## 2 Inner Ear Injury and Glucocorticoid Therapy
### Cochlear Implantation and Glucocorticoid Therapy
This also suggests that the drug reached the mid-range frequency zone of the cochlea, raising the possibility that a longer exposure time may allow glucocorticoids to reach more distally inside the cochlea. Unlike in the case of a systemic or intratympanic glucocorticoid delivery, a direct intracochlear delivery places the drug at the site of damage, avoiding the reliance on drug diffusion. A clinical study by [PERSON] et al. showed that a single intracochlear dose of triamcinolone prior to an electrode insertion lowered the electrode impedance [41]. The difference in the electrode impedance levels between the treated and the control groups was maintained for up to 17 days post-operation, but was then lost. [PERSON] et al. speculated that this significant, albeit short-term, effect was due to a low concentration of the drug and conducted a study using a 5-fold greater dose and a custom-designed catheter that reached deeper into the cochlea [42]. The results confirmed that there was a significant difference between the high-dose group and the control group for up to an average of 39.53 days. When the high-dose and low-dose groups were compared, there was no significant difference at any point of the trial. Nevertheless, the significance between the low-dose group and the control group was lost at an earlier stage than with the high-dose group. It is important to note that when subdividing the electrode surfaces into basal, middle and apical contact sites, a significant difference was only observed in the basal and middle regions despite the deep insertion of the drug [42]. Glucocorticoid delivery routes may also be combined. A retrospective cohort study compared an intratympan treatment during surgery with an intratympanic treatment plus a systemic two-week oral glucocorticoid taper beginning three days prior to surgery [43]. The results suggest that patients who received the combined regimen had a higher degree of hearing preservation. In that study, the three days of preoperative oral glucocorticoids may have resulted in higher perilymph glucocorticoid concentrations, augmenting the effect of the intratympanic glucocorticoid therapy. According to a randomized controlled trial, a combination of transtympanic glucocorticoids 24 h prior to surgery then local glucocorticoids during surgery achieved superior pure-tone average outcomes compared with either monotherapies [44]. It is reasonable to propose that a preoperative glucocorticoid administration, whether systemic or local, may precondition the tissue and, together with a local intratympanic treatment during surgery, lead to improved outcomes. As the great majority of cochlear implants are planned ahead of time, the concept of preconditioning is worth exploring. In an attempt to optimize the impact of dexamethasone within the inner ear compartment, _drug-eluting electrode arrays_ were developed. In this method, dexamethasone-loaded silicone rings are introduced between the stimulating channels that diffuse dexamethasone directly into the cochlea [32]. The rationale behind these eluting electrode arrays is that they are able to release dexamethasone for an extended duration, possibly addressing a later-appearing fibrosis. Positive outcomes have been demonstrated in guinea pig and non-human primate models. In the guinea pig model, three dexamethasone doses were tested, resulting in significant dose-dependent positive outcomes; at two months post-surgery, the electrode impedance was still superior to the control electrode arrays [45]. The immunostaining of the organ of Corti depicted preserved outer hair cells whereas the control group showed missing patches of both inner and outer hair cells. In a parallel study, the fibrosis around the electrode was diminished alongside an electrode impedance [46]. These observations may offer an important development as they advance into clinical trials such as in the CI-DEX study (NCT04750642).