Predicting the preclinical efficacy of anti-fibrosis agents using a force-sensing fibrosis on chip system

Abstract

The high attrition rate of drug candidates contributes to the long duration and high cost in modern drug development. A major barrier in drug development is the poor predicting power of the preclinical models. In the current study, a human pulmonary fibrosis on chip system was developed for the preclinical evaluation of anti-fibrosis drugs. Pulmonary fibrosis is a severe disease characterized by progressive tissue stiffening that leads to respiration failure. To recapitulate the unique biomechanical feature of the fibrotic tissues, we developed flexible micropillars that can serve as in-situ force sensors to detect the changes in the mechanical properties of engineered lung microtissues. Using this system, we modeled the fibrogenesis of the alveolar tissues including the tissue stiffening and the expression of α-smooth muscle actin (α-SMA) and pro-collagen. Two anti-fibrosis drug candidates that are currently under clinical trials (KD025 and BMS-986020) were tested for their potential anti-fibrosis efficacy and the results were compared to those of FDA-approved anti-fibrosis drugs pirfenidone and nintedanib. Both pre-approval drugs were effective in inhibiting transforming growth factor beta 1 (TGF-β1) induced increases in tissue contractile force, stiffness and expressions of fibrotic biomarkers, which are similar to the effects of FDA-approved anti-fibrosis drugs. These results demonstrated the potential utility of the force-sensing fibrosis on chip system in the pre-clinical development of anti-fibrosis drugs.