{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T20:00:54Z","timestamp":1790971254953,"version":"4.1.0"},"reference-count":120,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T00:00:00Z","timestamp":1785715200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Funct. Biomater.","JFB"],"abstract":"<jats:p>Osteomyelitis is a severe, progressive bone infection affecting approximately 21.8 per 100,000 individuals in the United States and remains a major challenge in orthopedic and reconstructive medicine. Staphylococcus aureus (S. aureus), responsible for nearly 75% of cases, is the most common causative pathogen. Current gold-standard management involves culture-directed antibiotic therapy administered for 4\u20136 weeks, often combined with surgical debridement and the use of antibiotic-loaded cement spacers. Despite these interventions, treatment frequently fails to achieve complete infection eradication, with recurrent or persistent disease reported in up to 40% of cases, contributing to chronic inflammation, impaired bone healing, and long-term functional deficits. These limitations highlight the need for therapeutic strategies that address infection control and bone regeneration. A narrative literature review was conducted to evaluate emerging tissue-engineered scaffold-based biomaterials as potential alternatives to conventional treatment. Emerging evidence suggests antimicrobial-loaded matrices, bioactive scaffolds, and stimuli-responsive biomaterials can provide localized drug delivery, structural support, and enhanced osteogenesis while improving infection control and osteointegration. Advances in targeted drug delivery, immunomodulatory biomaterials, and computational scaffold design further suggest opportunities for more effective therapies. These findings highlight the potential of scaffold-based biomaterials to improve osteomyelitis management, although further clinical studies are required.<\/jats:p>","DOI":"10.3390\/jfb17080379","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T10:24:07Z","timestamp":1785752647000},"page":"379","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Engineering Smart Scaffolds for Osteomyelitis: Integrating Nanotechnology, Drug Delivery, and Tissue Regeneration\u2014A Narrative Review"],"prefix":"10.3390","volume":"17","author":[{"given":"Chayse","family":"Baker","sequence":"first","affiliation":[{"name":"Kirk Kerkorian School of Medicine, University of Nevada, Las Vegas, NV 89106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caleb","family":"Jolley","sequence":"additional","affiliation":[{"name":"Kirk Kerkorian School of Medicine, University of Nevada, Las Vegas, NV 89106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6821-2531","authenticated-orcid":false,"given":"Ian","family":"Alexander","sequence":"additional","affiliation":[{"name":"Kirk Kerkorian School of Medicine, University of Nevada, Las Vegas, NV 89106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-5774-8202","authenticated-orcid":false,"given":"Elijah","family":"Lee","sequence":"additional","affiliation":[{"name":"Kirk Kerkorian School of Medicine, University of Nevada, Las Vegas, NV 89106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8228-8172","authenticated-orcid":false,"given":"Hemalatha","family":"Kanniyappan","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Riccio College of Engineering, University of Massachusetts Amherst, Amherst, MA 01003, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0969-2539","authenticated-orcid":false,"given":"Aftab","family":"Merchant","sequence":"additional","affiliation":[{"name":"Kirk Kerkorian School of Medicine, University of Nevada, Las Vegas, NV 89106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"837","DOI":"10.2106\/JBJS.N.01350","article-title":"Trends in the epidemiology of osteomyelitis a population-based study, 1969 to 2009","volume":"97","author":"Kremers","year":"2015","journal-title":"J. Bone Jt. Surg.-Am. Vol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2392","DOI":"10.1080\/10717544.2021.1998246","article-title":"Recent advances in the local antibiotics delivery systems for management of osteomyelitis","volume":"28","author":"Wassif","year":"2021","journal-title":"Drug Deliv."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1093\/cid\/ciy381","article-title":"A Guide to Utilization of the Microbiology Laboratory for Diagnosis of Infectious Diseases: 2018 Update by the Infectious Diseases Society of America and the American Society for Microbiology","volume":"67","author":"Miller","year":"2018","journal-title":"Clin. Infect. