{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T18:40:23Z","timestamp":1793040023684,"version":"4.5.0"},"reference-count":37,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2022,6,28]],"date-time":"2022-06-28T00:00:00Z","timestamp":1656374400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the research project PRINTAID","award":["722467"],"award-info":[{"award-number":["722467"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Bacterial infections are a serious healthcare complication in orthopedic and trauma surgery worldwide. Compared to systemic, local antibiotic prophylaxis has been shown to provide a higher antibiotic dose and bioavailability at the bone site with minimum toxic effects. However, there are still not enough biomaterial and antibiotic combinations available for personalized implant sizes for patients. The aim of this study was to develop a bone fixation plate coating made of a composite of poly-\u03b5-caprolactone, hydroxyapatite and halloysite nanotubes loaded with gentamicin sulphate and fabricated via fused filament fabrication 3D printing technology. The mechanical and thermal properties of the biomaterial were analyzed. The in vitro release kinetics of gentamicin sulphate were evaluated for 14 days showing a burst release during the first two days that was followed by a sustained release of bactericidal concentrations. The composite loaded with 2 and 5% gentamicin sulphate exhibited complete antimicrobial killing of Staphylococcus aureus in an ex vivo mouse femur fixation plate infection model. Moreover, a fixation plate of the composite loaded with 5% of gentamicin sulphate was able to prevent S. aureus infection in the bone and surrounding tissue in an in vivo mouse bone fixation plate infection model 3 days post-surgery. In conclusion, the newly developed composite material successfully prevented infection in vivo. Additionally, the ability to use fused filament fabrication 3D printing to produce patient-specific implants may provide a wider range of personalized solutions for patients.<\/jats:p>","DOI":"10.3390\/pharmaceutics14071363","type":"journal-article","created":{"date-parts":[[2022,6,29]],"date-time":"2022-06-29T01:48:38Z","timestamp":1656467318000},"page":"1363","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["3D-Printed Gentamicin-Releasing Poly-\u03b5-Caprolactone Composite Prevents Fracture-Related Staphylococcus aureus Infection in Mice"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4334-1561","authenticated-orcid":false,"given":"Clara","family":"Guarch-P\u00e9rez","sequence":"first","affiliation":[{"name":"Department of Medical Microbiology and Infection Prevention, Amsterdam Institute for Infection and Immunity, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1870-5132","authenticated-orcid":false,"given":"Bahaa","family":"Shaqour","sequence":"additional","affiliation":[{"name":"Mechanical and Mechatronics Engineering Department, Faculty of Engineering & Information Technology, An-Najah National University, Nablus P.O. Box 7, Palestine"},{"name":"Laboratory for Microbiology, Parasitology and Hygiene (LMPH), Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5444-3179","authenticated-orcid":false,"given":"Martijn","family":"Riool","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Infection Prevention, Amsterdam Institute for Infection and Immunity, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bart","family":"Verleije","sequence":"additional","affiliation":[{"name":"Voxdale bv, Bijkhoevelaan 32, 2110 Wijnegem, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koen","family":"Beyers","sequence":"additional","affiliation":[{"name":"Voxdale bv, Bijkhoevelaan 32, 2110 Wijnegem, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1291-6054","authenticated-orcid":false,"given":"Chris","family":"Vervaet","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmaceutical Technology, Department of Pharmaceutics, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4361-8911","authenticated-orcid":false,"given":"Paul","family":"Cos","sequence":"additional","affiliation":[{"name":"Laboratory for Microbiology, Parasitology and Hygiene (LMPH), Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9589-186X","authenticated-orcid":false,"given":"Sebastian A. J.","family":"Zaat","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Infection Prevention, Amsterdam Institute for Infection and Immunity, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1016\/j.cmi.2020.02.010","article-title":"\u2018Pathogenesis and Management of Fracture-Related Infection\u2019\u2014Author\u2019s Reply","volume":"26","author":"Depypere","year":"2020","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1038\/s41413-019-0061-z","article-title":"Evolving Concepts in Bone Infection: Redefining \u201cBiofilm\u201d, \u201cAcute vs. Chronic Osteomyelitis\u201d, \u201cthe Immune Proteome\u201d and \u201cLocal Antibiotic Therapy\u201d","volume":"7","author":"Masters","year":"2019","journal-title":"Bone Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.actbio.2016.07.029","article-title":"Injectable Gentamicin-Loaded Thermo-Responsive Hyaluronic Acid Derivative Prevents Infection in a Rabbit Model","volume":"43","author":"Arens","year":"2016","journal-title":"Acta Biomater."