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提案将专注于开发和测试一种新型的，市场上第一个可植入的生物传感器， 用于动物研究的γ-氨基丁酸（GABA）和谷氨酸（GLU）的体内实时感测。GABA 和GLU是神经递质（NT），对信息处理和可塑性、记忆和 其他功能。GLU是主要的兴奋性NT，GABA是主要的抑制性NT; 它们对正常的大脑功能至关重要。GLU-GABA失调在几种脑疾病中起关键作用， 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） 和帕金森氏症（今天影响着150万美国人）。对NT稳态的基本理解 包括它的时间成分和它对大脑区域内和跨大脑区域的行为事件的作用， 更好地了解人类大脑的功能，以及更有效的新治疗方法。现有NT传感 方法一次只能测量一个NT，时空分辨率差，不能测量NT 电路级的动态，连续的真实的时间。我们的目标是开发一种超小型、灵活的（150 µm） 神经探针，用于GLU和GABA的慢性、直接和同时安培检测，亚秒 时间分辨率和没有外部施加的试剂。第一阶段的重点是制造一个原型硅 具有4个微图案化传感器和一个微流体按需原位校准器的穿透柄型探针 （ODIC），优化酶功能化过程，并对测量进行可行性研究 自由活动大鼠在真实的时间内GLU和GABA水平的生理相关变化， 周第二阶段的目标是将探测器升级为大脑微动抵抗混合硅- 更高功能性的柔性聚合物探针（八极+ 2个ODIC微通道）， 功能化和在颞叶癫痫大鼠模型中验证探针。多功能ODIC 将用于执行慢性测量的原位校准，并调查3 通过化学调制在须桶皮质中的相邻皮质层。完成后，我们预计 提供市场上独一无二的双NT探头，具有出色的可靠性和上级灵敏度、选择性， 稳定性，所有性能参数等于或优于当前技术提供的性能参数。到 为了实现这一目标，Alcorix将与路易斯安那理工大学的电流NT传感研究专家合作。和 来自NeuroNexus的先进神经探针制造专家，他们将协助混合硅柔性 聚合物整合、体外和体内评估以及最终的市场进入。拟议的研究还将 实现替代用途，例如用于神经毒素或疾病生物标志物和神经信号的使用点传感器 记录或神经刺激结合特定的局部注射药物。2023年世界市场 电生理神经探针（Grand View Research）约为2.66亿美元，复合年增长率为3.1%。如果只有百分之一 市场可以捕捉到这种技术，这将是足够的理由，拟议的工作。