Implantable Microarray Probe for Real-Time Glutamate and GABA Detection

用于实时谷氨酸和 GABA 检测的植入式微阵列探针

基本信息

  • 批准号:
    9909493
  • 负责人:
  • 金额:
    $ 22.39万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-09-30 至 2021-08-31
  • 项目状态:
    已结题

项目摘要

Project Summary There is an enormous need for the development of a new class of neurotransmitter (NT) sensors that are versatile, selective, sensitive and reliable to allow investigation of the neurobiological mechanisms of behavior and disease symptoms. This STTR proposal will focus on implementing a novel microarray probe for in vivo, real-time sensing of glutamate (GLU) and gamma-aminobutyric acid (GABA). GLU and GABA are NTs that are essential for normal brain function, neuronal activity, information processing and plasticity, and network synchronization. GLU is a major excitatory NT and GABA is a major inhibitory NT, and they must maintain a proper balance for the brain to operate normally. A GLU-GABA dysregulation plays a critical role in several brain disorders, including epilepsy (a disorder affecting 1.2% of Americans), dementia (a disorder that will affect 130 million worldwide by 2050) and Parkinson’s (a disorder affecting 1.5 million Americans today). A fundamental understanding of NT homeostasis would likely lead to new and effective therapeutic strategies for patients. Existing monitoring methods suffer from the inability to measure dynamics continuously, in real time. Currently, the primary method being used is microdialysis, which has very poor temporal resolution and is therefore not suitable to evaluate behavioral events that occur on a timescale of seconds or less. In contrast, biosensors are easy to miniaturize and are suitable for in vivo studies; they selectively oxidize GLU-GABA into a secondary electroactive product in the presence of enzymes, which is then detected by amperometry. Unfortunately, previously available biosensors have been cumbersome, have relied on externally applied reagents, and have been grossly inaccurate because their calibration has been carried out in vitro and not in vivo. We overcame these problems with GLU-GABA detection and demonstrated a biosensor array probe capable of a 26-fold higher sensitivity to GABA, a four-fold higher sensitivity to GLU, and no need for external reagents. Here, we propose to develop the next generation of our biosensor microelectrode array (MEA) probe technology that will allow GLU-GABA detection in real-time with the highest sensitivity, selectivity, and reliability. The probes will have the following new features: At least 2 GABA and 2 GLU sites for measuring concentrations at different positions within the brain. Also, it will feature a microfluidic channel for the introduction of chemicals in the immediate vicinity of the microelectrodes. Finally, we will incorporate an On-Demand In-situ Calibrator (ODIC) that runs in-situ sensor calibration for accurate detection. The specific aims of this project are: (i) microfabrication and characterization of platinum MEAs with ODIC on a silicon probe, (ii) surface modification and optimization of GLU-GABA probe in vitro and (iii) demonstrate real-time GLU-GABA detection in an epileptic rat brain. The proposed research would also enable alternative applications for the technology, including: point-of-use sensors for neurotoxins, reactive oxygen species, and disease biomarkers. The estimated market based on neurostimulation devices is $16 billion by 2024. If only 1% of that market is accessible by biosensor probe technology, it would still be sufficient justification for the proposed work.
项目摘要 对于开发一种新型的神经递质(NT)传感器存在巨大的需求, 选择性、敏感性和可靠性,以允许行为和疾病症状的神经生物学机制的调查。 这个STTR的建议将集中在实现一种新的微阵列探针在体内,实时传感谷氨酸(GLU) 和γ-氨基丁酸(GABA)。GLU和GABA是正常脑功能、神经元功能和神经元功能所必需的NT。 活动性、信息加工和可塑性以及网络同步。GLU是一种主要的兴奋性NT,GABA是 一个主要的抑制NT,它们必须保持适当的平衡,使大脑正常运作。A GLU-GABA 失调在几种大脑疾病中起着关键作用,包括癫痫(影响1.2%的美国人的疾病), 痴呆症(到2050年将影响全球1.3亿人)和帕金森病(影响150万人 今日美国)。对NT稳态的基本理解可能会导致新的有效的治疗方法。 患者的策略。现有的监测方法不能连续地、真实的测量动态 时间目前,使用的主要方法是微透析,其具有非常差的时间分辨率,因此, 不适合评估发生在秒或更短时间尺度上的行为事件。相反,生物传感器易于 可降解,适用于体内研究;它们选择性地将GLU-GABA氧化成次级电活性产物 在酶的存在下,然后通过电流分析法检测。不幸的是,以前可用的生物传感器 已经很麻烦,依赖于外部应用的试剂,并且由于它们的校准而非常不准确, 已经在体外而不是在体内进行。我们用GLU-GABA检测克服了这些问题,并证明了 生物传感器阵列探针能够对GABA的灵敏度提高26倍,对GLU的灵敏度提高4倍,并且不需要 外部试剂。在这里,我们建议开发我们的下一代生物传感器微电极阵列(MEA)探针 该技术将允许以最高的灵敏度、选择性和可靠性实时检测GLU-GABA。的 探针将具有以下新功能:至少2个GABA和2个GLU位点,用于测量不同浓度下的浓度。 在大脑中的位置。此外,它还将具有一个微流体通道,用于立即引入化学品。 微电极附近。最后,我们将结合一个按需原位校准器(ODIC), 传感器校准,用于精确检测。该项目的具体目标是:(一) 铂MEAs与ODIC的硅探针,(ii)表面修饰和优化的GLU-GABA探针在体外 和(iii)证明癫痫大鼠脑中的实时GLU-GABA检测。这项研究还将使 该技术的替代应用,包括:神经毒素,活性氧的使用点传感器, 疾病生物标志物。到2024年,基于神经刺激设备的市场估计为160亿美元。如果只有百分之一 尽管生物传感器探针技术可以进入市场,但仍有足够的理由开展拟议工作。

项目成果

期刊论文数量(1)
专著数量(0)
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