Transcranial Sonothrombolysis with Diagnostic Ultrasound

超声诊断经颅超声溶栓

• 批准号: 8078052
• 负责人: THILO HOELSCHER
• 金额: $ 41.69万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8078052
• 关键词: Achievement; Acoustics; Alteplase; Ambulances; Aorta; Asses; Blood Clot; Blood Vessels; Blood coagulation; Brain; Clinical Trials; Coagulation Process; Contrast Media; Cytolysis; Diagnostic Equipment; Dimensions; Endothelium; Erythrocytes; Frequencies; Future; Goals; Health; Human; Image; In Vitro; Kidney; Knowledge; Learning; Microbubbles; Microbubbles Ultrasound Contrast Medium; Microcirculation; Modeling; Organ; Oryctolagus cuniculus; Patients; Phase; Property; Pulsatile Flow; Relative (related person); Renal Circulation; Site; System; Therapeutic; Therapeutic Uses; Thrombosis; Thrombus; Translating; Translations; Ultrasonography; Whole Blood; absorption; acute stroke; base; bone; cranium; human subject; in vitro Model; in vivo; intracranial artery; middle cerebral artery; renal artery; research study; sound; stroke therapy; thrombolysis

DESCRIPTION (provided by applicant): Microbubble-based ultrasound contrast agents (UCA) potentiate the effect of sonothrombolysis, without or in combination with tissue Plasminogen Activator (tPA). The underlying mechanisms of why ultrasound (US) accelerates thrombolysis, how to optimize the US settings for effective clot lysis in intracranial arteries and how microbubbles accelerate sonothrombolysis are poorly understood. While we aim to explore and optimize some of these parameters, our goal is to study the impact of US on thrombolysis in combination with tPA and/or UCA microbubbles at settings available on standard diagnostic equipment for transcranial vascular imaging. To achieve this we propose the following Aims: Aim 1 - In Vitro Sonothrombolysis Step 1 A flow system has been established which allows us to study thrombolysis of human whole blood clots exposed to circulating, pulsatile flow and to acquire the acoustic properties at the clot site simultaneously. The experiments planned for Step 1 will allow us to define preferred US parameter settings needed to successfully lyse thrombi and to study the effect of flow on clot lysis when US is applied alone or in combination with tPA and/or UCA. Step 2 Based on what we will learn during Step 1, the three most effective combinations will be repeated to optimize US transmit parameters now insonating through intervening wet human cadaveric temporal skull bone. Insonation through bone is limited by sound absorption, scattering and phase aberration. This experiments will allow us to study these effects and to characterize the acoustic parameters at the clot site during insonation through human cadaveric skull bone. This will help us optimize the US parameters, such as transmit frequency, power, focus etc to achieve transcranial thrombolysis. Aim 2 - In Vivo Sonothrombolysis A rabbit renal artery model has been established. Based on an erythrocyte-rich thrombus model local thrombosis is induced. Using the optimized US parameters determined in Aim 1 we will confirm the contribution of US alone and the combination of US with tPA or UCA or both on accelerating clot lysis in vivo. We believe that the interaction between thrombus and endothelium has an important impact on thrombolysis, which cannot be studied in an in vitro model. The proposed rabbit model will help us study these effects and their impact on thrombolysis in vivo in a system that resembles the middle cerebral artery. More important, it will allow us to asses macro- and microvascular recanalization. The most effective combinations, as determined in Aim 1, will be repeated to optimize the insonation parameters when sound is transmitted through the same wet human cadaveric temporal skull bone used for the in vitro experiments. Although the rabbit brain would be a more ideal organ to study, the rabbit skull will not allow us to translate the knowledge gained to human subjects because of the dramatic differences in skull geometry relative to the US beam. We will instead use the rabbit renal circulation since it presents an arterial bifurcation (aorta to renal) of similar dimensions as the MCA. This model will therefore allow us to study the effect of sonothrombolysis on the macro- and the microcirculation with intervening temporal human skull bone to more closely mimic the human setting. We believe that both aims of this project will contribute to a better understanding whether transcranial diagnostic US can be used for the therapeutic purpose of sonothrombolysis in acute stroke patients. We will learn if tPA activity can be augmented in combination with diagnostic US and if UCA microbubbles further enhance this effect. Moreover, we will learn if transcranial sonothrombolysis can already be achieved with diagnostic US alone and if the combination of diagnostic US plus UCA microbubbles, in absence of tPA, could be a serious therapeutic option in the future. The knowledge gained in this project would facilitate the translation into clinical trials, which is the ultimate goal. Noninvasive 'Image-Guided Sonothrombolysis' at the bedside or even in the ambulance vehicle would be a major achievement in stroke therapy. PUBLIC HEALTH RELEVANCE: The goal of this proposal is to study the impact of transcranial diagnostic ultrasound in combination with tPA and/or UCA microbubbles on thrombolysis. To achieve this we propose two different Aims to study the effect of ultrasound on thrombolysis in vitro and in vivo.

