Ultrasound Therapy Delivery Through Intact Skull

通过完整的颅骨进行超声治疗

基本信息

批准号：
8508176
负责人：
Kullervo Hynynen
金额：
$ 51.32万
依托单位：
SUNNYBROOK & WOMEN'S COLL HLTH SCIS CTR
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-02-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8508176
关键词：
Acoustics Address Animal Disease Models Animal Model Animals Antineoplastic Agents Area Automobile Driving Behavior Biological Blood - brain barrier anatomy Brain Brain Diseases Brain Neoplasms Brain Part Brain region Cell physiology Central Nervous System Diseases Clinic Clinical Clinical Research Clinical Trials Computer Simulation Data Deposition Development Devices Doxorubicin Drug Targeting Effectiveness Feedback Focused Ultrasound Therapy Frequencies Funding Future Goals Grant Heterogeneity Huntington Disease In Vitro Industry Institution Intervention Investigation Laboratories Location Magnetic Resonance Imaging Malignant neoplasm of brain Mediating Methods Microbubbles Microscopy Modeling Monitor Natural Killer Cells New Agents Outpatients Patient Care Performance Phase Recovery Research Resolution Roche brand of trastuzumab Safety Signal Transduction Small Interfering RNA Sonication Spottings System Technology Testing Therapeutic Therapeutic Agents Time Tissues Transducers Ultrasonic Therapy Ultrasonography Vascular blood supply Vision base behavior test bone brain cell brain surgery brain tissue chemotherapeutic agent chemotherapy clinically relevant cost cranium design expectation experience improved in vivo intravital microscopy models and simulation nonhuman primate novel therapeutics performance tests programs prototype research clinical testing research facility research study simulation sound frequency tumor two-photon

项目摘要

DESCRIPTION (provided by applicant): Invasive brain interventions often result in complications and long recovery times. In addition, the delivery of therapeutic agents via the blood supply is often impossible because the Blood-Brain Barrier (BBB) protects the brain tissue from foreign molecules. Laboratory experiments and first clinical trials have shown that focused ultrasound (FUS) beams can be used for noninvasive interventions. However, the utilization of FUS in the brain has been seriously limited by the difficulty of delivering ultrasound through the skull bone. The hypothesis of this grant has been that transcranial therapeutic ultrasound exposures can be delivered noninvasively through an intact skull. This hypothesis has now been validated in three clinical studies that demonstrate that brain tissue can be noninvasively coagulated in the central part of the brain. During the current grant period, we furthered our initial research and developed methods to enhance FUS interaction with tissue using microbubbles, thus making whole brain sonications feasible. We have further studied the impact of ultrasound exposures on brain tissue and demonstrated chemotherapy delivery across the BBB. We, and others, have used animal tumor models to demonstrate that chemotherapy treatment significantly increases animal survival when combined with FUS induced BBB disruption. We have also developed computer simulation programs, control technology and treatment methods that will improve the delivery of ultrasound energy. Our study plan is to extend our current research and further explore the feasibility of using intravascular microbubbles to enhance the trans-skull sonications. Our goals are: First, to use our prototype phased array ultrasound system with passive acoustic monitoring to provide acoustic signal feedback, and thus localize and control bubble- enhanced treatments. Second, to utilize our computer models to develop more precise focusing, using higher and multiple frequency sonications, such that the focal volume size is reduced. This will provide better control and allow nonuniform brain tissue to be adequately exposed. Third, to construct and test the new arrays designed using the computer simulations. Fourth, to perform in vivo two-photon microscopy and behavior studies to increase our understanding of ultrasound induced BBB disruption effects on delicate brain regions. Finally, to further test the effectiveness of the ultrasound-induced BBB disruption for the delivery of chemotherapeutic agents and natural killer cells for the treatment o malignant brain tumors, and the delivery of siRNA for the treatment of Huntington's disease. Our vision is that successful trans-skull delivery of FUS could have a major impact on the treatment of many brain disorders. If successful, this research will have a major impact on patient care.

描述（由申请人提供）：侵入性大脑干预通常会导致并发症和较长的恢复时间。此外，由于血脑屏障（BBB）保护脑组织免受外国分子的侵害，因此通常不可能通过血液供应递送治疗剂。实验室实验和第一次临床试验表明，聚焦超声（FUS）梁可用于无创干预措施。然而，由于难以通过颅骨传递超声波的困难，大脑中FU的利用受到了严重限制。这笔赠款的假设是，可以通过完整的头骨无创地传递经颅治疗超声暴露。现在，在三项临床研究中对这一假设进行了验证，这些临床研究表明脑组织在大脑的中央部分可以无创凝结。在当前赠款期间，我们进一步进行了初步研究，并开发了使用微泡增强FUS与组织相互作用的方法，从而使整个大脑超声处理可行。我们进一步研究了超声暴露对脑组织的影响，并在整个BBB中表现出化学疗法的递送。我们和其他人已经使用动物肿瘤模型来证明，当与FUS诱导的BBB破坏结合使用时，化学疗法治疗可显着增加动物的生存率。我们还开发了计算机模拟程序，控制技术和治疗方法，以改善超声能量的交付。我们的研究计划是扩展我们当前的研究，并进一步探索使用血管内微泡以增强反式乳房超声处理的可行性。我们的目标是：首先，将我们的原型分阶段阵列超声系统与被动声监视一起提供声学信号反馈，从而定位和控制气泡增强的处理。其次，利用我们的计算机模型来开发更精确的焦点，使用较高和多频率超声波，以减少焦点量的大小。这将提供更好的控制并允许不均匀的脑组织可充分暴露。第三，使用计算机模拟构造和测试设计的新阵列。第四，进行体内两光子显微镜和行为研究，以提高我们对超声引起的BBB破坏对精致大脑区域的影响。最后，为了进一步测试超声诱导的BBB破坏在化学治疗剂和天然杀伤细胞输送以治疗恶性脑肿瘤的有效性，以及用于治疗亨廷顿氏病的siRNA。我们的愿景是，FUS的成功反式kull分娩可能会对许多脑部疾病的治疗产生重大影响。如果成功，这项研究将对患者护理产生重大影响。