A Novel Ultrasound Phased Array and Sonication Method for Stroke Treatments

描述（由申请人提供）：为了开发聚焦超声治疗的潜力，需要具有大量元件的高功率相控阵换能器。目前的方法有两个主要缺点。首先，各个阵列元件的电阻抗随着它们的尺寸减小而变大。其次，阵列不能为一些高级应用提供足够的声功率。我们已经发现了一种方法来克服这两个限制，并建议开发新的相控阵技术的治疗超声基于这种方法。更具体地说，在本提案中，我们将开发一种基于该技术的中风治疗系统。尽管在过去的十年中花费了数百万美元用于急性卒中干预试验，但只有在发病后3 - 6小时内开放阻塞动脉和再灌注缺血半暗带的策略被证明是有效的。临床研究表明，经颅超声和多普勒超声与组织型纤溶酶原激活剂（tPA）联合应用可显著增加闭塞血管再通的患者数量。然而，仍然有大量的患者的动脉闭塞没有解决与目前使用的多普勒超声曝光。我们的假设是，使用相控阵探头和来自CT扫描的患者特定颅骨信息的经颅超声处理可以更好地定位脑内的超声能量，并且与现有方法相比，这将导致患者反应的进一步改善。超声能量在脑内的精确定位也可以使单独使用超声而不使用血栓溶解剂，从而消除这些物质的潜在副作用。在拨款期内，我们须完成的具体工作包括：第一，发展新的阵列技术;第二，发展治疗中风的超声波系统;第三，在所需的频率范围内测量颅骨的特性;以及 第四，用离体人头骨测试完整系统。此外，我们将使用离体和体内模型确定使用和不使用tPA的中风治疗的最佳超声暴露。最后，我们将在两种不同的动物模型中测试治疗的短期和长期影响。在这项研究的最后，我们将开发出一种相控阵技术，可以克服剩余的障碍，最佳地应用这项技术的超声治疗。此外，我们将完成一个原型系统，并将进行必要的临床前测试，以便为随后的急性中风治疗临床试验做好准备。 公共卫生相关性声明（由申请人提供）：尽管在过去十年中花费了数百万美元用于急性卒中干预试验，但只有在发病后3 - 6小时内开放阻塞动脉和再灌注缺血半暗带的策略被证明是有效的。然而，由于系统要求提供适当的护理，只有百分之几的中风患者接受血栓破坏治疗。我们的假设是，如果使用先进的相控阵系统来加速溶栓，更多的患者可以从这些治疗中受益。相控阵将允许可预测的超声暴露，并最大限度地减少对周围组织的影响。在这项研究中，我们计划开发这样一个系统，并在开始临床试验之前进行所有需要的实验。这项研究可能会对患者护理产生重大影响。

DESCRIPTION (provided by applicant): In order to exploit the potential of focused ultrasound therapy, high-power phased array transducers with large number of elements are required. Current methods have two major drawbacks. First, the electrical impedance of individual array elements becomes large as their size is reduced. Second, arrays are not able to deliver adequate acoustic power for some advanced applications. We have discovered a method to overcome both of these limitations and propose to develop new phased array technology for therapeutic ultrasound based on this approach. More specifically in this proposal we will develop a system based on this technology for the treatment of stroke. Despite millions of dollars spent on acute stroke intervention trials over the last decade, only strategies that open blocked arteries and reperfuse ischemic penumbra within 3-6 hours of onset have proven to be effective. Clinical studies have shown that transcranial ultrasound and Doppler ultrasound can significantly increase the number of patients that will have recanalization of the occluded vessel when administrated together with tissue plasminogen activator (tPA). However, there are still a large number of patients whose arterial occlusion is not resolved with the current use of Doppler ultrasound exposure. It is our hypothesis that transcranial sonication using phased array applicators and patient-specific skull information derived from CT scans can better localize ultrasound energy within the brain, and that this will result in further improvements in patient response as compared with existing approaches. Precise localization of ultrasound energy within the brain could also enable the use of ultrasound alone without a thrombolytic agent thus eliminating the potential side effects of these substances. The specific tasks to be completed during this grant period are: First, development of the new array technology, second, development of an ultrasound system for the treatment of stroke, third, measurements of skull properties at the required frequency range, and fourth, tests of the complete system with ex vivo human skulls. In addition we will determine the optimal ultrasound exposures for the stroke treatments with and without tPA using ex vivo and in vivo models. Finally, we will test the short and long term impact of the treatments in two different animal models. At the end of this research we will have developed a phased array technology that can overcome the remaining barriers in applying this technology optimally for ultrasound therapy. In addition we will have completed a prototype system and will have conducted pre-requisite preclinical testing to be in a position for subsequent clinical trials for the treatment of acute stroke. Public Health Relevance Statement (provided by applicant): Despite millions of dollars spent on acute stroke intervention trials over the last decade, only strategies that open blocked arteries and reperfuse ischemic penumbra within 3-6 hours of onset have proven to be effective. Only a few percent of all stroke patients receive clot-busting treatments, however, due to the system requirements to deliver appropriate care. It is our hypothesis that a larger number of patients could benefit from these treatments if advanced phased array systems are used to accelerate thrombolysis. The phased arrays would allow predictable ultrasound exposures and minimize impact on the surrounding tissues. During this research we plan to develop such a system and perform all of the experiments needed prior to starting clinical trials. This research may have a major impact on patient care.