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

• 批准号: 10761486
• 负责人: Prabhu Arumugam
• 金额: $ 90.4万
• 依托单位: ALCORIX
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-18 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10761486
• 关键词: Acceleration; Affect; Alzheimer' s Disease; American; Animal Model; Animals; Area; BRAIN initiative; Behavioral; Biological Markers; Biosensor; Brain; Brain Diseases; Calibration; Chemicals; Chronic; Communication; Cortical Column; Dementia; Detection; Development; Disease; Disease model; Drug Delivery Systems; Drug usage; Electrodes; Electrophysiology (science); Enzymes; Epilepsy; Equilibrium; Event; Feasibility Studies; Formulation; Glutamates; Goals; Healthcare; Homeostasis; Human; Hybrids; Hydrogels; Implant; In Situ; In Vitro; Inflammation; Lead; Louisiana; Marketing; Measurement; Measures; Mechanics; Memory; Mental disorders; Methods; Microdialysis; Microelectrodes; Microfluidics; Modeling; Monitor; Motion; National Institute of Neurological Disorders and Stroke; Neuronal Plasticity; Neurons; Neurosciences; Neurosciences Research; Neurotoxins; Neurotransmitters; Parkinson Disease; Pattern; Penetration; Performance; Peroxides; Pharmaceutical Preparations; Phase; Physiological; Platinum; Play; Polymers; Process; Property; Rattus; Reagent; Reproducibility; Research; Research Personnel; Resistance; Resolution; Role; Schizophrenia; Silicon; Small Business Technology Transfer Research; Techniques; Technology; Temporal Lobe Epilepsy; Testing; Therapeutic; Time; Universities; Validation; Vibrissae; Work; addiction; barrel cortex; biomaterial compatibility; cost; density; design; detection sensitivity; effective therapy; flexibility; functional improvement; gamma-Aminobutyric Acid; improved; in vivo; in vivo evaluation; information processing; manufacture; miniaturize; nervous system disorder; neural; neural implant; neurochemistry; neuronal circuitry; neurotransmission; novel; process improvement; prototype; response; sensor; somatosensory; spatiotemporal; temporal measurement; tool; usability

Project Summary This STTR proposal will focus on developing and testing a novel, first-on-the-market implantable biosensor for in vivo, real-time sensing of gamma-aminobutyric acid (GABA) and glutamate (GLU) for animal studies. GABA and GLU are neurotransmitters (NTs) that are essential for information processing and plasticity, memory, and other functions. GLU is the major excitatory NT and GABA is the major inhibitory NT; a proper balance between them is vital for normal brain function. GLU-GABA dysregulation plays a critical role in several brain disorders, including epilepsy (a disease affecting 1.2% of Americans), dementia (which will affect 130M worldwide by 2050) and Parkinson’s (which affects 1.5M Americans today). A fundamental understanding of NT homeostasis including its temporal components and its role on behavioral events within and across brain areas would lead to a better understanding of human brain function and to new and more effective treatments. Existing NT sensing methods measure only one NT at a time, suffer from poor spatiotemporal resolution, are unable to measure NT dynamics at the circuit level, continuously in real time. Our goal is to develop an ultra-small, flexible (50µm) neural probe for chronic, direct and simultaneous amperometric detection of GLU&GABA, with sub-second temporal resolution and with no externally applied reagents. Phase I focused on manufacturing a prototype Si penetrating shank-type probe with 4 micropatterned sensors and one microfluidic on-demand in-situ calibrator (ODIC), optimizing the enzyme functionalization process, and performing a feasibility study on the measurement of physiologically-relevant changes in the levels of GLU&GABA in real time for freely moving rats for up to 2 weeks. The objectives of Phase II are an upgrade of the probe into a brain micromotion-resistant hybrid Si- flexible polymer probe of higher functionality (octrode + 2 ODIC micro-channels), improvements in selective functionalization, and validation of the probes in a rat model of temporal lobe epilepsy. The multifunctional ODICs will be applied to perform in-situ calibrations for chronic measurements and to investigate the circuit activity of 3 adjacent cortical layers in the whisker barrel cortex via chemical modulation. Upon completion, we expect to deliver a unique-on-the-market dual NT probe of excellent reliability and superior sensitivity, selectivity, and stability, with all performance parameters equal to or better than those offered by current technologies. To achieve this, Alcorix will partner with experts in amperometric NT sensing research from Louisiana Tech U. and experts in the manufacture of advanced neuroprobes from NeuroNexus, who will assist with hybrid Si-flexible polymer integration, in vitro and in vivo evaluation, and eventual market entry. The proposed research will also enable alternative uses such as point-of-use sensors for neurotoxins or disease bio-markers, and neural signal recording or neurostimulation in conjunction with specific locally-injected drugs. The 2023 world market for electrophysiological neuro-probes (Grand View Research) is about $266M, CAGR of 3.1%. If only 1% of that market can be captured by this technology it would be more than sufficient justification for the proposed work.

项目摘要 该STTR提案将着重于开发和测试一个新颖的，即将植入的新型植入生物传感器 在体内，用于动物研究的γ-氨基丁酸（GABA）和谷氨酸（GLU）的实时感测。加巴 GLU是神经递质（NTS），对于信息处理和可塑性，记忆和 其他功能。 Glu是主要的兴奋NT，GABA是主要的抑制性NT。在 它们对于正常的大脑功能至关重要。 GLU-GABA失调在几种脑部疾病中起着至关重要的作用， 包括癫痫病（一种影响美国人1.2％的疾病），痴呆症（到2050年，全球将影响130亿个） 和帕金森氏症（今天影响150万美国人）。对NT稳态的基本了解 包括其临时组成部分及其在大脑区域内部和跨大脑区域的行为事件中的作用将导致 更好地了解人脑功能和新的和更有效的治疗方法。现有的NT感应 方法一次仅测量一个NT，时空分辨率差，无法测量NT 电路级别的动力学，连续实时连续。我们的目标是开发超小型，灵活的（50µm） 对GLU和GABA的慢性，直接和简单的安培检测的神经探针，次秒 临时分辨率，没有外部应用试剂。第一阶段专注于制造原型SI 带有4个微图案传感器和一个微流体的点击式校准器，穿透柄型探头 （ODIC），优化酶功能化过程，并对测量进行可行性研究 自由移动的大鼠的实时glu＆gaba水平与物理相关的变化，最多2 几周。第二阶段的目标是将探针升级到大脑微动功能的杂种中 较高功能（OCTRODE + 2 ODIC微通道）的柔性聚合物探针，选择性的改进 临时叶癫痫大鼠模型中问题的功能化和验证。多功能的ODICS 将应用于进行慢性测量的原位校准，并研究3的电路活性 通过化学调节，晶须桶皮层中的邻近皮层层。完成后，我们希望 提供出色的可靠性和卓越灵敏度，选择性和卓越的敏感性和唯一的市场双NT探针 稳定性，所有性能参数等于或优于当前技术提供的参数。到 实现这一目标，Alcorix将与路易斯安那大学U.和 神经龙的高级神经探针生产专家，他们将协助混合Si-Flexible 聚合物整合，体外和体内评估以及最终的市场进入。拟议的研究也将 启用替代用途，例如神经毒素或疾病生物标志物的使用点传感器和神经信号 与特定的局部注射药物结合记录或神经刺激。 2023年世界市场 电生理神经探针（大视图研究）约为2.66亿美元，复合年增长率为3.1％。如果只有1％ 这项技术可以捕获市场，对于拟议的工作来说，这将是足够的理由。