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

• 批准号: 8690251
• 负责人: Amy L Oldenburg
• 金额: $ 22.58万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8690251
• 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; 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; System; TNF gene; Techniques; Technology; Therapeutic; Thrombosis; Thrombus; Time; Ultrasonics; Ultrasonography; Whole Blood; Work; antibody conjugate; base; cytokine; design; flexibility; hemodynamics; imaging modality; improved; iron oxide; longitudinal animal study; mortality; pre-clinical; public health relevance; research study; signal processing; success; tool; tumor

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，用于输注血小板相互作用形成动脉血栓时的对比度增强成像。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变得闭塞并导致心脏病发作、中风或坏疽性四肢之前识别患者。这项技术也将指导开发，使用相关的动物模型，新的干预策略，最大限度地减少动脉粥样硬化血栓并发症。目前没有现有的临床成像方法来直接对比血小板或检测闭塞前、临床无症状血栓形成。超顺磁性氧化铁（SPIO）最近已成为一种新的超声造影剂，通过锁定检测SPIO机械耦合的回声物质（细胞或血凝块）的诱导磁运动来提供暗场成像。我们假设携带SPIO有效载荷的可再水化的冻干（RL）血小板可以通过磁动超声（MMUS）提供动脉血栓形成的功能对比，同时实现长期储存能力。 我们的研究策略采用灌注室作为一个灵活的平台，以表征这种新的成像技术的实时成像离体猪动脉。作为血管内皮反应性的模型，我们将首先去内皮化动脉作为损伤模型，或添加TNF细胞因子以诱导离体猪动脉的炎症。然后，作为血栓形成并发动脉粥样硬化的模型，我们将研究来自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血栓形成期间提供MMUS造影剂所需的SPIO-RL血小板的最低循环浓度，这将提供基线数据以告知临床可行性。作为该目标的一部分，我们将研究流速对血栓形成的影响，以及血栓大小对MMUS对比度的影响，同时优化成像参数。这一目标的探索性组成部分，提出了调查是否可以通过MMUS信号的振幅和频率依赖性提取血栓的硬度，这可能是相关的识别疾病，如高纤维蛋白原血症。我们的第二个具体目标是确定SPIO-RL血小板被纳入血栓后SPIO的命运，以预测药代动力学并为未来的策略（如治疗有效载荷）提供信息。 血小板在血栓形成中发挥的积极且重要的作用是功能成像的理想平台，预计它将比单功能靶向药物（例如抗体偶联的SPIO）提供更高的灵敏度。这项拟议的工作将验证SPIO-RL血小板在血液动力学条件下检测血栓形成的有效性，并可能导致显着改善的能力，揭示动脉粥样硬化斑块出血或临床前，非闭塞性血栓，证明临床干预，以减轻闭塞性血栓形成。