Development and evaluation of novel high-density intracortical microelectrode arrays for clinical applications

项目概要 Paradromics 正在开发高数据速率脑机接口技术作为医疗平台 设备应用程序。在第一阶段 SBIR 中，我们设计、构建并测试了一个基于 粘合到 CMOS 读出电子器件的大规模并行微丝电极阵列。该系统支持 以超过 32,000 Hz 的频率同时采样 65,536 个有源电极通道。我们用这个系统来记录 大鼠体内多达 1200 个微电极阵列（穿透，1 毫米深度）和局部场的动作电位 绵羊体内超过 30,000 个微电极（表面）的电位。这作为微线的演示 to-CMOS 接合架构将构成我们下一个设备（医疗植入物）的核心。 对于这种新型植入式医疗设备，我们开发了一种新的且经过大幅改进的方法 电极阵列制造。该方法通过放电产生更加有序、规则的阵列 加工（EDM），从而改进了第一阶段束结构的随机连接 能够在 GMP 下生产。一种新的定制 CMOS 传感器，也是根据 NIH SBIR 开发的 第一阶段的工作是对神经数据进行压缩感知，以减少系统中的功耗和数据需求 未来的设备。 当我们准备制造这种植入式医疗设备并将其推向市场时，广泛测试这一点至关重要 不同阵列设计的插入可靠性，以便生产出最适合插入和插入的器件 录音。在这里，我们建议使用 400-1600 个电极的无源阵列，比我们的第一阶段方法要小， 寻找用于临床转化的最佳电极阵列设计。我们将测试能够可靠地 插入绵羊皮层，在术中验证该阵列在人体组织中的插入（在 IRB 下）， 并评估长期植入绵羊体内的阵列长达 6 个月的组织反应。 未来阵列的总体目标是确保我们能够可靠地插入具有最小柄的阵列 以适当的节距（100 - 400 μm）和长度（即 1 mm）适合人类皮质。 此外，这些数据对于设计经过认证的 GLP 研究以及规划与 FDA 召开 IDE 前会议，我们需要制定最终的阵列设计和测试计划。 这项直接进入 II 期研究的目的如下： 具体目标 (SA) 1：确定最佳微电极阵列设计并验证绵羊体内的植入 术中使用 400-1600 个电极的无源阵列检测人体皮质组织。我们的目标是更好 了解高密度微丝电极阵列的几何参数如何影响插入可靠性 在绵羊（绵羊）模型（SA 1.1）中植入体内皮质组织，并在术中植入精细的几何形状 进入人类皮质（SA 1.2）。 具体目标 2：确定绵羊体内植入的无源阵列的长期可行性。 。我们将确定 通过将无源阵列长期植入绵羊体内，我们的高密度阵列的长期可行性。动物 将在 4、8、12 和 24 周内植入。将比较神经胶质疤痕和神经元损失的程度 在这些时间点上，高密度阵列和商业阵列之间的电极周围。

PROJECT SUMMARY Paradromics is developing high data rate brain computer interface technologies as a platform for medical device applications. In our Phase I SBIR, we designed, built, and tested a neural recording system based on massively parallel microwire electrode arrays bonded to CMOS readout electronics. That system supports up to 65,536 active electrode channels sampled simultaneously at over 32,000 Hz. We used this system to record action potentials from arrays of up to 1200 microelectrodes in rats (penetrating, 1mm depth) and local field potentials from >30,000 microelectrodes in sheep (surface). This serves as a demonstration of the microwire- to-CMOS bonding architecture that will form the core of our next device, a medical implant. For this new implantable medical device, we have developed a new and substantially improved method of electrode array fabrication. This method produces more ordered, regular arrays through Electrical Discharge Machining (EDM), thus improving on the stochastic connections of the bundle architecture from Phase I with the ability to be produced under GMP. A new, custom CMOS sensor, also developed following the NIH SBIR Phase I effort, performs compressive sensing of neural data to reduce power and data requirements in the future device. As we prepare to build this implantable medical device and take it to market, it is critical to extensively test the insertion reliability of different arrays designs in order to produce a device best optimized for insertion and recording. Here we propose to use passive arrays of 400-1600 electrodes, smaller than our Phase I approach, to find the optimal electrode array design for clinical translation. We will test array designs that can reliably insert into the sheep cortex, validate the insertion of that array in human tissue intraoperatively (under IRB), and evaluate the tissue response to the array over a period of up to 6 months, implanted chronically in sheep. The overall goal for the future array is to ensure that we can reliably insert the array with the smallest shank width to mitigate the chronic foreign body response at an appropriate pitch (100 - 400 μm) and length (i.e. 1 mm) suitable for the human cortex. Moreover, this data will also be critical for designing certified GLP studies, and for planning conversations with the FDA for pre-IDE meetings, where we will need a finalized array design and testing plan in place. The aims of this Direct to Phase II study are as follows: Specific Aim (SA) 1: Determine optimal microelectrode array design and validate implantation in sheep and human cortical tissue intraoperatively with passive arrays of 400-1600 electrodes. We aim to better understand how the geometric parameters of high density microwire electrode arrays impact insertion reliability into cortical tissue in vivo in an ovine (sheep) model (SA 1.1), with refined geometries implanted intraoperatively into human cortex (SA 1.2). Specific Aim 2: Determine long-term viability of implanted, passive arrays in sheep. . We will determine the long-term viability of our high-density array by chronically implanting the passive arrays in sheep. Animals will be implanted over 4, 8, 12, and 24 weeks. The degree of glial scarring and neuron loss will be compared around electrodes between high-density and commercial arrays over these timepoints.