A Novel Organ of Corti Explant Model for the Study of Cochlear Implantation Trauma

Abstract

This study presents a novel in vitro model of electrode insertion trauma-induced hair cell (HC) damage and loss and its application for testing the efficacy of otoprotective drugs. In the cochlear implant (CI) procedure as a treatment for profound deafness, an electrode array is surgically inserted to provide electrical stimulation to the auditory nerve. Mechanical trauma from insertion of a CI electrode into the scala tympani can lead to inflammation and a high level of oxidative stress, which can initiate the apoptosis of auditory HCs and intracochlear fibrosis. HC apoptosis and intracochlear fibrosis are thought to be causes of poor CI functional outcomes. In order to gain insight into the molecular mechanisms that initiate HC apoptosis and scala tympani fibrosis following electrode insertion trauma (EIT), and the otoprotective effects of dexamethasone (DXM) observed in previous studies, an in vitro model of EIT was designed. Here we present and characterize a novel, reproducible in vitro model for the study of cellular and molecular events that occur following an EIT procedure. Cochleae from 3-day-old rats were subjected to a cochleostomy and were then divided into three groups: (1) control, (2) EIT, and (3) EIT þ DXM (20 lg/mL). In Groups 2 and 3, a 0.28-mm diameter monofilament fishing line was introduced through the small cochleostomy located next to the round window area, allowing for an insertion of between 110 and 150 . HC counts, gene expression for pro-inflammatory cytokines (i.e., TNFa and IL-1b), pro-inflammatory inducible enzymes (i.e., iNOS and COX-2) and growth factors (i.e., TGFb1, TGFb3 and CTGF), oxidative stress (i.e., Cell-ROX), and analyses of apoptosis pathways (i.e., caspase-3, apoptosis induced factor and Endonuclease G) were carried out on all explants at different time points. The results of this EIT in vitro model show the initiation of wound healing in which an inflammatory response is followed by a proliferative-fibrosis phase. Moreover, DXM treatment of EIT explants inhibited the inflammatory response and promoted a nonscarring wound healing process. The novel in vitro model described here will improve our understanding of mechanisms underlying CI insertion trauma and protective strategies such as DXM treatment.

Effect of Both Local and Systemically Administered Dexamethasone on Long-Term Hearing and Tissue Response in a Guinea Pig Model of Cochlear Implantation

“…It is not possible to distinguish between these, as they proceed in concert and could potentially influence each other. Early after implantation, injury signalling is thought to lead to local production of inflammatory cytokines that attract immune-competent cells to the surgical site [Yamamoto et al, 2009;van De Water et al, 2010;Bas et al, 2012]. These are initially endogenous to the cochlea [Shi, 2010], but will also be recruited from the circulation after up-regulation of cell adhesion molecules, such as I-CAM1, on the endothelium of cochlear venules [Suzuki and Harris, 1995;Tornabene et al, 2006].…”

Application of a TNF-alpha-inhibitor into the scala tympany after cochlear electrode insertion trauma in guinea pigs: Preliminary audiologic results

“…Lessons from in vitro studies suggest that the noxious effect of TNF-alpha on auditory hair cells might as well be abrogated at least partially by glucocorticoids (Haake et al, 2009;Hoang et al, 2009;Bas et al, 2012b) and mannitol (Infante et al, 2012). Overall, etanercept as a direct inhibitor of TNF-alpha effects promises a more targeted approach.…”

“…It comprises early onset infl ammation by tissue injury (Jia et al, 2013) and delayed onset proliferation by foreign body reaction and chronic infl ammation (Bas et al, 2012b). Consequential for the outcome of cochlear implantation are apoptosis of auditory nerve fi bers, fi brous scar and bone formation (Jia et al, 2013), as it infl uences electrode impedance as well as electric stimulation and thereby dynamic range and power consumption (Duan et al, 2004).…”

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

“…Zou et al (2005) found broad TNF-alpha positive staining in Deiters' cells, hair cells, basilar membrane, spiral ligament, and spiral ganglion after transcranial vibration induced hearing loss in guinea pig. Bas et al (2012) studied the mRNA level of TNF-alpha in organ of Corti explants in well-established electrode insertion trauma model. The results demonstrated that mRNA levels in the basal turn were increased in all experimental groups (cochleostomy-only group, insertion-trauma group and dexamethasone-treatment group) 1 day and 4 days postoperatively.…”