Publications by authors named "Khokhlova V"

112 Publications

Design of HIFU Transducers for Generating Specified Nonlinear Ultrasound Fields.

IEEE Trans Ultrason Ferroelectr Freq Control 2017 02 20;64(2):374-390. Epub 2016 Oct 20.

Various clinical applications of high-intensity focused ultrasound have different requirements for the pressure levels and degree of nonlinear waveform distortion at the focus. The goal of this paper is to determine transducer design parameters that produce either a specified shock amplitude in the focal waveform or specified peak pressures while still maintaining quasi-linear conditions at the focus. Multiparametric nonlinear modeling based on the Khokhlov-Zabolotskaya-Kuznetsov (KZK) equation with an equivalent source boundary condition was employed. Peak pressures, shock amplitudes at the focus, and corresponding source outputs were determined for different transducer geometries and levels of nonlinear distortion. The results are presented in terms of the parameters of an equivalent single-element spherically shaped transducer. The accuracy of the method and its applicability to cases of strongly focused transducers were validated by comparing the KZK modeling data with measurements and nonlinear full diffraction simulations for a single-element source and arrays with 7 and 256 elements. The results provide look-up data for evaluating nonlinear distortions at the focus of existing therapeutic systems as well as for guiding the design of new transducers that generate specified nonlinear fields.
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http://dx.doi.org/10.1109/TUFFC.2016.2619913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5300962PMC
February 2017

Induction of Heat Shock Protein 70 as a Predictive Marker of the Tumor Cell Radiosensitization with Inhibitors of the Heat Shock Protein 90 Activity.

Radiats Biol Radioecol 2016 Sep;56(5):494-502

Inhibitors of the heat shock protein 90 (HSP90) activity are considered as potential radiosensitizers of tumors with a perspective of their application in radiotherapy. However, there are tumors and tumor cell lines whose radioresistance is not decreased after treatment with the HSP90 activity inhibitors; therefore, a predictive marker is needed, which would allow one to predict the response of target cells. As such a marker, herein it is proposed to use induction of the heat shock protein 70 (HSP70) that is an early cellular response to the HSP90 dysfunction and can easily be immunodetected. It follows from the data obtained that the radiosensitization of HSP90 inhibitor-treated cells occurs only when this treatment causes the prominent induction of HSP70 in them. Determination of this marker enables one: 1) to predict a possibility of radiosensitization of any cells by means of the HSP90 activity inhibitors, 2) to design the inhibitor concentration range upon which the radiosensitizing effect seems likely to occur, 3) to find whether this radiosensitization will be selective towards cancer cells.
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September 2016

Nonlinear Effects in Ultrasound Fields of Diagnostic-type Transducers Used for Kidney Stone Propulsion: Characterization in Water.

AIP Conf Proc 2015 Jun-Jul;1685. Epub 2015 Oct 28.

Physics Faculty, Moscow State University, Leninskie Gory, 119991 Moscow, Russian Federation; Center for Industrial and Medical Ultrasound, Applied Physics Laboratory, University of Washington, 1013 NE 40 Street, Seattle, WA 98105, USA.

Newer imaging and therapeutic ultrasound technologies require higher pressure levels compared to conventional diagnostic values. One example is the recently developed use of focused ultrasonic radiation force to move kidney stones and residual fragments out of the urinary collecting system. A commercial diagnostic 2.3 MHz C5-2 array probe is used to deliver the acoustic pushing pulses. The probe comprises 128 elements equally spaced at the 55 mm long convex cylindrical surface with 38 mm radius of curvature. The efficacy of the treatment can be increased by using higher transducer output to provide stronger pushing force; however, nonlinear acoustic saturation effect can be a limiting factor. In this work nonlinear propagation effects were analyzed for the C5-2 transducer using a combined measurement and modeling approach. Simulations were based on the 3D Westervelt equation; the boundary condition was set to match low power pressure beam scans. Focal waveforms simulated for increased output power levels were compared with the fiber-optic hydrophone measurements and were found in good agreement. It was shown that saturation effects do limit the acoustic pressure in the focal region of the transducer. This work has application to standard diagnostic probes and imaging.
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http://dx.doi.org/10.1063/1.4934397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4831865PMC
October 2015

Intracellular Impedance Measurements Reveal Non-ohmic Properties of the Extracellular Medium around Neurons.

