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However, diseases that feature chronic or dysregulated inflammation, such as non\u2010union fractures and osteonecrosis of the jaw (ONJ), have proven difficult to treat with current MSC\u2010based approaches. Here, it is investigated whether controlled delivery of immunomodulatory factors allows MSCs to simultaneously undergo osteogenic differentiation and modulate inflammation. First, a Design of Experiments approach is used to identify the type and concentrations of immunomodulatory factors (IMFs) that most effectively induce concurrent pro\u2010regenerative macrophages and MSC osteogenic differentiation, then these IMFs are loaded into polymeric microparticles for controlled release. Through in vitro models, it is demonstrated that microparticles releasing IL\u201010 and IL\u20104 promote na\u00efve MSC osteogenesis and modulate immune response, even in chronic, physiologically relevant, inflammatory conditions. Then this approach is applied to an in vivo rat model of ONJ as a clinically relevant example of such conditions. Clinically relevant sex\u2010based differences in inflammation and bone formation are observed that have not yet been reported. These data represent key findings that will facilitate the reversal of diseases that are linked to chronic bone loss and inflammation, such as ONJ.<\/jats:p>","DOI":"10.1002\/adhm.202502466","type":"journal-article","created":{"date-parts":[[2025,8,29]],"date-time":"2025-08-29T06:53:58Z","timestamp":1756450438000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Controlled Delivery of Immunomodulatory Factors for Mineralized Tissue Formation in an Inflammatory Microenvironment"],"prefix":"10.1002","volume":"15","author":[{"given":"Katherine H.","family":"Griffin","sequence":"first","affiliation":[{"name":"School of Veterinary Medicine University of California  Davis CA 95616 USA"},{"name":"Department of Orthopaedic Surgery UC Davis Health  Sacramento CA 95817 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabel S.","family":"Sagheb","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering University of California  Davis CA 95616 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas P.","family":"Coonan","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering University of California  Davis CA 95616 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Langston A.","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering University of California  Davis CA 95616 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas J.","family":"Rowland","sequence":"additional","affiliation":[{"name":"Center for Molecular and Genomic Imaging University of California  Davis CA 95616 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boaz","family":"Arzi","sequence":"additional","affiliation":[{"name":"Department of Surgical and Radiological Sciences School of Veterinary Medicine University of California  Davis CA 95616 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jamal S.","family":"Lewis","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering University of Florida  Gainesville FL 32611 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1673-3335","authenticated-orcid":false,"given":"J. 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