Journal of Materials Science: Materials in Medicine

, Volume 24, Issue 9, pp 2265–2274 | Cite as

Drug loading and release of Tobramycin from hydroxyapatite coated fixation pins

  • Mirjam Lilja
  • Jan Henrik Sörensen
  • Ulrika Brohede
  • Maria Åstrand
  • Philip Procter
  • Jörg Arnoldi
  • Hartwig Steckel
  • Maria StrømmeEmail author


This paper evaluates the loading and release properties of Tobramycin incorporated by adsorptive loading from a solution into plasma sprayed and biomimetically coated Hydroxyapatite (HA) fixation pins. The aim of this study is to contribute towards designing a functional implant surface offering local release of the antibiotic agent to prevent post-surgical infections. Cathodic arc deposition is used to coat stainless steel fixation pins with a bioactive, anatase phase dominated, TiO2 coating onto which a HA layer is grown biomimetically. The loading and release properties are evaluated by studying the subsequent release of Tobramycin using high performance liquid chromatography and correlated to the differences in HA coating microstructure and the physical conditions under loading. The results from these studies show that a dual loading strategy consisting of a solution temperature of 90 °C and a pressure of 6 bar during a loading time of 5 min release a sufficient amount of Tobramycin to guarantee the inhibition of Staphylococcus aureus up to 2 days for plasma sprayed HA coatings and for 8 days for biomimetic coatings. The present study emphasizes the advantages of the nanoporous structure of biomimetically deposited HA over the more dense structure of plasma sprayed HA coatings in terms of antibiotic incorporation and subsequent sustained release and provides a valuable outline for the design of implant surfaces aiming for a fast-loading and controlled, local drug administration.


High Performance Liquid Chromatography Sustained Release Tobramycin TiO2 Coating Nanoporous Structure 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Supplementary material

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Supplementary material 1 (DOCX 403 kb)