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"10-1128","DOI":"10.1128\/CMR.00084-17","article-title":"Staphylococcal osteomyelitis: Disease progression, treatment challenges, and future directions","volume":"31","author":"Kavanagh","year":"2018","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Lo, C., Sung, F.C., Mou, C.H., Lin, T.C., Tseng, C.H., and Tzeng, Y.L. (2017). Population study evaluating fracture risk among patients with chronic osteomyelitis. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0189743"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e363","DOI":"10.3928\/01477447-20110627-12","article-title":"Management of combined bone defect and limb-length discrepancy after tibial chronic osteomyelitis","volume":"34","author":"Liu","year":"2011","journal-title":"Orthopedics"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1016\/j.injury.2017.01.007","article-title":"Two stage management of Cierny-Mader type IV chronic osteomyelitis of the long bones","volume":"48","author":"Wu","year":"2017","journal-title":"Injury"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"254.e1","DOI":"10.1016\/j.cmi.2014.09.007","article-title":"The changing epidemiology of bacteraemic osteoarticular infections in the early 21st century","volume":"21","author":"Murillo","year":"2015","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2457","DOI":"10.1007\/s00264-020-04737-0","article-title":"Clinical characteristics, treatment, and prognosis of squamous cell carcinoma arising from extremity chronic osteomyelitis: A synthesis analysis of one hundred and seventy six reported cases","volume":"44","author":"Jiang","year":"2020","journal-title":"Int. Orthop."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1093\/cid\/cir842","article-title":"Systemic antibiotic therapy for chronic osteomyelitis in adults","volume":"54","author":"Spellberg","year":"2012","journal-title":"Clin. Infect. Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1056\/NEJM199704033361406","article-title":"Osteomyelitis","volume":"336","author":"Lew","year":"1997","journal-title":"N. Engl. J. Med."},{"key":"ref_12","unstructured":"Nimmana, B.K., and Savaliya, V. (2023). Osteomyelitis, StatPearls Publishing."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1056\/NEJMra1213956","article-title":"Acute Osteomyelitis in Children","volume":"370","author":"Peltola","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_14","first-page":"395","article-title":"Osteomyelitis: Diagnosis and Treatment","volume":"104","author":"Bury","year":"2021","journal-title":"Am. Fam. Physician"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"177S","DOI":"10.1097\/PRS.0b013e3182001f0f","article-title":"Treating osteomyelitis: Antibiotics and surgery","volume":"127","author":"Rao","year":"2011","journal-title":"Plast. Reconstr. Surg."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Bor, N., Dujovny, E., Rinat, B., Rozen, N., and Rubin, G. (2022). Treatment of chronic osteomyelitis with antibiotic-impregnated polymethyl methacrylate (PMMA)\u2014The Cierny approach: Is the second stage necessary?. BMC Musculoskelet. Disord., 23.","DOI":"10.1186\/s12891-021-04979-y"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Qiu, X.S., Chen, Y.X., Qi, X.Y., Shi, H.F., Wang, J.F., and Xiong, J. (2017). Outcomes of cement beads and cement spacers in the treatment of bone defects associated with post-traumatic osteomyelitis. BMC Musculoskelet. Disord., 18.","DOI":"10.1186\/s12891-017-1614-1"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.jcot.2013.11.005","article-title":"Bone cement","volume":"4","author":"Vaishya","year":"2013","journal-title":"J. Clin. Orthop. Trauma"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"S68","DOI":"10.1016\/S0020-1383(16)30842-7","article-title":"Masquelet technique: Myth or reality? A systematic review and meta-analysis","volume":"47","author":"Morelli","year":"2016","journal-title":"Injury"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Ramanathan, S., Lin, Y.C., Thirumurugan, S., Hu, C.C., Duann, Y.F., and Chung, R.J. (2024). Poly(methyl methacrylate) in Orthopedics: Strategies, Challenges, and Prospects in Bone Tissue Engineering. Polymers, 16.","DOI":"10.3390\/polym16030367"},{"key":"ref_21","first-page":"6984656","article-title":"Clinical Application of Antimicrobial Bone Graft Substitute in Osteomyelitis Treatment: A Systematic Review of Different Bone Graft Substitutes Available in Clinical Treatment of Osteomyelitis","volume":"2016","author":"Geurts","year":"2016","journal-title":"BioMed Res. Int."