Effects of a dexamethasone-releasing implant on cochleae: A functional, morphological and pharmacokinetic study

• Published in: Hearing research 2015-09, Vol.327, p.89-101
• Main Authors: Liu, Ya, Jolly, Claude, Braun, Susanne, Janssen, Thomas, Scherer, Elias, Steinhoff, Jochen, Ebenhoch, Harald, Lohner, Andrea, Stark, Thomas, Kiefer, Jan
• Format: Article
• Language: English
• Subjects: Acoustic Stimulation; Animals; Auditory Threshold - drug effects; Chromatography, High Pressure Liquid; Cochlea - drug effects; Cochlea - metabolism; Cochlea - pathology; Cochlea - physiopathology; Cochlear Implants; Dexamethasone - administration & dosage; Dexamethasone - pharmacokinetics; Disease Models, Animal; Drug Implants; Evoked Potentials, Auditory, Brain Stem - drug effects; Fibrosis; Glucocorticoids - administration & dosage; Glucocorticoids - pharmacokinetics; Guinea Pigs; Hearing - drug effects; Hearing Loss - diagnosis; Hearing Loss - etiology; Hearing Loss - metabolism; Hearing Loss - physiopathology; Hearing Loss - prevention & control; Otoacoustic Emissions, Spontaneous - drug effects; Perilymph - metabolism; Silicones - chemistry; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0378-5955; 1878-5891
• DOI: 10.1016/j.heares.2015.04.019

This study evaluated the impact of a dexamethasone-releasing silicone implant on hearing function preservation, cochlear morphology and perilymph pharmacokinetics after cochlear implantation. Guinea pigs were implanted unilaterally with silicone rods containing either 2% dexamethasone (DEXA group, n = 18) or no dexamethasone (control group, n = 17). Auditory brainstem response (ABR) and distortion product otoacoustic emissions (DPOAEs) were measured preoperatively and over 6 months postoperatively. Cochlear histology using standard hematoxylin and eosin (H&E) staining and tumor necrosis factor (TNF)-alpha staining was performed 1 month postoperatively. Twenty-two guinea pigs were involved in the pharmacokinetic study, and real-time drug concentrations in perilymph were investigated using high-performance liquid chromatography (HPLC). The Mann–Whitney U test (1-tailed) was used for statistical analyses. ABR and DPOAE testing demonstrated decreased hearing function immediately postoperatively followed by a progressive hearing loss within the first day postoperatively. There was almost no observable hearing improvement in the control group from 1 week to 6 months postoperatively, but hearing levels in the DEXA group improved gradually from 1 week to 12 weeks. Hearing loss in the DEXA and control group was 5.0 ± 3.4 dB and 21.7 ± 5.3 dB, respectively at a 16-kHz stimulus frequency 6 months postoperatively. The difference in threshold shifts was present throughout all measured frequencies, and it was significant at 4–24 kHz. The morphological study revealed new fibrosis formation in the scala tympani, which encapsulated the implanted electrode. TNF-alpha positive staining in the cochleae of the DEXA group was less evident than the control group. The pharmacokinetic study revealed a peak perilymph concentration 30 min postoperatively and sustained dexamethasone release at least 1 week postoperatively. Cochlear implants that incorporate dexamethasone can release drug chronically in the inner ear and induce significant long-term recovery and preservation of auditory function after implantation. •Cochlear implantation induces hearing loss immediately after operation.•Dexamethasone-releasing implants reduce ABR threshold shifts post operatively.•DPOAE levels are higher in the dexamethasone group than in the control group.•Dexamethasone-releasing implants inhibit TNF-alpha expression.•Dexamethasone concentration is detectable at least 1 week post operatively.