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Mater."],"published-print":{"date-parts":[[2026,12,1]]},"abstract":"Abstract<\/jats:title>\n \n The development of synthetic bone grafts that integrate osteogenic and immunomodulatory functions represents a critical strategy in regenerative orthopedics. In this study, we fabricated strontium- and magnesium-doped hydroxyapatite (HA\/Mg\/Sr) scaffolds derived from natural bovine cancellous bone. Physicochemical characterization confirmed the preservation of a three-dimensional interconnected porous architecture (\u223c80% porosity, \u223c350 \u03bcm pore size) with a homogeneous nanoparticulate surface. Doping with Mg and Sr enhanced scaffold degradation, sustained the release of bioactive ions (\n \n \n \n <\/jats:tex-math>\n \n \n \n C<\/mml:mtext>\n <\/mml:mrow>\n \n \n \n a<\/mml:mtext>\n <\/mml:mrow>\n \n 2<\/mml:mn>\n +<\/mml:mo>\n <\/mml:mrow>\n <\/mml:msup>\n <\/mml:mrow>\n <\/mml:mrow>\n <\/mml:math>\n <\/jats:inline-formula>\n ,\n \n \n \n <\/jats:tex-math>\n \n \n \n M<\/mml:mtext>\n <\/mml:mrow>\n \n \n \n g<\/mml:mtext>\n <\/mml:mrow>\n \n 2<\/mml:mn>\n +<\/mml:mo>\n <\/mml:mrow>\n <\/mml:msup>\n <\/mml:mrow>\n <\/mml:mrow>\n <\/mml:math>\n <\/jats:inline-formula>\n ,\n \n \n \n <\/jats:tex-math>\n \n \n \n S<\/mml:mtext>\n <\/mml:mrow>\n \n \n \n r<\/mml:mtext>\n <\/mml:mrow>\n \n 2<\/mml:mn>\n +<\/mml:mo>\n <\/mml:mrow>\n <\/mml:msup>\n <\/mml:mrow>\n <\/mml:mrow>\n <\/mml:math>\n <\/jats:inline-formula>\n ), and significantly increased compressive strength to levels comparable with human cancellous bone.\n In vitro<\/jats:italic>\n , HA\/Mg\/Sr scaffolds exhibited excellent biocompatibility, promoting adhesion and proliferation of both bone marrow-derived mesenchymal stem cells (BMSCs) and bone marrow-derived macrophages (BMMs). While Mg primarily facilitated direct osteogenic differentiation of BMSCs, Sr played a dominant role in directing macrophage polarization toward the anti-inflammatory M2 phenotype, as evidenced by increased CD206 and IL-10 expression alongside reduced CCR7 and pro-inflammatory cytokines (IL-1\n \u03b2<\/jats:italic>\n , IL-6, TNF-\n \u03b1<\/jats:italic>\n ). Notably, macrophage-conditioned medium from HA\/Mg\/Sr cultures substantially enhanced BMSC osteogenesis, highlighting immunomodulation as a central mechanism. Transcriptomic analysis indicated that the HA\/Mg\/Sr scaffolds promoted macrophage polarization toward the M2 phenotype and modulated immune responses potentially through the NF-\n \u03ba<\/jats:italic>\n B signaling pathway, which was validated by Western blot. In a rat femoral condyle defect model, HA\/Mg\/Sr scaffolds\u2014particularly those with 10% Sr content (HA\/Mg\/Sr\n 2<\/jats:sub>\n )\u2014demonstrated superior bone regeneration, characterized by bone volume fraction (BV\/TV), trabecular thickness (Tb.Th), trabecular number (Tb.N) and enhanced new bone ingrowth and integration, accompanied by elevated M2 macrophage infiltration\n in vivo<\/jats:italic>\n . Overall, these findings establish that HA\/Mg\/Sr scaffolds promote bone repair not only via direct osteoconduction but, more importantly, through immunomodulation\u2014fostering a pro-healing M2 macrophage microenvironment potentially in an NF-\n \u03ba<\/jats:italic>\n B\u2013dependent manner, thereby offering a promising dual-functional biomaterial strategy for critical-sized bone defect reconstruction. Collectively, this study underscores the therapeutic relevance of targeting macrophage polarization in bone repair and delineates a mechanistic framework for Sr-based immunomodulatory biomaterial design.\n <\/jats:p>","DOI":"10.1088\/1748-605x\/aeb780","type":"journal-article","created":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T22:58:42Z","timestamp":1792623522000},"page":"065001","update-policy":"https:\/\/doi.org\/10.1088\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Strontium- and magnesium-doped hydroxyapatite scaffolds enhance bone regeneration by promoting macrophage polarization toward the M2 phenotype"],"prefix":"10.1088","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-9260-0761","authenticated-orcid":true,"given":"Haihao","family":"Wu","sequence":"first","affiliation":[{"name":"Wenzhou Medical 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