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1038\/s41579-022-00686-0","article-title":"Skeletal Infections: Microbial Pathogenesis, Immunity and Clinical Management","volume":"20","author":"Masters","year":"2022","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1302\/2046-3758.77.BJR-2018-0043.R1","article-title":"The Effect of Local Antibiotic Prophylaxis When Treating Open Limb Fractures: A Systematic Review and Meta-Analysis","volume":"7","author":"Morgenstern","year":"2018","journal-title":"Bone Jt. Res."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Turgut, H., Sacar, S., Kaleli, I., Sacar, M., Goksin, I., Toprak, S., Asan, A., Cevahir, N., Tekin, K., and Baltalarli, A. (2005). Systemic and Local Antibiotic Prophylaxis in the Prevention of Staphylococcus Epidermidisgraft Infection. BMC Infect. Dis., 5.","DOI":"10.1186\/1471-2334-5-91"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1177\/0885328216630912","article-title":"In Vivo Quantification of Gentamicin Released from an Implant Coating","volume":"31","author":"Nast","year":"2016","journal-title":"J. Biomater. Appl."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/j.biomaterials.2010.08.089","article-title":"Polycaprolactone-Based Fused Deposition Modeled Mesh for Delivery of Antibacterial Agents to Infected Wounds","volume":"32","author":"Teo","year":"2011","journal-title":"Biomaterials"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Shaqour, B., Reigada, I., G\u00f3recka, \u017b., Choi\u0144ska, E., Verleije, B., Beyers, K., \u015awi\u0119szkowski, W., Fallarero, A., and Cos, P. (2020). 3D-Printed Drug Delivery Systems: The Effects of Drug Incorporation Methods on Their Release and Antibacterial Efficiency. Materials, 13.","DOI":"10.3390\/ma13153364"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1016\/j.msec.2018.02.019","article-title":"Effects of Polycaprolactone on Alendronate Drug Release from Mg-Doped Hydroxyapatite Coating on Titanium","volume":"88","author":"Bose","year":"2018","journal-title":"Mater. Sci. Eng. C"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.jconrel.2020.06.014","article-title":"Bactericidal Coating to Prevent Early and Delayed Implant-Related Infections","volume":"326","author":"Jahanmard","year":"2020","journal-title":"J. Control. Release"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1016\/j.msec.2017.02.087","article-title":"Improvement of Mechanical and Biological Properties of Polycaprolactone Loaded with Hydroxyapatite and Halloysite Nanotubes","volume":"75","author":"Torres","year":"2017","journal-title":"Mater. Sci. Eng. C"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.compositesa.2018.09.008","article-title":"Single-Layer Temperature-Adjusting Transition Method to Improve the Bond Strength of 3D-Printed PCL\/PLA Parts","volume":"115","author":"Lin","year":"2018","journal-title":"Compos. Part A Appl. Sci. Manuf."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Sanz-Horta, R., Elvira, C., Gallardo, A., Reinecke, H., and Rodr\u00edguez-Hern\u00e1ndez, J. (2020). Fabrication of 3D-Printed Biodegradable Porous Scaffolds Combining Multi-Material Fused Deposition Modeling and Supercritical CO2 Techniques. Nanomaterials, 10.","DOI":"10.3390\/nano10061080"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"119591","DOI":"10.1016\/j.ijpharm.2020.119591","article-title":"Screening of Pharmaceutical Polymers for Extrusion-Based Additive Manufacturing of Patient-Tailored Tablets","volume":"586","author":"Samaro","year":"2020","journal-title":"Int. J. Pharm."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"120922","DOI":"10.1016\/j.ijpharm.2021.120922","article-title":"Can Filaments, Pellets and Powder Be Used as Feedstock to Produce Highly Drug-Loaded Ethylene-Vinyl Acetate 3D Printed Tablets Using Extrusion-Based Additive Manufacturing?","volume":"607","author":"Samaro","year":"2021","journal-title":"Int. J. Pharm."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1177\/039139880803100913","article-title":"The selection of approprirate bacterial strains in preclinical evaluation of infection-resistant biomaterials","volume":"31","author":"Campoccia","year":"2008","journal-title":"Int. J. Artif. Organs."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1337","DOI":"10.1086\/315369","article-title":"Biomaterial-Associated Persistence of Staphylococcus Epidermidis in Pericatheter Macrophages","volume":"181","author":"Boelens","year":"2000","journal-title":"J. Infect. Dis."