Although progress is evident in the effective treatment of joint replacement-related infections, it still remains a serious issue in orthopedics. As an example, the local application of antibiotics-impregnated bone grafts supplies the high drug levels without systemic side effects. However, antibiotics in the powder or solution form could be a risk for local toxicity and do not allow sustained drug release. The present study evaluated the use of an antibiotic gel, a water-in-oil emulsion, and a PLGA microparticulate solid dispersion as depot delivery systems impregnating bone grafts for the treatment of joint replacement-related infections. The results of rheological and bioadhesive tests revealed the suitability of these formulations for the impregnation of bone grafts. Moreover, no negative effect on proliferation and viability of bone marrow mesenchymal stem cells was detected. An ex vivo dissolution test of vancomycin hydrochloride and gentamicin sulphate from the impregnated bone grafts showed a reduced burst and prolonged drug release. The PLGA-based formulation proved to be particularly promising, as one-day burst release drugs was only 15% followed with sustained antibiotics release with zero-order kinetics. The results of this study will be the basis for the development of a new product in the Tissue Section of the University Hospital for the treatment of bone defects and infections of joint replacements.

Department of Chemistry Faculty of Science University of Hradec Kralove Rokitanskeho 62 500 03 Hradec Kralove Czech Republic

Department of Clinical Biochemistry and Diagnostics University Hospital Hradec Kralove Sokolska 581 500 05 Hradec Kralove Czech Republic

Department of Histology and Embryology Faculty of Medicine Charles University Simkova 870 500 03 Hradec Kralove Czech Republic

Department of Orthopaedic Surgery University Hospital Hradec Kralove Sokolska 581 500 05 Hradec Kralove Czech Republic

Department of Pharmaceutical Technology Faculty of Pharmacy Charles University Akademika Heyrovskeho 1203 500 05 Hradec Kralova Czech Republic

Department of Physics Faculty of Science University of Hradec Kralove Rokitanskeho 62 500 03 Hradec Kralove Czech Republic

Faculty of Medicine Charles University Simkova 870 500 03 Hradec Kralove Czech Republic

Zobrazit více v PubMed

Basile G., Gallina M., Passeri A., Gaudio R.M., Castelnuovo N., Ferrante P., Calori G.M. Prosthetic joint infections and legal disputes: A threat to the future of prosthetic orthopedics. J. Orthop. Traumatol. 2021;22:44. doi: 10.1186/s10195-021-00607-6. PubMed DOI PMC

Kapadia B.H., Berg R.A., Daley J.A., Fritz J., Bhave A., Mont M.A. Periprosthetic joint infection. Lancet. 2016;387:386–394. doi: 10.1016/S0140-6736(14)61798-0. PubMed DOI

Diefenbeck M., Mückley T., Hofmann G.O. Prophylaxis and treatment of implant-related infections by local application of antibiotics. Injury. 2006;37((Suppl. 2)):S95–S104. doi: 10.1016/j.injury.2006.04.015. PubMed DOI

Anagnostakos K., Schröder K. Antibiotic-impregnated bone grafts in orthopaedic and trauma surgery: A systematic review of the literature. Int. J. Biomater. 2012;2012:538061. doi: 10.1155/2012/538061. PubMed DOI PMC

Peeters A., Putzeys G., Thorrez L. Current Insights in the Application of Bone Grafts for Local Antibiotic Delivery in Bone Reconstruction Surgery. J. Bone Jt. Infect. 2019;4:245–253. doi: 10.7150/jbji.38373. PubMed DOI PMC

Winkler H., Kaudela K., Stoiber A., Menschik F. Bone grafts impregnated with antibiotics as a tool for treating infected implants in orthopedic surgery-one stage revision results. Cell Tissue Bank. 2006;7:319–323. doi: 10.1007/s10561-006-9010-3. PubMed DOI

