PT Unknown AU Sörensen, JH TI Novel ultra-thin hydroxyapatite coatings on medical implants used as local drug delivery system – in-vitro and in-vivo characterization PY 2013 PU Christian-Albrechts-Universität zu Kiel WP https://macau.uni-kiel.de/receive/diss_mods_00013674 LA en DE Hydroxyapatite; coating; Tobramycin; drug delivery; implant; infection; Hydroxlapatit; Beschichtung; Arzneistofffreisetzung; Implantat; Infektion AB This thesis reports the successful development of a novel bioactive type of implant coating. A thin biomimetic hydroxyapatite coating on metal implants with unique properties capable of delivering pharmaceutically effective dosages of Tobramycin was developed and systematically analyzed. Biomimetic, nanoporous HA coatings were demonstrated to be versatile enough to potentially solve a number of problems for which satisfactory clinical solutions do not exist today. The surface pretreatment and HA coating was designed and optimized to homogeneously distribute needle like HA crystals on TiO2 layered stainless steel and anodized titanium type II surfaces in the range of 1 to 5 µm. The advantages of a nanoporous structure of biomimetically deposited HA over a more dense structure of plasma sprayed HA coatings in terms of antibiotic incorporation and subsequent sustained release were presented. The biomimetically deposited HA structure itself demonstrated good biomechanical resistance, excellent biocompatibility and osteoconductive surface properties in-vitro and in-vivo. The nanoporous structure allowed for controlled drug incorporation and tailorable local release. The use of Tobramycin should be noted as a model drug for incorporation, release and efficacy studies. Coating thickness, morphology and surface topography as well as loading parameters like temperature, pressure, ultrasound, pH were found to be important impacting on both drug loading and subsequent release profile. Agar diffusion tests demonstrated a sustained antibacterial effect against Staph. aureus over several days. A novel co-precipitation approach incorporating Tobramycin simultaneously at the time of nucleation was defined and optimized. The starting phase of crystallization represented a very important aspect for coating deposition. Both surface chemistry as well as process temperature are important factors impacting coating growth, thickness and the morphology of the drug-doped HA coatings. An animal test set-up was developed in order to assess the performance of the HA coating in-vivo. Overall, the insertion torques (during implantation) of the HA coated screws were comparable to uncoated, commercially available screws. After two weeks, increased early implant stabilization was demonstrated by significantly higher removal torques for HA coated screws. Furthermore, this conclusion was supported by higher pull-out forces, and histology. After 6 weeks, HA coated and non-coated screws demonstrated comparable removal-torque values as well as pull-out forces. Therefore, the HA coating resulted in more rapid early implant stabilization whilst assuring that the implant could be safely removed after full osseointegration. Furthermore, the efficacy of the Tobramycin loaded HA coating was evaluated in an in-vivo infection model. Five out of six implanted sites containing HA and Tobramycin presented biologically significant lower signs of infection based on macroscopical, microbiological, histopathological and radiological analyses. Overall, the novel biomimetic HA coating has demonstrated delivery of enhanced implant stabilization whilst at the same time enabling the implant to be easily disconnected from the bone upon screw removal. Finally the coating is also capable of delivering clinically effective dosages of an antibacterial agent over a relevant time period. PI Kiel ER