{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T22:38:48Z","timestamp":1792795128208,"version":"4.5.0"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,11,11]],"date-time":"2024-11-11T00:00:00Z","timestamp":1731283200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>In recent years, the treatment of chronic osteomyelitis mediated by biodegradable polymer platforms has received increasing attention. This paper reports an advanced drug delivery system, vancomycin (VA) and DGEA loaded microspheres embedded in injectable thermosensitive polypeptide hydrogels (i.e., hydrogel-microsphere (Gel-MP) construct), for continuous release of drugs with different mechanisms and more comprehensive treatment of chronic osteomyelitis. The Gel-MP construct exhibits continuous biodegradability and excellent biocompatibility. Microspheres (MP) are wrapped inside Gel. With the degradation of Gel, VA and MP are released from them, VA released with faster degradation speed, achieving a potent antibacterial effect and effectively controlling infection. Due to the slower degradation rate of MP compared to Gel, subsequently, DGEA is released from MP to induce bone formation and produce the effect of filling bone defects. Compared with other formulations, the <jats:italic>in vivo<\/jats:italic> combinational treatment of Gel\/VA-MP\/DGEA can simultaneously balance antibacterial and osteogenic effects. More importantly, local sustained-release drug delivery systems can significantly mitigate the systemic toxicity of drugs. Therefore, the injection local sequential drug delivery system has broad prospects in the clinical application of treating chronic osteomyelitis.<\/jats:p>","DOI":"10.3389\/fphar.2024.1499742","type":"journal-article","created":{"date-parts":[[2024,11,11]],"date-time":"2024-11-11T04:38:59Z","timestamp":1731299939000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["Treatment of chronic osteomyelitis with gradient release of DGEA and vancomycin hydrogel-microsphere system and its mechanism"],"prefix":"10.3389","volume":"15","author":[{"given":"Yuhao","family":"Zheng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fan","family":"Sheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxu","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenling","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiming","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,11,11]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1016\/j.jconrel.2022.02.029","article-title":"Drug-loaded biomaterials for orthopedic applications: a review","volume":"344","author":"Aggarwal","year":"2022","journal-title":"J. Control. Release Off. J. Control. Release Soc."},{"key":"B2","doi-asserted-by":"publisher","first-page":"421","DOI":"10.4067\/S0716-97602013000400013","article-title":"Osteogenic molecules for clinical applications: improving the BMP-collagen system","volume":"46","author":"Arrabal","year":"2013","journal-title":"Biol. Res."},{"key":"B3","doi-asserted-by":"publisher","first-page":"109","DOI":"10.3390\/polym10020109","article-title":"Collagen-coated poly(lactide-co-glycolide)\/hydroxyapatite scaffold incorporated with DGEA peptide for synergistic repair of skull defect","volume":"10","author":"Bi","year":"2018","journal-title":"Polymers"},{"key":"B4","first-page":"395","article-title":"Osteomyelitis: diagnosis and treatment","volume":"104","author":"Bury","year":"2021","journal-title":"Am. Fam. Physician"},{"key":"B5","doi-asserted-by":"publisher","first-page":"834","DOI":"10.1016\/j.ijbiomac.2020.11.039","article-title":"Study on the anti-infection ability of vancomycin cationic liposome combined with polylactide fracture internal fixator","volume":"167","author":"Cai","year":"2021","journal-title":"Int. J. Biol. Macromol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"426","DOI":"10.1038\/s41392-021-00830-x","article-title":"Current hydrogel advances in physicochemical and biological response-driven biomedical application diversity","volume":"6","author":"Cao","year":"2021","journal-title":"Signal Transduct. Target. Ther."