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Their unique ability to mimic native extracellular matrix environments through tunable biochemical and biophysical properties has enabled broad applications in tissue repair and regeneration. This review provides a comprehensive overview of the rational design principles, fabrication strategies, and biomedical applications of multifunctional hydrogels. The fundamental relationships between polymer composition, crosslinking mechanisms, network architecture, and biological performance were firstly discussed, highlighting how these parameters regulate mechanical properties, degradation behavior, and cellular interactions. Subsequently, representative hydrogel systems, including natural polymers, synthetic polymers, and hybrid composites, are critically compared regarding their advantages, limitations, and suitability for different regenerative scenarios. We further examine functional strategies such as controlled therapeutic delivery, immunomodulation, cell encapsulation, and stimuli\u2010responsive regulation, with emphasis on their mechanisms and translational potential. Applications in wound healing, bone and cartilage regeneration, neural repair, and cardiovascular tissue engineering are discussed alongside current clinical challenges. Finally, we highlight key barriers including scalability, standardization, regulatory considerations, and future opportunities toward clinically translatable multifunctional hydrogel technologies.<\/jats:p>","DOI":"10.1002\/mco2.71046","type":"journal-article","created":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T07:38:26Z","timestamp":1791272306000},"source":"Crossref","is-referenced-by-count":0,"title":["Multifunctional Hydrogels: Rational Design and Application in Regenerative Medicine"],"prefix":"10.1002","volume":"7","author":[{"given":"Linyang","family":"Song","sequence":"first","affiliation":[{"name":"Department of Orthopedics The 960th Hospital of PLA  Jinan China"},{"name":"Qilu Hospital of Shandong University  Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-0243-1566","authenticated-orcid":false,"given":"Epiphane K.","family":"Silli","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics 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