Fibrosis, as seen in end-stage idiopathic pulmonary fibrosis (IPF), heart failure, liver cirrhosis and kidney disease, leads to organ failure and currently has no cure. Candidates for anti-fibrotic therapies have been identified; however, the translation of these laboratory discoveries to clinical practice is hindered by the slow disease progression and the high cost associated with the clinical trials. To justify the development of new therapies in prolonged and expensive clinical trials, an in-vitro screening platform that can provide early evidence of efficacy of the anti-fibrotic therapies is desired. However, failure of the existing in vitro models to fully recapitulate the physio-pathological characteristics of the fibrotic disease, such as the reduced Forced vital capacity (FVC) and major extracellular matrix (ECM) remodeling in lung fibrosis, has significantly delayed the development of much needed anti-fibrotic therapies. The objective of this project is to develop a microphysiological lung fibrotic micro-tissue chip device that can enable the early screening of anti-fibrotic therapies. We have recently adopted micro-fabrication techniques to assemble 3D fibroblast-populated submillimeter micro-tissues in arrays of poly (dimethylsiloxane) (PDMS) micro-wells. In each micro-well, fibroblasts spontaneously contract and assemble the matrix proteins, such as collagen, into aligned micro-tissues that anchor between a pair of cantilevers. Our recent preliminary data have shown that distinct epithelium and ECM layers can be formed in micro-tissues due to boundary condition guided self-assembly of the cells and ECMs. With appropriate biochemical and mechanical stimuli, fibrotic differentiation of the resident cells can be further induced in these micro-tissues. In this project, we will fully characterize the fibrotic propertiesof the induced micro-tissue, such as its compliance under simulated forced ventilation and the deposition of ECM. We will then test its utility against two drugs that are very recently approved by FDA to treat IPF.
The Specific Aims of this application are: 1) Fabricate arrays of micro-tissues and induce fibrotic transition; 2) Calibrate the mechanical and histological characteristic of the fibrotic micro-tissues and optimize the system using a small set of training anti-fibrotic drugs; and 3) Evaluate the utility of the developed fibrotic tissue-chip in screening anti-fibrotic compounds. Upon completion of this project, it is our expectation that we will have developed a new approach that can significantly expedite the translation of anti-fibrotic therapies from the laboratories to the clinics. We are confident that such advancement in the technology will positively impact the practices to combat fibrotic diseases.
Fibrosis, as seen in end-stage idiopathic pulmonary fibrosis (IPF), heart failure, liver disease and kidney disease, leads to organ failure and currently has no cure. In the project, we propose to develop a microphysiological lung 'fibrotic micro-tissue chip' device that can enable the early screening of anti-fibrotic therapies. We anticipate that such advancement in the technology will expedite the drug discovery and positively impact the practices to combat fibrotic diseases.
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