Real-time Monitoring of cerebral tissue oxygen in ischemic stroke

摘要 大脑血流量的迅速下降导致区域的氧气水平非常低，这是一个主要的 缺血性卒中组织损伤的原因。已经开发了几种策略来抢救缺血性 使用动物模型，特别是啮齿动物的组织，但他们在临床试验中失败了。为了理性地 开发有效的治疗方法，了解缺血性中风对脑组织的影响是至关重要的 临床上脑缺血区和对侧的氧分压。 中肯的中风模型。然而，目前还没有合适的技术来重复测量大脑 这严重限制了人们对有效治疗方法的理解和开发，以改善 缺血性卒中的结局。 我们的目标是开发体内电子顺磁共振(EPR)血氧测定仪，使用一类新的 植入式谐振器实时监测栓塞性缺血性卒中患者脑组织氧分压 兔子体内的血块。兔血栓模型已经显示出很有希望的翻译潜力 人类缺血性卒中溶栓用纤溶酶原激活剂的研究进展。我们假设 脑缺血时血氧分压的变化可作为预测预后的指标， 通过与重组血管恢复血流结果的相关性检验该方法的有效性 组织纤溶酶原激活物(RtPA)。我们将通过使用提议的植入物来检验该假设 基于谐振器的EPR血氧仪。 我们将首先建立植入式谐振器技术，用于缺血和缺氧时的PO2测量 用EPR血氧测定仪测定兔对侧脑组织的血氧值。血栓栓塞术将诱发缺血性卒中 3h和6h后给予rtPA治疗，观察脑组织氧分压的时程变化。这个 可植入谐振器在大脑皮质下的位置、灌注量、表观弥散系数 水(ADC)和脑梗塞体积将通过MRI进行无创性评估。脑损伤程度的降低 RtPA治疗后缺血和复氧过程中的PO2及其对脑梗塞体积的影响 决心检验这一假说。此外，我们还将研究血流变化对 卒中患者脑氧分压和ADC值。来自这些研究的数据将有助于潜在的翻译 在兔血栓模型上建立治疗方法，利用MRI指导治疗。 研究小组，可汗博士和侯博士(体内EPR血氧仪和中风)，吉米博士(核磁共振)以及 顾问Swartz博士和Kuppusamy博士(EPR技术的先驱)，Gui博士(生物统计学家)和 卡尔普博士(中风研究)拥有开展这项研究所需的专业知识和资源。如果成功， 本项目将建立使用在体EPR血氧测定仪评估脑内PO2动态变化的有效性。 一种临床相关的缺血性中风模型，这是目前尚不具备的独特能力。

Abstract A rapid decline in the cerebral blood flow leads to regions with very low levels of oxygen, which is a major cause of tissue damage in ischemic stroke. Several strategies have been developed to rescue ischemic tissue using animal models, especially rodents, but they failed in the clinical trials. In order to rationally develop effective therapies, it is crucial to understand the effect of ischemic stroke on cerebral tissue oxygen (pO2, partial pressure of oxygen) in the ischemic as well as contralateral regions of a clinically pertinent model of stroke. However, there are no suitable techniques for repeated measurement of cerebral pO2 and this has severely limited the understanding and development of effective therapies to improve the outcome of ischemic stroke. Our goal is to develop in vivo Electron Paramagnetic Resonance (EPR) oximetry with a novel class of implantable resonators for real-time monitoring of cerebral pO2 during ischemic stroke induced by embolic clot in rabbits. The rabbit embolic clot model has shown promising translational potential with the development of plasminogen activator for thrombolysis during ischemic stroke in humans. We hypothesize that the changes in cerebral pO2 during ischemic stroke can be used as a marker to predict outcome, testing the validity of the method by correlating with outcome when blood flow is restored by recombinant tissue plasminogen activator (rtPA). We will test the hypothesis by using the proposed implantable resonator-based EPR oximetry. We will first establish the implantable resonator technology for pO2 measurement in the ischemic and contralateral regions of the rabbit brain by EPR oximetry. Ischemic stroke will be induced by embolic clot for 3 hour and 6 hour, followed by treatment with rtPA to investigate the temporal changes in cerebral pO2. The position of the implantable resonator in the cerebral subcortex, perfusion, apparent diffusion coefficient of water (ADC) and infarct volume will be assessed non-invasively by MRI. The extent of decrease in cerebral pO2 during ischemia and re-oxygenation after rtPA treatment and its effect on the infarct volume will be determined to test the hypothesis. Additionally, we will study the effect of changes in the blood flow on cerebral pO2 and ADC in stroke. The data from these studies will facilitate the potential translation of the approaches developed in rabbit embolic clot model to treat patient's using MRI to guide the treatment. The research team, Drs. Khan and Hou (in vivo EPR oximetry and stroke), and Dr. Gimi (MRI) along with the consultants Drs. Swartz and Kuppusamy (pioneers of EPR technique), Dr. Gui (biostatistician) and Dr. Culp (stroke research) have the expertise and resources necessary to carry out the study. If successful, this project will establish the validity of using in vivo EPR oximetry to assess the dynamics of cerebral pO2 in a clinically relevant model of ischemic stroke, a unique capability not available at present.