{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T08:17:49Z","timestamp":1769761069085,"version":"3.49.0"},"reference-count":94,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2019,2,22]],"date-time":"2019-02-22T00:00:00Z","timestamp":1550793600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P30AR069655"],"award-info":[{"award-number":["P30AR069655"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P50AR72000"],"award-info":[{"award-number":["P50AR72000"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R34DE025573"],"award-info":[{"award-number":["R34DE025573"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AR056696"],"award-info":[{"award-number":["R01AR056696"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AR070613"],"award-info":[{"award-number":["R01AR070613"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"AO Trauma Foundation","award":["Clinical Priority Program on Bone Infection"],"award-info":[{"award-number":["Clinical Priority Program on Bone Infection"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Osteomyelitis is a chronic bone infection that is often treated with adjuvant antibiotic-impregnated poly(methyl methacrylate) (PMMA) cement spacers in multi-staged revisions. However, failure rates remain substantial due to recurrence of infection, which is attributed to the poor performance of the PMMA cement as a drug release device. Hence, the objective of this study was to design and evaluate a bioresorbable calcium phosphate scaffold (CaPS) for sustained antimicrobial drug release and investigate its efficacy in a murine model of femoral implant-associated osteomyelitis. Incorporating rifampin and sitafloxacin, which are effective against bacterial phenotypes responsible for bacterial persistence, into 3D-printed CaPS coated with poly(lactic co-glycolic) acid, achieved controlled release for up to two weeks. Implantation into the murine infection model resulted in decreased bacterial colonization rates at 3- and 10-weeks post-revision for the 3D printed CaPS in comparison to gentamicin-laden PMMA. Furthermore, a significant increase in bone formation was observed for 3D printed CaPS incorporated with rifampin at 3 and 10 weeks. The results of this study demonstrate that osteoconductive 3D printed CaPS incorporated with antimicrobials demonstrate more efficacious bacterial colonization outcomes and bone growth in a single-stage revision in comparison to gentamicin-laden PMMA requiring a two-stage revision.<\/jats:p>","DOI":"10.3390\/pharmaceutics11020094","type":"journal-article","created":{"date-parts":[[2019,2,22]],"date-time":"2019-02-22T11:26:14Z","timestamp":1550834774000},"page":"94","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Calcium Phosphate Spacers for the Local Delivery of Sitafloxacin and Rifampin to Treat Orthopedic Infections: Efficacy and Proof of Concept in a Mouse Model of Single-Stage Revision of Device-Associated Osteomyelitis"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0479-5595","authenticated-orcid":false,"given":"Ryan P.","family":"Trombetta","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering, University of Rochester, Rochester, NY 14642, USA"},{"name":"Center for Musculoskeletal Research, University of Rochester, Rochester, NY 14642, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark J.","family":"Ninomiya","sequence":"additional","affiliation":[{"name":"Center for Musculoskeletal Research, University of Rochester, Rochester, NY 14642, USA"},{"name":"Department of Microbiology and Immunology, University of Rochester, Rochester, NY 14642, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ihab M.","family":"El-Atawneh","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University of Rochester, Rochester, NY 14642, USA"},{"name":"Center for Musculoskeletal Research, University of Rochester, Rochester, NY 14642, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emma K.","family":"Knapp","sequence":"additional","affiliation":[{"name":"Center for Musculoskeletal Research, University of Rochester, Rochester, NY 14642, USA"},{"name":"Department of Orthopedics, University of Rochester Medical Center, Rochester, NY 14642, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karen L.","family":"de Mesy Bentley","sequence":"additional","affiliation":[{"name":"Center for Musculoskeletal Research, University of Rochester, Rochester, NY 14642, USA"},{"name":"Department of Pathology &amp; Laboratory Medicine, University of Rochester, Rochester, NY 14642, USA"},{"name":"Department of Orthopedics, University of Rochester Medical Center, Rochester, NY 14642, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul