Development of Theranostic Ultrasound

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，以有效地增强静脉输注微泡存在时的溶栓。这些高声压引起微泡的惯性空化（IC），当使用经胸脉冲时，也可能引起不必要的生物效应，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），这可能产生与高IC水平相同的血栓溶解，但没有不必要的生物效应。不幸的是，没有任何方法可以监测感兴趣区域内空化的类型或程度。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，这是本项目的中心假设。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血管和微血管内最佳血栓溶解所需的条件。为了正确识别反馈，我们预测治疗区域的空化微泡的响应可以从返回询问换能器的局部气泡响应信号的非线性声学特征中推断出来，并且局部气泡响应特征反过来可以用来调整传输的超声能量以补偿衰减，确保在所需生物效应的位置传递能量。我们进一步假设，与中型血管相比，微血管水平上达到所需空化水平所需的传输振幅将有所不同。为了验证这一假设，FCDS已经被开发出来，它可以对微泡成像，应用治疗脉冲，并正确地提供实时反馈，以确定传输的脉冲是否会产生不同形式的SC（非破坏性和破坏性）与IC。在验证其判别能力后，治疗系统将被验证

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.