Micro-invasive biochemical sampling of brain interstitial fluid for investigating neural pathology

脑间质液微创生化取样用于研究神经病理学

• 批准号: 9885472
• 负责人: Michael J Cima
• 金额: $ 62.86万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9885472
• 关键词: Acetylcholine; Address; Agonist; Alloys; Analytical Chemistry; Animal Model; Animals; Anxiety; Behavior; Biochemical; Biological Markers; Biomedical Engineering; Blood capillaries; Brain; Brain region; Caliber; Characteristics; Chemicals; Chronic; Clinical; Cocaine; Collection; Coupled; Detection; Devices; Diffusion; Disease; Dynorphins; Family; Functional disorder; Future; Glutamates; Goals; Health; Human; Implant; In Vitro; Intercellular Fluid; Knowledge; Lead; Legal; Link; Liquid Chromatography; Liquid substance; Longitudinal Studies; Measurable; Measurement; Measures; Membrane; Memory; Methods; Microdialysis; Microfabrication; Microinvasive; Molecular; Monitor; Neuropeptides; Neurosciences; Neurotransmitters; Nucleus Accumbens; Opioid; Pathologic; Pathology; Pharmaceutical Preparations; Physiological; Pump; Rattus; Relapse; Resolution; Rodent; Rodent Model; Role; Sampling; Scientist; Self Administration; Shapes; Stress; Substance Use Disorder; Substance abuse problem; System; Techniques; Technology; Testing; Time; Translations; Wireless Technology; Withdrawal; accurate diagnosis; acute stress; addiction; analytical tool; biomaterial compatibility; design; flexibility; fluid flow; gamma-Aminobutyric Acid; human disease; human model; implantable device; in vivo; insight; kappa opioid receptors; materials science; mechanical properties; minimally invasive; monitoring device; nanofluidic; negative emotional state; neural circuit; neurochemistry; nitinol; relating to nervous system; response; sample collection; social; spatiotemporal; subcutaneous; tandem mass spectrometry; temporal measurement; tool

Project Summary The purpose of this study is for a team of materials scientists, biomedical engineers, analytical chemists, and neuroscientists at MIT to develop a micro-invasive implantable device for monitoring the biochemical composition of distinct brain regions. This analytical tool for sampling neurochemicals in brain interstitial fluid (ISF) promises to provide valuable insight into the dynamics of neural circuits in physiological and pathological states. We will apply this tool to study the role of neuropeptides in substance use disorder (SUD). The dynorphin family of neuropeptides has long been implicated in addiction, but no current analysis tool has been able to investigate the long-term spatiotemporal dynamics of these neurochemicals in vivo. Our goal is to demonstrate the efficacy of our sampling platform in measuring neuropeptide expression dynamically in a rodent model of SUD. This will lend greater insight into the biochemical basis of addiction and withdrawal, but perhaps more importantly establish our technology as an effective technique for understanding the onset and progression of neural diseases. Our specific goals are summarized as follows: 1) Design a minimally invasive and implantable device for sampling ISF chronically in vivo. The device will consist of a nanofluidic pump (nanopump) coupled to micro- scale probes (microprobes), with fluid flow characteristics optimized in vitro prior to translation to a stand-alone in vivo device. 2) Optimize the storage and processing of small volumes of sampled ISF, withdrawn via nanopump, for analysis via liquid chromatography-tandem mass spectrometry (LC-MS/MS). 3) Determine the detection limits for the dynorphin neuropeptide family in ISF in vitro prior to detection of these neurochemicals in in vivo samples at physiological and pathological concentrations. 4) Perform short-term monitoring of dynorphin at baseline and in acute stress to demonstrate the efficacy of this tool in tracking these large neuropeptides in real-time. 5) Track the dynorphin family of neuropeptides in a rodent model of cocaine SUD, lending greater insight into the biochemical basis of substance withdrawal and relapse. Our aim is to demonstrate the failsafe function of this sampling platform in vivo and establish its ability to monitor neuropeptide dynamics with precise spatiotemporal control. We aim to provide neuroscientists with a new tool for investigating the biochemical basis of neural pathology in well-established animal models, enabling more accurate diagnosis and treatment of neural disorders in humans in the future.

项目摘要 这项研究的目的是针对材料科学家，生物医学工程师，分析化学家和 麻省理工学院的神经科学家开发一种微侵入性植入器装置，用于监测生化组成 不同的大脑区域。这种分析工具用于在脑间隙流体（ISF）中抽样神经化学物质的承诺 为生理和病理状态中神经回路的动态提供宝贵的见解。我们将 应用此工具来研究神经肽在药物使用障碍（SUD）中的作用。 Dynorphin家族 长期以来，神经肽一直与成瘾有关，但是当前的分析工具无法调查 这些神经化学物在体内的长期时空动力学。我们的目标是证明功效 我们在SUD模型中动态测量神经肽表达的抽样平台的表达。这会 对成瘾和戒断的生化基础有更深入的了解，但也许更重要 建立我们的技术作为理解神经发作和发展的有效技术 疾病。我们的具体目标总结如下：1）设计一种微创和可植入的设备 用于抽样ISF长期在体内。该设备将由纳米流体泵（纳米泵）组成 比例尺探针（微探测 体内设备。 2）优化少量采样的ISF的存储和处理，撤回通过 纳米环，用于通过液相色谱串联质谱法（LC-MS/MS）进行分析。 3）确定 在检测这些神经化学物质之前 在生理和病理浓度下的体内样品。 4）对Dynorphin进行短期监测 在基线和急性应力下，以证明该工具在跟踪这些大型神经肽中的功效 即时的。 5）在可卡因SUD的啮齿动物模型中跟踪神经肽的动肽家族，贷款更大 深入了解物质戒断和复发的生化基础。我们的目的是证明故障安全 该抽样平台在体内的功能，并确定其精确监测神经肽动力学的能力 时空对照。我们旨在为神经科学家提供一种研究生化基础的新工具 神经病理学的动物模型中的神经病理学，可以更准确地诊断和治疗神经 未来人类的疾病。