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Methods: A biphasic poly(lactic-co-glycolic acid) (PLGA) scaffold incorporating doxycycline-lactoferrin (DOX-LF)-loaded calcium alginate microspheres and fibroblast growth factor 2\/bone morphogenetic protein 9 (FGF2\/BMP9)-loaded chitosan nanospheres was fabricated by low-temperature three-dimensional (3D) printing, porogen leaching, and freeze-drying. Material properties, antibacterial activity, macrophage polarization, periodontal ligament stem cell (PDLSC) osteogenesis, and human umbilical vein endothelial cell (HUVEC) angiogenesis were evaluated. Small interfering RNA (siRNA)-mediated milk fat globule-epidermal growth factor 8 (MFGE8) knockdown was used to investigate the underlying mechanism. Results: The scaffold formed an interconnected porous network and released approximately 88.4% of DOX and 60% of LF over 240 h. PLGA\/DOX-LF reduced Porphyromonas gingivalis viability to approximately 20% (p &lt; 0.001). In lipopolysaccharide (LPS)-stimulated macrophages, it produced the greatest suppression of M1-associated markers and induction of M2-associated markers, while MFGE8 knockdown significantly reduced MFGE8 expression (p &lt; 0.001) and attenuated these effects. Conditioned medium restored PDLSC migration, ALP activity, and mineralization to approximately 70%, 70\u201375%, and 80% of control levels, respectively, and increased HUVEC tube length (p &lt; 0.01) and angiogenic gene expression (all p &lt; 0.001). Conclusions: A 3D-printed biphasic PLGA scaffold incorporating DOX-LF-loaded calcium alginate microspheres and FGF2\/BMP9-loaded chitosan nanospheres was successfully constructed. These in vitro findings support PLGA\/DOX-LF as a proof-of-concept platform for antibacterial immunomodulation and osteogenic\u2013angiogenic coupling, pending in vivo validation.<\/jats:p>","DOI":"10.31083\/fbl54017","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T16:21:51Z","timestamp":1790698911000},"source":"Crossref","is-referenced-by-count":0,"title":["3D-Printed DOX-LF-Loaded PLGA Biphasic Composite Scaffold Modulates Macrophage Polarization and Enhances Osteogenic-Angiogenic Regenerative Potential for Periodontitis"],"prefix":"10.31083","volume":"31","author":[{"given":"Chunfeng","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Stomatology, Hunan University of Medicine, 418000 Huaihua, Hunan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caijuan","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Stomatology, The Eighth Affiliated Hospital, Southern Medical University (The First People's Hospital of Shunde, Foshan), 528308 Foshan, Guangdong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chan","family":"Xiao","sequence":"additional","affiliation":[{"name":"Department of Stomatology, Hunan University of Medicine, 418000 Huaihua, Hunan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8626-1425","authenticated-orcid":true,"given":"Yepo","family":"Hou","sequence":"additional","affiliation":[{"name":"Department of Stomatology, Hunan University of Medicine, 418000 Huaihua, Hunan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"16242","published-online":{"date-parts":[[2026,9,18]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","unstructured":"Jeon HH, Huang X, Rojas Cortez L, Sripinun P, Lee JM, Hong JJ, et al. 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