Development of Fibrotic Micro-Tissue Model for Predicting Anti-Fibrosis Drug Efficacy

Abstract

Fibrosis is a fatal pathological problem characterized by progressive stiffening of tissues. The increase in stiffness as a result of activated myofibroblast and extra cellular depositition of proteins such as collagen type I, would adversely influence the organ toward failure. A decisive barricade in developing new anti-fibrosis therapies is the absence of reliable cell based in vitro models that recapitulate dynamic changes in tissue mechanics during pathological trasformation. Here a novel platform is created to provide membranous human lung microtissues that captures key biomechanical properties of lung alveolar tissue. It will be demonstrated how this model would help us better model the pathological transition of initially compliant, membranous lung microtissue into a stiff and contractile state that matches that of interstitial lung fibrosis by leveraging the dynamic remodeling capabilities of suspended lung microtissue array. Through mechanical stretching and patterning stress concentration in the membranous microtissue, we were able to model other pathological features of the fibrotic lung, such as the decline in tissue compliance and traction force-induced bronchial dilation. Proof of principle is delivered by using this fibrotic tissue array for multi-parameter, phenotypic analysis of the therapeutic efficacy of two anti-fibrosis drugs; Nintedanib and Pirfenidone. The capability of this novel platform is also tested by coupling the microtissue array with cyclic stretching system to simulate breathing and testing the effect of the mentioned drugs on biomechanical properties of engineered lung alveoli membrane. These results highlight the multiscale and pathophysiologically relevant modeling capability of our novel fibrotic microtissue system, which can facilitate the clinical translation of anti-fibrotic therapies.