Biophys J 2016 Jan;110(1):234-46

Unité de Neurosciences, Information et Complexité, Centre National de la Recherche Scientifique, Gif-sur-Yvette, France. Electronic address:

Determining the electrical properties of the extracellular space around neurons is important for understanding the genesis of extracellular potentials, as well as for localizing neuronal activity from extracellular recordings. However, the exact nature of these extracellular properties is still uncertain. Here, we introduce a method to measure the impedance of the tissue, one that preserves the intact cell-medium interface using whole-cell patch-clamp recordings in vivo and in vitro. We find that neural tissue has marked non-ohmic and frequency-filtering properties, which are not consistent with a resistive (ohmic) medium, as often assumed. The amplitude and phase profiles of the measured impedance are consistent with the contribution of ionic diffusion. We also show that the impact of such frequency-filtering properties is possibly important on the genesis of local field potentials, as well as on the cable properties of neurons. These results show non-ohmic properties of the extracellular medium around neurons, and suggest that source estimation methods, as well as the cable properties of neurons, which all assume ohmic extracellular medium, may need to be reevaluated.
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http://dx.doi.org/10.1016/j.bpj.2015.11.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4805868PMC
January 2016

An ultrasonic caliper device for measuring acoustic nonlinearity.

Phys Procedia 2016 ;87:93-98

CIMU, Applied Physics Laboratory, University of Washington, 1013 NE 40 Street, Seattle, WA 98105, USA.

In medical and industrial ultrasound, it is often necessary to measure the acoustic properties of a material. A specific medical application requires measurements of sound speed, attenuation, and nonlinearity to characterize livers being evaluated for transplantation. For this application, a transmission-mode caliper device is proposed in which both transmit and receive transducers are directly coupled to a test sample, the propagation distance is measured with an indicator gage, and receive waveforms are recorded for analysis. In this configuration, accurate measurements of nonlinearity present particular challenges: diffraction effects can be considerable while nonlinear distortions over short distances typically remain small. To enable simple estimates of the nonlinearity coefficient from a quasi-linear approximation to the lossless Burgers' equation, the calipers utilize a large transmitter and plane waves are measured at distances of 15-50 mm. Waves at 667 kHz and pressures between 0.1 and 1 MPa were generated and measured in water at different distances; the nonlinearity coefficient of water was estimated from these measurements with a variability of approximately 10%. Ongoing efforts seek to test caliper performance in other media and improve accuracy via additional transducer calibrations.
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http://dx.doi.org/10.1016/j.phpro.2016.12.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5467533PMC
January 2016

Design of HIFU transducers to generate specific nonlinear ultrasound fields.

Phys Procedia 2016 ;87:132-138

CIMU, Applied Physics Laboratory, University of Washington, Seattle, WA.

Various clinical applications of high intensity focused ultrasound (HIFU) have different requirements on the pressure level and degree of nonlinear waveform distortion at the focus. Applications that utilize nonlinear waves with developed shocks are of growing interest, for example, for mechanical disintegration as well as for accelerated thermal ablation of tissue. In this work, an inverse problem of determining transducer parameters to enable formation of shocks with desired amplitude at the focus is solved. The solution was obtained by performing multiple direct simulations of the parabolic Khokhlov-Zabolotskaya-Kuznetsov (KZK) equation for various parameters of the source. It is shown that results obtained within the parabolic approximation can be used to describe the focal region of single element spherical sources as well as complex transducer arrays. It is also demonstrated that the focal pressure level at which fully developed shocks are formed mainly depends on the focusing angle of the source and only slightly depends on its aperture and operating frequency. Using the simulation results, a 256-element HIFU array operating at 1.5 MHz frequency was designed for a specific application of boiling-histotripsy that relies on the presence of 90-100 MPa shocks at the focus. The size of the array elements and focusing angle of the array were chosen to satisfy technical limitations on the intensity at the array elements and desired shock amplitudes in the focal waveform. Focus steering capabilities of the array were analysed using an open-source T-Array software developed at Moscow State University.
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http://dx.doi.org/10.1016/j.phpro.2016.12.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5451200PMC
January 2016

Acoustic holography as a metrological tool for characterizing medical ultrasound sources and fields.

