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Here, we investigated how collagen matrix densification modulates stem cell mechanosensing in\u00a0vitro and bone healing outcomes in\u00a0vivo using density\u2010tunable collagen microgels. Centrifugation\u2010based collagen densification produced a sixfold increase in stiffness and a compact fibrillar architecture that enhanced early mechanosensitive signaling in human mesenchymal stem cells, including YAP1 and Piezo1 upregulation, reaching levels comparable to biochemical osteoinduction. In\u00a0vivo, low\u2010 and high\u2010density microgels increased bone formation relative to untreated defects, though low\u2010density constructs supported more uniform and volumetric regeneration. Despite these differences in bone volume, bone mineral density and histological maturity were comparable across all groups, while complete bridging was observed only with autologous bone grafts. Our findings demonstrate that matrix densification promotes early mechanotransductive priming, but the microgel format did not achieve full regeneration for either gel group, suggesting that effective bone healing likely requires balancing mechanical stimulation with sufficient biological accessibility. Designing scaffolds with controlled density and adaptive mechanical properties may create dynamically permissive environments that support both early mechanosensing and late\u2010stage remodeling for functional bone repair.<\/jats:p>","DOI":"10.1002\/jbm.a.70163","type":"journal-article","created":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T06:35:57Z","timestamp":1791527757000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Assessing Hydrogel Microenvironment Density Effects on Mechanotransduction In\u00a0Vitro and Bone Regeneration In\u00a0Vivo"],"prefix":"10.1002","volume":"114","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8226-8083","authenticated-orcid":false,"given":"Sofia M.","family":"Vignolo","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering, School of Medicine Oregon Health &amp; Science University (OHSU)  Portland Oregon USA"},{"name":"Knight Cancer Precision Biofabrication Hub Knight Cancer Institute (KCI), OHSU  Portland Oregon USA"},{"name":"Cancer Early Detection Advanced Research Center (CEDAR), KCI, OHSU  Portland Oregon USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8156-4681","authenticated-orcid":false,"given":"Daniela M.","family":"Roth","sequence":"additional","affiliation":[{"name":"Knight Cancer Precision Biofabrication Hub Knight Cancer Institute (KCI), OHSU  Portland Oregon USA"},{"name":"Cancer Early Detection Advanced Research Center (CEDAR), KCI, OHSU  Portland Oregon USA"},{"name":"Department of Oral Rehabilitation and Biosciences School of Dentistry, OHSU  Portland Oregon USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9323-0862","authenticated-orcid":false,"given":"May A. 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