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.

Public Health Relevance

Microbubble technology advances ultrasound in medicine toward insightful diagnosis and effective therapy, but problematical dosimetry for cavitation-induced microlesions has potentially negative implications for public health. This project will measure thresholds for cavitation microlesions in heart and other tissue, theoretically analyze cavity dynamics in model tissue and create a dosimetric framework for assuring the safety and efficacy of microbubble enhanced ultrasound in medicine.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-BMIT-J (01))
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Danthi, Narasimhan
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
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Miller, Douglas L; Lu, Xiaofang; Dou, Chunyan et al. (2018) The Dependence of Glomerular Capillary Hemorrhage Induced by Contrast Enhanced Diagnostic Ultrasound on Microbubble Diameter. Ultrasound Med Biol 44:613-621
Miller, Douglas L; Lu, Xiaofang; Fabiilli, Mario et al. (2016) Do Anesthetic Techniques Influence the Threshold for Glomerular Capillary Hemorrhage Induced in Rats by Contrast-Enhanced Diagnostic Ultrasound? J Ultrasound Med 35:373-80
Miller, Douglas L; Lu, Xiaofang; Fabiilli, Mario et al. (2016) Frequency Dependence of Petechial Hemorrhage and Cardiomyocyte Injury Induced during Myocardial Contrast Echocardiography. Ultrasound Med Biol 42:1929-41
Church, Charles C; Miller, Douglas L (2016) A Two-Criterion Model for Microvascular Bio-Effects Induced In Vivo by Contrast Microbubbles Exposed to Medical Ultrasound. Ultrasound Med Biol 42:1385-98
Vlaisavljevich, Eli; Lin, Kuang-Wei; Warnez, Matthew T et al. (2015) Effects of tissue stiffness, ultrasound frequency, and pressure on histotripsy-induced cavitation bubble behavior. Phys Med Biol 60:2271-92