J Acoust Soc Am 2015 Sep;138(3):1515-32

Center for Industrial and Medical Ultrasound, Applied Physics Laboratory, University of Washington, 1013 Northeast 40th Street, Seattle, Washington 98105, USA.

Acoustic holography is a powerful technique for characterizing ultrasound sources and the fields they radiate, with the ability to quantify source vibrations and reduce the number of required measurements. These capabilities are increasingly appealing for meeting measurement standards in medical ultrasound; however, associated uncertainties have not been investigated systematically. Here errors associated with holographic representations of a linear, continuous-wave ultrasound field are studied. To facilitate the analysis, error metrics are defined explicitly, and a detailed description of a holography formulation based on the Rayleigh integral is provided. Errors are evaluated both for simulations of a typical therapeutic ultrasound source and for physical experiments with three different ultrasound sources. Simulated experiments explore sampling errors introduced by the use of a finite number of measurements, geometric uncertainties in the actual positions of acquired measurements, and uncertainties in the properties of the propagation medium. Results demonstrate the theoretical feasibility of keeping errors less than about 1%. Typical errors in physical experiments were somewhat larger, on the order of a few percent; comparison with simulations provides specific guidelines for improving the experimental implementation to reduce these errors. Overall, results suggest that holography can be implemented successfully as a metrological tool with small, quantifiable errors.
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http://dx.doi.org/10.1121/1.4928396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4575327PMC
September 2015

Mach stem formation in reflection and focusing of weak shock acoustic pulses.

J Acoust Soc Am 2015 Jun;137(6):EL436-42

Laboratoire de Mécanique des Fluides et d'Acoustique, Unité Mixte de Recherche 5509, Centre National de la Recherche Scientifique, Ecole Centrale de Lyon, Université Lyon I, 36 Avenue Guy de Collongue, F-69134 Ecully Cedex, France

The aim of this study is to show the evidence of Mach stem formation for very weak shock waves with acoustic Mach numbers on the order of 10(-3) to 10(-2). Two representative cases are considered: reflection of shock pulses from a rigid surface and focusing of nonlinear acoustic beams. Reflection experiments are performed in air using spark-generated shock pulses. Shock fronts are visualized using a schlieren system. Both regular and irregular types of reflection are observed. Numerical simulations are performed to demonstrate the Mach stem formation in the focal region of periodic and pulsed nonlinear beams in water.
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http://dx.doi.org/10.1121/1.4921681DOI Listing
June 2015

Mach-Zehnder interferometry method for acoustic shock wave measurements in air and broadband calibration of microphones.

J Acoust Soc Am 2015 Jun;137(6):3314-24

Laboratoire de Mécanique des Fluides et d'Acoustique, Unité Mixte de Recherche, Centre National de la Recherche Scientifique 5509, École Centrale de Lyon, Université Lyon, 36 Avenue Guy de Collongue, 69131 Écully Cedex, France.

A Mach-Zehnder interferometer is used to measure spherically diverging N-waves in homogeneous air. An electrical spark source is used to generate high-amplitude (1800 Pa at 15 cm from the source) and short duration (50 μs) N-waves. Pressure waveforms are reconstructed from optical phase signals using an Abel-type inversion. It is shown that the interferometric method allows one to reach 0.4 μs of time resolution, which is 6 times better than the time resolution of a 1/8-in. condenser microphone (2.5 μs). Numerical modeling is used to validate the waveform reconstruction method. The waveform reconstruction method provides an error of less than 2% with respect to amplitude in the given experimental conditions. Optical measurement is used as a reference to calibrate a 1/8-in. condenser microphone. The frequency response function of the microphone is obtained by comparing the spectra of the waveforms resulting from optical and acoustical measurements. The optically measured pressure waveforms filtered with the microphone frequency response are in good agreement with the microphone output voltage. Therefore, an optical measurement method based on the Mach-Zehnder interferometer is a reliable tool to accurately characterize evolution of weak shock waves in air and to calibrate broadband acoustical microphones.
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http://dx.doi.org/10.1121/1.4921549DOI Listing
June 2015

Characterization of spark-generated N-waves in air using an optical schlieren method.