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.biomaterials.2015.12.012","article-title":"Biomaterials approaches to treating implant-associated osteomyelitis","volume":"81","author":"Inzana","year":"2016","journal-title":"Biomaterials"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/S0140-6736(04)16727-5","article-title":"Osteomyelitis","volume":"364","author":"Lew","year":"2004","journal-title":"Lancet"},{"key":"ref_24","first-page":"1182","article-title":"Manufacturing Letters A Framework for Digital Twin Integration in Biofabrication and a Scaffold 3D Bioplotting Case Study","volume":"41","author":"Ahmed","year":"2024","journal-title":"Manuf. Lett."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Brankovi\u0107, M., Zivic, F., Grujovic, N., Stojadinovic, I., Milenkovic, S., and Kotorcevic, N. (2024). Review of Spider Silk Applications in Biomedical and Tissue Engineering. Biomimetics, 9.","DOI":"10.3390\/biomimetics9030169"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1007\/s10237-024-01817-7","article-title":"An explainable machine learning-based probabilistic framework for the design of scaffolds in bone tissue engineering","volume":"23","author":"Drakoulas","year":"2024","journal-title":"Biomech. Model. Mechanobiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e19363","DOI":"10.1016\/j.heliyon.2023.e19363","article-title":"3D and 4D printing hydroxyapatite-based scaffolds for bone tissue engineering and regeneration","volume":"9","author":"Soleymani","year":"2023","journal-title":"Heliyon"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2000310","DOI":"10.1002\/adhm.202000310","article-title":"Biomaterials against Bone Infection","volume":"9","author":"Lozano","year":"2020","journal-title":"Adv. Healthc. Mater."},{"key":"ref_29","first-page":"90","article-title":"Current Concepts in Scaffolding for Bone Tissue Engineering","volume":"6","author":"Ghassemi","year":"2018","journal-title":"Arch. Bone Jt. Surg."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"4020","DOI":"10.1021\/acsbiomaterials.3c00115","article-title":"Antimicrobial and Biodegradable 3D Printed Scaffolds for Orthopedic Infections","volume":"9","author":"Dubey","year":"2023","journal-title":"ACS Biomater. Sci. Eng."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/S0142-9612(00)00136-8","article-title":"Optimizing the sterilization of PLGA scaffolds for use in tissue engineering","volume":"22","author":"Holy","year":"2000","journal-title":"Biomaterials"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"10254","DOI":"10.1038\/s41598-021-89830-z","article-title":"Evaluation of a bone filler scaffold for local antibiotic delivery to prevent Staphylococcus aureus infection in a contaminated bone defect","volume":"11","author":"Beenken","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"122015","DOI":"10.1016\/j.biomaterials.2023.122015","article-title":"Evaluation of bacterial attachment on mineralized collagen scaffolds and addition of manuka honey to increase mesenchymal stem cell osteogenesis","volume":"294","author":"Dewey","year":"2023","journal-title":"Biomaterials"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"122774","DOI":"10.1016\/j.biomaterials.2024.122774","article-title":"Antibiotic-eluting scaffolds with responsive dual-release kinetics facilitate bone healing and eliminate S. aureus infection","volume":"313","author":"Sheehy","year":"2025","journal-title":"Biomaterials"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Li, X., Huang, X., Li, L., Wu, J., Yi, W., Lai, Y., and Qin, L. (2022). LL-37-Coupled Porous Composite Scaffold for the Treatment of Infected Segmental Bone Defect. Pharmaceutics, 15.","DOI":"10.3390\/pharmaceutics15010088"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2206","DOI":"10.1128\/AAC.42.9.2206","article-title":"Activities of LL-37, a Cathelin-Associated Antimicrobial Peptide of Human Neutrophils","volume":"42","author":"Turner","year":"1998","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1002\/cbic.202000670","article-title":"Chemically Diverse Multifunctional Peptide Platforms with Antimicrobial and Cell Adhesive Properties","volume":"22","author":"Ginebra","year":"2021","journal-title":"ChemBioChem"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"134091","DOI":"10.1016\/j.ijbiomac.2024.134091","article-title":"LL-37 and bisphosphonate co-delivery 3D-scaffold with antimicrobial and antiresorptive activities for bone regeneration","volume":"277","author":"Ye","year":"2024","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.actbio.2016.12.047","article-title":"Collagen Tethering of Synthetic Human Antimicrobial Peptides Cathelicidin LL37 and its Effects on Antimicrobial Activity and Cytotoxicity","volume":"52","author":"Lozeau","year":"2016","journal-title":"Acta Biomater."