Defining the Mechanisms and Clinical Impact of Neo-ossification after Cochlear Implantation

PROJECT ABSTRACT Cochlear implants (CI) provide an effective form of hearing rehabilitation for adult and pediatric patients with hearing loss. However, multiple factors, including neo-ossification, may negatively impact long term CI performance and hinder the consistency and durability of recipient benefit. Post-CI neo-ossification is ubiquitously seen in human cadaveric studies of CI recipients and has been associated with 1) worse speech recognition scores, 2) poor neural health and 3) delayed loss of residual acoustic hearing after cochlear implantation. Prior data shows a diverse pattern of post-CI neo-ossification within the cochlea, often forming both de-novo in the scala tympani, separate from direct from otic capsule endosteal extension. The factors which contribute to the cochlear pre-disposition to neo-ossification from varied insult (surgical trauma, infectious, autoimmune) remain unidentified. Objective CI measurements, including complex impedances measures (CIM) and electrically evoked compound actional potential (eCAP) derived measurements, are proposed as biomarkers sensitive to local changes in neural health and the electrode microenvironment (including neo-ossification). However, these biomarkers have not been validated with direct, in-vivo observations of the cochlear environment in humans. There is currently a lack of direct clinical assessments and basic mechanistic investigations of post- CI neo-ossification, creating a critical knowledge gap in understanding the clinical impact, time course and biologic mechanisms of post-CI neo-ossification. The goal of this proposal is to understand the time-course and clinical impact of post-CI neo-ossification in human CI recipients, validate proposed clinical biomarkers of post- CI neo-ossification and investigate the cellular mechanisms of post-CI neo-ossification in a mouse model. We hypothesize that post-CI neo-ossification negatively impacts clinical CI outcomes, is detectable through impedance and eCAP CI measures and that neo-ossification occurs through a process of endochondral ossification. To test this hypothesis, Aim 1 will leverage photon counting computed tomography and 3D X-ray microscopy imaging to obtain novel in-vivo, inner ear assessments of post-CI cochlear neo-ossification in human and mouse CI recipients to better understand the impact of neo-ossification on objective CI measures, neural health and clinical outcomes. Aim 2 will utilize a mouse model of cochlear implantation to define the pathophysiologic mechanisms of post-CI neo-ossification and identify relevant cellular populations and signaling pathways that contribute to the cochlear pre-disposition for neo-ossification. The expected results of this study will have high scientific and clinical relevance because they will 1) identify common mechanisms of post-CI neo- ossification relevant to both future studies of other causes of cochlear neo-ossification and the development of mitigative strategies to improve CI efficacy, 2) validate clinical biomarkers and radiologic protocols for assessing post-CI neo-ossification and 3) determine the effect of neo-ossification on CI outcomes.