CAREER: High Density Bio-Compatible Electro-Fluidic Neural Interfaces for Mapping the Brain

概述：这项工作的主要目标是开发紧凑，生物相容性，高灵敏度和高分辨率的神经接口，利用一个新的电-流体电容探针家族。这些探针将感知、刺激和抑制动作电位，并提供以高度靶向的方式给药的能力，以及以前所未有的时间和空间分辨率监测对药物的生理反应。拟议的研究需要半导体器件处理，电建模和模拟，以及体外和体内生理测量。预期的结果将使人们能够更深入地了解大量神经元的神经功能，确定神经探针的缩放限制，并与教育、指导和推广活动相结合。智力优势：该计划的动机是需要克服技术挑战，以理解人类感知、行动、学习和记忆的神经过程，并在控制这些过程（如肢体运动）方面取得进展。这需要开发具有分辨率的电-神经接口，可以在单个细胞或亚细胞水平上探测大量神经元网络。神经探针还需要具有生物相容性，稳定性，并具有可靠的接口，以实现持久的操作。这项任务可以通过可编程和靶向的微流控药物递送来减轻免疫系统的反应并增强探针的生物相容性。这样的功能和分辨率是任何现有技术都无法满足的。该项目将开发一种新的神经探针，即电-流-容性探针，以满足这些要求。这些探针将采用一种新的制造工艺，用于在密集配置中处理单个3D神经探针。这一过程首次在神经探针电极阵列领域增加了通过每个单独的神经探针位点的多路和高度靶向的药物传递通道，从而实现了一种新颖而强大的神经生理学平台。该平台将引领神经生理学的新研究方向和改善患者护理的新技术，因为：(1)该平台可扩展到非常密集的阵列。(2)该探针具有生物相容性，因为其传感机制依赖于电容耦合，消除了电极部位的电化学反应。(3)多路微流控药物输送端口将有助于减少免疫系统对植入电极的反应，而目前的方法是生物相容性涂层是暂时的，并随着时间的推移而耗尽。(4)微流体输送通道将首次实现靶向药物输送和潜在的离子传感，其尺寸与神经突大小和突触距离相当。(5)该工艺与硅兼容，便于与信号处理和调理硅电路集成。更广泛的影响：拟议的项目将通过开发工具来加强研究基础设施，这些工具将在生物传感和神经假肢设备开发领域具有深远的适用性。该提议的平台将提供神经科学的新见解，并与奥巴马总统最近公布的“推进创新神经技术”（Brain Initiative）的大脑研究直接相关。由此产生的设备将首次实现高度局部电干预和同时靶向药物递送，这对于实现高保真神经假体设备至关重要。此外，还提出了一项计划，通过开发和教授一门新的核心课程“医疗设备和接口”，加强医疗设备多学科领域的研究生和本科生课程，该课程将包括加州大学圣地亚哥分校研究生目前无法获得的实验室培训。通过参与加州大学圣地亚哥分校高通研究所协调的外展项目，PI将为来自代表性不足群体的高中生提供指导和研究经验。积极参与加州大学圣地亚哥分校雅各布斯工程学院正在进行的促进多样性的活动，将使PI能够在学年和整个奖励期间的夏季为本科生提供研究经验。

Overview: The primary goal of this work is to develop compact, bio-compatible, high sensitivity and high resolution neural interfaces utilizing a new family of electro-fluidic capacitive probes. These probes will sense, stimulate and inhibit action potentials, as well as provide the capacity to deliver drugs in a highly targeted manner as well as monitor the physiological response to the drug with unprecedented temporal and spatial resolution. The proposed research entails semiconductor device processing, electrical modeling and simulations, and both in-vitro and in-vivo physiological measurements. Anticipated results will enable deeper understanding of neural functionality in a large population of neurons, determine the scaling limits for neural probes, and be integrated with educational, mentoring and outreach activities.Intellectual Merit:The proposed program is motivated by the need to overcome technological challenges to understanding the neurological processes by which humans perceive, act, learn and remember, and in doing so make headway toward controlling some of these processes such as limb movements. This requires development of electro-neural interfaces with resolution that can probe at the single cell or sub-cellular level in a network of a large population of neurons. The neural probes need also to be biocompatible, stable, and possess reliable interfaces for durable operation. This task can be best achieved with programmable and targeted microfluidic drug delivery to mitigate the response of the immune system and enhance the probes biocompatibility. Such functionality and resolution is not met with any existing technologies. A new family of neural probes, electro-fluidic capacitive probes, that can meet these requirements will be developed in this program. These probes will utilize a new fabrication process for the purpose of addressing individual 3D neural probes in a dense configuration. This process adds, for the first time in the field of neural probe electrode arrays, multiplexed and highly targeted drug delivery channels through each individual neural probe site, thus enabling a novel and robust neurophysiology platform. Such a platform will lead to new research directions in neurophysiology and new technologies to improve patient care because: (1) The platform is scalable to very dense arrays. (2) The probes are biocompatible because the sensing mechanism relies on capacitive coupling and eliminates electrochemistry at the electrode sites. (3) The multiplexed microfluidic drug delivery ports will help reduce the response of the immune system to implanted electrodes, in contrast to current approaches where biocompatible coatings are temporary and deplete with time. (4) The microfluidic delivery channels will enable targeted drug delivery, and potentially ion sensing, at dimensions that are comparable to neurite size and synaptic distances for the first time. (5) The process is compatible with silicon, allowing ease of integration with signal processing and conditioning silicon circuits. Broader Impact:The proposed project will enhance the research infrastructure through development of tools that will have far reaching applicability in the areas of biosensing and neuroprosthetic device development. The proposed platform will deliver new insights into neuroscience and has direct relevance to the Brain Research though Advancing Innovative Neurotechnologies (BRAIN Initiative) recently unveiled by President Obama. The resulting devices will enable for the first time highly localized electrical intervention and simultaneous targeted drug delivery that are critical for realizing high fidelity neuroprosthetic devices. Also proposed are plans to enhance graduate and undergraduate curricula in the multidisciplinary area of medical devices by developing and teaching a new core course, Medical Devices and Interfaces, that will include laboratory training not currently available to UCSD graduate students. Through participation in outreach programs coordinated by UCSD's Qualcomm Institute, the PI will mentor and provide research experiences for high school students from underrepresented groups. Active participation in ongoing diversity-promoting initiatives of UCSD's Jacobs School of Engineering will enable the PI to provide research experiences for undergraduate students during the academic year as well as the summer throughout the award period.