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.biomaterials.2017.02.030","article-title":"Selective Laser Melting Porous Metallic Implants with Immobilized Silver Nanoparticles Kill and Prevent Biofilm Formation by Methicillin-Resistant Staphylococcus Aureus","volume":"140","author":"Riool","year":"2017","journal-title":"Biomaterials"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"774","DOI":"10.22203\/eCM.v041a49","article-title":"A Murine Staphylococcus Aureus Fracture-Related Infection Model Characterised by Fracture Non-Union, Staphylococcal Abscess Communities and Myeloid-Derived Suppressor Cells","volume":"41","author":"Hofstee","year":"2021","journal-title":"eCM"},{"key":"ref_21","first-page":"321","article-title":"Influence of Fracture Stability on Staphylococcus Epidermidis and Staphylococcus Aureus Infection in a Murine Femoral Fracture Model","volume":"34","author":"Zeiter","year":"2017","journal-title":"eCM"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.msec.2016.11.049","article-title":"Comparison between PCL\/Hydroxyapatite (HA) and PCL\/Halloysite Nanotube (HNT) Composite Scaffolds Prepared by Co-Extrusion and Gas Foaming","volume":"72","author":"Jing","year":"2017","journal-title":"Mater. Sci. Eng. C"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"16921","DOI":"10.1038\/s41598-021-96522-1","article-title":"Antibiotic Cement Plate Composite Structure Internal Fixation after Debridement of Bone Infection","volume":"11","author":"Wang","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1302\/0301-620X.87B2.14781","article-title":"Bacterial Survival in the Interfacial Gap in Gentamicin-Loaded Acrylic Bone Cements","volume":"87-B","author":"Hendriks","year":"2005","journal-title":"J. Bone Jt. Surg. Br. Vol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Neut, D., Kluin, O.S., Thompson, J., van der Mei, H.C., and Busscher, H.J. (2010). Gentamicin Release from Commercially-Available Gentamicin-Loaded PMMA Bone Cements in a Prosthesis-Related Interfacial Gap Model and Their Antibacterial Efficacy. BMC Musculoskelet. Disord., 11.","DOI":"10.1186\/1471-2474-11-258"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1279","DOI":"10.1007\/s00170-021-06918-6","article-title":"Gaining a Better Understanding of the Extrusion Process in Fused Filament Fabrication 3D Printing: A Review","volume":"114","author":"Shaqour","year":"2021","journal-title":"Int J. Adv. Manuf. Technol."},{"key":"ref_27","first-page":"102467","article-title":"Novel Design for an Additively Manufactured Nozzle to Produce Tubular Scaffolds via Fused Filament Fabrication","volume":"49","author":"Shaqour","year":"2021","journal-title":"Addit. Manuf."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1177\/0021955X13503842","article-title":"Characterizing the Viscoelastic Behaviour of Poly(Lactide-Co-Glycolide Acid)\u2013Hydroxyapatite Foams","volume":"49","author":"Leung","year":"2013","journal-title":"J. Cell. Plast."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1038\/nrmicro2508","article-title":"Are Bloodstream Leukocytes Trojan Horses for the Metastasis of Staphylococcus Aureus?","volume":"9","author":"Thwaites","year":"2011","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1016\/S8756-3282(03)00050-4","article-title":"Gentamicin Coating of Metallic Implants Reduces Implant-Related Osteomyelitis in Rats","volume":"32","author":"Lucke","year":"2003","journal-title":"Bone"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1016\/j.bone.2005.01.008","article-title":"Systemic versus Local Application of Gentamicin in Prophylaxis of Implant-Related Osteomyelitis in a Rat Model","volume":"36","author":"Lucke","year":"2005","journal-title":"Bone"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1002\/bit.20538","article-title":"Simulation of Gentamicin Delivery for the Local Treatment of Osteomyelitis","volume":"91","author":"Lee","year":"2005","journal-title":"Biotechnol. Bioeng."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2433","DOI":"10.1016\/j.injury.2015.09.028","article-title":"The Use of Gentamicin-Coated Nails in Complex Open Tibia Fracture and Revision Cases: A Retrospective Analysis of a Single Centre Case Series and Review of the Literature","volume":"46","author":"Metsemakers","year":"2015","journal-title":"Injury"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1097\/BTO.0000000000000067","article-title":"Gentamicin-Coated Tibia Nails: Can We Afford NOT to Use Them?","volume":"29","author":"Raschke","year":"2014","journal-title":"Tech. Orthop."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"334","DOI":"10.22203\/eCM.v042a22","article-title":"Current Osteomyelitis Mouse Models, a Systematic Review","volume":"42","author":"Riool","year":"2021","journal-title":"eCM"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.bone.2014.11.019","article-title":"A Novel Murine Model of Established Staphylococcal Bone Infection in the Presence of a Fracture Fixation Plate to Study Therapies Utilizing Antibiotic-Laden Spacers after Revision Surgery","volume":"72","author":"Inzana","year":"2015","journal-title":"Bone"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"431","DOI":"10.22203\/eCM.v037a26","article-title":"A Murine Femoral Ostectomy Model with Hardware Exchange to Assess Antibiotic-Impregnated Spacers for Implant-Associated Osteomyelitis","volume":"37","author":"Trombetta","year":"2019","journal-title":"eCM"}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/14\/7\/1363\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:39:32Z","timestamp":1760139572000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/14\/7\/1363"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,28]]},"references-count":37,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2022,7]]}},"alternative-id":["pharmaceutics14071363"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics14071363","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,28]]}}}