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The cartilage layer consists of a porous gelatin methacryloyl hydrogel (PGelMA) covalently crosslinked with the chondroinductive peptide CK2.1 via a \u201clinker\u201d acrylate\u2010PEG\u2010N\u2010hydroxysuccinimide (AC\u2010PEG\u2010NHS). This layer is optimized for remodeling the senescent microenvironment in the cartilage region, thereby establishing a regenerative microenvironment that supports chondrogenesis. For the bone layer, silk fibroin methacryloyl (SilMA) is coated onto a three dimensional (3D)\u2010printed 45S5 bioactive glass scaffold (BG scaffold). The \u201cexercise hormone\u201d N\u2010lactoyl\u2010phenylalanine (Lac\u2010Phe) is loaded onto the SilMA, endowing it with diversified functions to regulate the osteogenic microenvironment. Systematic analysis in vitro reveals that PGelMA\u2010CK2.1 shifts the microenvironment from a pro\u2010inflammatory into an anti\u2010inflammatory condition, and alleviates cellular senescence, thus modifying the cartilage microenvironment to improve the recruitment, proliferation and chondral differentiation of bone marrow mesenchymal stem cells (BMSCs). The scaffold bone layer enhances microvascular endothelial cell proliferation, migration, and angiogenic activities, which, couple with increased BMSC recruitment and regulatory mechanisms directing BMSC differentiation, favor a shift in the \u201costeogenesis\u2013adipogenesis\u201d balance toward enhanced osteogenesis. In vivo, it is found that this biphasic biomimetic scaffold favors simultaneous dual tissue regeneration. This approach facilitates the development of bioactive regenerative scaffolds and holds great potential for clinical application.<\/jats:p>","DOI":"10.1002\/adhm.202402329","type":"journal-article","created":{"date-parts":[[2024,11,12]],"date-time":"2024-11-12T03:10:37Z","timestamp":1731381037000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Bilayer Scaffolds Synergize Immunomodulation and Rejuvenation via Layer\u2010Specific Release of CK2.1 and the \u201cExercise Hormone\u201d Lac\u2010Phe for Enhanced Osteochondral Regeneration"],"prefix":"10.1002","volume":"14","author":[{"given":"Po\u2010Lin","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Orthopedic Surgery Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine  600 Yishan Road Shanghai 200233 China"},{"name":"School of Medicine Shanghai Jiao Tong University  227 South Chongqing Road 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