High Intensity Focused Ultrasound (HIFU) is used to perform surgical procedures non-invasively by using high amplitude focused sound waves to induce irreversible tissue damage within a mm-size focal `hot spot.'HIFU is rapidly gaining widespread clinical use and is poised to reach even broader patient populations. However, there has been a rising concern within all parts of the HIFU community that no standards exist for measuring or reporting of HIFU fields. It has been also realized that the relation between HIFU output and the produced bioeffects is poorly understood. This lack of standards and relations of acoustics to bioeffects is a major impediment to broad clinical adoption of HIFU. The proposal addresses this current gap in development of such standards as well as understanding the bioeffect mechanisms. Nonlinear acoustics is the study of high amplitude sound. Nonlinear acoustic propagation leads to shocks, discontinuities in the acoustic wave, which encompass a very broad range of frequencies. Shock formation and strong focusing distinguish HIFU from other medical ultrasound approaches and combine to make accurate measurements difficult. Also, since ultrasound energy losses that create heating are frequency dependent, the relatively high absorption in tissue counteracts nonlinear propagation, which means that no simple way exists to extrapolate water measurements directly to tissue. Since the broadest frequency content is in the shocks, absorption at the shocks is the critical mechanism of tissue heating.
The specific aims of this proposed project are: (1) Use combined simulations and measurements to determine the high amplitude acoustic output of HIFU sources in water. (2) Determine the fields in tissue phantoms and tissue and define methods to derate water measurements to tissue. (3) Quantify the mechanism of enhanced tissue heating due to nonlinear acoustics and corresponding bioeffects in ex-vivo tissue and in vivo animal studies (4) Synthesize results of Aims 1-3 into practical recommendations for characterization of HIFU devices to improve regulatory oversight, understanding bioeffects, and efficacy and safety of clinically relevant HIFU therapeutic devices. Our method is a combined approach of numerical simulation and experimental measurement. Our model includes nonlinear acoustic propagation effects, diffraction, absorption, and tissue heterogeneities. Our acoustic measurements tools include small broad bandwidth hydrophones and a new step-shock source to calibrate the hydrophones. Our thermal measurement techniques involve the noninvasive observation of boiling with high speed photography and active and passive acoustic transducers. Tissue phantoms, excised and in vivo tissue will be used in experiments and modeling. This proposed work will benefit public health by providing tools and recommendations to help regulate and control HIFU exposures, which will improve efficacy and safety and facilitate a more rapid clinical acceptance of this promising therapy.

Public Health Relevance

High Intensity Ultrasound (HIFU) is gaining wider acceptance in the clinic as a form of noninvasive or minimally invasive surgery. However, no agreed system for calibration of HIFU output currently exists today. This proposed work will benefit public health by providing tools and recommendations to help regulate and control HIFU exposures which will improve efficacy and safety and facilitate a more rapid clinical acceptance of this promising therapy.

National Institute of Health (NIH)
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Research Project (R01)
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Biomedical Imaging Technology Study Section (BMIT)
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Lopez, Hector
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University of Washington
Schools of Earth Sciences/Natur
United States
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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
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
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
Hunter, Christopher; Sapozhnikov, Oleg A; Maxwell, Adam D et al. (2016) An ultrasonic caliper device for measuring acoustic nonlinearity. Phys Procedia 87:93-98
Simon, Julianna C; Sapozhnikov, Oleg A; Khokhlova, Vera A et al. (2015) Ultrasonic atomization of liquids in drop-chain acoustic fountains. J Fluid Mech 766:129-146
Maxwell, Adam D; Cunitz, Bryan W; Kreider, Wayne et al. (2015) Fragmentation of urinary calculi in vitro by burst wave lithotripsy. J Urol 193:338-44
Simon, Julianna C; Sapozhnikov, Oleg A; Wang, Yak-Nam et al. (2015) Investigation into the mechanisms of tissue atomization by high-intensity focused ultrasound. Ultrasound Med Biol 41:1372-85
Khokhlova, Vera A; Fowlkes, J Brian; Roberts, William W et al. (2015) Histotripsy methods in mechanical disintegration of tissue: towards clinical applications. Int J Hyperthermia 31:145-62
Sapozhnikov, Oleg A; Tsysar, Sergey A; Khokhlova, Vera A et al. (2015) Acoustic holography as a metrological tool for characterizing medical ultrasound sources and fields. J Acoust Soc Am 138:1515-32
Maxwell, Adam D; Hsi, Ryan S; Bailey, Michael R et al. (2014) Noninvasive ureterocele puncture using pulsed focused ultrasound: an in vitro study. J Endourol 28:342-6

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