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Voronko, O.E., Khotina, V.A., Kashirskikh, D.A., Lee, A.A., and Gasanov, V.A.O. (2025). Antimicrobial Peptides of the Cathelicidin Family: Focus on LL-37 and Its Modifications. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26168103"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1258","DOI":"10.1089\/ten.tea.2016.0063","article-title":"Evaluation of Silver Ion-Releasing Scaffolds in a 3D Coculture System of MRSA and Human Adipose-Derived Stem Cells for Their Potential Use in Treatment or Prevention of Osteomyelitis","volume":"22","author":"Molina","year":"2016","journal-title":"Tissue Eng. Part A"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"18950","DOI":"10.1038\/s41598-020-76087-1","article-title":"Identification of mesenchymal stromal cell survival responses to antimicrobial silver ion concentrations released from orthopaedic implants","volume":"10","author":"Souter","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1080\/17435390902725914","article-title":"Nano-silver\u2014A Review of Available Data and Knowledge Gaps in Human and Environmental Risk Assessment","volume":"3","author":"Wijnhoven","year":"2009","journal-title":"Nanotoxicology"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1799","DOI":"10.1007\/s10856-013-4923-4","article-title":"Nano-composite scaffolds for bone tissue engineering containing silver nanoparticles: Preparation, characterization and biological properties","volume":"24","author":"Marsich","year":"2013","journal-title":"J. Mater. Sci. Mater. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1007\/s10661-025-13963-1","article-title":"Public health concerns of multifaceted exposures to metal and metalloid mixtures: A systematic review","volume":"197","author":"Udom","year":"2025","journal-title":"Environ. Monit. Assess."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"022004","DOI":"10.1088\/1748-605X\/adac97","article-title":"Material and technique fundamentals of nano-hydroxyapatite coatings towards biofunctionalization: A review","volume":"20","author":"Phogat","year":"2025","journal-title":"Biomed. Mater."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3162","DOI":"10.1021\/acsbiomaterials.2c00140","article-title":"Multifunctional Hydroxyapatite Composites for Orthopedic Applications: A Review","volume":"8","author":"George","year":"2022","journal-title":"ACS Biomater. Sci. Eng."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1007\/s10856-025-06928-w","article-title":"Nanohydroxyapatite and its composite scaffold for bone tissue engineering application: A systematic review","volume":"36","author":"Shendage","year":"2025","journal-title":"J. Mater. Sci. Mater. Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"112453","DOI":"10.1016\/j.msec.2021.112453","article-title":"Incorporation of 45S5 bioglass via sol-gel in \u03b2-TCP scaffolds: Bioactivity and antimicrobial activity evaluation","volume":"131","author":"Spirandeli","year":"2021","journal-title":"Mater. Sci. Eng. C"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2757","DOI":"10.1016\/j.biomaterials.2011.01.004","article-title":"A review of the biological response to ionic dissolution products from bioactive glasses and glass-ceramics","volume":"32","author":"Hoppe","year":"2011","journal-title":"Biomaterials"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Filip, D.G., Surdu, V.A., Paduraru, A.V., and Andronescu, E. (2022). Current Development in Biomaterials\u2014Hydroxyapatite and Bioglass for Applications in Biomedical Field: A Review. J. Funct. Biomater., 13.","DOI":"10.3390\/jfb13040248"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1586\/17434440.2.3.303","article-title":"Bioactive composite materials for tissue engineering scaffolds","volume":"2","author":"Boccaccini","year":"2005","journal-title":"Expert Rev. Med. Devices"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1089\/ten.teb.2010.0704","article-title":"Scaffolds based bone tissue engineering: The role of chitosan","volume":"17","author":"Reis","year":"2011","journal-title":"Tissue Eng. Part B Rev."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1016\/j.jconrel.2021.08.055","article-title":"The role of natural polymers in bone tissue engineering","volume":"338","author":"Guo","year":"2021","journal-title":"J. Control. Release"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"055004","DOI":"10.1088\/1748-605X\/ad5ba9","article-title":"Harnessing extracellular vesicles-mediated signaling for enhanced bone regeneration: Novel insights into scaffold design","volume":"19","author":"Kanniyappan","year":"2024","journal-title":"Biomed. Mater."