Cellular forces and matrix assembly coordinate fibrous tissue repair

Planar in vitro models have been invaluable tools to identify the mechanical basis of wound closure. Although these models may recapitulate closure dynamics of epithelial cell sheets, they fail to capture how a wounded fibrous tissue rebuilds its 3D architecture. Here we develop a 3D biomimetic model for soft tissue repair and demonstrate that fibroblasts ensconced in a collagen matrix rapidly close microsurgically induced defects within 24 h. Traction force microscopy and time-lapse imaging reveal that closure of gaps begins with contractility-mediated whole-tissue deformations. Subsequently, tangentially migrating fibroblasts along the wound edge tow and assemble a progressively thickening fibronectin template inside the gap that provide the substrate for cells to complete closure. Unlike previously reported mechanisms based on lamellipodial protrusions and purse-string contraction, our data reveal a mode of stromal closure in which coordination of tissue-scale deformations, matrix assembly and cell migration act together to restore 3D tissue architectureWe thank Vivek Shenoy, Britta Trappmann, Matthew Kutys, William Polacheck, Anant Chopra, Delphine Van Roosebeke, Merve Sakar and Andrew Petruska for helpful discussions and ideas. We are grateful to Britta Trappmann and Matthew Kutys for labelling fibronectin and collagen. We also thank George Chatzipirpiridis for his assistance in the development of the microrobotic platform, Dimitris Felekis for the characterization of cantilever stiffness and Patrik Frey for technical support in processing of images. This work was supported in part by Nano-Tera.ch within the Nanotera project FLUSITEX, RTD 2013, which was scientifically evaluated by the Swiss National Science Foundation and by grants from the National Institutes of Health (EB00262 and HL115553), the National Science Foundation (CMMI-1462710), the RESBIO Technology Resource for Polymeric Biomaterials and the Boston University Biological Design Center. (Nano-Tera.ch within the Nanotera project FLUSITEX, RTD; EB00262 - National Institutes of Health; HL115553 - National Institutes of Health; CMMI-1462710 - National Science Foundation; RESBIO Technology Resource for Polymeric Biomaterials; Boston University Biological Design Center)Published versio