描述（由申请人提供）：基于微泡的超声对比剂（UCA）增强了Sonothothrombolsyssis的影响，无需或与组织纤溶酶原激活剂（TPA）结合使用。超声（美国）为何加速溶栓的基本机制，如何优化美国设置以有效的颅内动脉中的有效的凝结裂解以及微泡如何加速Sonothothrombollombollombollombolsosis是不理理解的。虽然我们旨在探索和优化其中一些参数，但我们的目标是在可用于经颅血管成像的标准诊断设备上，研究美国对溶栓的影响与TPA和/或UCA Microbubbles结合使用。为了实现这一目标，我们提出了以下目的：目标1-在体外Sonothrombolsysy步骤1已经建立了流动系统，这使我们能够研究暴露于循环，脉冲流动的人类全血凝块的溶栓，并同时获得凝块位点的声学特性。第1步计划的实验将使我们能够定义成功绑定血栓的首选美国参数设置，并研究流动对单独使用或与TPA和/或UCA结合使用时的流动对凝块溶解的影响。步骤2基于我们在步骤1中学习的内容，将重复三个最有效的组合，以优化我们通过中间湿的人尸体颞头颅骨来传输参数。通过骨骼的渗透受声吸收，散射和相差的限制。该实验将使我们能够研究这些效果，并通过人尸体头骨骨骼进行染色期间的凝块位点的声学参数。这将有助于我们优化美国参数，例如发射频率，功率，焦点等，以实现经颅溶栓。 AIM 2-在体内Sonothrombolsysis已经建立了兔肾动脉模型。基于富含红细胞的血栓模型局部血栓形成。使用AIM 1中确定的优化的US参数，我们将确认我们单独的贡献以及我们与TPA或UCA的组合，或两者在体内加速凝块溶解方面。我们认为，血栓和内皮之间的相互作用对溶栓具有重要影响，溶栓是在体外模型中无法研究的。提出的兔子模型将帮助我们研究这些作用及其对类似于大脑中动脉的系统中体内溶栓的影响。更重要的是，它将使我们能够评估宏观和微血管再通行。在AIM 1中确定的最有效组合将重复重复以优化声音通过用于体外实验的相同湿的人尸体颞骨头骨头传输时。尽管兔子大脑将是一个更理想的研究器官，但兔子头骨不允许我们将获得的知识转化为人类受试者，因为相对于美国束相对于颅骨几何形状存在巨大差异。相反，我们将使用兔肾脏循环，因为它具有与MCA相似的维度的动脉分叉（主动脉至肾脏）。因此，该模型将使我们能够研究Sonothothrombolsys对宏观循环和微循环的影响，并与暂时的人颅骨骨骼中间，以更紧密地模仿人类环境。我们认为，该项目的两个目标都将有助于更好地理解是否可以将经颅诊断美国用于急性中风患者的Sonothothrombolsysis的治疗目的。我们将了解是否可以与诊断性的美国结合使用TPA活动，以及UCA Microbubbles是否进一步增强了这种效果。此外，我们将学会单独使用诊断我们的经颅Sonothrombolsysy，并且如果在没有TPA的情况下，诊断我们的诊断性和UCA Microbubbles的组合是否可能是一种严重的治疗选择。该项目获得的知识将促进转化为临床试验，这是最终目标。在床边甚至救护车上的无创“图像引导的Sonothrombolysy”将是中风疗法的重大成就。公共卫生相关性：该提案的目的是研究经颅诊断超声与TPA和/或UCA Microbubbles对溶栓的影响。为了实现这一目标，我们提出了两个不同的目的，以研究超声对体外和体内溶栓的影响。