J Acoust Soc Am 2015 Jun;137(6):3244-52

Laboratoire de Mécanique des Fluides et d'Acoustique, Unité Mixte de Recherche 5509, Centre National de la Recherche Scientifique, Ecole Centrale de Lyon, Université Lyon I, 36 Avenue Guy de Collongue, F-69134 Ecully Cedex, France.

Accurate measurement of high-amplitude, broadband shock pulses in air is an important part of laboratory-scale experiments in atmospheric acoustics. Although various methods have been developed, specific drawbacks still exist and need to be addressed. Here, a schlieren optical method was used to reconstruct the pressure signatures of nonlinear spherically diverging short acoustic pulses generated using an electric spark source (2.5 kPa, 33 μs at 10 cm from the source) in homogeneous air. A high-speed camera was used to capture light rays deflected by refractive index inhomogeneities, caused by the acoustic wave. Pressure waveforms were reconstructed from the light intensity patterns in the recorded images using an Abel-type inversion method. Absolute pressure levels were determined by analyzing at different propagation distances the duration of the compression phase of pulses, which changed due to nonlinear propagation effects. Numerical modeling base on the generalized Burgers equation was used to evaluate the smearing of the waveform caused by finite exposure time of the high-speed camera and corresponding limitations in resolution of the schlieren technique. The proposed method allows the study of the evolution of spark-generated shock waves in air starting from the very short distances from the spark, 30 mm, up to 600 mm.
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http://dx.doi.org/10.1121/1.4921026DOI Listing
June 2015

Ultrasonic atomization of liquids in drop-chain acoustic fountains.

J Fluid Mech 2015 Mar;766:129-146

Center for Industrial and Medical Ultrasound, Applied Physics Laboratory, University of Washington, Seattle, WA 98105, USA.

When focused ultrasound waves of moderate intensity in liquid encounter an air interface, a chain of drops emerges from the liquid surface to form what is known as a drop-chain fountain. Atomization, or the emission of micro-droplets, occurs when the acoustic intensity exceeds a liquid-dependent threshold. While the cavitation-wave hypothesis, which states that atomization arises from a combination of capillary-wave instabilities and cavitation bubble oscillations, is currently the most accepted theory of atomization, more data on the roles of cavitation, capillary waves, and even heat deposition or boiling would be valuable. In this paper, we experimentally test whether bubbles are a significant mechanism of atomization in drop-chain fountains. High-speed photography was used to observe the formation and atomization of drop-chain fountains composed of water and other liquids. For a range of ultrasonic frequencies and liquid sound speeds, it was found that the drop diameters approximately equalled the ultrasonic wavelengths. When water was exchanged for other liquids, it was observed that the atomization threshold increased with shear viscosity. Upon heating water, it was found that the time to commence atomization decreased with increasing temperature. Finally, water was atomized in an overpressure chamber where it was found that atomization was significantly diminished when the static pressure was increased. These results indicate that bubbles, generated by either acoustic cavitation or boiling, contribute significantly to atomization in the drop-chain fountain.
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http://dx.doi.org/10.1017/jfm.2015.11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4428615PMC
March 2015

Histotripsy methods in mechanical disintegration of tissue: towards clinical applications.

Int J Hyperthermia 2015 Mar 24;31(2):145-62. Epub 2015 Feb 24.

Center for Industrial and Medical Ultrasound, Applied Physics Laboratory, University of Washington , Seattle, Washington , USA .

