Chronic cochlear implantation with and without electric stimulation in a mouse model induces robust cochlear influx of CX3CR1+/GFP macrophages

Background: Cochlear implantation is an effective auditory rehabilitation strategy for those with profound hearing loss, including those with residual low frequency hearing through use of hybrid cochlear implan-tation techniques. Post-mortem studies demonstrate the nearly ubiquitous presence of intracochlear fi-brosis and neo-ossification following cochlear implantation. Current evidence suggests post-implantation intracochlear fibrosis is associated with delayed loss of residual acoustic hearing in hybrid cochlear im-plant (CI) recipients and may also negatively influence outcomes in traditional CI recipients. This study examined the contributions of surgical trauma, foreign body response and electric stimulation to intra-cochlear fibrosis and the innate immune response to cochlear implantation and the hierarchy of these contributions.Methods: Normal hearing CX3CR1 + /GFP mice underwent either round window opening (sham), acute CI insertion or chronic CI insertion with no, low-or high-level electric stimulation. Electric stimulation levels were based on neural response telemetry (NRT), beginning post-operative day 7 for 5 h per day. Subjects (n = 3 per timepoint) were sacrificed at 4 h, 1,4,7,8,11,14 and 21 days. An unoperated group (n = 3) served as controls. Cochleae were harvested at each time-point and prepared for immunohistochemistry with confocal imaging. The images were analyzed to obtain CX3CR1 + macrophage cell number and density in the lateral wall (LW), scala tympani (ST) and Rosenthal's canal (RC).Results: A ST peri-implant cellular infiltrate and fibrosis occurred exclusively in the chronically implanted groups starting on day 7 with a concurrent infiltration of CX3CR1 + macrophages not seen in the other groups. CX3CR1 + macrophage infiltration was seen in the LW and RC in all experimental groups within the first week, being most prominent in the 3 chronically implanted groups during the second and third week.Conclusions: The cochlear immune response was most prominent in the presence of chronic cochlear implantation, regardless of electric stimulation level. Further, the development of intracochlear ST fibro-sis was dependent on the presence of the indwelling CI foreign body. An innate immune response was evoked by surgical trauma alone (sham and acute CI groups) to a lesser degree. These data suggest that cochlear inflammation and intrascalar fibrosis after cochlear implantation are largely dependent on the presence of a chronic indwelling foreign body and are not critically dependent on electrical stimulation. Also, these data support a role for surgical trauma in inciting the initial innate immune response.(c) 2022 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/ )