Enhancing the Bionic Ear through Close-Field Electroporation Gene Therapy

The field of bionics is rapidly realising the potential to restore sensory and motor function lost through genetics, aging, the environment, or misadventure. The cochlear implant (CI) is the most advanced and widely utilised bionic prosthesis. Hundreds of thousands of severely hearing impaired individuals have taken the opportunity to perceive sound and improve their speech capability through implantation of the CI electrode array. The performance of the modern CI, or ‘bionic ear’, is largely constrained by the neural interface itself. The broad monopolar stimulation that CIs employ to stimulate the auditory nerve, using up to 22 electrodes, vastly reduces the potential for pitch discrimination that is tonotopically mapped by thousands of hair cells and spiral ganglion neurons (SGNs) along the length of the cochlea. We show in a deafened guinea pig model that neurotrophin gene therapy integrated into the cochlear implantation procedure can significantly improve neural recruitment. We utilised the CI array for novel ‘close-field’ electroporation (CFE) to efficiently transduce mesenchymal cells lining the cochlear perilymphatic ducts with naked plasmid DNA driving brain-derived neurotrophic factor (BDNF) and green fluorescent protein (GFP) expression. BDNF transgene expression caused regeneration of the SGN peripheral neurites to close apposition with the CI microarray, with localised ectopic branching. This neural remodelling lowered activation thresholds and expanded the dynamic range of the cochlear nerve using bipolar stimulation between internal electrodes of the CI to electrically evoke auditory brainstem responses. Electric field mapping of the CI-based gene electrotransfer pulses using an HEK293 cell monolayer model showed that a parallel multi-nodal (tandem) configuration of the electrodes generated comparatively high electric fields close to the array, resulting in surprisingly efficient and directed transfection of cells in a spherical shape. An ‘alternating’ CI array configuration produced a linear shaped field of transduced cells; demonstrating the potential for this focal gene delivery platform to control the size and shape of transduced cell fields. These proof of principal studies showing enhanced bionic interface performance with CFE BDNF gene delivery and the ‘dial-up’ control of the gene electrotransfer highlights the broad potential of this platform for local gene therapy applications within molecular medicine