Silicone-based AC102-loaded cochlear implant coatings protect residual hearing in an animal model of cochlear implantation

• Published in: Hearing research 2024-12, Vol.454, p.109150, Article 109150
• Main Authors: Nieratschker, Michael, Mistrik, Pavel, Petrasek, Zdenek, Yildiz, Erdem, Gadenstaetter, Anselm J., Gerlitz, Matthias, Kramer, Anne-Margarethe, Kwiatkowska, Monika, Braun, Susanne, Schlingensiepen, Reimar, Honeder, Clemens, Arnoldner, Christoph
• Format: Article
• Language: English
• Subjects: Action Potentials - drug effects; Animal model; Animals; Anti-apoptotic; Anti-inflammatory; Auditory Threshold - drug effects; Coated Materials, Biocompatible; Cochlea - drug effects; Cochlea - metabolism; Cochlea - physiopathology; Cochlear implantation; Cochlear Implantation - instrumentation; Cochlear Implants; Delayed-Action Preparations; Drug eluting electrode; Drug Liberation; Evoked Potentials, Auditory, Brain Stem - drug effects; Gerbillinae; Hearing - drug effects; Hearing Loss - physiopathology; Hearing Loss - prevention & control; Hearing preservation; Indoles - administration & dosage; Male; Models, Animal; Neurotrophic; Prosthesis Design; Silicones - chemistry; Small molecule; Time Factors
• ISSN: 0378-5955; 1878-5891; 1878-5891
• DOI: 10.1016/j.heares.2024.109150

•The Higuchi model of drug release predicts the release from AC102-loaded electrodes.•AC102-loaded electrodes reduce CAP threshold shifts in the middle and low frequencies in a gerbil animal model.•Cochleae implanted with AC102-loaded electrodes show preservation of hair cells, synapses, and nerve fibers in a gerbil animal model. Cochlear implant users with residual hearing benefit synergistically from combined electrical stimulation via the cochlear implant and preserved residual hearing after surgery. However, direct mechanical trauma and subsequent inflammation may deteriorate hearing function. AC102, a novel otoprotective pyridoindole with anti-apoptotic and anti-oxidative properties significantly improved hearing recovery following cochlear implantation when administered intratympanically prior to surgery. Additionally, AC102 exerts neurotrophic effects, possibly aiding in the preservation of auditory nerve fibers and spiral ganglion neurons. Rapid clearance of the drug, however, might be a limiting factor to further attenuate the inflammatory response and maintain neuronal health. The aim of the current study was to design an AC102-loaded electrode array for sustained drug delivery and investigate its effects in hearing preservation cochlear implantation. First, the release-kinetics of AC102 were investigated in vitro and modelled by the Higuchi equation of drug release. An electrode array coated with 10 % AC102 was manufactured, its release kinetics evaluated, and subsequently tested in vivo. 20 normal hearing Mongolian gerbils were unilaterally implanted with an AC102-loaded or an unloaded control electrode. Compound action potentials were measured prior to cochlear implantation and serially over 28 days. Hair cells, inner hair cell synapses, and auditory nerve fibers were quantified in cochlear whole-mounts by immunofluorescence staining. AC102 release from silicone coating could be predictably modelled by the Higuchi equation of drug release. The electrode array with an AC102-silicone depot enabled non-linear sustained drug release with initially higher release concentrations. In vivo, the AC102-loaded electrode array significantly recovered auditory threshold shifts near the maximum insertion depth over 28 days. In the apical region, a significant recovery was noticed only until day 14, after which threshold shifts aligned between groups. Histologically, AC102-loaded electrodes significantly preserved outer hair cells apical of the maximum inser