Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with no cure. IPF development follows a unique pattern with fibrosis starting at the lung periphery and progressing toward the lung center. Little is known about the mechanism underlying the periphery-to-center progression of the disease. Recent studies suggest that the higher level of parenchymal expansion (strain) in the lung periphery serve to amplify and perpetuate the progression of fibrosis upon initial lung injury. Systematic inquiry of the spatiotemporal progression of pulmonary fibrosis has been challenging and cost prohibitive, because (1) correlative data on both lung pathology and lung mechanics are difficult to obtain due to the prolonged disease progression in human; (2) the most commonly used mouse model of bleomycin-induced fibrosis spontaneously resolves and therefore fails to fully reflect human fibrosis, and (3) current in vitro lung tissue models do not reproduce an in vivo-like strain gradient and the complex biomechanics existing in the native alveolar structure. The objective of this project is to understand the spatiotemporal relation between pulmonary fibrosis and mechanical stretch in the lung and develop a stretched engineered lung slice (ELS) model to study the multiscale biomechanical mechanism of differential stretch-induced spatial progression of pulmonary fibrosis. The main hypothesis is that the high level mechanical stretch at the lung periphery amplifies the pro-fibrotic signaling in injured lung cells, thus initiating fibrosis and perpetuating the periphery-to-center fibrosis progression in the lung. Recently, investigator’s team have adopted decellularization technique to create ELSs that support the long term growth of lung cells in structurally-persevered human lung scaffolds. To utilize the ELS in the study of the fibrosis progression, investigators plan to adopt a multiscale biomimicry strategy where the integration of ELS with a gradient stretching device allows macroscopic modelling of the differential strains existing at the lung periphery and lung center, and the preserved structure in the ELS allows microscopic modelling of the mechanical signal transduction and cellular injury existing at the single alveolus level. The aims include characterizing the spatiotemporal evolution of pulmonary fibrosis and mechanical stretch in both human and rat fibrotic lung samples, developing a differentially-stretched, ELS model to test how realistic strain gradients affect spatial progression of fibrosis upon epithelial injury, and understanding the multiscale biomechanical mechanism of stretch induced fibrosis initiation and progression. The combination of mechanical stretching and computational modeling with the lung slice model will substantially improve the utility of this underutilized model for lung disease research, thus greatly facilitating the research efforts in pulmonary fibrosis and improving the understanding of a major disease mechanism t...