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Developing Contrast-Enhanced Ultrasound of Thrombosis via SPIO-RL Platelets

通过 SPIO-RL 血小板开发血栓形成的超声造影

基本信息

批准号：
8822917
负责人：
Amy L Oldenburg
金额：
$ 18.5万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8822917
关键词：
Amputation Angiography Animal Model Arterial Fatty Streak Arteries Atherosclerosis Benchmarking Binding Sites Biomedical Research Blood Circulation Blood Platelets Blood Vessels Blood coagulation Blood flow Blood specimen Cells Clinical Coagulation Process Contrast Media Contrast Sensitivity Coupled Cytokine Activation Data Dependence Deposition Detection Development Diagnostic Disease Drug Kinetics Early Intervention Effectiveness Event Family suidae Fibrinogen Frequencies Functional Imaging Future Gangrene Health Hemophilia A Hemorrhage Hemostatic function Image Imaging technology Inflammation Injury Intervention Kinetics Label Lead Limb structure Link Liver diseases Location Mass Spectrum Analysis Measures Mechanics Metals Methods Modeling Monitor Mono-S Morbidity - disease rate Motion Myocardial Infarction Noise Patients Perfusion Pharmaceutical Preparations Play Prevention Process Property Research Resolution Risk Role Signal Transduction Site Staging Stents Stroke Structure TNF gene Techniques Technology Therapeutic Thrombosis Thrombus Time Ultrasonics Ultrasonography Whole Blood Work antibody conjugate base contrast enhanced contrast imaging cytokine design flexibility hemodynamics imaging modality imaging platform imaging system improved iron oxide longitudinal animal study mortality pre-clinical research study signal processing success tool tumor

项目摘要

DESCRIPTION (provided by applicant): We propose to develop an ultrasound technology for contrast-enhanced imaging of infused platelets as they interact to form arterial thrombi. The ability to detect thrombosis at a clinically silent, pre-occlusive stage can potentially identify patients before the thrombi become occlusive and cause heart attacks, strokes, or gangrenous extremities. This technology will also guide the development, using relevant animal models, of new interventional strategies for minimizing thrombotic complications in atherosclerosis. There are currently no existing clinical imaging methods to directly contrast platelets or to detect pre-occlusive, clinically silent thrombosis. Superparamagnetic iron oxides (SPIOs) have recently emerged as a new contrast agent for ultrasound that offer dark-field imaging via lock-in detection of induced magnetomotion of echogenic materials (cells or blood clots) with which SPIOs are mechanically coupled. We hypothesize that rehydratable, lyophilized (RL) platelets carrying a payload of SPIOs can provide functional contrast to arterial thrombosis via magnetomotive ultrasound (MMUS), while enabling long-term storage capability. Our research strategy employs a perfusion chamber for real-time imaging of ex vivo porcine arteries as a flexible platform to characterize this new imaging technology. As a model of vascular endothelial reactivity, we will first de-endothelialize arteries as an injury model, or add TNF cytokine to induce inflammation of ex vivo porcine arteries. Then, as a model of thrombosis complicating atherosclerosis, we will study arteries from hypercholesterolemic pigs that have atherosclerotic plaques. Our first specific aim is to determine the minimum circulating concentration of SPIO-RL platelets needed to provide MMUS contrast during thrombus formation, which will provide baseline data to inform clinical feasibility. As part of this aim we will study the effects of flowrate on thrombus formation, and thrombus size on MMUS contrast, while optimizing imaging parameters. An exploratory component of this aim is proposed to investigate whether the stiffness of the thrombus can be extracted via the amplitude and frequency-dependence of the MMUS signals, which may be of relevance for identifying disorders such as hyperfibrinogenemia. Our second specific aim is to determine the fate of SPIOs after SPIO-RL platelets have been incorporated into a thrombus, in order to predict pharmacokinetics and to inform future strategies such as therapeutic payloads. The active and essential role that platelets play in thrombus formation is a desirable platform for functional imaging, which is expected to provide improved sensitivity over mono-functionally targeted agents such as antibody-conjugated SPIOs. This proposed work will validate the efficacy of SPIO-RL platelets for thrombosis detection in hemodynamic conditions, and may lead to significant improvement in the ability to reveal atherosclerotic plaque hemorrhage or preclinical, nonocclusive thrombi, justifying clinical interventions to mitigate occlusive thrombosis.

描述（由申请人提供）：我们建议开发一种超声技术，用于在输注的血小板相互作用形成动脉血栓时对它们进行对比增强成像。在临床上无症状的闭塞前阶段检测血栓形成的能力可以在血栓闭塞并导致心脏病发作、中风或四肢坏疽之前识别出患者。该技术还将指导使用相关动物模型开发新的介入策略，以最大限度地减少动脉粥样硬化的血栓并发症。目前还没有现有的临床成像方法可以直接对比血小板或检测闭塞前、临床无症状的血栓形成。超顺磁性氧化铁 (SPIO) 最近作为一种新型超声造影剂出现，通过锁定检测回声材料（细胞或血凝块）的感应磁动来提供暗场成像，SPIO 与机械耦合。我们假设携带 SPIO 有效负载的可再水合冻干 (RL) 血小板可以通过磁动超声 (MMUS) 提供与动脉血栓形成的功能对比，同时实现长期存储能力。我们的研究策略采用灌注室对离体猪动脉进行实时成像，作为表征这种新成像技术的灵活平台。作为血管内皮反应性模型，我们首先将动脉去内皮化作为损伤模型，或者添加TNF细胞因子来诱导离体猪动脉炎症。然后，作为动脉粥样硬化并发血栓形成的模型，我们将研究具有动脉粥样硬化斑块的高胆固醇血症猪的动脉。我们的第一个具体目标是确定在血栓形成过程中提供 MMUS 对比所需的 SPIO-RL 血小板的最低循环浓度，这将为临床可行性提供基线数据。作为该目标的一部分，我们将研究流量对血栓形成的影响以及血栓大小对 MMUS 对比度的影响，同时优化成像参数。该目标的一个探索性部分是研究是否可以通过 MMUS 信号的幅度和频率依赖性来提取血栓的硬度，这可能与识别高纤维蛋白原血症等疾病相关。我们的第二个具体目标是确定 SPIO-RL 血小板融入血栓后 SPIO 的命运，以预测药代动力学并为未来的策略（例如治疗有效负载）提供信息。血小板在血栓形成中发挥的积极而重要的作用是功能成像的理想平台，预计与单功能靶向药物（例如抗体偶联的 SPIO）相比，其灵敏度更高。这项拟议的工作将验证 SPIO-RL 血小板在血流动力学条件下检测血栓形成的功效，并可能显着提高揭示动脉粥样硬化斑块出血或临床前非闭塞性血栓的能力，从而证明减轻闭塞性血栓形成的临床干预措施是合理的。