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"3457","DOI":"10.1016\/j.actbio.2010.03.023","article-title":"Chitosan-poly(lactide-co-glycolide) microsphere-based scaffolds for bone tissue engineering: In vitro degradation and in vivo bone regeneration studies","volume":"6","author":"Jiang","year":"2010","journal-title":"Acta Biomater."},{"key":"ref_57","unstructured":"Sundaram, M.N., Deepthi, S., and Jayakumar, R. (2015). Chitosan-Gelatin composite scaffolds in bone tissue engineering. Chitin and Chitosan for Regenerative Medicine, Springer."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Gao, K., and Xu, K. (2025). Advancements and Prospects of pH-Responsive Hydrogels in Biomedicine. Gels, 11.","DOI":"10.3390\/gels11040293"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"20200112","DOI":"10.1002\/VIW.20200112","article-title":"Stimuli-responsive hydrogels: Fabrication and biomedical applications","volume":"3","author":"Li","year":"2022","journal-title":"View"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"3325","DOI":"10.1039\/D3MH00399J","article-title":"Stimuli-responsive dynamic hydrogels: Design, properties and tissue engineering applications","volume":"10","author":"Amirthalingam","year":"2023","journal-title":"Mater. Horiz."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1016\/S0169-409X(01)00203-4","article-title":"Environment-sensitive hydrogels for drug delivery","volume":"53","author":"Qiu","year":"2001","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Zhang, Y., and Wu, B.M. (2023). Current Advances in Stimuli-Responsive Hydrogels as Smart Drug Delivery Carriers. Gels, 9.","DOI":"10.3390\/gels9100838"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"2001125","DOI":"10.1002\/adhm.202001125","article-title":"Stimuli-Responsive Biomaterials: Scaffolds for Stem Cell Control","volume":"10","author":"Gelmi","year":"2021","journal-title":"Adv. Healthc. Mater."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"2084","DOI":"10.1016\/j.chempr.2018.07.002","article-title":"Multi-Stimuli-Responsive Polymer Particles, Films, and Hydrogels for Drug Delivery","volume":"4","author":"Fu","year":"2018","journal-title":"Chem"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"758","DOI":"10.3109\/10717544.2014.940091","article-title":"Stimuli-responsive hydrogels in drug delivery and tissue engineering","volume":"23","author":"Sood","year":"2016","journal-title":"Drug Deliv."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1002\/adem.200700355","article-title":"Stimuli-responsive polymeric systems for biomedical applications","volume":"10","author":"Mano","year":"2008","journal-title":"Adv. Eng. Mater."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Municoy, S., \u00c1lvarez Echaz\u00fa, M.I., Antezana, P.E., Galdop\u00f3rpora, J.M., Olivetti, C., Mebert, A.M., Foglia, M.L., Tuttolomondo, M.V., Alvarez, G.S., and Hardy, J.G. (2020). Stimuli-responsive materials for tissue engineering and drug delivery. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21134724"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"44929","DOI":"10.1038\/srep44929","article-title":"Genetic engineering of a temperate phage-based delivery system for CRISPR\/Cas9 antimicrobials against Staphylococcus aureus","volume":"7","author":"Park","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Cobb, L.H., Park, J., Swanson, E.A., Beard, M.C., McCabe, E.M., Rourke, A.S., Seo, K.S., Olivier, A.K., and Priddy, L.B. (2019). CRISPR-Cas9 modified bacteriophage for treatment of Staphylococcus aureus induced osteomyelitis and soft tissue infection. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0220421"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1146","DOI":"10.1038\/nbt.3043","article-title":"Exploiting CRISPR-cas nucleases to produce sequence-specific antimicrobials","volume":"32","author":"Bikard","year":"2014","journal-title":"Nat. Biotechnol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1038\/nbt.3011","article-title":"Sequence-specific antimicrobials using efficiently delivered rNA-guided nucleases","volume":"32","author":"Citorik","year":"2014","journal-title":"Nat. Biotechnol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1128\/AAC.45.4.999-1007.2001","article-title":"Riddle of biofilm resistance","volume":"45","author":"Lewis","year":"2001","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.biochi.2021.06.010","article-title":"Intestinal interplay of quorum sensing molecules and human