Preservation of Residual Hearing: Pharmaceutical Agents
Electrode insertion trauma (EIT) is thought to be a primary cause of loss of residual hearing during cochlear implantation (CI). Over the past three decades, improved surgical techniques and electrode design have partially preserved residual hearing and improved CI outcomes in many recipients.
Although EIT may cause loss of residual hearing through immediate tissue disruption and necrosis, histological studies suggest that the preponderance of damage results from secondary inflammation, fibrosis/osteogenesis, oxidative stress and apoptosis. In some cases, these programmed pathways may be blocked to varying extents by medications. Some of the pharmaceuticals currently under investigation for preservation of residual hearing in CI include:
Dexamethasone (Dex) has anti-inflammatory and anti-apoptotic characteristics. For example, Dex can suppress inflammatory cytokines, interleukins and TNF-alpha, increases expression of anti-apoptosis genes and decreases expression of pro-apoptosis genes in the cochlea. A single dose of systemic and/or topical steroids is often given just prior to implantation and has also been delivered orally in a two-week clinical trial (1).
Neuroprotective growth factors such as brain derived neural growth factor (BDNF), insulin-like growth factor (ILGF), hepatic growth factor (HGF) and neurotrophin-3 (NT3) have been used experimentally to enhance ganglion cell survival after cochlear implantation. Delivery methods include osmotic pumps (2) and drug eluting electrodes. Neurotrophins have also been delivered with gene therapy via viral vectors (3) and cell therapy in alginate microspheres (4).
N-acetyl cysteine (NAC) is a free radical scavenger that replenishes glutathione and L-cysteine. NAC provides protection against hydroxyl radicals and lipid peroxidase and blocks the MAPK/JNK apoptotic pathway in the cochlea.
Mannitol reduces oxidative stress by stabilizing blood flow, especially in ischemia-reperfusion injury that may result from EIT. It has been shown to protect hair cells from acoustic trauma, gentamicin toxicity and TNF alpha mediated hair cell loss.
Bas et al. in Prof Van De Water’s lab (5) at the University of Miami Ear Institute recently published an important paper showing that Dex, when delivered by a drug eluting electrode, protected guinea pig cochleas against loss of hair cells and other neural elements, loss of hearing, fibrosis and increasing electrical impedance. Responses were dose-dependent and optimal drug concentrations were established. By using drug eluting electrodes, the delivery of Dex was continued for 3 months.
The Van De Water electrode elutes Dex directly from the silastic carrier providing a possible advantage over other electrodes that utilize applied coatings. In such electrodes, applied coatings are eluted along with Dex and may tend to cause an inflammatory response in some cases.
Kikkawa et al. (6) of Prof. Ito’s laboratory at Kyoto University have recently reported a hydrogel-coated guinea pig electrode that releases insulin-like growth factor (IGF) and hepatocyte growth factor (HGF). Loss of hearing (increased ABR threshold) was reduced by IGF and HGF eluting electrodes but histological changes were not affected. Hydrogel coating of CI electrodes may also reduce frictional forces during insertion.
Polypyrrole (Ppy) coatings have also been used to deliver neurotrophins from CI electrodes in guinea pigs. Ppy is an electrical conductor and is eluted from electrodes during stimulation. In these experiments, reported by Richardson et al. (7) of Prof. O’Leary’s group at Melbourne University, NT3 enhanced spiral ganglion cell counts in ears that received electrical stimulation.
Several studies have demonstrated that the reactive oxygen species scavenger L-NAC, the osmotic regulator mannitol, and dexamethasone all have a protective effect after electrode insertion trauma. Each of these protective molecules has an independent mechanism of action that occurs at a different locus in the inflammatory/apoptotic cascade. Eshraghi et al (8) at the University of Miami Ear Institute initiated EIT in rats then explanted and cultured the organs of Corti in solutions containing graded concentrations of each molecule to identify effective dosage. Dose-response curves were developed to determine the drug concentration required to achieve 50% protection of HCs in vitro by each drug. A cocktail containing the three molecules was then evaluated in organotypic cultures. The combination of the three agents was 96% protective in vitro.
Clinical studies have suggested that improved surgical techniques and less traumatic electrodes can reduce EIT and enhance preservation of residual hearing. The next stage in hearing preservation may be expanded use of pharmaceutical agents. Steroids have shown promise in clinical and laboratory settings while neurotrophins, antioxidants, and mannitol have shown promise in the laboratory.
1. Sweeney AD, Carlson ML, Zuniga MG, Bennett ML et al. Impact of Perioperative Oral Steroid Use on Low-frequency. Otology & Neurotology (2015) 36:1480–1485.
2. Sly DJ, Hampson AJ, Minter RL…O'Leary SJ: Brain-derived neurotrophic factor modulates auditory function in the hearing cochlea. J Assoc Res Otolaryngol 2012, 13:1–16.
3. Wang H, Murphy R, Taaffe D, Yin S, Xia L, et al. Efficient cochlear gene transfection in guinea-pigs with adeno-associated viral vectors by partial digestion of round window membrane. Gene Ther 2012, 19:255–263.
4. Gillespie LN, Zania MP, Shepherd RK. Cell-based neurotrophin treatment supports long-term auditory neuron survival in the deaf guinea pig. J. Controlled Release. (2015) 198; 26 – 34.
5. Bas, E, Bohorquez, J…Van De Water, TR, et al. Electrode array-eluted dexamethasone protects against electrode insertion trauma induced hearing and hair cell losses, damage to neural elements, increases in impedance and fibrosis: A dose response study. Hearing Research (2016), doi: 10.1016/j.heares.2016.02.003.
6. Kikkawa YS, Nakagawa T, Ying L…Ito J. et al. Growth factor-eluting cochlear implant electrode: impact on residual auditory function, insertional trauma and fibrosis. Journal of Translational Medicine 2014, 12:280.
7. Richardson RT, Wise AK, Thompson BC…O’Leary SJ et al. Polypyrrole-coated electrodes for the delivery of charge and neurotrophins to cochlear neurons. Biomaterials(2009) 30; 2614–2624.
8. Eshraghi AA, Roell J…Van De Water, et al. A novel combination of drug therapy to protect residual hearing post cochlear implant surgery. Acta Otolaryngol (2016). http://dx.doi.org/10.3109/00016489.2015.1134809.