Biological 'Living Electrodes' Using Tissue Engineered Axonal Tracts to Probe and Modulate the Nervous System

描述（由申请人提供）：脑机接口（bmi）允许神经系统直接与外部设备通信，以减轻与神经退行性变相关的缺陷或驱动周围假肢。使用穿透微电极阵列和光遗传学策略已经取得了实质性进展；然而，这些方法的局限性在于，它们通常依赖于在大脑中放置非有机电极/电极，不可避免地导致炎症性异物反应，最终降低记录和刺激的质量。在另一种策略中，我们利用先进的微组织工程技术为慢性BMI创造了第一个生物“活电极”。新型的微组织工程神经网络（micro-Tissue Engineered Neural Networks, micro-TENNs）作为活电极，它是由由长轴突束连接在微型管状水凝胶中的离散神经元群组成的。这些活的微米级结构能够穿透大脑到规定的深度，与局部神经元/轴突结合，后一部分留在大脑表面，在那里使用下一代光学和电子接口收集功能信息。在移植到大鼠体内后，我们之前的研究表明，微tenn神经元存活，与局部宿主神经元整合，并维持其轴突结构。这些特征在目前的提议中被利用，以推进活电极作为往返于皮层深层的功能继电器。在这种激进的范式中，只有这些结构的生物成分才能穿透大脑，从而减弱慢性异物反应。此外，通过定制细胞和组织工程技术，我们可以影响与微tenn神经元形成突触的特定宿主神经元亚型，从而增加局部刺激和重新编码的特异性水平，这是目前传统微电极无法实现的。在这项提议中，我们将利用电生理、光遗传学和先进的显微镜技术来揭示大鼠微神经元突触与大脑神经网络整合以及与皮层表面微神经元交叉交流的证据。这些研究将证明这种多功能平台技术读取局部感觉运动活动并提供影响神经活动和功能的输入的能力。这将是组织工程“活电极”的第一次演示，该电极在功能上集成到原生神经网络中，并作为双向刺激和记录的管道。这种潜在的神经科学和工程学结合的变革性技术为预成型植入式神经网络作为传统电极的可行替代品奠定了基础。

DESCRIPTION (provided by applicant): Brain Machine Interfaces (BMIs) allow the nervous system to directly communicate with external devices in order to mitigate deficits associated with neurodegeneration or to drive peripheral prosthetics. There has been substantial progress using penetrating microelectrode arrays and optogenetics strategies; however, these approaches are limited in that they generally rely on placing non-organic electrodes/optrodes into the brain, inevitably leading to an inflammatory foreign body response that ultimately diminishes the quality of the recording and stimulation. In an alternative strategy, we are utilizig advanced micro-tissue engineering techniques to create the first biological "living electrodes" for chronic BMI. Novel micro-Tissue Engineered Neural Networks (micro-TENNs) serve as the living electrodes, which are composed of discrete population(s) of neurons connected by long axonal tracts within miniature tubular hydrogels. These living micron-scale constructs are able to penetrate the brain to a prescribed depth for integration with local neurons/axons, with the latter portion remaining externalized on the brain surface where functional information is gathered using a next-generation optical and electrical interface. Following transplant into rats, we have previously shown that micro-TENN neurons survive, integrate with local host neurons, and maintain their axonal architecture. These features are exploited in the current proposal to advance living electrodes as a functional relay to and from deep cortical layers. In this radical paradigm, only the biological component of these constructs penetrates the brain, thus attenuating a chronic foreign body response. Moreover, through custom cell and tissue engineering techniques, we may influence the specific host neuronal subtypes with which the micro-TENN neurons form synapses, thereby adding a level of specificity in local stimulation and recoding not currently attainable with conventional microelectrodes. In this proposal, we will utilize electrophysiological, optogenetic, and advanced microscopy techniques to reveal evidence of micro-TENN synaptic integration with brain neural networks and cross-communication with micro-TENN neurons on the cortical surface in rats. These studies will demonstrate the ability of this versatile platform technology to read out local sensorimotor activity and provide input to affect neural activity and function. This will be the first demonstration of tissue engineered "living electrodes" to functionally integrate into native neural networks and to serve as a conduit for bi-directional stimulation and recording. This potentially transformative technology at the interface of neuroscience and engineering lays the foundation for preformed implantable neural networks as a viable alternative to conventional electrodes.