receptors","volume":"189","author":"Krasulova","year":"2021","journal-title":"Biochimie"},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Holm, A., and Vikstr\u00f6m, E. (2014). Quorum sensing communication between bacteria and human cells: Signals, targets, and functions. Front. Plant Sci., 5.","DOI":"10.3389\/fpls.2014.00309"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"6365","DOI":"10.1007\/s00253-022-12150-3","article-title":"Biofilm formation and inhibition mediated by bacterial quorum sensing","volume":"106","author":"Wang","year":"2022","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"106551","DOI":"10.1016\/j.bioorg.2023.106551","article-title":"Quorum sensing inhibitors as Therapeutics: Bacterial biofilm inhibition","volume":"136","author":"Vashistha","year":"2023","journal-title":"Bioorganic Chem."},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Zhou, L., Zhang, Y., Ge, Y., Zhu, X., and Pan, J. (2020). Regulatory Mechanisms and Promising Applications of Quorum Sensing-Inhibiting Agents in Control of Bacterial Biofilm Formation. Front. Microbiol., 11.","DOI":"10.3389\/fmicb.2020.589640"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"2206154","DOI":"10.1002\/advs.202206154","article-title":"Flourishing Antibacterial Strategies for Osteomyelitis Therapy","volume":"10","author":"Wang","year":"2023","journal-title":"Adv. Sci."},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Nguyen Ngoc, D., Latalski, M., Danielewicz, A., Szponder, T., Wessely-Szponder, J., and Mazur, E. (2025). Application of Antimicrobial Peptides (AMPs) in Treatment of Osteomyelitis in Human and Veterinary Orthopedics. J. Funct. Biomater., 16.","DOI":"10.3390\/jfb16030090"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"5253","DOI":"10.1021\/acsnano.4c11956","article-title":"Metal Ion and Antibiotic Co-loaded Nanoparticles for Combating Methicillin-Rresistant Staphylococcus aureus-Induced Osteomyelitis","volume":"19","author":"Lv","year":"2025","journal-title":"ACS Nano"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1016\/j.nano.2015.02.013","article-title":"Nanotechnology in bone tissue engineering","volume":"11","author":"Walmsley","year":"2015","journal-title":"Nanomed. Nanotechnol. Biol. Med."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"2400232","DOI":"10.1002\/adhm.202400232","article-title":"Enhancement of Bone Tissue Regeneration with Multi-Functional Nanoparticles by Coordination of Immune, Osteogenic, and Angiogenic Responses","volume":"14","author":"Jeong","year":"2025","journal-title":"Adv. Healthc. Mater."},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Manzano, M., and Vallet-Reg\u00ed, M. (2025). Mesoporous Silica Nanoparticles in Biomedicine: Advances and Prospects. Adv. Mater., e12433.","DOI":"10.1002\/adma.202512433"},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Farjaminejad, S., Farjaminejad, R., and Garcia-Godoy, F. (2024). Nanoparticles in Bone Regeneration: A Narrative Review of Current Advances and Future Directions in Tissue Engineering. J. Funct. Biomater., 15.","DOI":"10.3390\/jfb15090241"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"283","DOI":"10.3349\/ymj.2014.55.2.283","article-title":"Cytotoxic potential of silver nanoparticles","volume":"55","author":"Zhang","year":"2014","journal-title":"Yonsei Med. J."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1016\/j.biomaterials.2015.09.027","article-title":"Controlled release of cytokines using silk-biomaterials for macrophage polarization","volume":"73","author":"Reeves","year":"2015","journal-title":"Biomaterials"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1016\/j.biomaterials.2014.10.017","article-title":"Sequential delivery of immunomodulatory cytokines to facilitate the M1-to-M2 transition of macrophages and enhance vascularization of bone scaffolds","volume":"37","author":"Spiller","year":"2015","journal-title":"Biomaterials"},{"key":"ref_88","first-page":"244","article-title":"Modulating macrophage activities to promote endogenous bone regeneration: Biological mechanisms and engineering approaches","volume":"6","author":"Niu","year":"2021","journal-title":"Bioact. Mater."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"4439","DOI":"10.1016\/j.biomaterials.2013.02.065","article-title":"Macrophage Functional Polarization (M1\/M2) in Response to Varying Fiber and Pore Dimensions of Electrospun Scaffolds","volume":"34","author":"Garg","year":"2013","journal-title":"Biomaterials"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"100466","DOI":"10.1016\/j.apmt.2019.100466","article-title":"Pore size-mediated macrophage M1-to-M2 transition influences new vessel formation within the compartment of a scaffold","volume":"18","author":"Yin","year":"2020","journal-title":"Appl. Mater. Today"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"755","DOI":"10.18063\/ijb.755","article-title":"Pore size-mediated macrophage M1 to M2 transition affects osseointegration of 3D-printed PEEK scaffolds","volume":"9","author":"Yang","year":"2023","journal-title":"Int. J. Bioprint."