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Primary FLS cells were co-cultured with DRGs at low or high concentrations, to simulate variable anatomical FLS densities, and failed in tension. Given their roles in collagen degradation and nociception, matrix-metalloproteinase (MMP-1) and neuronal expression of the neurotransmitter substance P were probed after gel failure. The amount of FLS did not alter (p\u2009&gt;\u20090.3) the gel failure force, displacement, or stiffness. FLS doubled regional strains at both low (p\u2009&lt;\u20090.01) and high (p\u2009=\u20090.01) concentrations. For high FLS, the collagen network showed more reorganization at failure (p\u2009&lt;\u20090.01). Although total MMP-1 and neuronal substance P were the same regardless of FLS concentration before loading, protein expression of both increased after failure, but only in low FLS gels (p\u2009\u2264\u20090.02). The concentration-dependent effect of FLS on microstructure and cellular responses implies that capsule regions with different FLS densities experience variable microenvironments. This study presents a novel DRG-FLS co-culture collagen gel system that provides a platform for investigating the complex biomechanics and physiology of human joint capsules, and is the first relating DRG and FLS interactions between each other and their surrounding collagen network.<\/jats:p>","DOI":"10.1115\/1.4044051","type":"journal-article","created":{"date-parts":[[2019,6,18]],"date-time":"2019-06-18T02:30:38Z","timestamp":1560825038000},"update-policy":"https:\/\/doi.org\/10.1115\/crossmarkpolicy-asme","source":"Crossref","is-referenced-by-count":8,"title":["Concentration-Dependent Effects of Fibroblast-Like Synoviocytes on Collagen Gel Multiscale Biomechanics and Neuronal Signaling: Implications for Modeling Human Ligamentous Tissues"],"prefix":"10.1115","volume":"141","author":[{"given":"Meagan E.","family":"Ita","sequence":"first","affiliation":[{"name":"Department of Bioengineering, University of Pennsylvania, 240 Skirkanich Hall, 210 South 33rd Street, Philadelphia, PA 19104 e-mail:"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Beth A.","family":"Winkelstein","sequence":"additional","affiliation":[{"name":"Mem. 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