Cochlear implants provide partial restoration of hearing for profoundly deaf patients by electrically stimulating spiral ganglion neurons (SGNs); however, these neurons gradually degenerate following the onset of deafness. Although the exogenous application of neurotrophins (NTs) can prevent SGN loss, current techniques to administer NTs for long periods of time have limited clinical applicability. We have used encapsulated choroid plexus cells (NTCells; Living Cell Technologies, Auckland, New Zealand) to provide NTs in a clinically viable manner that can be combined with a cochlear implant. Neonatal cats were deafened and unilaterally implanted with NTCells and a cochlear implant. Animals received chronic electrical stimulation (ES) alone, NTs alone, or combined NTs and ES (ES + NT) for a period of as much as 8 months. The opposite ear served as a deafened unimplanted control. Chronic ES alone did not result in increased survival of SGNs or their peripheral processes. NT treatment alone resulted in greater SGN survival restricted to the upper basal cochlear region and an increased density of SGN peripheral processes. Importantly, chronic ES in combination with NTs provided significant SGN survival throughout a wider extent of the cochlea, in addition to an increased peripheral process density. Re-sprouting peripheral processes were observed in the scala media and scala tympani, raising the possibility of direct contact between peripheral processes and a cochlear implant electrode array. We conclude that cell-based therapy is clinically viable and effective in promoting SGN survival for extended durations of cochlear implant use. These findings have important implications for the safe delivery of therapeutic drugs to the cochlea.

Exogenous neurotrophin delivery to the deaf cochlea can prevent deafness-induced auditory neuron degeneration, however, we have previously reported that these survival effects are rapidly lost if the treatment stops. In addition, there are concerns that current experimental techniques are not safe enough to be used clinically. Therefore, for such treatments to be clinically transferable, methods of neurotrophin treatment that are safe, biocompatible and can support long-term auditory neuron survival are necessary. Cell transplantation and gene transfer, combined with encapsulation technologies, have the potential to address these issues. This study investigated the survival-promoting effects of encapsulated BDNF over-expressing Schwann cells on auditory neurons in the deaf guinea pig. In comparison to control (empty) capsules, there was significantly greater auditory neuron survival following the cell-based BDNF treatment. Concurrent use of a cochlear implant is expected to result in even greater auditory neuron survival, and provide a clinically relevant method to support auditory neuron survival that may lead to improved speech perception and language outcomes for cochlear implant patients.

Spiral ganglion neurons (SGNs) are the target cells of the cochlear implant, a neural prosthesis designed to provide important auditory cues to severely or profoundly deaf patients. The ongoing degeneration of SGNs that occurs following a sensorineural hearing loss is therefore considered a limiting factor in cochlear implant efficacy. We review neurobiological techniques aimed at preventing SGN degeneration using exogenous delivery of neurotrophic factors. Application of these proteins prevents SGN degeneration and can enhance neurite outgrowth. Furthermore, chronic electrical stimulation of SGNs increases neurotrophic factor-induced survival and is correlated with functional benefits. The application of neurotrophic factors has the potential to enhance the benefits that patients can derive from cochlear implants; moreover, these techniques may be relevant for use with neural prostheses in other neurological conditions.

Auditory neurons, the target neurons of the cochlear implant, degenerate following a sensorineural hearing loss. The goal of this research is to direct the differentiation of embryonic stem cells (SCs) into bipolar auditory neurons that can be used to replace degenerating neurons in the deafened mammalian cochlea. Successful replacement of auditory neurons is likely to result in improved clinical outcomes for cochlear implant recipients. We examined two post-natal auditory co-culture models with and without neurotrophic support, for their potential to direct the differentiation of mouse embryonic SCs into characteristic, bipolar, auditory neurons. The differentiation of SCs into neuron-like cells was facilitated by co-culture with auditory neurons or hair cell explants, isolated from post-natal day five rats. The most successful combination was the co-culture of hair cell explants with whole embryoid bodies, which resulted in significantly greater numbers of neurofilament-positive, neuron-like cells. While further characterization of these differentiated cells will be essential before transplantation studies commence, these data illustrate the effectiveness of post-natal hair cell explant co-culture, at providing valuable molecular cues for directed differentiation of SCs towards an auditory neuron lineage.