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To overcome these limitations, injectable hydrogels are engineered for the local and sustained delivery of baricitinib, a representative JAK inhibitor. Hydrogels are formed via disulfide crosslinking of thiolated hyaluronic acid macromers. Dynamic thioimidate bonds are introduced between the thiolated hyaluronic acid and nitrile\u2010containing baricitinib for drug tethering, which is confirmed with <jats:sup>1<\/jats:sup>H and <jats:sup>13<\/jats:sup>C nuclear magnetic resonance (NMR). Release of baricitinib is tunable over six weeks in vitro and active in inhibiting JAK signaling in a cell line containing a luciferase reporter reflecting interferon signaling. For in vivo activity, baricitinib hydrogels or controls are injected intradermally into an imiquimod\u2010induced mouse model of psoriasis. Imiquimod increases epidermal thickness in mice, which is unaffected when treated with baricitinib or hydrogel alone. Treatment with baricitinib hydrogels suppresses the increased epidermal thickness in mice treated with imiquimod, suggesting that the sustained and local release of baricitinib is important for a therapeutic outcome. This study is the first to utilize a thioimidate chemistry to deliver JAK inhibitors to the skin through injectable hydrogels, which has translational potential for treating inflammatory disorders.<\/jats:p>","DOI":"10.1002\/adhm.202303256","type":"journal-article","created":{"date-parts":[[2024,1,11]],"date-time":"2024-01-11T15:09:26Z","timestamp":1704985766000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Local and Sustained Baricitinib Delivery to the Skin through Injectable Hydrogels Containing Reversible Thioimidate Adducts"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1424-0481","authenticated-orcid":false,"given":"Leo L.","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Dermatology Perelman School of Medicine University of Pennsylvania  1053 Biomedical Research Building, 421 Curie Blvd Philadelphia PA 19104 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