Abstract
The possibility to fast-load biomimetic hydroxyapatite coatings on surgical implant with the antibiotics Amoxicillin, Gentamicin sulfate, Tobramycin and Cephalothin has been investigated in order to develop a multifunctional implant device offering sustained local anti-bacterial treatment and giving the surgeon the possibility to choose which antibiotics to incorporate in the implant at the site of surgery. Physical vapor deposition was used to coat titanium surfaces with an adhesion enhancing gradient layer of titanium oxide having an amorphous oxygen poor composition at the interface and a crystalline bioactive anatase TiO2 composition at the surface. Hydroxyapatite (HA) was biomimetically grown on the bioactive TiO2 to serve as a combined bone in-growth promoter and drug delivery vehicle. The coating was characterized using scanning and transmission electron microscopy, X-ray diffraction and X-ray photoelectron spectroscopy. The antibiotics were loaded into the HA coatings via soaking and the subsequent release and antibacterial effect were analyzed using UV spectroscopy and examination of inhibition zones in a Staphylococcus aureus containing agar. It was found that a short drug loading time of 15 min ensured antibacterial effects after 24 h for all antibiotics under study. It was further found that the release processes of Cephalothin and Amoxicillin consisted of an initial rapid drug release that varied unpredictably in amount followed by a reproducible and sustained release process with a release rate independent of the drug loading times under study. Thus, implants that have been fast-loaded with drugs could be stored for ~10 min in a simulated body fluid after loading to ensure reproducibility in the subsequent release process. Calculated release rates and measurements of drug amounts remaining in the samples after 22 h of release indicated that a therapeutically relevant dose could be achieved close to the implant surface for about 2 days. Concluding, the present study provides an outline for the development of a fast-loading slow-release surgical implant kit where the implant and the drug are separated when delivered to the surgeon, thus constituting a flexible solution for the surgeon by offering the choice of quick addition of antibiotics to the implant coating based on the patient need.
Similar content being viewed by others
References
Christenson EM, et al. Nanobiomaterial applications in orthopedics. J Orthop Res. 2007;25:11–22. doi:10.1002/jor.20305.
Ratner BD, et al. Biomaterials science; an introduction to materials in medicine. 2nd ed. San Diego: Elsevier Academic Press; 2004.
Qiu Y, et al. Biomaterial strategies to reduce implant-associated infections. Int J Artif Organs. 2007;30:828–41.
Ginebra MP, et al. Calcium phosphate cements as bone drug delivery systems: a review. J Control Release. 2006;113:102–10. doi:10.1016/j.jconrel.2006.04.007.
Teller M, et al. Release of gentamicin from bone regenerative materials: an in vitro study. J Biomed Mater Res B. 2007;81B:23–9. doi:10.1002/jbm.b.30631.
Stigter M, et al. Incorporation of tobramycin into biomimetic hydroxyapatite coating on titanium. Biomaterials. 2002;23:4143–53. doi:10.1016/S0142-9612(02)00157-6.
Stigter M, et al. Incorporation of different antibiotics into carbonated hydroxyapatite coatings on titanium implants, release and antibiotic efficacy. J Control Release. 2004;99:127–37. doi:10.1016/j.jconrel.2004.06.011.
Vallet-Regi M, et al. Bioceramics and pharmaceuticals: a remarkable synergy. Solid State Sci. 2007;9:768–76. doi:10.1016/j.solidstatesciences.2007.03.026.
Kalicke T, et al. Effect on infection resistance of a local antiseptic and antibiotic coating on osteosynthesis implants: an in vitro and in vivo study. J Orthop Res. 2006;24:1622–40. doi:10.1002/jor.20193.
Gristina AG. Biomaterial-centered infection—microbial adhesion versus tissue integration. Science. 1987;237:1588–95. doi:10.1126/science.3629258.
Wang J, et al. Biomimetic and electrolytic calcium phosphate coatings on titanium alloy: physicochemical characteristics and cell attachment. Biomaterials. 2004;25:583–92. doi:10.1016/S0142-9612(03)00559-3.
Kuijer R, et al. Assessing infection risk in implanted tissue-engineered devices. Biomaterials. 2007;28:5148–54. doi:10.1016/j.biomaterials.2007.06.003.
Yang YZ, et al. Review on calcium phosphate coatings produced using a sputtering process—an alternative to plasma spraying. Biomaterials. 2005;26:327–37. doi:10.1016/j.biomaterials.2004.02.029.
Ha SW, et al. Plasma-sprayed hydroxylapatite coating on carbon-fiber-reinforced thermoplastic composite-materials. J Mater Sci Mater Med. 1994;5:481–4. doi:10.1007/BF00058987.
