Nanobiosensing Neural Probes for Traumatic Brain Injury Applications

用于创伤性脑损伤应用的纳米生物传感神经探针

• 批准号: 8984835
• 负责人: Allison Hess Dunning
• 金额: --
• 依托单位: LOUIS STOKES CLEVELAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8984835
• 关键词: Acute; Behavior; Biochemical; Biosensing Techniques; Biosensor; Boron; Brain; Brain Injuries; Calibration; Carbon; Carbon Nanotubes; Clinical; Cognitive; Development; Diamond; Disease; Electrodes; Electronics; Electrophysiology (science); Ensure; Environment; Enzymes; Feedback; Film; Functional disorder; Glutamates; Goals; Gold; Growth; Health; Hospitals; Hydrogen Peroxide; Immobilization; Implant; In Vitro; Inflammatory Response; Injury; Intensive Care Units; Intervention; Liquid substance; Long-Term Effects; Measures; Mechanics; Metals; Methods; Microfabrication; Monitor; Motor; Needles; Nervous System Trauma; Neurologic; Oxidases; Pharmacotherapy; Physiological; Polymers; Population; Process; Property; Quality of life; Regulation; Rehabilitation Outcome; Rehabilitation therapy; Research; Resolution; Rodent Model; Role; Site; Stimulus; Stroke; Symptoms; System; Techniques; Technology; Temperature; Testing; Time; Tissues; Translations; Traumatic Brain Injury; Treatment outcome; Veterans; Wireless Technology; Work; absorption; base; brain tissue; clinical application; combat; data exchange; disability; drug rehabilitation; enzyme immobilization; extracellular; implantation; improved; in vivo; injured; meetings; microsystems; nanocomposite; nanodevice; nanoelectromechanical system; nanoscale; nanostructured; nanosystems; nanowire; nervous system disorder; neurochemistry; neurodevelopment; neurotransmission; novel; operation; oxidation; polypyrrole; programs; psychologic; public health relevance; relating to nervous system; research study; sensor; spatiotemporal; temporal measurement; tool; treatment strategy; vinyl acetate

