Nanostructured titania coatings for drug-eluting medical implantsReport as inadecuate

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Lausanne: EPFL, 2009

Medical implants delivering drugs are used to ensure efficient medication at body sites, at which the conventional administration of drugs is insufficient. The application of drug-delivery coatings is a beneficial concept for implants exposed to mechanical loads, such as orthopedic implants or cardiovascular stents. Many of the commercially available coated stent-implants are designed to release a drug locally and at a predefined rate out of a polymer matrix in order to prevent the re-blocking of the artery. The polymer matrices of such so-called drug-eluting stents (DES) can either be bio-degradable or inert. In spite of their successful drug-release capability, they often fail with regard to biocompatibility and long-term chemical and mechanical stability. The aim of the project is to create a novel, nanostructured, ceramic drug-delivering coating for stents, which exhibits an improved performance as compared to the one of conventional DES-implants. The present work addresses the processing and characterization of a nanoporous coating, its drug-loading and release behavior as well as its cytocompatibility. A nanostructured titania (TiO2) coating was deposited on either 316L stainless steel or silicon wafer supports by a multi-step dip coating process involving TiO2-nanoparticle and polymer template suspensions. A subsequent sintering step burned the polymer template particles to create drug reservoirs in the thin coating, which has a thickness of 1.2 µm. These drug reservoirs have a diameter of 1 µm and are surrounded by a porous ceramic structure. This surrounding ceramic structure exhibits a mean pore width of 76 nm and has an open porosity of 50 % as was determined by small angle neutron scattering and mercury intrusion porosimetry. The presence of the drug reservoirs further increases the porosity and hence the drug-load capability of the coating. In addition, the coating was characterized with regard to the specific surface area by the Brunauer-Emmett-Teller (BET)-method, the crystal phases of TiO2 by X-ray diffraction (XRD) and the elemental composition by X-ray photoelectron spectroscopy (XPS). From cardiovascular DESs, therapeutical agents, which either reduce the activation of the immune system or inhibit cell growth, are released into the coronary artery tissue to prevent the local re-blocking of the artery. In the present study, the cell growth inhibiting drug paclitaxel (PTX) was successfully loaded into the highly porous titania coatings by a low-pressure, solvent evaporation technique. The pharmaceutical was accumulated in the drug reservoirs, in the pores of the surrounding ceramic structure and on top of the coating. The total quantity of loaded drug could be varied by changing the coating's structure or the parameters of the drug-loading process. The maximum quantity of PTX incorporated into the coatings was comparable with the amount of PTX in the commercially available TaxusTM DES of 1 µg/mm2. The in vitro release tests of PTX from the coatings into ultra pure water revealed a slow, continuous liberation of the therapeutical agent. After one month of testing, only 11 % of initially incorporated drug were released. The obtained release profile is similar to the one of a PTX-eluting stent. Further release tests of PTX from the titania coatings into bovine plasma were performed and the findings compared to a release profile of the TaxusTM stent. In vitro cytotoxicity tests were accomplished, in which isolated, primary, bovine endothelial cells were brought in direct contact to the non-PTX-loaded titania coatings. First results indicate that the nanostructured TiO2-coatings on wafer and 316L stainless steel supports are cytocompatible. A technology platform has been established, which comprises the characterization of the titania coatings, the loading and quantification of PTX as well as the cytotoxicity evaluation. Factors affecting each of these issues were identified. The findings of the present study will contribute to optimize the nanostructured, ceramic drug-eluting coating for its implementation in DESs and to adapt it to various biomedical applications.

Keywords: nanostructured coating ; drug-eluting stent ; cytotoxicity Thèse École polytechnique fédérale de Lausanne EPFL, n° 4478 (2009)Programme doctoral Sciences et Génie des matériauxFaculté des sciences et techniques de l'ingénieurInstitut des matériauxLaboratoire de technologie des poudres Reference doi:10.5075/epfl-thesis-4478Print copy in library catalog

Author: Dittmar, KarinAdvisor: Hofmann, Heinrich


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