M.","family":"Dunman","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Rochester, Rochester, NY 14642, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edward M.","family":"Schwarz","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University of Rochester, Rochester, NY 14642, USA"},{"name":"Center for Musculoskeletal Research, University of Rochester, Rochester, NY 14642, USA"},{"name":"Department of Pathology &amp; Laboratory Medicine, University of Rochester, Rochester, NY 14642, USA"},{"name":"Department of Orthopedics, University of Rochester Medical Center, Rochester, NY 14642, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen L.","family":"Kates","sequence":"additional","affiliation":[{"name":"Center for Musculoskeletal Research, University of Rochester, Rochester, NY 14642, USA"},{"name":"Department of Orthopaedic Surgery, Virginia Commonwealth University School of Medicine, Richmond, VA 0153, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hani A.","family":"Awad","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University of Rochester, Rochester, NY 14642, USA"},{"name":"Center for Musculoskeletal Research, University of Rochester, Rochester, NY 14642, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,2,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1422","DOI":"10.1056\/NEJMra035415","article-title":"Treatment of infections associated with surgical implants","volume":"350","author":"Darouiche","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1501","DOI":"10.1016\/j.injury.2016.04.011","article-title":"Risk factors for infection after operative fixation of Tibial plateau fractures","volume":"47","author":"Momaya","year":"2016","journal-title":"Injury"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1097\/BOT.0000000000000203","article-title":"Complications of high-energy bicondylar tibial plateau fractures treated with dual plating through 2 incisions","volume":"29","author":"Ruffolo","year":"2015","journal-title":"J. Orthop. Trauma"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/j.injury.2012.10.032","article-title":"Prolonged operative time increases infection rate in tibial plateau fractures","volume":"44","author":"Colman","year":"2013","journal-title":"Injury"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e196","DOI":"10.1097\/BOT.0b013e318284704e","article-title":"Risk factors of infection after ORIF of bicondylar tibial plateau fractures","volume":"27","author":"Morris","year":"2013","journal-title":"J. Orthop. Trauma"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/j.artd.2017.05.003","article-title":"Infection burden in total hip and knee arthroplasties: An international registry-based perspective","volume":"3","author":"Springer","year":"2017","journal-title":"Arthroplast. Today"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/j.jhin.2010.03.012","article-title":"Risk factors for treatment failure in patients with prosthetic joint infections","volume":"75","author":"Lee","year":"2010","journal-title":"J. Hosp. Infect."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1086\/499234","article-title":"Outcome of prosthetic joint infections treated with debridement and retention of components","volume":"42","author":"Marculescu","year":"2006","journal-title":"Clin. Infect. Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.arth.2010.04.011","article-title":"Periprosthetic Joint Infection: The Economic Impact of Methicillin-Resistant Infections","volume":"25","author":"Parvizi","year":"2010","journal-title":"The J. Arthroplast."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.jhin.2012.04.025","article-title":"Bone and joint infections in hospitalized patients in France, 2008: Clinical and economic outcomes","volume":"82","author":"Baron","year":"2012","journal-title":"J. Hosp. Infect."},{"key":"ref_11","unstructured":"National Joint Registry for England (2014). Wales and Northern Ireland: 11th Annual Report, NJR Centre."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1093\/cid\/cis803","article-title":"Diagnosis and Management of Prosthetic Joint Infection: Clinical Practice Guidelines by the Infectious Diseases Society of America","volume":"56","author":"Osmon","year":"2013","journal-title":"Clin. Infect. Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"914","DOI":"10.1093\/clinids\/24.5.914","article-title":"Staphylococcus aureus Prosthetic Joint Infection Treated with Debridement and Prosthesis Retention","volume":"24","author":"Brandt","year":"1997","journal-title":"Clin. Infect. Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1056\/NEJMcp0905029","article-title":"Infection Associated with Prosthetic Joints","volume":"361","author":"Patel","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1186\/s13063-016-1213-8","article-title":"One-stage or two-stage revision surgery for prosthetic hip joint infection\u2014The INFORM trial: A study protocol for a randomised controlled trial","volume":"17","author":"Strange","year":"2016","journal-title":"Trials"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"74","DOI":"10.4103\/jotr.jotr_18_17","article-title":"Antibiotic laden bone cement in chronic osteomyelitis","volume":"9","author":"Mohapatra","year":"2017","journal-title":"J. Orthop. Traumatol. Rehabil."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1016\/j.injury.2016.09.019","article-title":"Infection after fracture fixation: Current surgical and microbiological concepts","volume":"49","author":"Metsemakers","year":"2018","journal-title":"Injury"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"950","DOI":"10.1016\/S0736-0266(01)00022-5","article-title":"Toxic effect of rifampicin on human osteoblast-like cells","volume":"19","author":"Isefuku","year":"2001","journal-title":"J. Orthop. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1136\/bmj.3.5713.24","article-title":"Rifampicin-induced immune thrombocytopenia","volume":"3","author":"Blajchman","year":"1970","journal-title":"Br. Med. J."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1093\/infdis\/158.4.693","article-title":"Fibronectin, fibrinogen, and laminin act as mediators of adherence of clinical staphylococcal isolates to foreign material","volume":"158","author":"Herrmann","year":"1988","journal-title":"J. Infect. Dis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1111\/j.1574-695X.2007.00357.x","article-title":"Osteomyelitis and the role of biofilms in chronic infection","volume":"52","author":"Brady","year":"2008","journal-title":"FEMS Immunol. Med. Microbiol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Romeo, T. (2008). Multidrug tolerance of biofilms and persister cells. Bacterial Biofilms, Springer.","DOI":"10.1007\/978-3-540-75418-3"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"a010306","DOI":"10.1101\/cshperspect.a010306","article-title":"Bacterial biofilms: Development, dispersal, and therapeutic strategies in the dawn of the postantibiotic era","volume":"3","author":"Kostakioti","year":"2013","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1455","DOI":"10.1093\/jac\/dkt072","article-title":"Antibiotic activity against small-colony variants of Staphylococcus aureus: Review of in vitro, animal and clinical data","volume":"68","author":"Garcia","year":"2013","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1093\/clinids\/20.1.95","article-title":"Persistent and relapsing infections associated with small-colony variants of Staphylococcus aureus","volume":"20","author":"Proctor","year":"1995","journal-title":"Clin. Infect. Dis."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1002\/emmm.201000115","article-title":"Staphylococcus aureus phenotype switching: An effective bacterial strategy to escape host immune response and establish a chronic infection","volume":"3","author":"Tuchscherr","year":"2011","journal-title":"EMBO Mol. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e01910-14","DOI":"10.1128\/mBio.01910-14","article-title":"Clinical Characteristics and Outcomes of Prosthetic Joint Infection Caused by Small Colony Variant Staphylococci","volume":"5","author":"Tande","year":"2014","journal-title":"mBio"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Proctor, R.A. (2000). Microbial Pathogenic Factors: Small-Colony Variants. Infections Associated with Indwelling Medical Devices, American Society of Microbiology. [3rd ed.].","DOI":"10.1128\/9781555818067.ch3"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1302\/0301-620X.33B1.110","article-title":"First recurrence of osteomyelitis eighty years after infection","volume":"33-b","author":"Gallie","year":"1951","journal-title":"J. Bone Jt. Surg. Br."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"193","DOI":"10.3109\/17453670902884700","article-title":"Elution of gentamicin and vancomycin from polymethylmethacrylate beads and hip spacers in vivo","volume":"80","author":"Anagnostakos","year":"2009","journal-title":"Acta Orthop."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1152","DOI":"10.1016\/j.arth.2007.08.020","article-title":"In vitro release of antibiotics from commercial PMMA beads and articulating hip spacers","volume":"23","author":"Moojen","year":"2008","journal-title":"J. Arthroplast."