High mechanical index impulses from a diagnostic ultrasound system have been utilized in small animal models to efficiently enhance thrombolysis in the presence of intravenously infused microbubbles. These high acoustic pressures induce inertial cavitation (IC) of the microbubbles, which may also cause unwanted bioeffects such as hemorrhage, cell death, and cardiac arrhythmias when using transthoracic impulses. At a lower mechanical index (MI), lower to moderate levels of IC as well as high levels of stable cavitation (SC) of microbubbles are induced which may produce equivalent thrombus dissolution as that achieved with high IC levels, but without unwanted bioeffects. Unfortunately, there are no methods by which one can monitor the type, or level, of cavitation within a region of interest. It s the central hypothesis of this project that the different forms and levels of cavitation can be detected and monitored with a feedback cavitation detection system (FCDS). When combined with image-guided ultrasound, we postulate that the dynamic assessment of cavitation signals will permit one to identify what is required for optimal thrombus dissolution both within medium sized vessels as well as the microvasculature. To correctly identify feedback, we predict that the response of the cavitating microbubble in the treatment region can be inferred from the non-linear acoustic signature of the local bubble response signals that return to the interrogating transducer, and that the local bubble response signature, in turn, can be used to adjust the transmitted ultrasound energy to compensate for attenuation, ensuring the energy delivered at the site of the desired bioeffect. We further postulate that the transmit amplitude required to achieve the desired level of cavitation will be different at microvascular level when compared to a medium-sized vessel. To test this hypothesis, a FCDS has been developed which can image microbubbles, apply therapeutic impulses, and correctly provide real time feedback as to whether the transmitted impulses are producing different forms of SC (non-destructive and destructive) versus IC. After validating its discriminative ability, the theranostic system will be tested during a microbubble infusion with an ex vivo model of normal microvasculature. Following this, microvascular and vascular thrombi will be created where varying levels of attenuation are created with tissue mimicking phantoms to mimick transthoracic and transcranial attenuation. In these models, we will determine a) whether the FCDS can still identify and effectively monitor the desired cavitation response;and b) the degree of thrombus dissolution achieved when either a consistent IC or SC feedback is achieved. The impact of such a non-invasive therapeutic tool will be significant, as development of a FCDS to non-invasively treat acute ischemic stroke and acute myocardial infarction would lead to more rapid treatment of these two disease entities, which remain the leading causes of death and disability in the world. The developed FCDS would also permit a cost-effective, safe, and immediate treatment that could potentially be initiated at the point of patient contact.

Public Health Relevance

Targeted ultrasound cavitation of intravenously administered microbubbles has emerged as a potential non-invasive method of treating the blood clots that cause acute stroke and acute myocardial infarction. Although cavitation of the microbubble is the presumed mechanism by which these therapeutic effects occur, it is unclear whether stable or inertial cavitation is required, and for ultrasound and microbubbles to be effective in treating blood clots, a system that can treat these clots must be able to image the microbubbles and determine what type and level of cavitation is being created by the ultrasound. This project will create a theranostic system which combines the diagnostic and therapeutic effects of ultrasound with real time feedback to control the type and level of cavitation induced, resulting i a non-invasive technique which could be used to rapidly treat patients with stroke or myocardial infarction at the point of initial contact with the patient.

National Institute of Health (NIH)
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1-BMIT-J (01))
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Lopez, Hector
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University of Nebraska Medical Center
Internal Medicine/Medicine
Schools of Medicine
United States
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Porter, Thomas R; Xie, Feng; Lof, John et al. (2017) The Thrombolytic Effect of Diagnostic Ultrasound-Induced Microbubble Cavitation in Acute Carotid Thromboembolism. Invest Radiol 52:477-481
Porter, Thomas R; Radio, Stanley; Lof, John et al. (2016) Diagnostic Ultrasound High Mechanical Index Impulses Restore Microvascular Flow in Peripheral Arterial Thromboembolism. Ultrasound Med Biol 42:1531-40
Wu, Juefei; Xie, Feng; Kumar, Tanmay et al. (2014) Improved sonothrombolysis from a modified diagnostic transducer delivering impulses containing a longer pulse duration. Ultrasound Med Biol 40:1545-53
Vignon, Francois; Shi, William T; Powers, Jeffry E et al. (2013) Microbubble cavitation imaging. IEEE Trans Ultrason Ferroelectr Freq Control 60:661-70