Idiopathic pulmonary fibrosis (IPF), characterized by the progressive stiffening of lung tissues, is a severe disease with no cure. The understanding of the IPF pathogenesis is incomplete, but inflammation has been identified as one of the major mediators and has been proposed as a therapeutic target for the development of anti-IPF drugs. However, since existing in vitro fibrosis models are composed of limited cell types and utilize rigid 2D culture formats, they cannot recapitulate the interaction between multiple profibrotic cells (macrophage, myofibroblast) and the physiological stresses (shear flow, matrix stiffening, tissue contraction) in the fibrotic tissue. As a result, these models are not able to provide the efficacy readout on the ?therapeutic targets? of the anti-fibrosis drugs. The objective of this renewal project is to develop a co-cultured fibrotic microtissue system that can model the fibrogenesis event caused by the inflammation and predict the therapeutic efficacy of the anti-fibrotic drugs that target inflammation pathways. Investigators have previously developed a static, mono- cultured fibrotic microtissue system that can recapitulate the late-stage fibrogenic changes in tissue biomechanics and histology caused by myofibroblast differentiation. However, this system is limited in predicting the efficacy of drugs that target important early stage fibrogenesis events. In the current project, investigators propose to expand the fibrosis modeling capacity of the existing system by including early-stage fibrogenesis events, such as flow-mediated profibrotic activation of the macrophages and inflammation induced myofibroblast differentiation. With this improved modeling capability, the new system will allow the examination of the drug efficacy on the inflammatory pathways, thus validating the mechanism of action of the drug on the intended target.
The aims will include to develop a co-cultured fibrotic microtissue system that can model inflammation-induced fibrogenesis of the lung interstitial tissue and to evaluate the screening capacity of the microtissue system for anti-fibrosis drugs that target the inflammatory pathway. It is expected that such a system will be able to simulate the therapeutic effects of the drug candidates on inflammatory pathways, thus allowing the delineation of the therapeutic mechanism of the drug. Such a new approach can significantly expedite the translation of anti-fibrotic therapies from the laboratories to the clinics. 1
Pulmonary fibrosis is a severe health problem, but the development of anti-fibrosis therapies is facing major obstacles. In this project, we propose to develop a microfluidic coupled, co-cultured fibrotic microtissue chip system that can predict targeted therapeutic efficacy of the anti-fibrotic drugs. It is expected that such a system can help to delineate the therapeutic mechanism of the drug, thus expediting the drug discovery process. 1
