The cochlear implant (CI) is the first effective treatment for deafness and severe losses in hearing. As such, the CI is now widely regarded as one of the great advances in modern medicine. This paper reviews the key events and discoveries that led up to the current CI systems, and we review and present some among the many possibilities for further improvements in device design and performance. The past achievements include: (1) development of reliable devices that can be used over the lifetime of a patient; (2) development of arrays of implanted electrodes that can stimulate more than one site in the cochlea; and (3) progressive and large improvements in sound processing strategies for CIs. In addition, cooperation between research organizations and companies greatly accelerated the widespread availability and use of safe and effective devices. Possibilities for the future include: (1) use of otoprotective drugs; (2) further improvements in electrode designs and placements; (3) further improvements in sound processing strategies; (4) use of stem cells to replace lost sensory hair cells and neural structures in the cochlea; (5) gene therapy; (6) further reductions in the trauma caused by insertions of electrodes and other manipulations during implant surgeries; and (7) optical rather electrical stimulation of the auditory nerve. Each of these possibilities is the subject of active research. Although great progress has been made to date in the development of the CI, including the first substantial restoration of a human sense, much more progress seems likely and certainly would not be a surprise.

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.

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Cochlear implants are currently the most effective solution for profound sensorineural hearing loss, and vestibular prostheses are under development to treat bilateral vestibulopathies. Electrical current spread in these neuroprostheses limits channel independence and, in some cases, may impair their performance. In comparison, optical stimuli that are spatially confined may result in a significant functional improvement. Pulsed infrared radiation (IR) has previously been shown to elicit responses in neurons. This study analyzes the response of neonatal rat spiral and vestibular ganglion neurons in vitro to IR (wavelength = 1,863 nm) using Ca(2+) imaging. Both types of neurons responded consistently with robust intracellular Ca(2+) ([Ca(2+)]i) transients that matched the low-frequency IR pulses applied (4 ms, 0.25-1 pps). Radiant exposures of ∼637 mJ/cm(2) resulted in continual neuronal activation. Temperature or [Ca(2+)] variations in the media did not alter the IR-evoked transients, ruling out extracellular Ca(2+) involvement or primary mediation by thermal effects on the plasma membrane. While blockage of Na(+), K(+), and Ca(2+) plasma membrane channels did not alter the IR-evoked response, blocking of mitochondrial Ca(2+) cycling with CGP-37157 or ruthenium red reversibly inhibited the IR-evoked [Ca(2+)]i transients. Additionally, the magnitude of the IR-evoked transients was dependent on ryanodine and cyclopiazonic acid-dependent Ca(2+) release. These results suggest that IR modulation of intracellular calcium cycling contributes to stimulation of spiral and vestibular ganglion neurons. As a whole, the results suggest selective excitation of neurons in the IR beam path and the potential of IR stimulation in future auditory and vestibular prostheses.

Molecular mechanisms involved in programmed cell death of HCs are different than the ones involved in programmed cell death of SCs. Local delivery of AM-111 provided a significant level of protection against EIT-induced hearing losses, HC losses, and damage to neural elements.

BACKGROUND AND PURPOSE Exposure to an ototoxic level of an aminoglycoside can result in hearing loss. In this we study investigated the otoprotective efficacy of dexamethasone (DXM), melatonin (MLT) and tacrolimus (TCR) in gentamicin (GM)-treated animals and cultures. EXPERIMENTAL APPROACH Wistar rats were divided into controls (treated with saline); exposed to GM only (GM); and three GM-exposed groups treated with either DXM, MLT or TCR. Auditory function and cochlear surface preparations were studied. In vitro studies of oxidative stress, pro-inflammatory cytokine mRNA levels, the MAPK pathway and caspase-3 activation were performed in organ of Corti explants from 3-day-old rats. KEY RESULTS DXM, MLT and TCR decreased levels of reactive oxygen species in GM-exposed explants. The mRNA levels of TNF-α, IL-1β and TNF-receptor type 1 were significantly reduced in GM + DXM and GM + MLT groups. Phospho-p38 MAPK levels decreased in GM + MLT and GM + TCR groups, while JNK phosphorylation was reduced in GM + DXM and GM + MLT groups. Caspase-3 activation decreased in GM + DXM, GM + MLT and GM + TCR groups. These results were consistent with in vivo results. Local treatment of GM-exposed rat cochleae with either DXM, MLT or TCR preserved auditory function and prevented auditory hair cell loss. CONCLUSIONS AND IMPLICATIONS In organ of Corti explants, GM increased oxidative stress and initiated an inflammatory response that led to the activation of MAPKs and apoptosis of hair cells. The three compounds tested demonstrated otoprotective properties that could be beneficial in the treatment of ototoxicity-induced hearing loss.

At 6 h post-EIT the SCs immunolabeled for the presence of phosphorylated-Jun and activated caspase-3. Phosphorylated p-Jun labeling was observed at 12 h in both the HCs and SCs of middle and basal cochlear turns. Cleaved caspase-3 was not observed in HCs of any cochlear turn at up to 24 h post-EIT. Lipid peroxidation (HNE immunostaining) was first observed at 12 h post-EIT in both the HCs and SCs of the basal turn, and reached the apical turn by 24 h post-EIT.

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