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

描述(申请人提供)：脑机接口(BMI)允许神经系统与外部设备直接通信，以减轻与神经退行性变相关的缺陷或驱动外围假体。使用穿透性微电极阵列和光遗传学策略已经取得了实质性的进展；然而，这些方法受到限制，因为它们通常依赖于将非有机电极/光学电极放置到大脑中，不可避免地导致炎性异物反应，最终降低记录和刺激的质量。在另一种策略中，我们正在利用先进的微组织工程技术来创造第一个治疗慢性BMI的生物“活电极”。新型微组织工程神经网络(Micro-Tens，Micro-Tenns)是由离散的神经元群体(S)在微小的管状水凝胶中通过长轴索连接而成的活电极。这些活的微米级结构能够穿透大脑到指定的深度，与局部神经元/轴突整合，后者保持在大脑表面的外部，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，我们先前已经证明，微Tenn神经元存活，与局部宿主神经元整合，并保持其轴突结构。这些特征在当前的提案中被利用，以推动活电极作为功能继电器进出深层皮质。在这种激进的模式中，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，我们可以影响微Tenn神经元与之形成突触的特定宿主神经元亚型，从而在局部刺激和记录方面增加目前用传统微电极无法达到的特异性水平。在这个方案中，我们将利用电生理学、光遗传学和先进的显微镜技术来揭示大鼠大脑表面微Tenn突触与脑神经网络整合以及与皮质表面微Tenn神经元交叉通讯的证据。这些研究将展示这一多功能平台技术读出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。这将是第一次展示组织工程“活电极”在功能上整合到天然神经网络中，并作为双向刺激和记录的管道。这项神经科学和工程学交界的潜在变革性技术为预制可植入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.