Translational Neuroscience Facility and Department of Physiology, School of Medical Sciences, University of New South Wales, UNSW Australia, Sydney, New South Wales 2052, Australia.
Sci Transl Med. 2014 Apr 23;6(233):233ra54. doi: 10.1126/scitranslmed.3008177.
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.
人工耳蜗是最成功的仿生假体，改变了许多重度听力损失患者的生活。然而，“仿生耳”的性能在很大程度上仍然受到神经接口本身的限制。当前，广泛的单极刺激螺旋神经节神经元胞体所固有的电流扩散，消除了耳蜗神经的固有音调映射。我们在豚鼠中表明，神经营养因子基因治疗与人工耳蜗结合可以通过刺激螺旋神经节神经突再生来改善其性能。我们使用人工耳蜗电极阵列进行新型“近场”电穿孔，将排列在耳蜗外淋巴道的间充质细胞转染为一种裸露的互补 DNA 基因构建体，该构建体驱动脑源性神经营养因子 (BDNF) 和绿色荧光蛋白 (GFP) 报告基因的表达。特定人工耳蜗电极构型聚焦电场导致相邻间充质细胞的基因传递效率惊人地高。由此产生的 BDNF 表达刺激了螺旋神经节神经突的再生，在双侧感音神经性耳聋模型中，这种神经突在耳毒性治疗 2 周后已经萎缩。在该模型中，递送仅 GFP 的对照载体未能恢复神经元结构，萎缩的神经元与未植入的耳蜗无法区分。使用 BDNF 治疗后，再生的螺旋神经节神经突延伸至人工耳蜗电极附近，并出现局部异位分支。这种神经重塑使通过人工耳蜗阵列进行双极刺激成为可能，电诱发听脑干反应确定了较低的刺激阈值和扩大的耳蜗神经动态范围。这一发展可能会广泛改善神经接口并扩展分子医学的应用。
