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CAREER:Genetic approaches to establish design rules for implantable neurotechnology

职业：建立植入式神经技术设计规则的遗传方法

基本信息

批准号：
1943716
负责人：
Erin Purcell
金额：
$ 54.33万
依托单位：
Michigan State University
依托单位国家：
美国
项目类别：
Continuing Grant
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1943716&HistoricalAwards=false
关键词：
CAREER Genetic approaches establish design

项目摘要

Brain cells communicate through the generation and transmission of electrical signals. Neurological diseases, such as Parkinson’s disease and Alzheimer’s disease, and injuries can result from faulty or interrupted signaling between networks of brain cells. The development of implanted electrodes, which are medical devices capable of “write-in” or “read-out” of electrical signals to and from the brain, has significantly improved the treatment and understanding of these neurological diseases and injuries. However, following implantation, the body recognizes the implanted device as a foreign object. The tissue response to the implant often results in a build-up of scar tissue and loss of signal-generating cells surrounding the device. This, in turn, is believed to contribute to a loss of function of the implant over time. This CAREER project seeks to answer fundamental questions regarding the tissue response to electrodes implanted in the brain: what are the critical biological events that most strongly impact long-term device performance, and how are they influenced by design features of the electrodes? To answer these questions, new techniques in molecular biology will be applied to reveal biological markers that can predict device performance; then device design choices will be systematically tested to determine the influence of materials and dimensions on these markers. As a result, the project is expected to deliver new understanding of how to design implanted electrodes with optimized biocompatibility and performance. The complementary educational objectives of the project are to strengthen the new graduate curricula in biomedical engineering at Michigan State University through the development of novel assessments of the success of the program, while creating a new peer-mentoring program for undergraduate women interested in entering the field of biomedical engineering. The Investigator’s long-term research goal is to create fully integrated neural electrode-tissue interfaces. Towards this goal, the goal of this CAREER project is to develop new approaches to understand and control biological responses to brain implants, which are believed to be a key limitation to device function, stability, and lifespan. The Research Plan is organized under three objectives. The FIRST Objective is to identify biomarkers of device-tissue interaction through RNA-sequencing. Laser capture microscopy (LCM) will be used to excise selected portions of brain tissue for extraction of RNA and subsequent sequencing to provide a comprehensive view of possible changes in gene expression induced by single shank, non-functional silicon-based devices implanted in the motor cortex of adult rats. Results will be compared to contralateral tissue samples receiving an insertion injury only (to control for “stab” wound effects), which will enable identification of a subset of genes that will be further screened as potentially key biomarkers of long-term chronic performance. The SECOND Objective is to test biomarker effects on signal detection through knockdown of the three gene expressions that were the most highly differentially expressed at the interface relative to control in the first objective. Knockdown will be via stable, viral-mediated expression surrounding functional, 16-channel, single-shank silicon microelectrode arrays implanted in the motor cortex of rats. Changes will be assessed in terms of the number of “units” detected per device, longevity of detected unit activity, signal-to-noise ratio (SNR), and amplitude of units and local field potentials, in comparison to contralateral control tissue treated with an empty vector. The THIRD Objective is to define design rules via systematic tests of electrode materials and feature sizes. Planar style, single shank arrays, will be fabricated from silicon, Parylene, polycrystalline diamond and polydimethylsiloxane. The impact of device dimensions, Young’s modulus, bending stiffness, and feature size on both traditional histological measures and the expression of biomarkers identified in the first two objectives will be tested. These results will provide guidance on design parameters that should be pursued to optimize the biointegration of electrodes with the brain.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

脑细胞通过产生和传输电信号进行交流。帕金森氏症和阿尔茨海默氏症等神经系统疾病和损伤可能是由于脑细胞网络之间的信号传递错误或中断造成的。植入式电极是一种医疗设备，能够将电信号写入或读出大脑，极大地提高了对这些神经疾病和损伤的治疗和理解。然而，植入后，人体会将植入的设备识别为异物。组织对植入物的反应通常会导致疤痕组织的堆积和设备周围产生信号的细胞的丢失。这反过来又被认为是随着时间的推移导致植入物功能丧失的原因。这个职业项目试图回答关于植入大脑的电极的组织反应的基本问题：什么是对长期设备性能影响最大的关键生物事件，以及电极的设计特征如何影响它们？为了回答这些问题，将应用分子生物学的新技术来揭示可以预测设备性能的生物标记；然后将系统地测试设备设计选择，以确定材料和尺寸对这些标记的影响。因此，该项目有望为如何设计具有最佳生物兼容性和性能的植入电极带来新的理解。该项目的互补教育目标是通过开发对该项目成功的新评估来加强密歇根州立大学新的生物医学工程研究生课程，同时为有兴趣进入生物医学工程领域的本科生女性创建一个新的同行指导计划。研究人员的长期研究目标是创建完全集成的神经电极-组织界面。为了实现这一目标，这个职业项目的目标是开发新的方法来了解和控制脑植入的生物反应，这被认为是设备功能、稳定性和寿命的关键限制。研究计划是按照三个目标组织的。第一个目标是通过RNA测序识别设备-组织相互作用的生物标记物。激光捕获显微镜(LCM)将被用于切除大脑组织的选定部分，以提取RNA并随后进行测序，以全面了解植入成年大鼠运动皮质的单柄、无功能的硅基设备可能诱导的基因表达变化。结果将与只接受插入损伤的对侧组织样本进行比较(以控制“刺伤”效应)，这将使识别将被进一步筛选为潜在的长期慢性行为关键生物标记物的基因子集成为可能。第二个目标是通过敲除三个基因表达来测试生物标记物对信号检测的影响，这三个基因在第一个目标中的界面上相对于对照表达的差异最大。基因敲除将通过在植入大鼠运动皮质的16通道单柄功能性硅微电极阵列周围稳定、病毒介导的表达来实现。与用空载体处理的对侧对照组织相比，将根据每个设备检测到的单位数量、检测到的单位活动的寿命、信噪比(SNR)以及单位和局部场电位的幅度来评估变化。第三个目标是通过对电极材料和特征尺寸的系统测试来确定设计规则。平面式单柄阵列将由硅、对二甲苯、多晶钻石和聚二甲基硅氧烷制成。将测试器械尺寸、杨氏模数、弯曲刚度和特征尺寸对传统组织学测量和前两个目标中确定的生物标记物表达的影响。这些结果将为设计参数提供指导，以优化电极与大脑的生物集成。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。