},{"key":"B7","doi-asserted-by":"publisher","first-page":"3493","DOI":"10.2147\/IJN.S157463","article-title":"Construction of injectable, pH sensitive, antibacterial, mineralized amino acid yolk-shell microspheres for potential minimally invasive treatment of bone infection","volume":"13","author":"Chen","year":"2018","journal-title":"Int. J. Nanomedicine"},{"key":"B8","doi-asserted-by":"publisher","first-page":"450","DOI":"10.1016\/j.actbio.2017.11.009","article-title":"Multifunctional pH sensitive 3D scaffolds for treatment and prevention of bone infection","volume":"65","author":"Cicu\u00e9ndez","year":"2018","journal-title":"Acta Biomater."},{"key":"B9","doi-asserted-by":"publisher","first-page":"CD004439","DOI":"10.1002\/14651858.CD004439.pub3","article-title":"Antibiotics for treating chronic osteomyelitis in adults","volume":"2013","author":"Conterno","year":"2013","journal-title":"Cochrane Database Syst. Rev."},{"key":"B10","doi-asserted-by":"publisher","first-page":"258","DOI":"10.26355\/eurrev_201904_17500","article-title":"Systemic antibiotic treatment of chronic osteomyelitis in adults","volume":"23","author":"Fantoni","year":"2019","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"B11","doi-asserted-by":"publisher","first-page":"797","DOI":"10.1016\/j.carbpol.2014.10.045","article-title":"Polysaccharide-based aerogel microspheres for oral drug delivery","volume":"117","author":"Garc\u00eda-Gonz\u00e1lez","year":"2015","journal-title":"Carbohydr. Polym."},{"key":"B12","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1172\/JCI19190","article-title":"Osteopontin: a bridge between bone and the immune system","volume":"112","author":"Gravallese","year":"2003","journal-title":"J. Clin. Invest."},{"key":"B13","doi-asserted-by":"publisher","first-page":"107","DOI":"10.3389\/fcimb.2020.00107","article-title":"Prevalence and therapies of antibiotic-resistance in Staphylococcus aureus","volume":"10","author":"Guo","year":"2020","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1557\/s43578-021-00423-y","article-title":"Collagen-derived peptide, DGEA, inhibits pro-inflammatory macrophages in biofunctional hydrogels","volume":"37","author":"Jha","year":"2022","journal-title":"J. Mat. Res."},{"key":"B15","first-page":"159","article-title":"Bioabsorbable materials in orthopaedics","volume":"73","author":"Kontakis","year":"2007","journal-title":"Belg."},{"key":"B16","doi-asserted-by":"publisher","first-page":"591","DOI":"10.18063\/ijb.v8i3.591","article-title":"Bone sialoprotein immobilized in collagen type I enhances bone regeneration in vitro and in vivo","volume":"8","author":"Kriegel","year":"2022","journal-title":"Int. J. Bioprinting"},{"key":"B17","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1016\/j.gendis.2019.09.014","article-title":"Osteogenic and antibacterial dual functions of a novel levofloxacin loaded mesoporous silica microspheres\/nano-hydroxyapatite\/polyurethane composite scaffold","volume":"8","author":"Kuang","year":"2021","journal-title":"Genes Dis."},{"key":"B18","doi-asserted-by":"publisher","first-page":"6706","DOI":"10.21037\/apm-21-1290","article-title":"Clinical observations of vancomycin-loaded calcium phosphate cement in the 1-stage treatment of chronic osteomyelitis: a randomized trial","volume":"10","author":"Lang","year":"2021","journal-title":"Palliat. Med."},{"key":"B19","article-title":"Cy5.5-Asp-Gly-Glu-Ala (DGEA)","volume-title":"Mol. Imaging contrast agent database MICAD","author":"Leung","year":"2004"},{"key":"B20","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1007\/s00774-015-0734-7","article-title":"An overview of osteocalcin progress","volume":"34","author":"Li","year":"2016","journal-title":"J. Bone Min. Metab."},{"key":"B21","doi-asserted-by":"publisher","first-page":"1255","DOI":"10.1016\/j.bioactmat.2020.10.018","article-title":"Synergistic anti-inflammatory and osteogenic n-HA\/resveratrol\/chitosan composite microspheres for osteoporotic bone regeneration","volume":"6","author":"Li","year":"2021","journal-title":"Bioact. Mat."