Development of Theranostic Ultrasound

描述（由申请人提供）：在小动物模型中使用诊断超声系统的高机械指数脉冲，在存在静脉输注微泡的情况下有效增强血栓溶解。这些高声压引起微泡的惯性空化（IC），当使用经胸脉冲时，这也可能引起不希望的生物效应，例如出血、细胞死亡和心律失常。在较低的机械指数（MI）下，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水平相当的血栓溶解，但不会产生不必要的生物效应。不幸的是，没有可以监测感兴趣区域内的空化类型或水平的方法。本课题的核心假设是利用反馈空化检测系统（FCDS）可以检测和监测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在中等大小的血管以及微血管内最佳血栓溶解所需的内容。为了正确地识别反馈，我们预测可以从返回到询问换能器的局部气泡响应信号的非线性声学特征推断治疗区域中的空化微泡的响应，并且局部气泡响应特征进而可以用于调节所发射的超声能量以补偿衰减，确保在所需生物效应的位点处递送能量。我们进一步假设，当与中等大小的血管相比时，实现所需空化水平所需的传输幅度在微血管水平将是不同的。为了测试该假设，已经开发了FCDS，其可以对微泡成像，施加治疗脉冲，并且正确地提供关于所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的真实的时间反馈。在验证其辨别能力之后，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测试。在此之后，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水平的衰减，以模拟经胸和经颅衰减。在这些模型中，我们将确定a）FCDS是否仍然可以识别并有效监测所需的空化响应;以及B）当实现一致的IC或SC反馈时实现的血栓溶解程度。这种非侵入性治疗工具的影响将是显著的，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塞的FCDS将导致这两种疾病实体的更快速治疗，这两种疾病实体仍然是世界上死亡和残疾的主要原因。开发的FCDS还将允许在患者接触点处潜在地启动的具有成本效益的、安全的和即时的治疗。

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.