The Tissue-Engineered Electronic Nerve Interface (TEENI)

项目概要： 对于截肢者来说，利用最先进的假肢的全部功能，快速精细的运动控制和高 分辨率感觉知觉，一个神经接口，具有大量可靠和独立的运动和运动通道， 需要感官信息。神经中最强的信号源是朗维尔结，其基本上是 随机分布在一个小的三维空间中。因此，为了全面地参与神经的电活动， 神经接口应该在相同尺度的3D体积中询问神经。到目前为止，临床可翻译性， 所有现有神经接口的性能和/或操作寿命：限于低通道计数和/或 非3D电极排列，能够仅在非常低的信号幅度下检测单个单位活动， 被噪声淹没，和/或触发与随时间降低的信道性能相关的异物响应。我们 一种用于3-D可扩展神经接口的范式转换方法是集成一堆多电极薄膜聚酰亚胺， 将金属电极阵列（“线”）插入组织工程化的可生物降解的基于细胞外基质的水凝胶神经中 脚手架我们称这种新的神经接口为组织工程电子神经接口（TEENI）。在 初步研究表明，我们可以（1）微制造多电极阵列，可以生存高- 通过使用无定形碳化硅和钛的温度反应加速老化（RAA）浸泡试验 在金属和聚酰亚胺层之间的粘合层，（2）通过集成 将聚合物-金属多电极阵列植入包裹有小肠的基于细胞外基质的水凝胶支架中， 粘膜下层（SIS）以支撑水凝胶，提供可缝合的端部用于附接到神经，并且便于容易的手术 操作和植入，而不限制电极阵列的设计或损坏它，（3）实现坚固的 血管和神经纤维再生到TEENI支架中，以及（4）获得单个单位的慢性记录。 TEENI植入物内的活动。然而，我们提出了两个意见，促使我们提出这项建议的具体目标。 首先，我们观察到每根线周围的紧密组织反应，这可能会限制三维TEENI多点成像的密度。 电极线集成。其次，我们观察到只有一小部分再生的神经组织优先生长， 沿着微制造的多电极阵列，剩余部分沿着沿着SIS包裹物的内表面生长， 在两者之间具有不完全降解的水凝胶。在具体目标1中，我们建议减少外国公司的规模， 与植入脑组织的微加工探针相同的身体反应：减少 植入物的宽度和厚度分别为~10 µm和~1 µm。在具体目标2中，我们建议使用 微通道模板水凝胶，以增加轴突和雪旺细胞再生的数量和均匀性， TEENI微加工多电极阵列。为了深入了解青少年的表现，我们将 可视化电极、节点、轴突、脉管系统和内部接口周围的任何组织反应的三维分布 再生的神经，采用设备捕获组织学，显微镜，和光片显微镜。

PROJECT SUMMARY: For amputees to exploit the full capability of state-of-the-art prosthetic limbs with rapid fine-movement control and high- resolution sensory percepts, a nerve-interface with a large number of reliable and independent channels of motor and sensory information is needed. The strongest signal sources in nerves are the nodes of Ranvier, which are essentially distributed randomly within a small 3-D volume. Thus, to comprehensively engage with the electrical activity of a nerve, a neural interface should interrogate a nerve in a 3-D volume of the same scale. To date, the clinical translatability, performance, and/or operational lifetime of all existing nerve-interfaces are either: limited to low channel counts and/or non-3-D electrode arrangements, capable of detecting single-unit activity at only very low signal amplitudes that are often swamped by noise, and/or trigger a foreign body response linked to diminished channel performance over time. Our paradigm-shifting approach for 3-D scalable nerve interfaces is to integrate a stack of multi-electrode thin-film polyimide- metal electrode arrays (“threads”) into tissue-engineered biodegradable extracellular-matrix-based hydrogel nerve scaffold. We call this new class of neural interface Tissue-Engineered Electronic Nerve Interfaces (TEENI). In preliminary studies we demonstrated that we can (1) microfabricate multi-electrode arrays that can survive high- temperature reactive-accelerated aging (RAA) soak tests through the use of amorphous silicon-carbide and titanium adhesion layers between the metal and polyimide layers, (2) form a 3-D array of electrodes by integrating a stack of polymer-metal multi-electrode arrays into an extracellular-matrix-based hydrogel scaffold wrapped with small-intestinal submucosa (SIS) to support the hydrogel, provide suturable ends for attachment to the nerve, and facilitate easy surgical handling and implantation without limiting the design of the electrode array or damaging it, (3) achieve robust regeneration of vasculature and neural fibers into the TEENI scaffold, and (4) obtain chronic recordings of single-unit activity inside TEENI implants. However, we made two observations that motivated the specific aims for this proposal. First, we observed a tight tissue response around each thread that that could limit the density of 3-D TEENI multi- electrode-thread integration. Second, we observed that only a fraction of the regenerated nerve tissue preferentially grew along the microfabricated multi-electrode arrays, with the remainder growing along the inner surface of the SIS wrap and with incompletely degraded hydrogel between the two. In Specific Aim 1 we propose to reduce the size of the foreign body response in the same manner it has been achieved with microfabricated probes implanted into brain tissue: reduce the width and thickness of the implant to ~10 µm and ~1 µm respectively. In Specific Aim 2 we propose to use microchannel-templated hydrogels to increase the number and uniformity of axons and Schwann cells regenerating near the TEENI microfabricated multi-electrode arrays. To gain unique insight into the performance of TEENIs, we will visualize the 3-D distribution of electrodes, nodes, axons, vasculature, and any tissue response around the interface inside the regenerated nerve by employing device-capture histology, CLARITY, and light sheet microscopy.