A mouse model of cochlear implantation with chronic electric stimulation

Abstract

Objectives Cochlear implants provide an effective treatment option for those with severe hearing loss, including those with preserved low frequency hearing. However, certain issues can reduce implant efficacy including intracochlear tissue response and delayed loss of residual acoustic hearing. We describe a mouse model of cochlear implantation with chronic electric stimulation that can be used to study cochlear implant biology and related pathologies. Methods Twelve normal hearing adult CBA/J mice underwent unilateral cochlear implantation and were evenly divided into one group receiving electric stimulation and one not. Serial impedance and neural response telemetry (NRT) measurements were made to assess implant functionality. Functionality was defined as having at least one electrode with an impedance ≤ 35 kOhms. Mouse cochleae were harvested for histology and 3D x-ray microscopy 21 days post-operatively, or, in case the implant was still functional, at a later time point when the implant failed. A separate experiment measured the hearing preservation rate in 7 adult CBA/J mice undergoing unilateral cochlear implantation with serial auditory brainstem response (ABR) and distortion product otoacoustic emissions (DPOAE). Results Implants maintained functionality for a mean of 35 days in the non-stimulated group and 19.8 days in the stimulated group. Reliable NRT and behavioral responses to electric stimulation were recorded. A robust intracochlear peri-implant tissue response with neo-ossification was seen in all cochleae. Six of seven mice maintained intact low frequency hearing up to 6 weeks following cochlear implantation. Conclusions We demonstrate the feasibility of cochlear implantation and behaviorally significant electric stimulation in the mouse, with the potential for hearing preservation. This model may be combined with established mouse models of hearing loss and the large genetic and molecular research toolkit unique to the mouse for mechanistic and therapeutic investigations of cochlear implant biology.

Ramped pulse shapes are more efficient for cochlear implant stimulation in an animal model

“…1f). The smaller eABR amplitude observed with more basal electrode-stimulation is likely due to the slightly longer distance from the basal electrodes to the modulus relative to the apical electrodes, as was recently indicated in a x-ray image of a CI-implanted mouse cochlea 18 . This is also supported by a study in guinea pigs which showed that electrode position within scala tympani affects eABR threshold 19 .…”

Chronic Cochlear Implantation with and without Electric Stimulation in a Mouse Model Induces Robust Cochlear Influx of CX3CR1+/GFP Macrophages

“…The robust peri-implant cellular infiltrate in the ST of the chronically implanted groups was similar in extent to that previously published in the mouse CI model, in which the ST was occupied with fibrotic tissue and areas of neo-ossification confined to the depth of CI insertion. (Claussen et al, 2019). CX3CR1+ cells were seen to comprise a substantial element of the ST response between days 7 and 11, accounting for over 50% of the cells within the ST of some subjects.…”

“…This heterotopic tissue response is often most robust in the peri-implant region of the scala tympani (ST) forming a 'fibrous sheath' around the CI, but is sometimes seen to extend distal to the implant tip and into other scala (Linthicum et al, 2017;Nadol et al, 2014;Seyyedi & Nadol, 2014). A similar pattern of post-implantation cochlear tissue response has been seen in several animal models of cochlear implantation, including guinea pig, cat, mouse and sheep (Clark et al, 1975;Claussen et al, 2019;Kaufmann et al, 2020;O'Leary et al, 2013). Deleterious CI outcomes have been associated with the cochlear tissue response and neo-ossification, including poorer word recognition scores (Kamakura & Nadol, 2016), impedance increases with subsequent poorer battery life and decreased dynamic range (Needham et al, 2020;Wilk et al, 2016) and loss of residual acoustic hearing after cochlear implantation (Quesnel et al, 2016;Scheperle et al, 2017).…”

“…Five experimental groups (n=3 per timepoint) comprised this study: Sham Surgery, the approach to the round window niche was made, opening the round window but not inserting a CI; Acute Insertion (AI), the round window was opened and a CI briefly placed and removed; Chronic Insertion (ChI), full implantation of a CI without electric stimulation; Low Stimulation (LS), full CI implantation with low level electric stimulation starting on post-operative day 7; High Stimulation (HS), full CI implantation with high level electric stimulation starting on post-operative day 7. Surgery was performed exclusively on left ears through a round window approach with a custom 3 half-banded electrode CI (Cochlear Ltd., AUS), as previously described (Claussen et al, 2019). Mice were followed for varying timepoints until sacrifice and cochlear histology, including 4, 24 and 96 hours, 7, 11, 14, and 21 days post-operatively (Figure 1 depicts the experimental timeline).…”

“…Understanding of this initial inflammatory response and contributing factors will be important in the development of strategies to mitigate the intracochlear tissue response and improve CI efficacy. This study utilizes our previously published mouse model of chronic cochlear implantation with electric stimulation in a CX3CR1 +/GFP reporter mouse to study the initial innate immune response to cochlear implantation (Claussen et al, 2019). CX3CR1 is the receptor to the chemokine, fractalkine (CX3CL1) and is expressed in monocytes, macrophages, microglia, NK cells and some T cells.…”