fibrosis progression. Our system provides a unique method for emulating liver function through a vitro liver fibrosis-on-a-chip, potentially paving the way for investigating human liver fibrosis and related drug development.