Bidossi A.M., Logoluso N., De Vecchi E. In Vitro Evaluation of Gentamicin or Vancomycin Containing Bone Graft Substitute in the Prevention of Orthopedic Implant-Related Infections. Int. J. Mol. Sci. 2020;21:9250. doi: 10.3390/ijms21239250. PubMed DOI PMC

Winkler H., Janata O., Berger C., Wein W., Georgopoulos A. In vitro release of vancomycin and tobramycin from impregnated human and bovine bone grafts. J. Antimicrob. Chemother. 2000;46:423–428. doi: 10.1093/jac/46.3.423. PubMed DOI

Klapkova E., Nescakova M., Melichercik P., Jahoda D., Dunovska K., Cepova J., Prusa R. Vancomycin and its crystalline degradation products released from bone grafts and different types of bone cement. Folia Microbiol. (Praha) 2020;65:475–482. doi: 10.1007/s12223-019-00752-w. PubMed DOI

Frazer R.Q., Byron R.T., Osborne P.B., West K.P. PMMA: An essential material in medicine and dentistry. J. Long Term Eff. Med. Implants. 2005;15:629–639. doi: 10.1615/JLongTermEffMedImplants.v15.i6.60. PubMed DOI

El-Husseiny M., Patel S., MacFarlane R.J., Haddad F.S. Biodegradable antibiotic delivery systems. J. Bone Joint Surg. Br. 2011;93:151–157. doi: 10.1302/0301-620X.93B2.24933. PubMed DOI

Duminis T., Shahid S., Hill R.G. Apatite Glass-Ceramics: A Review. Front. Mater. 2017;3:1–15. doi: 10.3389/fmats.2016.00059. DOI

Garvin K., Feschuk C. Polylactide-polyglycolide antibiotic implants. Clin. Orthop. Relat. Res. 2005;437:105–110. doi: 10.1097/01.blo.0000175720.99118.fe. PubMed DOI

Kanellakopoulou K., Giamarellos-Bourboulis E.J. Carrier Systems for the Local Delivery of Antibiotics in Bone Infections. Drugs. 2000;59:1223–1232. doi: 10.2165/00003495-200059060-00003. PubMed DOI

Kucera T., Ryskova L., Soukup T., Malakova J., Cermakova E., Mericka P., Suchanek J., Sponer P. Elution kinetics of vancomycin and gentamicin from carriers and their effects on mesenchymal stem cell proliferation: An in vitro study. BMC Musculoskelet. Disord. 2017;18:381. doi: 10.1186/s12891-017-1737-4. PubMed DOI PMC

Colucci G., Santamaria-Echart A., Silva S.C., Fernandes I.P.M., Sipoli C.C., Barreiro M.F. Development of Water-in-Oil Emulsions as Delivery Vehicles and Testing with a Natural Antimicrobial Extract. Molecules. 2020;25:2105. doi: 10.3390/molecules25092105. PubMed DOI PMC

McClements D.J., Jafari S.M. Improving emulsion formation, stability and performance using mixed emulsifiers: A review. Adv. Colloid Interface Sci. 2018;251:55–79. doi: 10.1016/j.cis.2017.12.001. PubMed DOI

Zhu Q., Pan Y., Jia X., Li J., Zhang M., Yin L. Review on the Stability Mechanism and Application of Water-in-Oil Emulsions Encapsulating Various Additives. Compr. Rev. Food Sci. Food Saf. 2019;18:1660–1675. doi: 10.1111/1541-4337.12482. PubMed DOI

Bjerregaard S., Pedersen H., Vedstesen H., Vermehren C., Söderberg I., Frokjaer S. Parenteral water/oil emulsions containing hydrophilic compounds with enhanced in vivo retention: Formulation, rheological characterisation and study of in vivo fate using whole body gamma-scintigraphy. Int. J. Pharm. 2001;215:13–27. doi: 10.1016/S0378-5173(00)00656-6. PubMed DOI