  1. 1.
    Chao EYS, Hein TJ. Mechanical performance of standard Orthotics external fixate. Orthopedics. 1988;11:1057–69.Google Scholar
  2. 2.
    Huiskes R, Chao EYS, Crippen TE. Parametric analyses of pin-bone stresses in external fracture fixation devices. J Ortho Res. 1985;3:341–9.CrossRefGoogle Scholar
  3. 3.
    Are HT, Markel MD, Chao EYS. Cortical bone reactions at the interface of external fixation half-pins under different loading condition. J Trauma. 1995;35:776–85.CrossRefGoogle Scholar
  4. 4.
    Temple J, Santee J. Pin site care for preventing infections associated with external bone fixators and pins. Cochrane Database Syst Rev 2004;CD004551.Google Scholar
  5. 5.
    Hutson JJ, Zych GA. Infections in periarticular fractures of the lower extremity treated with tensioned wire hybrid fixators. J Orthop Trauma. 1998;12:214–8.CrossRefGoogle Scholar
  6. 6.
    Mahan J, Seligson D, Henry SL, Hynes P, Doffins J. Factors in pin tract infections. Orthopedics. 1991;14:305–8.Google Scholar
  7. 7.
    Masse A, Bruno A, Bosetti M, Biasibetti A, Cannas M, Gallinaro P. Prevention of pin track infection in external fixation with silver coated pins: clinical and microbiological results. J Biomed Mater Res. 2000;53:600–4.CrossRefGoogle Scholar
  8. 8.
    Green SA. Complications in external skeletal fixation. Clin Orthop. 1983;180:109–16.Google Scholar
  9. 9.
    Brunski JB, Puleo DA, Nanci A. Biomaterials and biomechanics of oral and maxillofacial implants: current status and future developments. Int J Oral Max Impl. 2000;15:15–46.Google Scholar
  10. 10.
    Hetrick EM, Schoenfisch MH. Reducing implant-related infections: active release strategies. Chem Soc Rev. 2006;35:780–9.CrossRefGoogle Scholar
  11. 11.
    Price JS, Tencer AF, Arm DM, Bohach GA. Controlled release of antibiotics from coated orthopedic implants. J Biomed Mater Res. 1996;30:281–6.CrossRefGoogle Scholar
  12. 12.
    Stigter M, Bezemer J, de Groot K, Layrolle P. Incorporation of different antibiotics into carbonated hydroxyapatite coatings on titanium implants, release and antibiotic efficacy. J control release. 2004;99:127–37.CrossRefGoogle Scholar
  13. 13.
    DeJong ES, DeBerardino TM, Brooks DE, Nelson BJ, Campbell AA, Bottoni CR. Antimicrobial efficacy of external fixator pins coated with a lipid stabilized hydroxyapatite/chlorhexidine complex to prevent pin tract infection in a goat model. J Trauma. 2001;50:1008–14.CrossRefGoogle Scholar
  14. 14.
    Brohede U, Forsgren J, Roos S, Mihranyan A, Engqvist H, Strømme M. Multifunctional implant coatings providing possibilities for fast antibiotics loading with subsequent slow release. J Mater Sci Mater Med. 2009;20:1859–67.CrossRefGoogle Scholar
  15. 15.
    Wu P, Grainger DW. Drug/device combinations for local drug therapies and infection prophylaxis. Biomaterials. 2006;27:2450–67.CrossRefGoogle Scholar
  16. 16.
    Gold HS, Moellering RC Jr. Antimicrobial-drug resistance. N Engl J Med. 1996;335:1445–53.CrossRefGoogle Scholar
  17. 17.
    Gransden WR. Nosocomial gram-negative infection. J Med Microbiol. 1997;46:436–9.CrossRefGoogle Scholar
  18. 18.
    Poelstra KA, Barekzi NA, Rediske AM, Felts AG, Slunt JB, Grainger DW. Prophylactic treatment of gram-positive and gram-negative abdominal implant infections using locally delivered polyclonal antibodies. J Biomed Mater Res. 2002;60:206–15.CrossRefGoogle Scholar
  19. 19.
    Zilbermann M, Elsner JJ. Antibiotic-eluting medical devices for various applications. J Control Release. 2008;130:202–15.CrossRefGoogle Scholar
  20. 20.
    Anderson JH. Biological responses to materials. Annu Rev Mater Res. 2001;31:81–110.CrossRefGoogle Scholar
  21. 21.
    Ginebra MP, Traykova T, Planell JA. Calcium phosphate cements as bone drug delivery systems. J Control Release. 2006;113:102–10.CrossRefGoogle Scholar
  22. 22.
    Teller M, Gopp U, Neumann HG, Kühn KD. Release of gentamicin from bone regenerative materials: an in vitro study. J Biomed Mater Res B. 2007;81B:23–9.CrossRefGoogle Scholar
  23. 23.
    Stigter M, de Groota K, Layrolle P. Incorporation of tobramycin into biomimetic hydroxyapatite coating on titanium. Biomaterials. 2002;23:4143–53.CrossRefGoogle Scholar
  24. 24.
    Shepperd JAN, Apthorp H. A contemporary snapshot of the use of hydroxyapatite coating in orthopaedic surgery. J Bone Joint Surg. 2005;87B:1046–9.Google Scholar
  25. 25.
    Geesink RGT, Manley MT. Hydroxyapatite coatings in orthopaedic surgery. New York: Raven Press; 1993. p. 171.Google Scholar
  26. 26.
    Caja VL, Moroni A. Hydroxyapatite coated external fixation pins. CORR. 1996;325:269–75.CrossRefGoogle Scholar
  27. 27.
    Magyar G, Toksvig-Larsen S, Moroni A. Hydroxyapatite coating of threaded pins enhances fixation. J Bone Joint Surg. 1997;79B:487–9.CrossRefGoogle Scholar
  28. 28.
    Moroni A, Caja VL, Maltarello MC, Savarino L, Marinelli F, Stea S, Visentin M, Giannini S. Biomechanical, scanning electron microscopy and microhardness analyses of the bone-pin interface in hydroxyapatite coated versus uncoated pins. J Orthop Trauma. 1997;11:154–61.CrossRefGoogle Scholar