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2487","DOI":"10.2106\/JBJS.E.01126","article-title":"Antibiotic-Loaded Bone Cement for Infection Prophylaxis in Total Joint Replacement","volume":"88","author":"Jiranek","year":"2006","journal-title":"JBJS"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1002\/jbm.b.31220","article-title":"Properties of antibiotic-loaded acrylic bone cements for use in cemented arthroplasties: A state-of-the-art review","volume":"89B","author":"Lewis","year":"2009","journal-title":"J. Biomed. Mater. Res. Part B Appl. Biomater."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1002\/jor.23611","article-title":"Viable bacteria persist on antibiotic spacers following two-stage revision for periprosthetic joint infection","volume":"36","author":"Ma","year":"2018","journal-title":"J. Orthop. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2095","DOI":"10.1016\/j.injury.2017.08.021","article-title":"Determining potential of PMMA as a depot for rifampin to treat recalcitrant orthopaedic infections","volume":"48","author":"Shiels","year":"2017","journal-title":"Injury"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"232","DOI":"10.22203\/eCM.v030a16","article-title":"3D printed bioceramics for dual antibiotic delivery to treat implant-associated bone infection","volume":"30","author":"Inzana","year":"2015","journal-title":"Eur. Cell Mater."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.mser.2014.04.001","article-title":"Biomimetic porous scaffolds for bone tissue engineering","volume":"80","author":"Wu","year":"2014","journal-title":"Mater. Sci. Eng. R Rep."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.mattod.2015.10.008","article-title":"Calcium phosphates in biomedical applications: Materials for the future?","volume":"19","author":"Habraken","year":"2016","journal-title":"Mater. Today"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"4026","DOI":"10.1016\/j.biomaterials.2014.01.064","article-title":"3D printing of composite calcium phosphate and collagen scaffolds for bone regeneration","volume":"35","author":"Inzana","year":"2014","journal-title":"Biomaterials"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2874","DOI":"10.1007\/s11999-015-4300-3","article-title":"Rifamycin Derivatives Are Effective Against Staphylococcal Biofilms In Vitro and Elutable From PMMA","volume":"473","author":"Sanchez","year":"2015","journal-title":"Clin. Orthop. Relat. Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e00422-18","DOI":"10.1128\/mSphere.00422-18","article-title":"A High-Throughput Screening Approach to Repurpose FDA-Approved Drugs for Bactericidal Applications against Staphylococcus aureus Small-Colony Variants","volume":"3","author":"Trombetta","year":"2018","journal-title":"mSphere"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Trombetta, R.P., de Mesy Bentley, K.L., Schwarz, E.M., Kates, S.L., and Awad, H.A. (2019). A murine femoral ostectomy model with hardware exchange to assess antibiotic-impregnated spacers for implant-associated osteomyelitis. Eur. Cell Mater., accepted.","DOI":"10.22203\/eCM.v037a26"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3178","DOI":"10.1016\/j.jbiomech.2007.04.004","article-title":"Micro-computed tomography prediction of biomechanical strength in murine structural bone grafts","volume":"40","author":"Reynolds","year":"2007","journal-title":"J. Biomech."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1389","DOI":"10.1002\/jor.22672","article-title":"Passive Immunization with Anti-Glucosaminidase Monoclonal Antibodies Protects Mice from Implant-Associated Osteomyelitis by Mediating Opsonophagocytosis of Staphylococcus aureus Megaclusters","volume":"32","author":"Varrone","year":"2014","journal-title":"J. Orthop. Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1070","DOI":"10.1002\/jor.21343","article-title":"Effect of various concentrations of antibiotics on osteogenic cell viability and activity","volume":"29","author":"Rathbone","year":"2011","journal-title":"J. Orthop. Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1182","DOI":"10.1128\/AAC.00740-10","article-title":"Treatment with Linezolid or Vancomycin in Combination with Rifampin Is Effective in an Animal Model of Methicillin-Resistant Staphylococcus aureus Foreign Body Osteomyelitis","volume":"55","author":"Vergidis","year":"2011","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"e18","DOI":"10.1093\/cid\/ciq146","article-title":"Clinical practice guidelines by the infectious diseases society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children","volume":"52","author":"Liu","year":"2011","journal-title":"Clin. Infect. Dis."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1055\/s-0029-1214162","article-title":"Local Antibiotic Therapy in Osteomyelitis","volume":"23","author":"Gogia","year":"2009","journal-title":"Semin. Plast. Surg."