Penn-Barwell J.G., Murray C.K., Wenke J.C. Local antibiotic delivery by a bioabsorbable gel is superior to PMMA bead depot in reducing infection in an open fracture model. J. Orthop. Trauma. 2014;28:370–375. doi: 10.1097/BOT.0b013e3182a7739e. PubMed DOI

Khiste R., Bhapkar N., Kulkarni N. A Review on Applications of Hydroxy Propyl Methyl Cellulose and Natural polymers for the development of modified release drug delivery systems. Res. J. Pharm. Technol. 2021;14:1163–1170. doi: 10.5958/0974-360X.2021.00208.0. DOI

Mašková E., Kubová K., Raimi-Abraham B.T., Vllasaliu D., Vohlídalová E., Turánek J., Mašek J. Hypromellose-A traditional pharmaceutical excipient with modern applications in oral and oromucosal drug delivery. J. Control. Release. 2020;324:695–727. doi: 10.1016/j.jconrel.2020.05.045. PubMed DOI

Vallejo Diaz A., Deimling C., Morgenstern M., D’Este M., Puetzler J., Zeiter S., Arens D., Metsemakers W.J., Richards R.G., Eglin D., et al. Local Application of a Gentamicin-Loaded Hydrogel Early After Injury Is Superior to Perioperative Systemic Prophylaxis in a Rabbit Open Fracture Model. J. Orthop. Trauma. 2020;34:231–237. doi: 10.1097/BOT.0000000000001707. PubMed DOI

Aguilera-Correa J.J., Garcia-Casas A., Mediero A., Romera D., Mulero F., Cuevas-López I., Jiménez-Morales A., Esteban J. A New Antibiotic-Loaded Sol-Gel Can Prevent Bacterial Prosthetic Joint Infection: From in vitro Studies to an in vivo Model. Front. Microbiol. 2019;10:2935. doi: 10.3389/fmicb.2019.02935. PubMed DOI PMC

Ren T., Chen J., Qi P., Xiao P., Wang P. Goserelin/PLGA solid dispersion used to prepare long-acting microspheres with reduced initial release and reduced fluctuation of drug serum concentration in vivo. Int. J. Pharm. 2022;615:121474. doi: 10.1016/j.ijpharm.2022.121474. PubMed DOI

Martins C., Sousa F., Araújo F., Sarmento B. Functionalizing PLGA and PLGA Derivatives for Drug Delivery and Tissue Regeneration Applications. Adv. Healthc. Mater. 2018;7:1701035. doi: 10.1002/adhm.201701035. PubMed DOI

Snejdrova E., Dittrich M., Drastik M. Plasticized branched aliphatic oligoesters as potential mucoadhesive drug carriers. Int. J. Pharm. 2013;458:282–286. doi: 10.1016/j.ijpharm.2013.10.030. PubMed DOI

Jin S., Xia X., Huang J., Yuan C., Zuo Y., Li Y., Li J. Recent advances in PLGA-based biomaterials for bone tissue regeneration. Acta Biomater. 2021;127:56–79. doi: 10.1016/j.actbio.2021.03.067. PubMed DOI

Han F.Y., Thurecht K.J., Whittaker A.K., Smith M.T. Bioerodable PLGA-Based Microparticles for Producing Sustained-Release Drug Formulations and Strategies for Improving Drug Loading. Front. Pharmacol. 2016;7:1–11. doi: 10.3389/fphar.2016.00185. PubMed DOI PMC

Snejdrova E., Loskot J., Martiska J., Soukup T., Prokes L., Frolov V., Kucera T. Rifampicin-loaded PLGA nanoparticles for local treatment of musculoskeletal infections: Formulation and characterization. J. Drug Deliv. Sci. Technol. 2022;73:103435. doi: 10.1016/j.jddst.2022.103435. DOI

