Dosimetry of Cavitation Microlesions in Microbubble Enhanced Medical Ultrasound

描述（由申请人提供）：微泡技术将超声在医学上推向深刻的诊断和有效的治疗，但超声空化的剂量学存在问题。稳定的微泡随血液循环，并被超声脉冲激活，产生微泡特有的回声。该技术启用了对比增强诊断模式，可以在毛细血管水平显示组织灌注。然而，在微泡超声造影剂被批准用于临床使用后，即使在高机械指数（MI）间歇扫描的诊断成像中，也会发现微病变，包括毛细血管破裂和心脏细胞的致命损伤。相反，这些现象也为基因治疗、靶向药物输送和溶栓等治疗应用提供了动力。稳定微泡在血液中形成的惯性空化是生物效应的来源。遗憾的是，基于理论空化阈值的屏幕上MI及其监管上限是在超声造影剂发明之前建立的，基本上没有为微泡增强医学超声（MEMU）提供剂量学指导。这种对空化引起的微损伤的剂量测定方法存在问题，对公众健康有潜在的负面影响。本课题的目标是解决剂量学问题，并建立一个新的剂量学指数公式，以衡量临床中空化生物效应的大小。最近的研究表明，MEMU肾小球毛细血管出血的压幅阈值(p)与超声频率(f)成正比，因此（p/f）是恒定的。中心假设驱动

DESCRIPTION (provided by applicant): Microbubble technology advances ultrasound in medicine toward insightful diagnosis and effective therapy, but has problematical dosimetry for ultrasonic cavitation. Stabilized microbubbles circulate with the blood and are activated by ultrasound pulses to yield microbubble-specific echos. This technology has enabled contrast-enhanced diagnostic modes, which can reveal tissue perfusion at the capillary level. However, after approval of microbubble-based ultrasound contrast agents for clinical use, microlesions, including capillary rupture and lethal injury of heart cells, were found to occur even during diagnostic imaging with high Mechanical Index (MI) intermittent scans. Conversely these phenomena also power therapeutic applications, such as gene therapy, targeted drug delivery and thrombolysis. Inertial cavitation nucleated in blood from the stabilized microbubbles is the source of the bioeffects. Unfortunately, the on-screen MI, which was based on theoretical cavitation thresholds, and its regulatory upper limit were established before the invention of ultrasound contrast agents and essentially have provided no dosimetric guidance for microbubble enhanced medical ultrasound (MEMU). This problematical dosimetry for cavitation-induced microlesions presents potentially negative implications for public health. The objective of this project is to solve the dosimetry problem and create a new dosimetric index formula for gauging the magnitude of cavitational bioeffects in the clinic. Recent research has shown that pressure amplitude thresholds (p) for glomerular capillary hemorrhage from MEMU are proportional to ultrasonic frequency (f), so that (p/f) is constant. The central hypothesis driving this research is that this experimental finding has revealed a fundamental rule for cavitational bioeffects in tissue. The theoretical explanation of this rule may be that the mechanical energy dose at a cavity site is roughly proportional to (p/f)2, which would imply that thresholds should be proportional to frequency. Our research strategy has three specific aims: (1) determine the variation with frequency of capillary leakage and cardiomyocyte injury thresholds in heart and with capillary size in liver, (2) theoretically analyze cavity dynamics under threshold conditions o explain the p/f rule and its tissue variations, and (3) build a dosimetric framework for estimating microlesion impact in the clinic. The outcomes expected from achieving these aims are the ability to mitigate risks of diagnostic MEMU and to optimize the efficacy of therapeutic applications. The new dosimetric index for MEMU will challenge the old MI paradigm and assist clinicians in gauging the microlesion potential during examinations or treatments. The lack of microlesion dosimetry has impeded greatly the advancement of microbubble technology in clinical practice. The solution of the cavitation dosimetry problem with unresolved safety implications for MEMU is arguably the most pressing research need in medical ultrasound today. The overall impact of this project will be to enable the confident implementation of microbubble technology in medicine and the fulfillment of the promise of safe diagnosis and effective treatment for the patient.