A new ultra-low field in-vivo EPR technology for biomedical applications

用于生物医学应用的新型超低场体内 EPR 技术

• 批准号: 8137636
• 负责人: Inseob Hahn
• 金额: $ 20.05万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-15 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8137636
• 关键词: 2,4-Dinitrophenol; Algae; Alzheimer' s Disease; Biomedical Technology; Caliber; Cardiology; Chemicals; Chlorella; Clinical; Detection; Devices; Electron Spin Resonance Spectroscopy; Electrons; Exercise; Foundations; Free Radicals; Frequencies; Generations; Goals; Heating; Human; Human Volunteers; Human body; Hybrids; Hyperbaric Oxygen; In Situ; Inorganic Sulfates; Ionizing radiation; Iron; Laboratories; Lead; Life; Light; Magnetic Resonance Imaging; Magnetism; Measurement; Measures; Methods; Mind; Modeling; Neurodegenerative Disorders; Neurology; Neurosciences; Nitric Oxide; Operating System; Oxidation-Reduction; Oxygen; Parkinson Disease; Penetration; Performance; Photosynthesis; Physiologic pulse; Play; Poisoning; Premature Infant; Radiation-Induced Cancer; Relaxation; Request for Applications; Resolution; Role; Safety; Sampling; Scheme; Shapes; Signal Transduction; Site; Spectrometry; Spectrum Analysis; Spin Labels; Suspension substance; Suspensions; System; Techniques; Technology; Temperature; Testing; Toxicology; Ultraviolet Rays; Unspecified or Sulfate Ion Sulfates; Work; absorption; base; biological systems; cost; cost effective; cryogenics; design; human disease; human study; human subject; improved; in vivo; instrument; magnetic field; microwave electromagnetic radiation; novel; oncology; operation; oxygen toxicity; prevent; public health relevance; research study; sensor; superconducting quantum interference device; technology development

DESCRIPTION (provided by applicant): The most successful uses of in vivo EPR have been non-invasive measurement of oxygen, nitric oxide, bioradicals, pH and redox state, with applications in oncology, cardiology, neuroscience and toxicology. These studies have been performed only in small size subjects due to fundamental limitations associated with the traditional high-frequency detection scheme. Current generation EPR systems typically use GHz or higher frequencies (L-, X-, Q- band) to achieve the required resolution. There are several key factors, which make in vivo EPR methods of human body at high frequencies extremely difficult, the principal ones being limits on the size and shape of the systems that can be measured and safety issues related to the absorption of high-level RF by biological systems. We will develop a new ultra-low field in vivo EPR spectrometer system that is safe for use in humans and has high sensitivity and good penetration depth. The new device will overcome the limitations associated with conventional EPR at high frequencies yet still achieve 100 to 1000 fold improved SNR over existing technology. We will achieve this goal by employing two state- of-the-art technologies developed in our lab: (1) a new microwave superconducting quantum interference device (MSQUID) (2) a cryogen-free, superconducting gradiometer system. Operation at 5MHz with a low power RF excitation will completely eliminate the problems associated with finite penetration depth and sample-heating. Our aims are: 1A) Demonstrate ?M-level EPR signal detection (both CW and pulse methods) using paramagnetic samples (e.g. spin probes) at room temperature using cryogenic detection with the new hybrid SQUID readout system. 1B) Demonstrate the NMR signal detection using the same detection system, with hybrid NMR/EPR spectroscopy systems in mind. 2) Use a cryogen-free cooling system with a large field-of-view detection coil to demonstrate EPR spectroscopy performance, using parameters suitable for the human study. 3) Demonstrate detection and measurement of electron paramagnetic resonance in biological systems at physiologically relevant concentrations. 3A. Using living suspensions of Chlorella pyroidenosa, we will attempt to detect the expected electron spin resonance under dark conditions, and to detect and quantify the ESR increase that occurs during photosynthesis. These technical aims form the foundations for the application of the advanced technology to human use. With the long term goal of a clinical device, we will also perform limited human testing. Our aim3B is to perform in vivo human experiments to detect increased free radical concentration during intense exercise. Our ultimate objective is to create a device for human in vivo biomedical EPR that is practical from the perspectives of safety, cost, siting and complexity, without compromising sensitivity and signal quality. PUBLIC HEALTH RELEVANCE (provided by applicant): Free radicals play a major role in human diseases such as iron sulfate poisoning, ionizing radiation, oxygen toxicity in premature infants treated with hyperbaric oxygen, ultraviolet radiation-induced cancer and very likely in Parkinson's, Alzheimer's and other neurodegenerative disorders. Electron paramagnetic resonance (EPR) is a non-invasive spectroscopic technique to detect and measure free radicals in chemical and biological system that has been applied in- vivo EPR to measure oxygen, nitric oxide, bioradicals, pH and redox state, with applications in oncology, cardiology, neurology and toxicology. To date, these studies have been performed only in small size subjects due to fundamental technical and safety limits of the conventional high-frequency detection scheme. We propose here to develop a novel ultra low-frequency EPR approach using a state-of-the-art magnetic flux sensor to enable safe, cost- effective and practical in vivo EPR humans, with an instrument ultimately capable of simultaneous NMR measurement.

