High Intensity Focused Ultrasound (HIFU) is an emerging medical technology for thermally ablating targeted tissue within a mm-size focal 'hot spot'without damaging intervening tissues. In recent HIFU studies, there has also been significant interest in using purely mechanical destruction of tissue without thermal coagulation (histotripsy). Despite successful use of HIFU for the treatment of some benign and malignant tumors, broader clinical acceptance of this technology is impeded by incomplete regulatory standards for safety and efficacy. Current limitations include (a) a lack of established metrology standards to characterize HIFU fields;(b) an incomplete mechanistic understanding of thermal and mechanical bioeffects at high acoustic intensities, which hinders the quantification of dose given exposimetry information;and (c) clinical challenges such as long treatment times, acoustic obstacles like ribs, and the limited availability of cost-effective image guidance. This proposal addresses these limitations with a particular focus on treatments at high power levels. In the initial years of the grant, we explored HIFU treatments that utilize nonlinear acoustics and developed metrology tools for characterizing intense acoustic fields. We showed that shock formation leads to ultrasound absorption that is 10-100 times greater than for harmonic waves of the same intensity;consequently, boiling conditions at 100?C can be reached within milliseconds. We developed a treatment method that uses sequences of millisecond-long, high-pressure pulses to deliver shocks waves at the focus. In such treatment regimes, tissue ablation is accelerated, the initiation of boiling facilitates image guidance with ultrasound, and tissue lesions can be controlled to exhibit mechanical damage, thermal damage, or both.
The specific aims of this proposal build upon the previous work to advance nonlinear HIFU methods toward clinical adoption.
In Aim 1, we will extend HIFU transducer characterization to complex array sources, and we will define methods suitable for standard use in performance assessment of clinical HIFU systems.
In Aim 2, high power transducers will be built and the methods for correlating exposimetry with bioeffects in tissue (ex vivo) will be developed for a range of therapeutic regimes such as purely thermal, mechanical, or combined.
In Aim 3, we examine tumor treatment in two target organs, the liver and the kidney, using a healthy porcine model. We will implement a range of nonlinear HIFU protocols using a 2D phased array representative of modern clinical systems. These studies will address interference from ribs and respiratory tissue motion, allowing careful assessment of the precision and control of lesion formation in a clinical setting. Previous work targeted at high-power clinical treatments has not involved the detailed fundamental characterizations that we propose here. The work will benefit public health care by providing tools for accurate evaluation of HIFU exposure, thereby aiding the development of regulatory guidelines to facilitate FDA approval of new HIFU therapies while identifying poorly controlled systems. The work will also advance HIFU toward faster and safer clinical treatments.
High Intensity Ultrasound (HIFU) is gaining acceptance in the clinic as a form of noninvasive or minimally invasive surgery. This proposed work will benefit public health by facilitating development of regulatory guidelines and developing HIFU technology toward faster and safer clinical treatments with ultrasound guidance.
| Khokhlova, Tatiana; Rosnitskiy, Pavel; Hunter, Christopher et al. (2018) Dependence of inertial cavitation induced by high intensity focused ultrasound on transducer F-number and nonlinear waveform distortion. J Acoust Soc Am 144:1160 |
| Ghanem, Mohamed A; Maxwell, Adam D; Kreider, Wayne et al. (2018) Field Characterization and Compensation of Vibrational Nonuniformity for a 256-Element Focused Ultrasound Phased Array. IEEE Trans Ultrason Ferroelectr Freq Control 65:1618-1630 |
| Rosnitskiy, Pavel B; Vysokanov, Boris A; Gavrilov, Leonid R et al. (2018) Method for Designing Multielement Fully Populated Random Phased Arrays for Ultrasound Surgery Applications. IEEE Trans Ultrason Ferroelectr Freq Control 65:630-637 |
| Brayman, Andrew A; MacConaghy, Brian E; Wang, Yak-Nam et al. (2018) Inactivation of Planktonic Escherichia coli by Focused 1-MHz Ultrasound Pulses with Shocks: Efficacy and Kinetics Upon Volume Scale-Up. Ultrasound Med Biol 44:1996-2008 |
| Rosnitskiy, Pavel B; Yuldashev, Petr V; Sapozhnikov, Oleg A et al. (2017) Design of HIFU Transducers for Generating Specified Nonlinear Ultrasound Fields. IEEE Trans Ultrason Ferroelectr Freq Control 64:374-390 |
| Chevillet, John R; Khokhlova, Tatiana D; Giraldez, Maria D et al. (2017) Release of Cell-free MicroRNA Tumor Biomarkers into the Blood Circulation with Pulsed Focused Ultrasound: A Noninvasive, Anatomically Localized, Molecular Liquid Biopsy. Radiology 283:158-167 |
| Maxwell, Adam D; Yuldashev, Petr V; Kreider, Wayne et al. (2017) A Prototype Therapy System for Transcutaneous Application of Boiling Histotripsy. IEEE Trans Ultrason Ferroelectr Freq Control 64:1542-1557 |
| Khokhlova, Tatiana D; Haider, Yasser A; Maxwell, Adam D et al. (2017) Dependence of Boiling Histotripsy Treatment Efficiency on HIFU Frequency and Focal Pressure Levels. Ultrasound Med Biol 43:1975-1985 |
| Khokhlova, Tatiana D; Monsky, Wayne L; Haider, Yasser A et al. (2016) Histotripsy Liquefaction of Large Hematomas. Ultrasound Med Biol 42:1491-8 |
| Hunter, Christopher; Sapozhnikov, Oleg A; Maxwell, Adam D et al. (2016) An ultrasonic caliper device for measuring acoustic nonlinearity. Phys Procedia 87:93-98 |
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