Snejdrova E., Martiška J., Loskot J., Paraskevopoulos G., Kováčik A., Regdon Jr G., Budai-Szűcs M., Palát K., Konečná K. PLGA-based film forming systems for superficial fungal infections treatment. Eur. J. Pharm. Sci. 2021;163:105855. doi: 10.1016/j.ejps.2021.105855. PubMed DOI

Bayer I.S. Recent Advances in Mucoadhesive Interface Materials, Mucoadhesion Characterization, and Technologies. Adv. Mater. Interfaces. 2022;9:2200211. doi: 10.1002/admi.202200211. DOI

Nair A.K., Gautieri A., Chang S.W., Buehler M.J. Molecular mechanics of mineralized collagen fibrils in bone. Nat. Commun. 2013;4:1724–1732. doi: 10.1038/ncomms2720. PubMed DOI PMC

Szűcs M., Sandri G., Bonferoni M.C., Caramella C.M., Vaghi P., Szabó-Révész P., Erős I. Mucoadhesive behaviour of emulsions containing polymeric emulsifier. Eur. J. Pharm. Sci. 2008;34:226–235. doi: 10.1016/j.ejps.2008.03.005. PubMed DOI

Baus R.A., Zahir-Jouzdani F., Dünnhaupt S., Atyabi F., Bernkop-Schnürch A. Mucoadhesive hydrogels for buccal drug delivery: In vitro-in vivo correlation study. Eur. J. Pharm. Biopharm. 2019;142:498–505. doi: 10.1016/j.ejpb.2019.07.019. PubMed DOI

Prochazka E., Soukup T., Hroch M., Fuksa L., Brcakova E., Cermanova J., Kolouchova G., Urban K., Mokry J., Micuda S. Methotrexate released in vitro from bone cement inhibits human stem cell proliferation in S/G2 phase. Int. Orthop. 2010;34:137–142. doi: 10.1007/s00264-008-0717-6. PubMed DOI PMC

Boltnarova B., Kubackova J., Skoda J., Stefela A., Smekalova M., Svacinova P., Pavkova I., Dittrich M., Scherman D., Zbytovska J., et al. PLGA-based Nanospheres as a Potent Macrophage-Specific Drug Delivery System. Nanomaterials. 2021;11:749. doi: 10.3390/nano11030749. PubMed DOI PMC

Safety and Efficacy of Hydroxypropyl Methyl Cellulose for All Animal Species. [(accessed on 2 August 2022)]. Available online: https://efsa.onlinelibrary.wiley.com/doi/epdf/10.2903/j.efsa.2020.6214. DOI

Siepmann J., Peppas N.A. Modeling of drug release from delivery systems based on hydroxypropyl methylcellulose (HPMC) Adv. Drug Deliv. Rev. 2001;48:139–157. doi: 10.1016/S0169-409X(01)00112-0. PubMed DOI

Bode C., Kranz H., Fivez A., Siepmann F., Siepmann J. Often neglected: PLGA/PLA swelling orchestrates drug release: HME implants. J. Control. Release. 2019;306:97–107. doi: 10.1016/j.jconrel.2019.05.039. PubMed DOI

Yeh C.-C., Chen C.-N., Li Y.-T., Chang C.-W., Cheng M.-Y., Chang H.-I. The Effect of Polymer Molecular Weight and UV Radiation on Physical Properties and Bioactivities of PCL Films. Cell. Polym. 2011;30:261–276. doi: 10.1177/026248931103000503. DOI

Snejdrova E., Podzimek S., Martiska J., Holas O., Dittrich M. Branched PLGA derivatives with tailored drug delivery properties. Acta Pharm. 2020;70:63–75. doi: 10.2478/acph-2020-0011. PubMed DOI

Reyes M., Lund T., Lenvik T., Aguiar D., Koodie L., Verfaillie C.M. Purification and ex vivo expansion of postnatal human marrow mesodermal progenitor cells. Blood. 2001;98:2615–2625. doi: 10.1182/blood.V98.9.2615. PubMed DOI