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1097\/01.blo.0000143741.92384.18","article-title":"The current status of material used for depot delivery of drugs","volume":"427","author":"Nelson","year":"2004","journal-title":"Clin. Orthop. Relat. Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1693","DOI":"10.1007\/s11999-009-0847-1","article-title":"Hand-mixed and Premixed Antibiotic-loaded Bone Cement Have Similar Homogeneity","volume":"467","author":"McLaren","year":"2009","journal-title":"Clin. Orthop. Relat. Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1080\/000164700317362280","article-title":"Gentamicin release from polymethylmethacrylate bone cements and Staphylococcus aureus biofilm formation","volume":"71","author":"Neut","year":"2000","journal-title":"Acta Orthop. Scand."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1016\/S0883-5403(96)80135-5","article-title":"Elution characteristics of vancomycin and tobramycin combined in acrylic bone-cement","volume":"11","author":"Penner","year":"1996","journal-title":"J. Arthroplast."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/S0883-5403(99)90128-6","article-title":"The in vitro elution characteristics of antibiotic-loaded CMW and Palacos-R bone cements","volume":"14","author":"Penner","year":"1999","journal-title":"J. Arthroplast."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Mariconda, M., Ascione, T., Balato, G., Rotondo, R., Smeraglia, F., Costa, G.G., and Conte, M. (2013). Sonication of antibiotic-loaded cement spacers in a two-stage revision protocol for infected joint arthroplasty. BMC Musculoskelet. Disord., 14.","DOI":"10.1186\/1471-2474-14-193"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Schmolders, J., Hischebeth, G.T., Friedrich, M.J., Randau, T.M., Wimmer, M.D., Kohlhof, H., Molitor, E., and Gravius, S. (2014). Evidence of MRSE on a gentamicin and vancomycin impregnated polymethyl-methacrylate (PMMA) bone cement spacer after two-stage exchange arthroplasty due to periprosthetic joint infection of the knee. BMC Infect. Dis., 14.","DOI":"10.1186\/1471-2334-14-144"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"S407","DOI":"10.1093\/clinids\/5.Supplement_3.S407","article-title":"Rifampin: Mechanisms of action and resistance","volume":"5","author":"Wehrli","year":"1983","journal-title":"Rev. Infect. Dis."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1093\/jac\/17.2.173","article-title":"Comparative in-vitro activity of antibiotics incorporated in acrylic bone cement","volume":"17","author":"Beeching","year":"1986","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1284","DOI":"10.1128\/AAC.42.5.1284","article-title":"Antibacterial Activities and Inhibitory Effects of Sitafloxacin (DU-6859a) and Its Optical Isomers against Type II Topoisomerases","volume":"42","author":"Akasaka","year":"1998","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1377","DOI":"10.3390\/polym3031377","article-title":"Poly Lactic-co-Glycolic Acid (PLGA) as Biodegradable Controlled Drug Delivery Carrier","volume":"3","author":"Makadia","year":"2011","journal-title":"Polymers"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"2529","DOI":"10.1016\/S0142-9612(00)00121-6","article-title":"Scaffolds in tissue engineering bone and cartilage","volume":"21","author":"Hutmacher","year":"2000","journal-title":"Biomaterials"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1359\/jbmr.060120","article-title":"VEGF Scaffolds Enhance Angiogenesis and Bone Regeneration in Irradiated Osseous Defects","volume":"21","author":"Kaigler","year":"2009","journal-title":"J. Bone Miner. Res."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1817","DOI":"10.1016\/j.biomaterials.2007.12.034","article-title":"Polylactide\/polyglycolide copolymer in bone defect healing in humans","volume":"29","author":"Bertoldi","year":"2008","journal-title":"Biomaterials"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1089\/ten.2006.12.789","article-title":"Porous poly(DL-lactic-co-glycolic acid)\/calcium phosphate cement composite for reconstruction of bone defects","volume":"12","author":"Ruhe","year":"2006","journal-title":"Tissue Eng."