},{"key":"B22","doi-asserted-by":"publisher","first-page":"526","DOI":"10.1016\/j.bjid.2013.12.005","article-title":"Recommendations for the treatment of osteomyelitis","volume":"18","author":"Lima","year":"2014","journal-title":"Braz. J. Infect. Dis. Off. Publ. Braz. Soc. Infect. Dis."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1042128","DOI":"10.3389\/fbioe.2022.1042128","article-title":"Current research progress of local drug delivery systems based on biodegradable polymers in treating chronic osteomyelitis","volume":"10","author":"Liu","year":"2022","journal-title":"Front. Bioeng. Biotechnol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1786","DOI":"10.1002\/jbm.a.37432","article-title":"Injectable hydrogel as a carrier of vancomycin and a cathelicidin-derived peptide for osteomyelitis treatment","volume":"110","author":"Machado","year":"2022","journal-title":"J. Biomed. Mat. Res. A"},{"key":"B25","doi-asserted-by":"publisher","first-page":"3516","DOI":"10.1002\/jbm.a.35497","article-title":"The collagen I mimetic peptide DGEA enhances an osteogenic phenotype in mesenchymal stem cells when presented from cell-encapsulating hydrogels","volume":"103","author":"Mehta","year":"2015","journal-title":"J. Biomed. Mat. Res. A"},{"key":"B26","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1016\/j.ejps.2016.06.008","article-title":"Dual functioning microspheres embedded crosslinked gelatin cryogels for therapeutic intervention in osteomyelitis and associated bone loss","volume":"91","author":"Pandey","year":"2016","journal-title":"Eur. J. Pharm. Sci. Off. J. Eur. Fed. Pharm. Sci."},{"key":"B27","doi-asserted-by":"publisher","first-page":"e1260","DOI":"10.1002\/mbo3.1260","article-title":"Impact of antibiotics on the human microbiome and consequences for host health","volume":"11","author":"Patangia","year":"2022","journal-title":"MicrobiologyOpen"},{"key":"B28","doi-asserted-by":"publisher","first-page":"2034","DOI":"10.3390\/ijms23042034","article-title":"PLGA-based composites for various biomedical applications","volume":"23","author":"Rocha","year":"2022","journal-title":"Int. J. Mol. Sci."},{"key":"B29","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1016\/j.actbio.2021.04.009","article-title":"PEG-based thermosensitive and biodegradable hydrogels","volume":"128","author":"Shi","year":"2021","journal-title":"Acta Biomater."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1397","DOI":"10.1080\/10717544.2021.1938756","article-title":"PLGA-based biodegradable microspheres in drug delivery: recent advances in research and application","volume":"28","author":"Su","year":"2021","journal-title":"Drug Deliv."},{"key":"B31","doi-asserted-by":"publisher","first-page":"e00932","DOI":"10.1128\/IAI.00932-19","article-title":"Staphylococcus aureus osteomyelitis: bone, bugs, and surgery","volume":"88","author":"Urish","year":"2020","journal-title":"Infect. Immun."},{"key":"B32","doi-asserted-by":"publisher","first-page":"4617","DOI":"10.1007\/s12010-023-04318-y","article-title":"An overview of collagen-based composite scaffold for bone tissue engineering","volume":"195","author":"Vijayalekha","year":"2023","journal-title":"Appl. Biochem. Biotechnol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"257","DOI":"10.3238\/arztebl.2012.0257","article-title":"Treatment algorithms for chronic osteomyelitis","volume":"109","author":"Walter","year":"2012","journal-title":"Int"},{"key":"B34","doi-asserted-by":"publisher","first-page":"1069932","DOI":"10.3389\/fbioe.2022.1069932","article-title":"Research progress of stimulus-responsive antibacterial materials for bone infection","volume":"10","author":"Wang","year":"2022","journal-title":"Front. Bioeng. Biotechnol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"10225536231206921","DOI":"10.1177\/10225536231206921","article-title":"Evaluation of the osteoconductivity and the degradation of novel hydroxyapatite\/polyurethane combined with mesoporous silica microspheres in a rabbit osteomyelitis model","volume":"31","author":"Wang","year":"2023","journal-title":"J. Orthop. Surg. Hong Kong"},{"key":"B36","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.ocl.2009.07.003","article-title":"Bone defects caused by high-energy injuries, bone loss, infected nonunions, and nonunions","volume":"41","author":"Wiese","year":"2010","journal-title":"Orthop. Clin. North Am."