},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Perier-Metz, C., Duda, G.N., and Checa, S. (2022). A mechanobiological computer optimization framework to design scaffolds to enhance bone regeneration. Front. Bioeng. Biotechnol., 10.","DOI":"10.3389\/fbioe.2022.980727"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"107555","DOI":"10.1016\/j.compbiomed.2023.107555","article-title":"The enlightening role of explainable artificial intelligence in medical & healthcare domains: A systematic literature review","volume":"166","author":"Ali","year":"2023","journal-title":"Comput. Biol. Med."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"4218","DOI":"10.1038\/s41598-024-82728-6","article-title":"Machine learning integrated with in vitro experiments for study of drug release from PLGA nanoparticles","volume":"15","author":"Sun","year":"2025","journal-title":"Sci. Rep."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1016\/j.jconrel.2021.03.033","article-title":"Electrospinning for drug delivery applications: A review","volume":"334","author":"Luraghi","year":"2021","journal-title":"J. Control. Release"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"2806","DOI":"10.1039\/D5BM00259A","article-title":"Supervised machine learning for predicting drug release from acetalated dextran nanofibers","volume":"13","author":"Woodring","year":"2025","journal-title":"Biomater. Sci."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"342","DOI":"10.18063\/ijb.v7i1.342","article-title":"Application of Machine Learning in 3D Bioprinting: Focus on Development of Big Data and Digital Twin","volume":"7","author":"An","year":"2021","journal-title":"Int. J. Bioprint."},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Zimmermann, J., Budde, K., Arbeiter, N., Molina, F., Storch, A., Uhrmacher, A.M., and van Rienen, U. (2021). Using a Digital Twin of an Electrical Stimulation Device to Monitor and Control the Electrical Stimulation of Cells in vitro. Front. Bioeng. Biotechnol., 9.","DOI":"10.3389\/fbioe.2021.765516"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.actbio.2015.09.005","article-title":"Silk fibroin as biomaterial for bone tissue engineering","volume":"31","author":"Melke","year":"2016","journal-title":"Acta Biomater."},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Nie, K., Zhou, S., Li, H., Tian, J., Shen, W., and Huang, W. (2023). Advanced silk materials for musculoskeletal tissue regeneration. Front. Bioeng. Biotechnol., 11.","DOI":"10.3389\/fbioe.2023.1199507"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1021\/acsbiomaterials.5c01425","article-title":"Silk Fibroin as a Platform for Advanced Antibacterial Biomaterials: Structure, Immune Modulation, and Biomedical Applications","volume":"12","author":"Li","year":"2026","journal-title":"ACS Biomater. Sci. Eng."},{"key":"ref_102","first-page":"1236","article-title":"Enhanced osteogenesis of human mesenchymal stem cells by self-assembled peptide hydrogel functionalized with glutamic acid templated peptides","volume":"14","author":"Onak","year":"2020","journal-title":"J. Tissue Eng. Regen. Med."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"324","DOI":"10.3390\/biophysica2040030","article-title":"Supramolecular-Covalent Peptides Self-Assembly: From Design to Regenerative Medicine and Beyond","volume":"2","author":"Pugliese","year":"2022","journal-title":"Biophysica"},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"Li, S., Yu, Q., Li, H., Chen, M., Jin, Y., and Liu, D. (2023). Self-Assembled Peptide Hydrogels in Regenerative Medicine. Gels, 9.","DOI":"10.3390\/gels9080653"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"11837","DOI":"10.7150\/thno.49784","article-title":"NIR light-assisted phototherapies for bone-related diseases and bone tissue regeneration: A systematic review","volume":"10","author":"Wan","year":"2020","journal-title":"Theranostics"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"2458","DOI":"10.7150\/thno.16183","article-title":"Beyond the barriers of light penetration: Strategies, perspectives and possibilities for photodynamic therapy","volume":"6","author":"Mallidi","year":"2016","journal-title":"Theranostics"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1186\/s40824-023-00458-8","article-title":"Phototherapy techniques for the management of musculoskeletal disorders: Strategies and recent advances","volume":"27","author":"Zhang","year":"2023","journal-title":"Biomater. Res."