Dosimetry of Cavitation Microlesions in Microbubble Enhanced Medical Ultrasound

描述(申请人提供)：微泡技术使医学中的超声朝着有洞察力的诊断和有效的治疗方向发展，但超声空化的剂量学存在问题。稳定的微泡随血液循环，并被超声波脉冲激活，产生微泡特有的回声。这项技术使对比度增强的诊断模式成为可能，可以在毛细血管水平显示组织的灌注情况。然而，在微泡超声造影剂被批准用于临床后，发现即使在高机械指数(MI)间歇扫描的诊断成像过程中，也会发生包括毛细血管破裂和心脏细胞致死性损伤在内的微小病变。相反，这些现象也为治疗应用提供了动力，如基因治疗、靶向药物输送和溶栓治疗。由稳定的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上MI及其调节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。空化引起的微小损伤的这种有问题的剂量学对公众健康具有潜在的负面影响。本项目的目标是解决剂量学问题，并创建一种新的剂量学指数公式，用于临床测量空化生物效应的大小。最近的研究表明，MEMU对肾小球毛细血管出血的压力幅度阈值(P)与超声频率(F)成正比，因此(p/f)是恒定的。核心假说驱动 这项研究表明，这一实验发现揭示了组织中空化生物效应的基本规律。对这一规律的理论解释可能是，空穴部位的机械能剂量大致与(p/f)2成正比，这意味着阈值应该与频率成正比。我们的研究策略有三个具体目标：(1)确定心脏毛细血管渗漏和心肌细胞损伤阈值随频率和肝脏毛细血管大小的变化；(2)从理论上分析阈值条件下的空洞动力学，以解释p/f规则及其组织变化；(3)建立估算的剂量学框架。 微小病变在临床上的影响。实现这些目标的预期结果是能够降低诊断性MEMU的风险并优化治疗应用的效果。新的MEMU剂量学指数将挑战旧的MI范例，并帮助临床医生在检查或治疗期间测量微损伤潜力。微损伤剂量学的缺乏极大地阻碍了微气泡技术在临床实践中的发展。解决MEMU尚未解决的空化剂量学问题，可以说是当今医学超声最迫切的研究需求。该项目的总体影响将是使微泡技术能够在医学上有信心地实施，并实现为患者提供安全诊断和有效治疗的承诺。

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.