},{"key":"B37","doi-asserted-by":"publisher","first-page":"3075","DOI":"10.3390\/polym13183075","article-title":"A review on the enhancement of calcium phosphate cement with biological materials in bone defect healing","volume":"13","author":"Wong","year":"2021","journal-title":"Polymers"},{"key":"B38","doi-asserted-by":"publisher","first-page":"3697","DOI":"10.7150\/ijms.61080","article-title":"The role of the immune microenvironment in bone regeneration","volume":"18","author":"Yang","year":"2021","journal-title":"J. Med. Sci."},{"key":"B39","doi-asserted-by":"publisher","first-page":"6053","DOI":"10.1021\/acsbiomaterials.0c01228","article-title":"Phenomenology of the initial burst release of drugs from PLGA microparticles","volume":"6","author":"Yoo","year":"2020","journal-title":"ACS Biomater. Sci. Eng."},{"key":"B40","doi-asserted-by":"publisher","first-page":"944","DOI":"10.3390\/ijms22020944","article-title":"Biomineralization of collagen-based materials for hard tissue repair","volume":"22","author":"Yu","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"B41","doi-asserted-by":"publisher","first-page":"602","DOI":"10.1186\/s13018-024-05097-w","article-title":"Sequential release of vancomycin and BMP-2 from chitosan\/nano-hydroxyapatite thermosensitive hydrogel for the treatment of chronic osteomyelitis","volume":"19","author":"Zhan","year":"2024","journal-title":"J. Orthop. Surg."},{"key":"B42","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1186\/s41232-023-00285-3","article-title":"Enhancement of bone regeneration by coadministration of angiogenic and osteogenic factors using messenger RNA","volume":"43","author":"Zhang","year":"2023","journal-title":"Inflamm. Regen."},{"key":"B43","doi-asserted-by":"publisher","first-page":"1163933","DOI":"10.3389\/fbioe.2023.1163933","article-title":"Vancomycin-loaded silk fibroin microspheres in an injectable hydrogel for chronic osteomyelitis therapy","volume":"11","author":"Zhang","year":"2023","journal-title":"Front. Bioeng. Biotechnol."},{"key":"B44","doi-asserted-by":"publisher","first-page":"1213","DOI":"10.1166\/jbn.2019.2773","article-title":"Electrospun polylactide-nano-HydroxyapatiteVancomycin composite scaffolds for advanced osteomyelitis therapy","volume":"15","author":"Zhao","year":"2019","journal-title":"J. Biomed. Nanotechnol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"3487","DOI":"10.1021\/acsami.6b15245","article-title":"Injectable hydrogel-microsphere construct with sequential degradation for locally synergistic chemotherapy","volume":"9","author":"Zheng","year":"2017","journal-title":"ACS Appl. Mat. Interfaces"},{"key":"B46","doi-asserted-by":"publisher","first-page":"1286","DOI":"10.3389\/fphar.2020.01286","article-title":"Shear speed-regulated properties of long-acting docetaxel control release poly (lactic-Co-glycolic acid) microspheres","volume":"11","author":"Zheng","year":"2020","journal-title":"Front. Pharmacol."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2024.1499742\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,11]],"date-time":"2024-11-11T04:39:02Z","timestamp":1731299942000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2024.1499742\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,11]]},"references-count":46,"alternative-id":["10.3389\/fphar.2024.1499742"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2024.1499742","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,11,11]]},"article-number":"1499742"}}