Development of long-termed implants: In vivo and in vitro characterisation of the interactions of inner ear cells with platinum corrosion products in the context of cochlear implant stimulation

• Applicants: Professor Dr. Martin Durisin; Professor Dr.-Ing. Hans Jürgen Maier; Dr. Kirsten Wissel
• Subject Area: Otolaryngology, Phoniatrics and Audiology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 450597484

So far, it was supposed that an increase of electrical impedance extending 10 kΩ following cochlear implant insertion was due to technical defects of the electrode, induction of inflammatory processes and/or formation of scar tissue along the electrode. Recent studies, however, reported eroded surfaces of the platinum (Pt) electrode contacts as the reason for high impedances. Furthermore, the presence of Pt oxides, Pt protein complexes and particular Pt could be demonstrated at the electrode-nerve-interface and in the inner ear tissues. Whereas the cytotoxicity of of ionic Pt is well documented, the toxic potential of particular Pt depends not only on the particle size, concentration and cell type, but also on its susceptibility to oxidation by hydrolytic enzymes in the lysosomes following internalization. It is supposed that the oxidation product of the Pt particles may form complexes with DNA and subsequently induce DNA strand breakings. In fact, long-term effects of Pt corrosion, compositions of its corrosion products as well as their interactions with neural tissues are not well understood. Especially, molecular mechanisms of cell death induced by Pt corrosion products need to be clarified to enable protection of neuronal tissues against oxidative stress induced cell damage and manufacturing of electrodes preventing extensive corrosion product release.Current studies demonstrate that cisplatin mediated ototoxicity is not only triggered by apoptotic pathways, but also via necroptosis and autophagy. However, Pt corrosion products have not been identified as inductors for necroptosis or autophagy related signal pathways. Thus, detailed in vitro-analysis of cell death related signal pathways induced by the Pt corrosion products are in the focus of the project described herein. For this, in vitro cell culture models of primary rat spiral ganglion neurons, HEI-OC1 cell line of the immortalized mouse organ of Corti cells and organotypic cultivation of the rat organ of Corti will be established to characterize and quantify cytotoxic effects following administration of Pt nanoparticles and Pt corrosion products. Hereby, electrical stimulation of Pt wires will be used as source of corrosion products. Determination of the Pt concentration inducing cell death of 50 % of the cell culture constitutes the basis of the examination of the molecular mechanisms of Pt triggred oxidative stress and subsequent cell death. The obtained data will allow the examination of potential inhibitors/inductors of the cross points in apoptosis/necroptosis/autophagy signaling to prevent severe cell damage following Pt exposure. Consequently, the in vitro data has to be evaluated in vivo using rats as animal model.

• DFG Programme: Research Grants
• Co-Investigator: Dr. Gudrun Brandes