  29. 29.
    Moroni A, Toksvig-Larsen S, Maltarello MC, Orienti L, Stea S, Giannini S. A comparison of hydroxyapatite coated, titanium coated and uncoated tapered external fixation pins. J Bone Joint Surg. 1998;80A:547–54.Google Scholar
  30. 30.
    Mihranyan A, Forsgren J, Strømme M, Engqvist H. Assessing surface area evolution during biomimetic growth of hydroxyapatite coatings. Langmuir. 2009;25:1292–5.CrossRefGoogle Scholar
  31. 31.
    Brohede U, Zhao S, Lindberg F, Mihranyan A, Forsgren J, Strømme M, Engqvist H. A novel graded bioactive high adhesion implant coating. Appl Surf Sci. 2009;225:7723–8.CrossRefGoogle Scholar
  32. 32.
    Lu X, Leng Y. Theoretical analysis of calcium phosphate precipitation in simulated body fluid. Biomaterials. 2005;26:1097–108.CrossRefGoogle Scholar
  33. 33.
    Raschke MJ, Schmidmaier G. Biological coating of implants in trauma and orthopedic surgery. Unfallchirur. 2004;107:65363.Google Scholar
  34. 34.
    Wildemann B, Lange K, Strobel C, Fassbender M, Willie B, Schmidmaier G. Short term in vivo biocompatibility testing of biodegradable poly(d, l-lactide)-growth factor coating for orthopaedic implants. Biomaterials. 2005;26:4035–40.CrossRefGoogle Scholar
  35. 35.
    Piskounova S, Forsgren J, Brohede U, Engqvist H, Strømme M. In vitro characterization of bioactive titanium dioxide/hydroxyapatite surfaces functionalized with BMP-2. J Biomed Mater Res B. 2009;91B:780–7.CrossRefGoogle Scholar
  36. 36.
    Forsgren J, Brohede U, Engqvist H, Strømme M. Co-loading of bisphosphonates and antibiotics to a biomimetic hydroxyapatite coating. Biotechnol Lett. 2011;33:1265–8.CrossRefGoogle Scholar
  37. 37.
    Yang BC, Uchidab M, Kimc HM, Zhanga X, Kokubo T. Preparation of bioactive titanium metal via anodic oxidation treatment. Biomaterials. 2004;25:1003–10.CrossRefGoogle Scholar
  38. 38.
    Lilja M, Genvad A, Åstrand M, Strømme M, Enqvist H. Influence of microstructure and chemical composition of sputter deposited TiO2 thin films on in vitro bioactivity. J Mater Sci Mater Med. 2011;22:2727–34.CrossRefGoogle Scholar
  39. 39.
    Chai F, Hornez JC, Blanchemain N, Neut C, Descamps M. Antibacterial activation of hydroxyapatite (HA) with controlled porosity by different antibiotics. Biomol Eng. 2007;24:510–4.CrossRefGoogle Scholar
  40. 40.
    Nijhof MW, Dhert WJA. Prophylaxis of implant-related staphylococcal infections using tobramycin-containing bone cement. J Biomed Mater Res. 2000;52:754–61.CrossRefGoogle Scholar
  41. 41.
    Lilja M, Welch K, Åstrand M, Engqvist H, Strømme M. Effect of deposition parameters on the photocatalytic activity and bioactivity of TiO2 thin films deposited by vacuum arc on Ti-6Al-4V substrates. J Biomed Mater Res B. 2012;100:1078–85.Google Scholar
  42. 42.
    Lilja M, Forsgren J, Welch K, Åstrand M, Engqvist H, Strømme M. Photocatalytic and antimicrobial properties of surgical implant coatings of titanium dioxide deposited though cathodic arc evaporation. Biotechnol Lett. 2012;34:2299–305.CrossRefGoogle Scholar
  43. 43.
    Sambrook J, Maniatis T, Russel D. Molecular cloning: a laboratory manual. 3rd ed. Cold Spring Harbor: Cold Spring Harbor Laboratory Press; 2001.Google Scholar
  44. 44.
    HPLC detection of Gentamicin sulphate. British Pharmacopoeia 1999;I:695–697.Google Scholar
  45. 45.
    Fabre H, Sekkat M, Blanchin MD, Mandrou B. Determination of aminoglycosides in pharmaceutical formulations—II. High-performance liquid chromatography. J Pharmaceut Biomed. 1989;17:1711–8.CrossRefGoogle Scholar
  46. 46.
    D’Arrigo M, Ginestra G, Mandalari G, Furneri PM. Synergism and postantibiotic effect of tobramycin and Melaleuca alternifolia (teatree)oil against Staphylococcus aureus and Escherichia coli. Phytomedicine. 2010;17:317–22.CrossRefGoogle Scholar
  47. 47.
    Yamamura K, Iwata H, Yotsuyanagi T. Synthesis and antibiotic-loaded hydroxyapatite beads and in vitro drug release testing. J Biomed Mater Res. 1992;1227:397–403.Google Scholar
  48. 48.
    Åberg J, Brohede U, Mihranyan A, Strømme M, Engqvist H. Bisphosphonate incorporation in surgical implant coatings by fast loading and co-precipitation at low drug concentrations. J Mater Sci Mater Med. 2009;10:2053–61.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Mirjam Lilja
    • 1
    • 3
  • Jan Henrik Sörensen
    • 2
  • Ulrika Brohede
    • 3
  • Maria Åstrand
    • 3
  • Philip Procter
    • 4
  • Jörg Arnoldi
    • 4
  • Hartwig Steckel
    • 2
  • Maria Strømme
    • 1
    Email author
  1. 1.Division for Nanotechnology and Functional Materials, Department of Engineering Sciences, The Ångström LaboratoryUppsala UniversityUppsalaSweden
  2. 2.Department of Pharmaceutics and BiopharmaceuticsChristian-Albrechts UniversityKielGermany
  3. 3.Sandvik CoromantStockholmSweden
  4. 4.Stryker Osteosynthesis AGSelzachSwitzerland

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