Data_Sheet_2_Computational Simulation Expands Understanding of Electrotransfer-Based Gene Augmentation for Enhancement of Neural Interfaces.pdf

The neural interface is a critical factor in governing efficient and safe charge transfer between a stimulating electrode and biological tissue. The interface plays a crucial role in the efficacy of electric stimulation in chronic implants and both electromechanical properties and biological properties shape this. In the case of cochlear implants, it has long been recognized that neurotrophins can stimulate growth of the target auditory nerve fibers into a favorable apposition with the electrode array, and recently such arrays have been re-purposed to enable electrotransfer (electroporation)-based neurotrophin gene augmentation to improve the “bionic ear.” For both this acute bionic array-directed electroporation and for chronic conventional cochlear implant arrays, the electric fields generated in target tissue during pulse delivery are central to efficacy, but are challenging to map. We present a computational model for predicting electric fields generated by array-driven DNA electrotransfer in the cochlea. The anatomically realistic model geometry was reconstructed from magnetic resonance images of the guinea pig cochlea and an eight-channel electrode array embedded within this geometry. The model incorporates a description of both Faradaic and non-Faradaic mechanisms occurring at the electrode-electrolyte interface with frequency dependency optimized to match experimental impedance spectrometry measurements. Our simulations predict that a tandem electrode configuration with four ganged cathodes and four ganged anodes produces three to fourfold larger area in target tissue where the electric field is within the range for successful gene transfer compared to an alternate paired anode-cathode electrode configuration. These findings matched in vivo transfection efficacy of a green fluorescent protein (GFP) reporter following array-driven electrotransfer of the reporter-encoding plasmid DNA. This confirms utility of the developed model as a tool to optimize the safety and efficacy of electrotransfer protocols for delivery of neurotrophin growth factors, with the ultimate aim of using gene augmentation approaches to improve the characteristics of the electrode-neural interfaces in chronically implanted neurostimulation devices.

神经接口在调控刺激电极与生物组织之间高效且安全的电荷转移过程中起着至关重要的作用。该接口在慢性植入的电动刺激效果中扮演着决定性的角色，其中电机械特性和生物学特性共同塑造了这一效果。在耳蜗植入的案例中，长期以来人们已经认识到神经营养因子能够刺激目标听觉神经纤维的生长，使其与电极阵列形成有利的接触，而最近，此类阵列已被重新设计以实现基于电转移（电穿孔）的神经营养因子基因增强，从而改善“生物耳”的功能。对于这种急性生物阵列导向的电穿孔以及慢性传统耳蜗植入阵列，脉冲传递过程中在目标组织中产生的电场对于效果至关重要，但其分布却难以精确描绘。我们提出了一种计算模型，用于预测耳蜗中由阵列驱动DNA电转移产生的电场。该模型的几何形状基于豚鼠耳蜗的磁共振图像以及嵌入该几何形状中的八通道电极阵列重建。模型包含了电极-电解质界面处发生的法拉第效应和非法拉第效应的描述，其频率依赖性经过优化，以匹配实验阻抗光谱测量。我们的模拟预测，与交替的阴阳电极配置相比，串联电极配置（四个并联阴极和四个并联阳极）在目标组织中产生更大的区域，其中电场在成功基因转移的范围内，可达三至四倍。这些发现与绿色荧光蛋白（GFP）报告基因在阵列驱动电转移报告基因编码质粒DNA后的体内转染效率相匹配。这证实了所开发模型作为优化电转移协议安全性和有效性的工具的实用性，最终目的是利用基因增强方法来改善慢性植入神经刺激装置中的电极-神经接口特性。