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: 10304119
• 负责人: Michael J Cima
• 金额: $ 62.59万
• 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/10304119
• 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; Withdrawal; accurate diagnosis; acute stress; addiction; analytical tool; biomaterial compatibility; design; detection limit; detection platform; 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; wireless

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 这项研究的目的是为材料科学家、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将开发一种用于监测生化成分的微创植入式设备 不同的大脑区域。这种采样脑间质液(ISF)中神经化学物质的分析工具承诺 对生理和病理状态下神经回路的动力学提供有价值的见解。我们会 应用这个工具来研究神经肽在物质使用障碍(SUD)中的作用。强啡肽家族 长期以来，神经肽一直被认为与成瘾有关，但目前还没有分析工具能够研究 这些神经化学物质在体内的长期时空动力学。我们的目标是证明它的功效 我们的采样平台在动态测量SUD啮齿动物模型中神经肽的表达方面发挥了重要作用。这将是 更深入地了解成瘾和戒断的生物化学基础，但也许更重要的是 将我们的技术确立为了解神经发生和发展的有效技术 疾病。我们的具体目标概括如下：1)设计一种微创可植入装置 用于在活体内长期采集ISF样本。该装置将由一个纳米流体泵(纳米泵)组成，该泵耦合到微 标尺探头(微探头)，在转换为独立的之前，具有体外优化的流体流动特性 活体装置。2)优化小容量采样ISF的存储和处理，通过以下方式提取 纳米泵，通过LC-MS/MS(LC-MS/MS)进行分析。3)确定 ISF中强啡肽家族在检测这些神经化学物质之前的体外检测限 生理和病理浓度的活体样品。4)对强啡肽进行短期监测 在基线和急性应激状态下，以证明该工具在跟踪这些大的神经肽在 实时的。5)在可卡因苏D的啮齿动物模型中追踪强啡肽家族，提供了更多 深入了解物质戒断和复发的生物化学基础。我们的目标是展示故障保险 该采样平台在体内的功能，并建立其精确监测神经肽动态的能力 时空控制。我们的目标是为神经科学家提供一种研究生化基础的新工具。 在建立完善的动物模型中进行神经病理学的研究，使神经疾病的诊断和治疗更加准确 未来人类的疾病。