The Tissue-Engineered Electronic Nerve Interface (TEENI)

组织工程电子神经接口 (TEENI)

• 批准号: 9910474
• 负责人: Jack W Judy
• 金额: $ 60.17万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-15 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9910474
• 关键词: 3-Dimensional; Action Potentials; Adhesions; Adverse effects; Aging; Amputation; Amputees; Axon; Basal lamina; Biological Markers; Brain; Caliber; Cellular Assay; Cellular Morphology; Charge; Chronic; Cicatrix; Data; Dependence; Devices; Dimensions; Electrodes; Electrophysiology (science); Engineering; Environment; Extracellular Matrix; Fiber; Film; Foreign Bodies; Formulation; Foundations; Freedom; Geometry; Goals; Hand; High temperature of physical object; Histologic; Histology; Human; Hydrogels; Hydrogen Peroxide; Implant; In Vitro; Length; Light; Limb Prosthesis; Limb structure; Link; Magnetism; Mechanics; Metals; Methods; Microelectrodes; Microscopy; Mission; Modeling; Motor; Movement; Natural regeneration; Nerve; Nerve Fibers; Nerve Regeneration; Nerve Tissue; Neurons; Noise; Operative Surgical Procedures; Pathway interactions; Performance; Peripheral Nerves; Phase; Polymers; Population; Process; Property; Protocols documentation; Quality of life; Ranvier' s Nodes; Rattus; Reporting; Research; Resolution; Sampling; Schwann Cells; Sensory; Sensory Receptors; Signal Transduction; Small Intestinal Submucosa; Source; Spinal Ganglia; Surface; Surgical sutures; System; Technology; Testing; Thick; Thinness; Time; Tissue Engineering; Tissues; Titanium; United States National Institutes of Health; Width; arm movement; axon regeneration; base; biocompatible polymer; brain tissue; capsule; cell motility; clinically translatable; cost; crosslink; density; design; disability; electric impedance; experimental study; implantation; improved; in vivo; insight; microdevice; multi-electrode arrays; regenerative; relating to nervous system; response; scaffold; sciatic nerve; silicon carbide

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.

项目概要： 让截肢者能够充分利用最先进的假肢的全部功能，具有快速的精细运动控制和高强度 分辨率感觉知觉，一种具有大量可靠且独立的运动和运动通道的神经接口 需要感官信息。神经中最强的信号源是朗飞结，本质上是 随机分布在一个小的 3-D 体积内。因此，为了全面参与神经的电活动， 神经接口应该询问相同比例的 3D 体积中的神经。迄今为止，临床可转化性 所有现有神经接口的性能和/或工作寿命是：仅限于低通道数和/或 非 3-D 电极排列，能够仅以非常低的信号幅度检测单个单元的活动，而这些信号幅度通常是 被噪音淹没，和/或触发异物反应，导致通道性能随着时间的推移而下降。我们的 3D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”）植入组织工程可生物降解的基于细胞外基质的水凝胶神经中 脚手架。我们将这种新型神经接口称为组织工程电子神经接口（TEENI）。在 初步研究表明，我们可以（1）微制造能够承受高电压的多电极阵列。 使用非晶碳化硅和钛进行温度反应加速老化 (RAA) 浸泡测试 金属层和聚酰亚胺层之间的粘合层，(2) 通过集成堆叠的电极形成 3D 电极阵列 将聚合物-金属多电极阵列放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）支撑水凝胶，提供可缝合的末端以连接神经，并便于手术 处理和植入不会限制电极阵列的设计或损坏它，（3）实现稳健 将脉管系统和神经纤维再生到 TENI 支架中，以及 (4) 获得单个单元的长期记录 TEENI 植入物内部的活动。然而，我们提出了两项​​观察，激发了该提案的具体目标。 首先，我们观察到每条线周围都有紧密的组织反应，这可能会限制 3-D TEENI 多线的密度。 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 沿着微加工的多电极阵列，其余部分沿着 SIS 包裹的内表面生长， 两者之间有不完全降解的水凝胶。在具体目标 1 中，我们建议减少外国企业的规模。 身体反应的方式与植入脑组织的微型探针所实现的方式相同：减少 植入物的宽度和厚度分别为约 10 µm 和约 1 µm。在具体目标 2 中，我们建议使用 微通道模板水凝胶可增加轴突和雪旺细胞附近再生的数量和均匀性 TENI 微加工多电极阵列。为了获得对 TEENI 表现的独特见解，我们将 可视化电极、节点、轴突、脉管系统以及内部界面周围任何组织反应的 3D 分布 通过使用设备捕获组织学、CLARITY 和光片显微镜来观察再生神经。