Time-reversal acoustic device for enhanced drug delivery for brain gliomas

描述（由申请人提供）：这项SBIR I期申请的主要目的是证明一种基于时间反转声学（TRA）原理的聚焦超声新技术的可行性，以提高药物向大脑的对流增强输送（CED）的有效性。CED是一种很有前途的药物输送到大脑的方法，用于治疗几种疾病。CED绕过血脑屏障，通过针头或微导管将化合物直接注入脑实质或脑肿瘤。输液在组织中建立压力梯度，使输液流远离针头。临床前和临床研究表明，治疗的结果在很大程度上取决于药物进入大脑的扩散速度和渗透程度。研究结果表明，将超声聚焦与超声聚焦相结合可以显著提高穿透深度。由于颅骨的不规则形状会扭曲声波前，因此超声在脑内的体内聚焦非常复杂。TRA原理允许补偿任何类型的声波前畸变，并在复合异质介质中提供有效聚焦，特别是在封闭的混响腔中，例如在颅骨中。微型压电换能器连接在注射药物的针尖上，作为一个必要的信标，将超声波精确聚焦到注射药物的确切区域。使用TRA原理对超声进行高精度聚焦，最大限度地减少健康组织暴露于高强度超声。这项研究的目标是开发一种超声增强治疗多种脑部疾病的声学装置，最终可用于临床。最佳的超声暴露参数将被确定，以达到最大程度地增强输液的渗透，对健康细胞的损害最小。TRA聚焦系统的性能和增强输注穿透将在组织模拟和动物体内实验中进行测试。公共卫生相关性：该项目的长期目标是开发、建立并将一种声学系统推向市场，该系统可将高度精确的超声聚焦到大脑中选定的部位，以改善对流增强药物输送，这是治疗脑部疾病（包括脑肿瘤）的一种有前景的新疗法。该项目开发的技术将提高治疗的效果，最终将为患有各种脑部恶性肿瘤的患者带来更好的结果。

DESCRIPTION (provided by applicant): The main objective of this SBIR Phase I application is to demonstrate the feasibility of a novel technology for focusing ultrasound based on time-reversal acoustics (TRA) principle to improve the effectiveness of convection-enhanced delivery (CED) of drugs to the brain. CED is a promising method of drug delivery to the brain for the treatment of several disorders. CED bypasses the blood-brain barrier by infusing compounds through a needle or microcatheter directly into brain parenchyma or brain tumor. The infusion establishes a pressure gradient in the tissue that drives a flow of infusate away from the needle. Preclinical and clinical studies suggest that the outcome of the therapy depends strongly on the diffusion rate and extent of penetration of the drug into the brain. It has been shown that dramatic increase of the penetration depth can be obtained by combining the CED with focused ultrasound. In vivo focusing of ultrasound in the brain is complicated because of the irregular shape of the skull which distorts the acoustic wave front. TRA principles allow for compensation of any kind of acoustic wave front distortion and provide efficient focusing in composite heterogeneous media, especially within closed reverberating cavities, such as in the skull. A miniature piezotransducer attached to tip of the needle used for injecting the drug, acts as a beacon necessary for accurate focusing of ultrasound to exactly the region where the drug is injected. Highly accurate focusing of ultrasound using the TRA principle minimizes the exposure of healthy tissue to high intensity ultrasound. The goal of the proposed research is to develop an acoustic device for ultrasound-enhanced therapy for several brain disorders that can ultimately be used in a clinical setting. Optimal ultrasound exposure parameters will be determined in order to achieve the maximum enhancement of the penetration of the infusate with minimum damage to healthy cells. The performance of the TRA focusing system and enhancement of infusate penetration will be tested in tissue mimicking phantoms and in animal experiments in vivo. PUBLIC HEALTH RELEVANCE: The long-term goal of this project is to develop, build and bring to the market an acoustic system for highly accurate focusing ultrasound to selected sites in the brain to improve convection enhanced drug delivery, which is a promising new therapy for the treatment of brain disorders, including brain tumors. The technology developed in the project will improve the efficacy of the therapy, which eventually should lead to better outcomes in patients suffering from a variety of brain malignancies.