DESCRIPTION The primary goal of the proposed work is to take the first steps toward an independent research program that focuses on the development and application of biomedical micro/nanosystems based on independently optimized materials for the study, monitoring, and treatment of neurological conditions, including traumatic brain injury (TBI) and stroke. Specifically, this project concerns the development of a platform technology involving the integration of optimal electrode, enzyme immobilization, and substrate materials for an electrochemical sensor to continuously monitor extracellular glutamate levels with high spatiotemporal resolution, sensitivity, selectivity, stability, and wide linear range. This multi-scale materials system will incorporate a bio-adaptive polymer nanocomposite substrate, gold and graphene electrodes, and polymer nanowires for enzyme immobilization. This combination of materials will provide a sensor with the requisite properties for long-term implantation for neurochemical monitoring during normal activity. Though glutamate is the focus of this work, the methods to develop this sensor can be applied to many different bioanalytes, which will be integrated in later implementations of this biosensor. A means to continuously monitor the neurochemical state outside of the hospital environment will 1) provide enhanced understanding regarding the pathophysiology associated with the long-term effects of TBI at the site of the injury 2) delineate the relationship between neurochemistry and clinical dysfunction, 3) allow for long term monitoring of rehabilitation and drug interventions and 4) allow for the novel drug therapies to be developed with highly controlled delivery. The first aim toward the overall goal is to provide a stable neural interface with high-sensitivity (>500 nA.¿M-1.cm-2) to changes in in vivo glutamate concentration through efficient glutamate oxidase immobilization. This with be achieved using microfabrication processes customized for the unique materials set proposed to achieve this goal. A novel stimuli-responsive polymer nanocomposite, poly (vinyl acetate) (PVAc-NC), substrate will be implemented to minimize the inflammatory response to the implant, thus maximizing the stability of the biotic/abiotic interface. PVAc-NC has a high elastic modulus (Edry ~ 4 GPa) in its dry state, permitting needle- like insertion into brain tissue, but displays a three order-of-magnitude reduction in elastic modulus (Ewet ~ 12 MPa) after absorption of physiological fluids, greatly reducing mechanical mismatch with cortical tissue (Ecortex ~ 10 kPa). High glutamate sensitivity and selectivity will be established by coating the gold electrode site with a nanostructured conductive polymer nanowire layer, such as polypyrrole, which will serve to immobilize glutamate oxidase, an enzyme that selectively reacts with glutamate to form several products, including hydrogen peroxide. The hydrogen peroxide will then by oxidized by a potential applied to the electrode via external electronics and the oxidation current will be measured. The magnitude of this current is linearly-related to the concentration of glutamate near the electrode. The second aim is to expand the dynamic linear range of the glutamate sensor to ensure linearity between measured current and actual glutamate concentration is maintained through the entire range expected in normal and injured brains. Toward this end, thin-film gold electrodes will be replaced with a carbon-based graphene electrode site. A transfer process will be required to integrate graphene onto PVAc-NC, as PVAc-NC is incompatible with graphene growth temperatures. These electrodes will then be functionalized with glutamate oxidase using methods comparable to those developed toward the first objective, but adapted for use on a graphene-based electrode. The two types of electrochemical sensors will be characterized and calibrated in vitro, then tested in vivo in a rodent model of TBI to assess electrode stability and the correspondence of in vivo behavior with the determined in vitro calibration parameters. PUBLIC HEALTH RELEVANCE: Traumatic brain injury (TBI) and other neurological disorders are important concerns with regard to veterans' health, especially for those veterans involved with recent combat operations. Many of the symptoms and effects of severe neurotrauma persist and progress for years beyond the initial injury, causing permanent severe disability. These sequelae are related to alterations in neurochemical regulation, but are not well understood due to the lack of tools available to monitor neurochemical levels continuously outside of the realm of an intensive care unit in a hospital. The proposed biosensor will continuously monitor neurochemical levels during normal activity with very high spatial and temporal resolution. By augmenting the functionality of well-established sensors for detecting and interpreting electrical neural signals, we will gain new understanding of the long-term effects of neurotrauma, the relationship between behavior and neurochemistry, and develop new ways to treat neurotrauma and regulate neurochemistry.

描述 第一步的主要目标是行业计划计划，重点介绍了基于生物医学/纳米系统的开发和应用程序，以进行研究，以监测响亮的创伤性脑损伤（TBI）和中风。涉及的平台，酶固定和底物材料，用于连续监测具有较高矩形分辨率，灵敏度，选择性，稳定性和宽线性范围的纤维化分辨率和宽度范围。电极和固定酶的聚合物纳米植物在正常活动中进行神经化学监测。损伤部位的长期效果TBI 2）划定 神经化学与临床功能障碍之间的关系，3）允许长期监测康复和药物间隔以及4）或新型药物疗法是 使用较高的设计，第一个AIRD的整体目标是提供具有高敏性的稳定的神经界面（> 500 Na.m-1.cm-2），以改变体内谷氨酸浓度的变化。为拟议的材料定制，旨在实现THIP osive聚合物纳米复合材料，聚（乙酸乙酸乙烯酸乙二醇）（PVAC-NC），将实施底物，以最大程度地降低植入物的脚趾，从而最大化生物/非生物界面。 模量（Edry〜4 GPA）是干燥状态，允许针状插入脑组织，但在吸收生理流体后显示了三个型魔力的暴力模量（EWET〜12 MPa），大大减少了与皮质组织不匹配的机械性组织不匹配的。 （Ecortex 〜10 kPa）。将是电流的tet，以在电极附近张开E。用石墨烯的生长温度与谷氨酸氧化酶进行官能化的Atrele。具有确定的体外校准参数的体内行为无色。 公共卫生相关性： 创伤性的脑损伤（TBI）和其他神经系统疾病是对退伍军人健康的重要问题，尤其是对于那些严重的神经疾病的症状而言，使用永久性隔壁的症状与最初的损伤有关。在hosspital中监测重症监护病房的神经化学水平。