Should we measure and modulate inflammation before cochlear implantation to improve long-term hearing outcomes?

Background: deaf children undergoing cochlear implantation have the potential to meet developmental milestones in line with their biological hearing peers. Unfortunately, hearing and language outcomes following implantation are variable. The biological factors contributing to underperformance are poorly understood. This study aims to determine whether the inflammatory/immune state of the ear is one factor contributing to underperformance. <br/><br/>Insertion of an electrode array elicits a variable inflammatory response which can result in scar tissue (fibrosis) around the array1. An aberrant response can result in increased inflammation and fibrosis and contribute to poorer hearing2. <br/>Macrophages, tissue-resident immune cells, acquire ‘memory’ to previous insults (infections) which can result in an increased inflammatory response to subsequent insults3. Within the ear, an increased inflammatory response will cause tissue damage and contribute to hearing loss4; after implantation, this may contribute to greater fibrosis and poorer hearing outcomes. Early identification of inflammatory risk could mitigate this. <br/><br/><br/>Methods: CHIEF (cochlear implants and inner ear inflammation) is a cross-sectional study of children and young people undergoing cochlear implantation. Tissue and fluid samples will be collected from the ear/(s) being implanted during surgery including middle ear mucosa, a middle ear swab and cochlear fluid. A nasal swab and blood sample will be collected at the time of surgery. Following implantation, routine clinical outcome measures and health data will be collected for up to five years. <br/>We hypothesise that the tissue response to inflammation varies due to the individual inflammatory differences in the ear at the time of implantation. We will use CosMx5, a spatial transcriptomics technique that measures spatial gene expression, to measure the inflammatory state of the middle ear mucosal samples. We will characterise the expression profile of the major cell types identified in the middle ear mucosa samples. <br/><br/>Results: to gather pilot data, we will generate a spatial gene expression profile of the key immune regulators in the middle ear (macrophages) and the surrounding cells. We will use bioinformatic analysis to determine if there are differences in gene expression of the cells within and between samples and determine whether these cells are communicating with each other. This pilot data will allow us to determine whether this technique yields valuable gene expression data for the major middle ear cell types and whether this technique should be used to analyse all mucosal samples collected in CHIEF. <br/><br/><br/>Conclusion: this will be the first spatial gene analysis of cells in the middle ear of children and young people undergoing cochlear implantation. This work will provide new knowledge of the immune biology of the ear in children undergoing implantation and inform our understanding of biological factors that can influence hearing outcomes with an implant. <br/><br/>Through CHIEF, we will generate a database containing clinical and medical history of children undergoing cochlear implantation and a tissue bank. We will analyse the relationship between the biological data and clinical data (collected over five years) to interrogate how the immune state of the ear is associated with long-term hearing outcomes with an implant. If a predictable relationship is determined, there is potential to improve long-term hearing outcomes in children following implantation by modulating inflammation, using anti-inflammatory therapies. <br/><br/>Reference <br/>1.Seyyedi, M. &amp; Nadol, J. B. Intracochlear inflammatory response to cochlear implant electrodes in humans. Otology and Neurotology 35, 1545–1551 (2014).<br/>2.Hough, K. et al. Inflammation at the tissue-electrode interface in a case of rapid deterioration in hearing performance leading to explant after cochlear implantation. Otology &amp; Neurotology 42, e445–e450 (2021).<br/>3.Cunningham, C., Wilcockson, D. C., Campion, S., Lunnon, K. &amp; Perry, V. H. Central and systemic endotoxin challenges exacerbate the local inflammatory response and increase neuronal death during chronic neurodegeneration. Journal of Neuroscience 25, 9275–9284 (2005).<br/>4.Xia, A. et al. Chronic suppurative otitis media causes macrophage-associated sensorineural hearing loss. J Neuroinflammation 19, 224 (2022).<br/>5.He, S. et al. High-plex imaging of RNA and proteins at subcellular resolution in fixed tissue by spatial molecular imaging. Nat Biotechnol 40, 1794–1806 (2022).<br/> <br/><br/>