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A considerable number of fractures suffer from delayed healing, and the unresolved acute pain may transition to chronic and maladaptive pain. Current management of pain involves treatment with NSAIDs and opioids with substantial adverse effects. Herein, we tested the hypothesis that the purine molecule, adenosine, can simultaneously alleviate pain and promote healing in a mouse model of tibial fracture by targeting distinctive adenosine receptor subtypes in different cell populations. To achieve this, a biomaterial\u2010assisted delivery of adenosine is utilized to localize and prolong its therapeutic effect at the injury site. The results demonstrate that local delivery of adenosine inhibited the nociceptive activity of peripheral neurons through activation of adenosine A1 receptor (ADORA1) and mitigated pain as demonstrated by weight bearing and open field movement tests. Concurrently, local delivery of adenosine at the fracture site promoted osteogenic differentiation of mesenchymal stromal cells through adenosine A2B receptor (ADORA2B) resulting in improved bone healing as shown by histological analyses and microCT imaging. This study demonstrates the dual role of adenosine and its material\u2010assisted local delivery as a feasible therapeutic approach to treat bone trauma and associated pain.<\/jats:p>","DOI":"10.1002\/advs.202303567","type":"journal-article","created":{"date-parts":[[2023,11,8]],"date-time":"2023-11-08T15:50:39Z","timestamp":1699458639000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Multi\u2010Functional Small Molecule Alleviates Fracture Pain and Promotes Bone Healing"],"prefix":"10.1002","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9143-9227","authenticated-orcid":false,"given":"Yu\u2010Ru V.","family":"Shih","sequence":"first","affiliation":[{"name":"Department of Orthopaedic Surgery Duke University School of Medicine  Durham NC 27710 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Kingsley","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery Duke University School of Medicine  Durham NC 27710 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hunter","family":"Newman","sequence":"additional","affiliation":[{"name":"Department of Mechanical Engineering and Materials Science Duke University  Durham NC 27710 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaul","family":"Hoque","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery Duke University School of Medicine  Durham NC 27710 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ankita","family":"Gupta","sequence":"additional","affiliation":[{"name":"Translational Research in Pain Program Department of Clinical Sciences College of Veterinary Medicine North Carolina State University  Raleigh NC 27607 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B. 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