Development of Theranostic Ultrasound

超声治疗诊断的发展

• 批准号: 8605539
• 负责人: THOMAS R PORTER
• 金额: $ 14.6万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8605539
• 关键词: Acoustics; Acute; Acute myocardial infarction; Animal Model; Area; Arrhythmia; Arterial Fatty Streak; Attenuated; Beds; Blood Vessels; Blood capillaries; Blood coagulation; Carotid Artery Thrombosis; Cause of Death; Cell Death; Clinical; Clinical Trials; Coagulation Process; Detection; Development; Devices; Diagnostic; Disease; Effectiveness; Ensure; Failure; Family suidae; Feedback; Healthcare; Hemorrhage; Image; Imagery; Infusion procedures; Injury; Intervention; Ischemic Stroke; Lead; Mechanics; Methods; Microbubbles; Microcirculatory Bed; Modeling; Monitor; Myocardial Infarction; Obstruction; Outcome; Outcomes Research; Patients; Physiologic pulse; Preparation; Rattus; Risk; Rupture; Signal Transduction; Simulate; Site; Stroke; System; Techniques; Testing; Therapeutic; Therapeutic Effect; Thick; Thrombolytic Therapy; Thrombosis; Thrombus; Time; Tissues; Transducers; Ultrasonic Therapy; Ultrasonography; acute coronary syndrome; acute stroke; arteriole; attenuation; base; capillary; cost effective; detector; disability; improved; in vivo; indexing; interest; pre-clinical; pressure; public health relevance; response; restoration; simulation; theranostics; thrombolysis; tool; vascular bed

DESCRIPTION (provided by applicant): High mechanical index impulses from a diagnostic ultrasound system have been utilized in small animal models to efficiently enhance thrombolysis in the presence of intravenously infused microbubbles. These high acoustic pressures induce inertial cavitation (IC) of the microbubbles, which may also cause unwanted bioeffects such as hemorrhage, cell death, and cardiac arrhythmias when using transthoracic impulses. At a lower mechanical index (MI), lower to moderate levels of IC as well as high levels of stable cavitation (SC) of microbubbles are induced which may produce equivalent thrombus dissolution as that achieved with high IC levels, but without unwanted bioeffects. Unfortunately, there are no methods by which one can monitor the type, or level, of cavitation within a region of interest. It s the central hypothesis of this project that the different forms and levels of cavitation can be detected and monitored with a feedback cavitation detection system (FCDS). When combined with image-guided ultrasound, we postulate that the dynamic assessment of cavitation signals will permit one to identify what is required for optimal thrombus dissolution both within medium sized vessels as well as the microvasculature. To correctly identify feedback, we predict that the response of the cavitating microbubble in the treatment region can be inferred from the non-linear acoustic signature of the local bubble response signals that return to the interrogating transducer, and that the local bubble response signature, in turn, can be used to adjust the transmitted ultrasound energy to compensate for attenuation, ensuring the energy delivered at the site of the desired bioeffect. We further postulate that the transmit amplitude required to achieve the desired level of cavitation will be different at microvascular level when compared to a medium-sized vessel. To test this hypothesis, a FCDS has been developed which can image microbubbles, apply therapeutic impulses, and correctly provide real time feedback as to whether the transmitted impulses are producing different forms of SC (non-destructive and destructive) versus IC. After validating its discriminative ability, the theranostic system will be tested during a microbubble infusion with an ex vivo model of normal microvasculature. Following this, microvascular and vascular thrombi will be created where varying levels of attenuation are created with tissue mimicking phantoms to mimick transthoracic and transcranial attenuation. In these models, we will determine a) whether the FCDS can still identify and effectively monitor the desired cavitation response; and b) the degree of thrombus dissolution achieved when either a consistent IC or SC feedback is achieved. The impact of such a non-invasive therapeutic tool will be significant, as development of a FCDS to non-invasively treat acute ischemic stroke and acute myocardial infarction would lead to more rapid treatment of these two disease entities, which remain the leading causes of death and disability in the world. The developed FCDS would also permit a cost-effective, safe, and immediate treatment that could potentially be initiated at the point of patient contact.

描述（由申请人提供）：来自诊断超声系统的高机械指数脉冲已被用于小动物模型中，以在存在静脉输注微泡的情况下有效地增强血栓溶解。这些高声压会引起微泡的惯性空化（IC），这也可能在使用经胸脉冲时引起不良的生物效应，例如出血、细胞死亡和心律失常。在较低的机械指数 (MI) 下，会诱导较低至中等水平的 IC 以及高水平的微泡稳定空化 (SC)，这可能会产生与高 IC 水平所实现的等效血栓溶解效果，但不会产生不良生物效应。不幸的是，没有任何方法可以监测感兴趣区域内的空化类型或水平。该项目的中心假设是可以使用反馈空化检测系统（FCDS）来检测和监控不同形式和水平的空化。当与图像引导超声相结合时，我们假设空化信号的动态评估将允许人们确定中等大小的血管以及微脉管系统内最佳血栓溶解所需的条件。为了正确识别反馈，我们预测治疗区域中空化微泡的响应可以从返回到询问传感器的局部气泡响应信号的非线性声学特征推断出来，并且局部气泡响应特征在转，可用于调整发射的超声能量以补偿衰减，确保能量传递到所需的生物效应部位。我们进一步假设，与中等尺寸的血管相比，在微血管水平上实现所需的空化水平所需的传输幅度将有所不同。为了检验这一假设，我们开发了 FCDS，它可以对微泡进行成像，施加治疗脉冲，并正确提供实时反馈，以确定传输的脉冲是否产生不同形式的 SC（非破坏性和破坏性）与 IC。在验证其辨别能力后，治疗诊断系统将被 在用正常微脉管系统的离体模型进行微泡输注期间进行了测试。此后，将创建微血管和血管血栓，其中使用组织模拟体模创建不同程度的衰减，以模仿经胸和经颅的衰减。在这些模型中，我们将确定 a) FCDS 是否仍能识别并有效监控所需的空化响应； b) 当获得一致的 IC 或 SC 反馈时所达到的血栓溶解程度。这种非侵入性治疗工具的影响将是巨大的，因为开发用于非侵入性治疗急性缺血性中风和急性心肌梗死的 FCDS 将导致对这两种疾病的更快治疗，而这两种疾病仍然是死亡的主要原因和世界上的残疾。开发的 FCDS 还可以提供一种经济高效、安全且立即的治疗，这种治疗有可能在患者接触时就开始。