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1002\/jbm.a.31572","article-title":"Apatite-coated poly(lactic-co-glycolic acid) microspheres as an injectable scaffold for bone tissue engineering","volume":"85A","author":"Kang","year":"2008","journal-title":"J. Biomed. Mater. Res. Part A"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"015004","DOI":"10.1088\/1758-5090\/7\/1\/015004","article-title":"Fabrication of individual alginate-TCP scaffolds for bone tissue engineering by means of powder printing","volume":"7","author":"Castilho","year":"2015","journal-title":"Biofabrication"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1281","DOI":"10.1007\/s10856-009-3697-1","article-title":"Mechanical and in vitro performance of apatite\u2013wollastonite glass ceramic reinforced hydroxyapatite composite fabricated by 3D-printing","volume":"20","author":"Suwanprateeb","year":"2009","journal-title":"J. Mater. Sci. Mater. Med."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1016\/j.jcms.2010.01.009","article-title":"3D powder printed calcium phosphate implants for reconstruction of cranial and maxillofacial defects","volume":"38","author":"Klammert","year":"2010","journal-title":"J. Cranio-Maxillofac. Surg."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1002\/jbm.a.36270","article-title":"Three dimensional printed calcium phosphate and poly(caprolactone) composites with improved mechanical properties and preserved microstructure","volume":"106","author":"Vella","year":"2018","journal-title":"J. Biomed. Mater. Res. A"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"19468","DOI":"10.1038\/srep19468","article-title":"Design and Fabrication of 3D printed Scaffolds with a Mechanical Strength Comparable to Cortical Bone to Repair Large Bone Defects","volume":"6","author":"Newman","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"2637","DOI":"10.1007\/s10856-007-3362-5","article-title":"Fabrication of bioactive hydroxyapatite\/bis-GMA based composite via three dimensional printing","volume":"19","author":"Suwanprateeb","year":"2008","journal-title":"J. Mater. Sci. Mater. Med."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Gullberg, E., Cao, S., Berg, O.G., Ilb\u00e4ck, C., Sandegren, L., Hughes, D., and Andersson, D.I. (2011). Selection of resistant bacteria at very low antibiotic concentrations. PLoS Pathog., 7.","DOI":"10.1371\/journal.ppat.1002158"},{"key":"ref_72","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_73","doi-asserted-by":"crossref","first-page":"1590","DOI":"10.1002\/jor.23801","article-title":"Immunotherapy synergizes with debridement and antibiotic therapy in a murine 1-stage exchange model of MRSA implant-associated osteomyelitis","volume":"36","author":"Yokogawa","year":"2018","journal-title":"J. Orthop. Res."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Kunutsor, S.K., Whitehouse, M.R., Blom, A.W., Beswick, A.D., and Team, I. (2015). Re-Infection Outcomes following One- and Two-Stage Surgical Revision of Infected Hip Prosthesis: A Systematic Review and Meta-Analysis. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0139166"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1015","DOI":"10.1016\/j.arth.2009.07.017","article-title":"Modern Treatment of Infected Total Knee Arthroplasty with a 2-Stage Reimplantation Protocol","volume":"25","author":"Westrich","year":"2010","journal-title":"J. Arthroplast."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1007\/s11999-008-0480-4","article-title":"Midterm to Long-term Followup of Staged Reimplantation for Infected Hip Arthroplasty","volume":"467","author":"Berry","year":"2009","journal-title":"Clin. Orthop. Relat. Res."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"3142","DOI":"10.1002\/jor.24155","article-title":"Topical rifampin powder for orthopaedic trauma part II: Topical rifampin allows for spontaneous bone healing in sterile and contaminated wounds","volume":"36","author":"Shiels","year":"2018","journal-title":"J. Orthop. Res."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"161","DOI":"10.2106\/00004623-200002000-00002","article-title":"Ciprofloxacin inhibition of experimental fracture healing","volume":"82","author":"Huddleston","year":"2000","journal-title":"J. Bone Jt. Surg. Am."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1097\/01.blo.0000087322.60612.14","article-title":"Levofloxacin and trovafloxacin inhibition of experimental fracture-healing","volume":"414","author":"Perry","year":"2003","journal-title":"Clin. Orthop. Relat. Res."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1312","DOI":"10.1002\/jbm.a.35248","article-title":"Improving bone repair of femoral and radial defects in rabbit by incorporating PRP into PLGA\/CPC composite scaffold with unidirectional pore structure","volume":"103","author":"He","year":"2015","journal-title":"J. Biomed. Mater. Res. Part A"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1007\/s00776-012-0262-4","article-title":"Repair of segmental bone defects in rabbit tibia promoted by a complex of \u03b2-tricalcium phosphate and hepatocyte growth factor","volume":"17","author":"Goshima","year":"2012","journal-title":"J. Orthop. Sci."