Close-Field Electroporation Gene Delivery Using the Cochlear Implant Electrode Array Enhances the Bionic Ear

Abstract

The cochlear implant is the most successful bionic prosthesis and has transformed the lives of people with profound hearing loss. However, the performance of the "bionic ear" is still largely constrained by the neural interface itself. Current spread inherent to broad monopolar stimulation of the spiral ganglion neuron somata obviates the intrinsic tonotopic mapping of the cochlear nerve. We show in the guinea pig that neurotrophin gene therapy integrated into the cochlear implant improves its performance by stimulating spiral ganglion neurite regeneration. We used the cochlear implant electrode array for novel "close-field" electroporation to transduce mesenchymal cells lining the cochlear perilymphatic canals with a naked complementary DNA gene construct driving expression of brain-derived neurotrophic factor (BDNF) and a green fluorescent protein (GFP) reporter. The focusing of electric fields by particular cochlear implant electrode configurations led to surprisingly efficient gene delivery to adjacent mesenchymal cells. The resulting BDNF expression stimulated regeneration of spiral ganglion neurites, which had atrophied 2 weeks after ototoxic treatment, in a bilateral sensorineural deafness model. In this model, delivery of a control GFP-only vector failed to restore neuron structure, with atrophied neurons indistinguishable from unimplanted cochleae. With BDNF therapy, the regenerated spiral ganglion neurites extended close to the cochlear implant electrodes, with localized ectopic branching. This neural remodeling enabled bipolar stimulation via the cochlear implant array, with low stimulus thresholds and expanded dynamic range of the cochlear nerve, determined via electrically evoked auditory brainstem responses. This development may broadly improve neural interfaces and extend molecular medicine applications.

Improved Auditory Nerve Survival with Nanoengineered Supraparticles for Neurotrophin Delivery into the Deafened Cochlea

“…Given the potential infection risks of implantable pump devices [26] and the limitations of systemic delivery in crossing the blood-labyrinth barrier, research has focused on localised neurotrophins delivery strategies that are clinically translatable and that can be combined with a cochlear implant. These include cell-based therapies [32–34], gene therapies [35–41], electrode coating materials [42–45] and biocompatible carrier systems including nanoparticles [46–49]. Although each approach has advantages and limitations, the use of nanoengineered carriers offers promise of delivering therapeutic levels of neurotrophins in a safe manner that is effective over the long term.…”

Translational Animal Models for Regenerative Medicine Research

“…Attempts to model human physiology and pathology employ immunodeficient mice transplanted with human stem cells as discussed later in this chapter in the section on immunodeficient mice. Using a guinea pig model, Pinyon et al [43] recently employed electronic pulses delivered by a cochlear implant to deliver DNA coding for neurotrophin into the auditory nerve, and this initiated regeneration.…”

Optogenetic stimulation of the auditory pathway for research and future prosthetics

“…AAV-mediated gene transfer to the human eye has been proven to be efficient and safe in clinical trials following single-term subretinal injection [41]. Future work toward clinical translation should also consider nonviral transduction such as electroporation by CI electrodes [14 ]. Moreover, considering the case of deafness with major loss of SGNs, that may in the future be served by grafting stem cell-derived otic neural precursor cells to regenerate functionally connected SGNs [42], the specific and confined optical stimulation of ChR-expressing grafted cells could help evaluating the function of grafted cells and provide a one step procedure for regenerating SGN and CI with improved frequency resolution.…”

“…Research toward better frequency resolution of electrical CIs includes multipolar stimulation [12], intraneural electrodes [13 ], efforts to achieve outgrowth of neurites toward CI contacts (e.g. ref [14 ]) and most recently optical stimulation [15 ,16 ].…”