Development of Theranostic Ultrasound

描述(申请人提供)：来自诊断超声系统的高机械指数脉冲已经在小动物模型中被利用，以在存在静脉注射微泡的情况下有效地增强血栓溶解。这些高声压会导致微泡的惯性空化(IC)，当使用经胸脉冲时，这也可能导致不必要的生物效应，如出血、细胞死亡和心律失常。在较低的机械指数(MI)下，可诱导较低至中等水平的IC以及较高水平的稳定空化(SC)，这可能会产生与较高IC水平相当的血栓溶解，但不会产生有害的生物效应。不幸的是，没有任何方法可以用来监测感兴趣区域内空化的类型或水平。S是该项目的中心假设，即可以使用反馈空化检测系统(FCDS)来检测和监测不同形式和程度的空化。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使人们能够确定在中等大小的血管内以及微血管系统中需要什么来实现最佳的血栓溶解。为了正确识别反馈，我们预测，可以从返回到询问换能器的本地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气泡的响应，并且可以使用本地气泡响应信号来调整传输的超声能量以补偿衰减，从而确保在期望的生物效应部位传递的能量。我们进一步假设，与中等大小的血管相比，达到期望的空化水平所需的传输幅度在微血管水平上将有所不同。为了验证这一假设，已经开发出一种FCDS，它可以对微泡进行成像，施加治疗脉冲，并正确地提供实时反馈，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。在验证其识别能力后，治疗鼻音系统将被 在微泡输注中用正常微血管的体外模型进行测试。在此之后，微血管和血管血栓将被创造出来，其中产生不同程度的衰减，组织模仿模体来模拟经胸和经颅的衰减。在这些模型中，我们将确定a)FCDS是否仍然可以识别和有效地监控所需的空化反应；以及b)当获得一致的IC或SC反馈时，血栓溶解的程度。这种非侵入性治疗工具的影响将是巨大的，因为开发一种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，这两种疾病仍然是世界上导致死亡和残疾的主要原因。开发的FCDS还将允许具有成本效益的、安全的和立即的治疗，这种治疗可能在患者接触时启动。

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.