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.stem.2015.12.012","article-title":"Material Cues as Potent Regulators of Epigenetics and Stem Cell Function","volume":"18","author":"Crowder","year":"2016","journal-title":"Cell Stem Cell"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.ydbio.2017.08.032","article-title":"Bioelectric signaling in regeneration: Mechanisms of ionic controls of growth and form","volume":"433","author":"McLaughlin","year":"2018","journal-title":"Dev. Biol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"6307","DOI":"10.1038\/s41598-018-24892-0","article-title":"Combining electrical stimulation and tissue engineering to treat large bone defects in a rat model","volume":"8","author":"Leppik","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"101664","DOI":"10.1016\/j.mtbio.2025.101664","article-title":"Biomimetic structural design in 3D-printed scaffolds for bone tissue engineering","volume":"32","author":"Huang","year":"2025","journal-title":"Mater. Today Bio"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"1700612","DOI":"10.1002\/adhm.201700612","article-title":"Biomimetic materials and fabrication approaches for bone tissue engineering","volume":"6","author":"Kim","year":"2017","journal-title":"Adv. Healthc. Mater."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1186\/s12938-025-01381-w","article-title":"Advances in 3D-printed scaffold technologies for bone defect repair: Materials, biomechanics, and clinical prospects","volume":"24","author":"Sun","year":"2025","journal-title":"Biomed. Eng. Online"},{"key":"ref_114","doi-asserted-by":"crossref","unstructured":"Li, T., Chen, L., Yuan, Y., and Shi, R. (2023). The Current Status, Prospects, and Challenges of Shape Memory Polymers Application in Bone Tissue Engineering. Polymers, 15.","DOI":"10.3390\/polym15030556"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"114460","DOI":"10.1016\/j.eurpolymj.2025.114460","article-title":"Shape memory polymers: From materials to emerging biomedical applications","volume":"243","author":"Khan","year":"2026","journal-title":"Eur. Polym. J."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"4597","DOI":"10.1016\/j.actbio.2014.07.020","article-title":"A bioactive \u2018self-fitting\u2019 shape memory polymer scaffold with potential to treat cranio-maxillo facial bone defects","volume":"10","author":"Zhang","year":"2014","journal-title":"Acta Biomater."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1186\/s13018-022-02980-2","article-title":"Antibiotic-loaded calcium sulfate in clinical treatment of chronic osteomyelitis: A systematic review and meta-analysis","volume":"17","author":"Shi","year":"2022","journal-title":"J. Orthop. Surg. Res."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"2552","DOI":"10.1111\/dom.16254","article-title":"Efficacy and safety of a bio-absorbable antibiotic delivery in calcium sulphate granules for the treatment of osteomyelitis in patients with diabetic foot: A randomized, double blinded, controlled clinical study The BIG D-FOOT study","volume":"27","author":"Monami","year":"2025","journal-title":"Diabetes Obes. Metab."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"e35597","DOI":"10.1002\/jbm.b.35597","article-title":"Safety and Efficacy of S53P4 Bioactive Glass in Osteomyelitis Management: A Systematic Review and Meta-Analysis","volume":"113","author":"Nguyen","year":"2025","journal-title":"J. Biomed. Mater. Res. Part B Appl. Biomater."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"194","DOI":"10.7150\/jbji.20404","article-title":"Treatment of Cavitary Bone Defects in Chronic Osteomyelitis: Bioactive glass S53P4 vs. Calcium Sulphate Antibiotic Beads","volume":"2","author":"Ferrando","year":"2017","journal-title":"J. Bone Jt. Infect."}],"container-title":["Journal of Functional Biomaterials"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-4983\/17\/8\/379\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T11:04:31Z","timestamp":1785755071000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-4983\/17\/8\/379"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,3]]},"references-count":120,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["jfb17080379"],"URL":"https:\/\/doi.org\/10.3390\/jfb17080379","relation":{},"ISSN":["2079-4983"],"issn-type":[{"value":"2079-4983","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,3]]}}}