Combining Cell-Based Therapies and Neural Prostheses to Promote Neural Survival

Abstract

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.

Effects of Brain-Derived Neurotrophic Factor (BDNF) and Electrical Stimulation on Survival and Function of Cochlear Spiral Ganglion Neurons in Deafened, Developing Cats

“…However, the use of osmotic pumps to deliver neurotrophic factors clearly is not a good option for clinical application, particularly due to concerns about infection Staecker et al 2010). Numerous recent studies have explored alternative strategies for cochlear delivery of neurotrophins (Hendricks et al 2008;Richardson et al 2008), including cell-based therapies (Warnecke et al 2007;Pettingill et al 2008;Wise et al 2011), hydrogels (Endo et al 2005, and gene therapy using adenovirus-mediated expression of neurotrophic factors (Nakaizumi et al 2004;Rejali et al 2007;Chikar et al 2008;Wise et al 2010). These methods may provide better alternatives in the future, but they are still under development and concerns about potential side effects and risks have not yet been adequately addressed.…”

Plasma-Assisted Hydrophilization of Cochlear Implant Electrode Array Surfaces Enables Adhesion of Neurotrophin-Secreting Cells

“…It has been shown that the application of neurotrophins into the scala tympani enhances the survival and density of peripheral processes of the SGNs [2], attracts neurites into the scala tympani [3], and even reduces electrically evoked auditory brainstem response thresholds [4]. Cell-based approaches have been suggested for a sustained neurotrophin supply.…”

“…Cell-based approaches have been suggested for a sustained neurotrophin supply. For example, xenogenic choroid plexus cells [2] and genetically modified fibroblasts [5] have been implanted into the scala tympani. Adipose-derived stem cells (ASCs), multipotent stem cells that can be harvested from adult individuals, are also known to produce neurotrophins [6] and can be used autologously, thereby being more suitable for the application in patients.…”

Neurotrophins and their role in the cochlea

“…Although introducing alien cells into the cochlea bears risk of immune response or migration, several techniques have been developed to considerably minimize these risks (Rejali et al, 2007;Pettingill et al, 2011;Wise et al, 2011). Rejali et al (2007) showed that BDNF-releasing fibroblasts attached to a cochlear implant electrode have a positive effect on SGC survival in the basal half of the cochlea after 48 h. However, the life span of these fibroblasts was limited to several weeks, probably due to fixation of the cells to the electrode.…”