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，以在注入的血小板相互作用以形成动脉血栓时进行对比增强成像。在临床沉默，占有前的阶段检测血栓形成的能力可能会在血栓变为闭塞并引起心脏病发作，中风或坏疽性肢体之前识别患者。该技术还将使用相关动物模型指导开发的新介入策略，以最大程度地减少动脉粥样硬化中的血栓形成并发症。目前尚无现有的临床成像方法直接对比血小板或检测临床上无声的血栓形成。超声氧化铁（SPIO）最近已成为一种超声的新对比剂，可通过锁定诱导的回声材料（细胞或血液凝块）机械地耦合的回声材料（细胞或血液凝块）提供暗场成像。我们假设携带有效载荷SPIO的可补液，冻干的（RL）血小板可以通过磁通超声（MMU）与动脉血栓形成功能对比，同时启用长期存储能力。 我们的研究策略采用了一个灌注室来实时成像，将离体猪动脉作为一个灵活的平台来表征这种新的成像技术。作为血管内皮反应性的模型，我们将首先将动脉降低为损伤模型，或者添加TNF细胞因子诱导离体猪动脉的炎症。然后，作为血栓形成复杂性动脉粥样硬化的模型，我们将研究具有动脉粥样硬化斑块的高胆固醇猪的动脉。我们的第一个具体目的是确定在血栓形成过程中提供MMU对比度所需的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。作为此目的的一部分，我们将研究流量对血栓形成的影响，而血栓大小对MMU对比度的影响，同时优化成像参数。提出了该目标的探索性成分，以研究是否可以通过MMUS信号的幅度和频率依赖性提取血栓的刚度，这对于识别诸如高纤维蛋白原血症等疾病的疾病可能与之相关。我们的第二个具体目的是确定SPIO-RL血小板已纳入血栓后的SPIO的命运，以预测药代动力学并告知未来策略，例如治疗有效载荷。 血小板在血栓形成中起的积极和重要作用是功能成像的理想平台，该平台有望比单功能靶向剂（如抗体偶联的SPIO）提高灵敏度。这项提出的工作将验证SPIO-RL血小板在血液动力学条件下对血栓形成检测的功效，并可能导致揭示动脉粥样硬化斑块出血或临床前，无核的血栓，证明临床干预措施减轻闭塞性血栓形成的临床干预措施的能力显着提高。