Abstract
Fibrosis is a severe health problem characterized by progressive stiffening of tissues which causes organ malfunction and failure. A major bottleneck in developing new anti-fibrosis therapies is the lack of in vitro models that recapitulate dynamic changes in tissue mechanics during fibrogenesis. Here we create membranous human lung microtissues to model key biomechanical events occurred during lung fibrogenesis including progressive stiffening and contraction of alveolar tissue, decline in alveolar tissue compliance and traction force-induced bronchial dilation. With these capabilities, we provide proof of principle for using this fibrotic tissue array for multi-parameter, phenotypic analysis of the therapeutic efficacy of two anti-fibrosis drugs recently approved by the FDA. Preventative treatments with Pirfenidone and Nintedanib reduce tissue contractility and prevent tissue stiffening and decline in tissue compliance. In a therapeutic treatment regimen, both drugs restore tissue compliance. These results highlight the pathophysiologically relevant modeling capability of our novel fibrotic microtissue system.
Highlights
Fibrosis is a severe health problem characterized by progressive stiffening of tissues which causes organ malfunction and failure
Progression of lung fibrosis is characterized by stiffening of the membranous tissue that makes up the alveolar air sacs, caused by the accumulation of highly contractile and collagen-producing myofibroblasts[4,5,6]
Comparison between different microtissue designs showed that large-size and medium-size designs both result in relatively high S/t ratios, which are ideal to model alveolar tissues, they are associated with different levels of stress concentrations that may affect the structural integrity of the microtissues differently (Fig. 1c; Supplementary Figs. 1, 2)
Summary
Fibrosis is a severe health problem characterized by progressive stiffening of tissues which causes organ malfunction and failure. We create membranous human lung microtissues to model key biomechanical events occurred during lung fibrogenesis including progressive stiffening and contraction of alveolar tissue, decline in alveolar tissue compliance and traction force-induced bronchial dilation. With these capabilities, we provide proof of principle for using this fibrotic tissue array for multi-parameter, phenotypic analysis of the therapeutic efficacy of two antifibrosis drugs recently approved by the FDA. Both anti-fibrosis drugs restore tissue compliance to different degree in a therapeutic treatment regimen Together, these studies highlight the pathophysiologically relevant modeling capability of our innovative fibrotic microtissue system. The application of this system will expedite the efficacy analysis of anti-fibrotic therapies and help to unveil their potential mode of action
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