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      Cyclic Stretching of Fibrotic Microtissue Array for Evaluation of Anti-Fibrosis Drugs

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          Abstract

          Introduction

          Progression of pulmonary fibrosis, characterized by the deterioration of lung tissue’s mechanical properties, is affected by respiratory motion-induced dynamic loading. Since the development of anti-fibrosis drugs faces major hurdles in animal tests and human clinical trials, preclinical models that can recapitulate fibrosis progression under physiologically-relevant cyclic loading hold great promise. However, the integration of these two functions has not been achieved in existing models.

          Methods

          Recently we developed static human lung microtissue arrays that recapitulate the progressive changes in tissue mechanics during lung fibrogenesis. In the current study, we integrate the lung microtissue array with a membrane stretching system to enable dynamic loading to the microtissues. The effects of a pro-fibrotic agent and anti-fibrosis drugs were tested under cyclic stretching.

          Results

          Cyclic stretching that mimics respiratory motion was shown to affect the cytoskeletal organization and cellular orientation in the microtissue and cause the increase in microtissue contractility and stiffness. Fibrosis induction using TGF-β1 further promoted fibrosis-related mechanical activity of the lung microtissues. Using this system, we examined the therapeutic effects of two FDA approved anti-fibrotic drugs. Our results showed that Nintedanib was able to fully inhibit TGF-β1 induced force increase but only partially inhibited stretching induced force increase. In contrast, Pirfenidone was able to fully inhibit both TGF-β1 induced force increase and stretching-induced force increase.

          Conclusions

          Together, these results highlight the pathophysiologically-relevant modeling capability of the current fibrotic microtissue system and demonstrated the potential of this system to be used for anti-fibrosis drug screening.

          Electronic supplementary material

          The online version of this article (10.1007/s12195-019-00590-3) contains supplementary material, which is available to authorized users.

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          Author and article information

          Contributors
          rgzhao@buffalo.edu
          Journal
          Cell Mol Bioeng
          Cell Mol Bioeng
          Cellular and Molecular Bioengineering
          Springer US (New York )
          1865-5025
          1865-5033
          28 August 2019
          October 2019
          : 12
          : 5
          : 529-540
          Affiliations
          [1 ] GRID grid.273335.3, ISNI 0000 0004 1936 9887, Department of Biomedical Engineering, , State University of New York at Buffalo, ; Buffalo, NY 14260 USA
          [2 ] GRID grid.273335.3, ISNI 0000 0004 1936 9887, Department of Industrial and Systems Engineering, , State University of New York at Buffalo, ; Buffalo, NY 14260 USA
          Author notes

          Associate Editor Stephanie Michelle Willerth oversaw the review of this article.

          Author information
          http://orcid.org/0000-0002-5351-0843
          Article
          PMC6816662 PMC6816662 6816662 590
          10.1007/s12195-019-00590-3
          6816662
          31719931
          64003b89-a8b9-4488-83a2-e202f6024fdd
          © Biomedical Engineering Society 2019
          History
          : 13 February 2019
          : 17 August 2019
          Funding
          Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
          Award ID: R01EB019411
          Award Recipient :
          Categories
          Article
          Custom metadata
          © Biomedical Engineering Society 2019

          Nintedanib,Tissue mechanics,Pirfenidone,Drug screening,Microtissue array,Cyclic stretching,Lung fibrosis

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