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The matrix stiffness is a crucial factor during bone tissue development. However, most in vitro models to study the osteogenesis of mesenchymal stem cells (MSCs) are static or stiffening in a 2D environment. Here, a dynamic and controllable stiffening 3D biomimetic model is created to regulate the osteogenic differentiation of MSCs with a dual\u2010functional gelatin macromer that can generate a double\u2010network hydrogel by sequential enzymatic and light\u2010triggered crosslinking reactions. The findings show\u00a0that these dynamic hydrogels allowed cells to spread and expand prior to the secondary crosslinking and to sense high stiffness after stiffening. The MSCs in the dynamic hydrogels, especially the hydrogel stiffened at the late period, present\u00a0significantly elevated osteogenic ECM secretion, gene expression, and nuclear localization of Yes\u2010associated protein (YAP) and transcriptional coactivator with PDZ\u2010binding motif (TAZ). In vivo evaluation of animal experiments further indicates\u00a0that the enhancement of dynamic stiffening on osteogenesis of MSCs substantially promotes bone remodeling. Consequently, this work reveals that the 3D dynamic stiffening microenvironment as a critical biophysical cue not only mediates the stem cell fate in vitro, but also augments bone restoration in vivo.<\/jats:p>","DOI":"10.1002\/adhm.202300326","type":"journal-article","created":{"date-parts":[[2023,8,29]],"date-time":"2023-08-29T15:49:04Z","timestamp":1693324144000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":42,"title":["Dynamic Stiffening Hydrogel with Instructive Stiffening Timing Modulates Stem Cell Fate In Vitro and Enhances Bone Remodeling In Vivo"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8143-1122","authenticated-orcid":false,"given":"Xiaomeng","family":"Li","sequence":"first","affiliation":[{"name":"School of Mechanics and Safety Engineering Zhengzhou University  Zhengzhou 450001 China"},{"name":"National Center for International Joint Research of Micro\u2010Nano Moulding 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