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1002\/jor.20453","article-title":"Accelerated fracture healing in the geriatric, osteoporotic rat with recombinant human platelet-derived growth factor-bb and an injectable beta-tricalcium phosphate\/collagen matrix","volume":"26","author":"Hollinger","year":"2008","journal-title":"J. Orthop. Res."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"9656","DOI":"10.1073\/pnas.152324099","article-title":"Vascular endothelial growth factor stimulates bone repair by promoting angiogenesis and bone turnover","volume":"99","author":"Street","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_84","first-page":"133","article-title":"Study of Mesenchymal Stem Cells Cultured on a Poly(Lactic-co-Glycolic Acid) Scaffold Containing Simvastatin for Bone Healing","volume":"15","author":"Mendes","year":"2017","journal-title":"J. Appl. Biomater. Funct. Mater."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1558","DOI":"10.1016\/j.bjps.2008.03.040","article-title":"Osteogenic growth peptide incorporated into PLGA scaffolds accelerates healing of segmental long bone defects in rabbits","volume":"61","author":"Shuqiang","year":"2008","journal-title":"J. Plast. Reconstr. Aesthet. Surg."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1717","DOI":"10.1097\/01.brs.0000172155.17239.fa","article-title":"Experimental Spinal Fusion with Recombinant Human Bone Morphogenetic Protein-2 Delivered by a Synthetic Polymer and \u03b2-Tricalcium Phosphate in a Rabbit Model","volume":"30","author":"Namikawa","year":"2005","journal-title":"Spine"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"411","DOI":"10.3415\/VCOT-14-03-0036","article-title":"BMP-2 delivered from a self-cross-linkable CaP\/hydrogel construct promotes bone regeneration in a critical-size segmental defect model of non-union in dogs","volume":"27","author":"Minier","year":"2014","journal-title":"Vet. Comp. Orthop. Traumatol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"44130","DOI":"10.1038\/srep44130","article-title":"An Innovative Approach for Enhancing Bone Defect Healing Using PLGA Scaffolds Seeded with Extracorporeal-shock-wave-treated Bone Marrow Mesenchymal Stem Cells (BMSCs)","volume":"7","author":"Chen","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/j.actbio.2014.12.021","article-title":"Fabrication of novel Si-doped hydroxyapatite\/gelatine scaffolds by rapid prototyping for drug delivery and bone regeneration","volume":"15","author":"Cabanas","year":"2015","journal-title":"Acta Biomater."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1097\/BPO.0b013e3181901c3a","article-title":"Comparative severity of pediatric osteomyelitis attributable to methicillin-resistant versus methicillin-sensitive Staphylococcus aureus","volume":"29","author":"Hawkshead","year":"2009","journal-title":"J. Pediatr. Orthop."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1086\/345476","article-title":"Comparison of mortality associated with methicillin-resistant and methicillin-susceptible Staphylococcus aureus bacteremia: A meta-analysis","volume":"36","author":"Cosgrove","year":"2003","journal-title":"Clin. Infect. Dis."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"2123","DOI":"10.2106\/00004623-200212000-00001","article-title":"Recombinant Human Bone Morphogenetic Protein-2 for Treatment of Open Tibial Fractures: A Prospective, Controlled, Randomized Study of Four Hundred and Fifty Patients","volume":"84","author":"Govender","year":"2002","journal-title":"JBJS"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1111\/j.1532-950X.2006.00142.x","article-title":"Mesenchymal Stem Cells and Bone Regeneration","volume":"35","author":"Kraus","year":"2006","journal-title":"Vet. Surg."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1007\/s11420-005-0111-5","article-title":"The Clinical Use of Allografts, Demineralized Bone Matrices, Synthetic Bone Graft Substitutes and Osteoinductive Growth Factors: A Survey Study","volume":"1","author":"Bostrom","year":"2005","journal-title":"HSS J."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/11\/2\/94\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:34:05Z","timestamp":1760186045000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/11\/2\/94"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,2,22]]},"references-count":94,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2019,2]]}},"alternative-id":["pharmaceutics11020094"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics11020094","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,2,22]]}}}