Blind O, et al. Characterization of hydroxyapatite films obtained by pulsed-laser deposition on Ti and Ti-6AL-4v substrates. Dent Mater. 2005;21:1017–24. doi:10.1016/j.dental.2004.12.003.
Lee SH, et al. Nano-sized hydroxyapatite coatings on Ti substrate with TiO2 buffer layer by e-beam deposition. J Am Ceram Soc. 2007;90:50–6. doi:10.1111/j.1551-2916.2006.01351.x.
Jonasova L, et al. Biomimetic apatite formation on chemically treated titanium. Biomaterials. 2004;25:1187–94. doi:10.1016/j.biomaterials.2003.08.009.
Mihranyan A, et al. Assessing surface area evolution during biomimetic growth of hydroxyapatite coatings. Langmuir. 2009;25:1292–5. doi:10.1021/la803520k.
Lu X, Leng Y. Theoretical analysis of calcium phosphate precipitation in simulated body fluid. Biomaterials. 2005;26:1097–108. doi:10.1016/j.biomaterials.2004.05.034.
Yang BC, et al. Preparation of bioactive titanium metal via anodic oxidation treatment. Biomaterials. 2004;25:1003–10. doi:10.1016/S0142-9612(03)00626-4.
Forsgren J, et al. Formation and adhesion of biomimetic hydroxyapatite deposited on titanium substrates. Acta Biomater. 2007;3:980–4. doi:10.1016/j.actbio.2007.03.006.
Dunn CJ, et al. Etidronic acid—a review of its pharmacological properties and therapeutic efficacy in resorptive bone-disease. Drugs Aging. 1994;5:446–74. doi:10.2165/00002512-199405060-00006.
Aebli N, et al. Effects of bone morphogenetic protein-2 and hyaluronic acid on the osseointegration of hydroxyapatite-coated implants: an experimental study in sheep. J Biomed Mater Res A. 2005;73A:295–302. doi:10.1002/jbm.a.30299.
Kim HW, et al. Hydroxyapatite porous scaffold engineered with biological polymer hybrid coating for antibiotic Vancomycin release. J Mater Sci Mater Med. 2005;16:189–95. doi:10.1007/s10856-005-6679-y.
Hildebrand HF, et al. Surface coatings for biological activation and functionalization of medical devices. Surf Coat Technol. 2006;200:6318–24. doi:10.1016/j.surfcoat.2005.11.086.
Eberhardt C, et al. The bisphosphonate ibandronate accelerates osseointegration of hydroxyapatite-coated cementless implants in an animal model. J Orthop Sci. 2007;12:61–6. doi:10.1007/s00776-006-1081-2.
Hetrick EM, Schoenfisch MH. Reducing implant-related infections: active release strategies. Chem Soc Rev. 2006;35:780–9. doi:10.1039/b515219b.
Neut D, et al. Gentamicin-loaded bone cement with clindamycin or fusidic acid added: biofilm formation and antibiotic release. J Biomed Mater Res A. 2005;73A:165–70. doi:10.1002/jbm.a.30253.
Peter B, et al. Calcium phosphate drug delivery system: influence of local zoledronate release on bone implant osteointegration. Bone. 2005;36:52–60. doi:10.1016/j.bone.2004.10.004.
Brohede U, et al. A novel graded bioactive high adhesion implant coating. Appl Surf Sci. 2009; in press. doi:10.1016/j.apsusc.2009.04.149.
Bunker BC, et al. Ceramic thin-film formation on functionalized interfaces through biomimetic processing. Science. 1994;264:48–55. doi:10.1126/science.264.5155.48.
Bourgeois B, et al. Calcium-deficient apatite: a first in vivo study concerning bone ingrowth. J Biomed Mater Res A. 2003;65A:402–8. doi:10.1002/jbm.a.10518.
Streng WH. Microionization constants of commercial cephalosporins. J Pharm Sci. 1978;67:666–9. doi:10.1002/jps.2600670525.
Rolinson GN. Laboratory evaluation of amoxicillin. J Infect Dis. 1974;129:139.
Acknowledgements
The Swedish funding agency Vinnova and the Göran Gustafsson foundation are acknowledged for funding the present work. The Knut and Alice Wallenberg Foundation is also acknowledged for financing the analysis equipment used.
Author information
Authors and Affiliations
Corresponding authors
Additional information
U. Brohede and J. Forsgren have contributed equally.
Rights and permissions
About this article
Cite this article
Brohede, U., Forsgren, J., Roos, S. et al. Multifunctional implant coatings providing possibilities for fast antibiotics loading with subsequent slow release. J Mater Sci: Mater Med 20, 1859–1867 (2009). https://doi.org/10.1007/s10856-009-3749-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10856-009-3749-6