Dosimetry of Cavitation Microlesions in Microbubble Enhanced Medical Ultrasound

微泡增强医学超声中空化微损伤的剂量测定

• 批准号: 8436606
• 负责人: DOUGLAS LAWRENCE MILLER
• 金额: $ 38.85万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-15 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8436606
• 关键词: Animal Testing; Automobile Driving; Blood; Blood capillaries; Brain; Cardiac Myocytes; Cessation of life; Church; Clinic; Clinical; Complex; Contrast Media; Contrast echocardiography procedure; Dependence; Deposition; Diagnosis; Diagnostic; Diagnostic Imaging; Dose; Drug Delivery Systems; Extravasation; Family suidae; Frequencies; Glomerular Capillary; Health; Heart; Hemorrhage; Injury; Kidney; Liver; Measures; Mechanics; Medicine; Methods; Microbubbles; Modality; Modeling; Outcome; Patients; Perfusion; Physiologic pulse; Public Health; Rattus; Research; Risk; Rupture; Safety; Scanning; Science; Site; Solutions; Source; Technology; Therapeutic; Tissue Model; Tissues; Treatment Efficacy; Ultrasonics; Ultrasonography; Variant; Yang; attenuation; base; capillary; clinical practice; dosimetry; effective therapy; gene therapy; heart cell; improved; indexing; physical model; pressure; public health relevance; thrombolysis

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.

描述（由申请人提供）：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，但超声空化的剂量测定存在问题。稳定的微泡随血液循环，并被超声脉冲激活以产生微泡特异性回波。该技术实现了对比度增强诊断模式，可以揭示毛细血管水平的组织灌注。然而，在基于微泡的超声造影剂被批准用于临床使用后，发现即使在具有高机械指数（MI）间歇扫描的诊断成像期间也会发生微损伤，包括毛细血管破裂和心脏细胞的致命损伤。相反，这些现象也为治疗应用提供动力，例如基因治疗、靶向药物递送和血栓溶解。稳定的微泡在血液中形成的惯性空化是生物效应的来源。不幸的是，基于理论空化阈值的屏上MI及其监管上限是在超声造影剂发明之前建立的，并且基本上没有为微泡增强医学超声（MEMU）提供剂量学指导。这种有问题的空化诱导的微病变的剂量测定提出了潜在的负面影响，对公众健康。本研究的目的是解决剂量学问题，并建立一个新的剂量学指数公式，用于测量空化生物效应的大小。最近的研究表明，MEMU引起的肾小球毛细血管出血的压力振幅阈值（p）与超声频率（f）成正比，因此（p/f）是常数。核心假设驱动 这项研究是，这项实验发现揭示了组织中空化生物效应的基本规律。这一规则的理论解释可能是，在一个洞的位置的机械能剂量大致成比例的（p/f）2，这将意味着阈值应成比例的频率。我们的研究策略有三个具体的目标：（1）确定心脏毛细血管渗漏频率和心肌细胞损伤阈值以及肝脏毛细血管大小的变化;（2）理论分析阈值条件下的腔动力学，以解释p/f规则及其组织变化;（3）建立一个剂量学框架，以估计 临床上的微损伤影响。实现这些目标的预期结果是能够减轻诊断MEMU的风险并优化治疗应用的功效。MEMU的新剂量测定指数将挑战旧的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泡造影技术在临床应用中的发展。空化剂量学问题的解决方案与未解决的安全问题MEMU可以说是当今医学超声领域最迫切的研究需求。该项目的总体影响将是使微泡技术在医学中的可靠实施和实现对患者的安全诊断和有效治疗的承诺。