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Abstract
Conservation of a patient's residual hearing and prevention of fibrous tissue/new bone formation around an electrode array are some of the major challenges in cochlear implant (CI) surgery. Although it is well-known that fibrotic tissue formation around the electrode array can interfere with hearing performance in implanted patients, and that associated intracochlear inflammation can initiate loss of residual hearing, little is known about the molecular and cellular mechanisms that promote this response in the cochlea. In vitro studies in neonatal rats and in vivo studies in adult mice were performed to gain insight into the pro-inflammatory, proliferative, and remodeling phases of pathological wound healing that occur in the cochlea following an electrode analog insertion. Resident Schwann cells (SC), macrophages, and fibroblasts had a prominent role in the inflammatory process in the cochlea. Leukocytes were recruited to the cochlea following insertion of a nylon filament in adult mice, where contributed to the inflammatory response. The reparative stages in wound healing are characterized by persistent neuro-inflammation of spiral ganglion neurons (SGN) and expression of regenerative monocytes/macrophages in the cochlea. Accordingly, genes involved in extracellular matrix (ECM) deposition and remodeling were up-regulated in implanted cochleae. Maturation of scar tissue occurs in the remodeling phase of wound healing in the cochlea. Similar to other damaged peripheral nerves, M2 macrophages and de-differentiated SC were observed in damaged cochleae and may play a role in cell survival and axonal regeneration. In conclusion, the insertion of an electrode analog into the cochlea is associated with robust early and chronic inflammatory responses characterized by recruitment of leukocytes and expression of pro-inflammatory cytokines that promote intracochlear fibrosis and loss of the auditory hair cells (HC) and SGN important for hearing after CI surgery.
Highlights
We found a significant increase in the number of leukocyte-leukocyte (a, 70 ± 3, N = 9 regions of interest, p < 0.001) and leukocyte- cochlear tissue (b, 9 ± 1, N = 11 regions of interest, p < 0.001) interactions between the leukocytes co-cultured with the electrode analog insertion trauma (EIT) explant group compared to the undamaged cochlear tissue explants (Figures 2A,B)
DXM treatment did not affect the number of interactions between leukocytes and leukocyte-cochlear tissue explants, when compared to the EIT group of explants (DXM treated: leukocyteleukocyte, a: 62 ± 6, N = 9 regions of interest, p > 0.05; leukocyte-cochlear tissue, b: 9 ± 1, N = 11 regions of interest, p > 0.05 The duration of interactions between leukocytes in the EIT group of explants was significantly increased compared to values obtained in the undamaged control group of explants (458.20 ± 30.95 EIT vs. 71.76 ± 12.15 control explants, N = 278, p < 0.001) (Figure 2C)
cochlear implant (CI) surgery initiates a strong inflammatory response in the cochlea that can promote loss of spiral ganglion neurons (SGN) and remaining auditory hair cells (HC) that are crucial for hearing perception
Summary
Cell regeneration (Löwenheim et al, 1999; Stone and Rubel, 2000; Kawamoto et al, 2003; Levic et al, 2007; Chen et al, 2013; Mizutari et al, 2013; Shi et al, 2013) and stem cells (Ito et al, 2001; Li et al, 2003; Martinez-Monedero and Edge, 2007; Koehler et al, 2013; Bas et al, 2014) are emerging therapies that aim to restore hearing in patients with deafness Despite promising results, these novel therapies will take a long time to reach clinical application due to concerns regarding both safety and efficacy. There have been many triumphs in CI research, long-term residual hearing preservation and prevention of fibrous tissue formation around an electrode array are still major challenges in cochlear implantation (Santa Maria et al, 2013)
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