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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
1R01EB019411-01A1
Application #
8964276
Study Section
Biomaterials and Biointerfaces Study Section (BMBI)
Program Officer
Selimovic, Seila
Project Start
2015-09-01
Project End
2019-05-31
Budget Start
2015-09-01
Budget End
2016-05-31
Support Year
1
Fiscal Year
2015
Total Cost
Indirect Cost
Name
State University of New York at Buffalo
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
038633251
City
Amherst
State
NY
Country
United States
Zip Code
14228
Zhao, Han; Chen, Zhaowei; Zhao, Ruogang et al. (2018) Exceptional point engineered glass slide for microscopic thermal mapping. Nat Commun 9:1764
Mistriotis, Panagiotis; Bajpai, Vivek K; Wang, Xiaoyan et al. (2017) NANOG Reverses the Myogenic Differentiation Potential of Senescent Stem Cells by Restoring ACTIN Filamentous Organization and SRF-Dependent Gene Expression. Stem Cells 35:207-221
Chen, Zhaowei; Wang, Qixin; Asmani, Mohammadnabi et al. (2016) Lung Microtissue Array to Screen the Fibrogenic Potential of Carbon Nanotubes. Sci Rep 6:31304