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While ECM stiffness has been extensively studied, the role of ECM viscoelasticity (e.g., stress relaxation) in the bone marrow niche and its effects on macrophage function remain unclear. Here, this study reveals how matrix viscoelasticity orchestrates osteogenesis by modulating macrophage metabolism through vasodilator\u2010stimulated phosphoprotein (VASP) \/ hypoxia\u2010inducible factor 1 alpha (HIF1\u03b1) signaling. In the rapid maxillary expansion (RME) model, significant stress relaxation occurs in regenerated bone marrow during the initial 17 days, coinciding with increased transforming growth factor\u2010beta 1 (TGF\u2010\u03b21<jats:sup>+<\/jats:sup>) F4\/80+ macrophages. Fast stress relaxation enhances macrophage recruitment of mesenchymal stem cells (MSCs) by upregulating TGF\u2010\u03b21. Using a hydrogel\u2010macrophage system mimicking bone marrow viscoelasticity, cranial defect regeneration is significantly improved. Moreover, fast stress relaxation shifts macrophage metabolism from glycolysis to oxidative phosphorylation (OXPHOS) via VASP\/HIF1\u03b1 signaling, facilitating a reparative phenotype. These findings elucidate the relationship between ECM viscoelasticity and macrophage metabolism, suggesting new therapeutic avenues for bone regeneration through mechanomedicine.<\/jats:p>","DOI":"10.1002\/adhm.202405097","type":"journal-article","created":{"date-parts":[[2025,3,11]],"date-time":"2025-03-11T11:21:22Z","timestamp":1741692082000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Matrix Viscoelasticity Orchestrates Osteogenesis via Mechanotransduction Mediated Metabolic Switch in Macrophages"],"prefix":"10.1002","volume":"14","author":[{"given":"Dihao","family":"Tao","sequence":"first","affiliation":[{"name":"State Key Laboratory of Oral and Maxillofacial Reconstruction and Regeneration National Clinical Research Center for Oral Disease Shaanxi International Joint Research Center for Oral Diseases Center for Tissue Engineering School of Stomatology The Fourth Military Medical University  Xi'an Shaanxi 710032 P. 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