描述（由申请人提供）：体内EPR最成功的用途是无创测量氧气、一氧化氮、生物自由基、pH值和氧化还原状态，应用于肿瘤学、心脏病学、神经科学和毒理学。由于传统高频检测方案的基本局限性，这些研究仅在小体型受试者中进行。当前一代EPR系统通常使用GHz或更高的频率（L-、X-、Q-频带）来实现所需的分辨率。有几个关键因素使得在高频下对人体进行体内EPR方法极其困难，主要因素是对可测量系统的尺寸和形状的限制以及与生物系统吸收高水平RF相关的安全问题。我们将开发一种新的超低场体内EPR光谱仪系统，该系统可安全用于人体，具有高灵敏度和良好的穿透深度。新器件将克服传统EPR在高频下的局限性，但仍能实现比现有技术提高100至1000倍的SNR。我们将通过采用我们实验室开发的两种最先进的技术来实现这一目标：（1）一种新的微波超导量子干涉器件（MSQUID）（2）一种无致冷剂的超导梯度仪系统。在低功率RF激励下以5 MHz操作将完全消除与有限穿透深度和样品加热相关的问题。我们的目标是：1A）演示？在室温下使用顺磁样品（例如自旋探针）进行M级EPR信号检测（CW和脉冲方法），使用新型混合SQUID读出系统进行低温检测。1B）使用相同的检测系统演示NMR信号检测，考虑混合NMR/EPR光谱系统。2)使用具有大视场检测线圈的无冷冻剂冷却系统来证明EPR光谱性能，使用适合于人类研究的参数。3)演示在生理相关浓度下，生物系统中电子顺磁共振的检测和测量。3A.使用生活的悬浮液的小球藻pyrochlorosa，我们将试图检测预期的电子自旋共振在黑暗条件下，并检测和量化的ESR增加，发生在光合作用。这些技术目标构成了将先进技术应用于人类用途的基础。为了实现临床器械的长期目标，我们还将进行有限的人体试验。我们的aim 3B是进行人体实验，以检测在激烈的运动过程中增加的自由基浓度。我们的最终目标是创造一种用于人类体内生物医学EPR的设备，该设备从安全性，成本，选址和复杂性的角度来看是实用的，而不会影响灵敏度和信号质量。 公共卫生相关性（由申请人提供）：自由基在人类疾病中起着重要作用，如硫酸铁中毒、电离辐射、高压氧治疗的早产儿氧中毒、紫外线辐射诱发的癌症，以及很可能在帕金森氏症、阿尔茨海默氏症和其他神经退行性疾病中起着重要作用。电子顺磁共振（EPR）是一种非侵入性的光谱技术，可用于检测化学和生物体系中的自由基，并可用于体内测量氧、一氧化氮、生物自由基、pH值和氧化还原状态，在肿瘤学、心脏病学、神经病学和毒理学等领域有着广泛的应用。迄今为止，由于传统高频检测方案的基本技术和安全限制，这些研究仅在小体型受试者中进行。我们在这里提出开发一种新的超低频EPR方法，使用最先进的磁通量传感器，以实现安全，成本效益和实用的体内EPR人类，最终能够同时NMR测量的仪器。