In high intensity focused ultrasound (HIFU) therapy, an ultrasound beam is focused within the body to locally affect the targeted site without damaging intervening tissues. The most common HIFU regime is thermal ablation. Recently there has been increasing interest in generating purely mechanical lesions in tissue (histotripsy). This paper provides an overview of several studies on the development of histotripsy methods toward clinical applications. Two histotripsy approaches and examples of their applications are presented. In one approach, sequences of high-amplitude, short (microsecond-long), focused ultrasound pulses periodically produce dense, energetic bubble clouds that mechanically disintegrate tissue. In an alternative approach, longer (millisecond-long) pulses with shock fronts generate boiling bubbles and the interaction of shock fronts with the resulting vapour cavity causes tissue disintegration. Recent preclinical studies on histotripsy are reviewed for treating benign prostatic hyperplasia (BPH), liver and kidney tumours, kidney stone fragmentation, enhancing anti-tumour immune response, and tissue decellularisation for regenerative medicine applications. Potential clinical advantages of the histotripsy methods are discussed. Histotripsy methods can be used to mechanically ablate a wide variety of tissues, whilst selectivity sparing structures such as large vessels. Both ultrasound and MR imaging can be used for targeting and monitoring the treatment in real time. Although the two approaches utilise different mechanisms for tissue disintegration, both have many of the same advantages and offer a promising alternative method of non-invasive surgery.
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http://dx.doi.org/10.3109/02656736.2015.1007538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4448968PMC
March 2015

Investigation into the mechanisms of tissue atomization by high-intensity focused ultrasound.

Ultrasound Med Biol 2015 May 3;41(5):1372-85. Epub 2015 Feb 3.

Center for Industrial and Medical Ultrasound, Applied Physics Laboratory, University of Washington, Seattle, Washington, USA.

Ultrasonic atomization, or the emission of a fog of droplets, was recently proposed to explain tissue fractionation in boiling histotripsy. However, even though liquid atomization has been studied extensively, the mechanisms underlying tissue atomization remain unclear. In the work described here, high-speed photography and overpressure were used to evaluate the role of bubbles in tissue atomization. As static pressure increased, the degree of fractionation decreased, and the ex vivo tissue became thermally denatured. The effect of surface wetness on atomization was also evaluated in vivo and in tissue-mimicking gels, where surface wetness was found to enhance atomization by forming surface instabilities that augment cavitation. In addition, experimental results indicated that wetting collagenous tissues, such as the liver capsule, allowed atomization to breach such barriers. These results highlight the importance of bubbles and surface instabilities in atomization and could be used to enhance boiling histotripsy for transition to clinical use.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2014.12.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4398613PMC
May 2015

Laboratory-scale experiment to study nonlinear N-wave distortion by thermal turbulence.

J Acoust Soc Am 2014 Aug;136(2):556-66

Laboratoire de Mécanique des Fluides et d'Acoustique, UMR CNRS 5509, École Centrale de Lyon, Université de Lyon, 36, avenue Guy de Collongue, 69134 Écully Cedex, France.

The nonlinear propagation of spark-generated N-waves through thermal turbulence is experimentally studied at the laboratory scale under well-controlled conditions. A grid of electrical resistors was used to generate the turbulent field, well described by a modified von Kármán model. A spark source was used to generate high-amplitude (~1500 Pa) and short duration (~50 μs) N-waves. Thousands of waveforms were acquired at distances from 250 to 1750 mm from the source (~15 to 100 wavelengths). The mean values and the probability densities of the peak pressure, the deviation angle, and the rise time of the pressure wave were obtained as functions of propagation distance through turbulence. The peak pressure distributions were described using a generalized gamma distribution, whose coefficients depend on the propagation distance. A line array of microphones was used to analyze the effect of turbulence on the propagation direction. The angle of deviation induced by turbulence was found to be smaller than 15°, which validates the use of the parabolic equation method to model this kind of experiment. The transverse size of the focus regions was estimated to be on the order of the acoustic wavelength for propagation distances longer than 50 wavelengths.
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http://dx.doi.org/10.1121/1.4887458DOI Listing
August 2014

Characterization of a multi-element clinical HIFU system using acoustic holography and nonlinear modeling.

IEEE Trans Ultrason Ferroelectr Freq Control 2013 Aug;60(8):1683-98

High-intensity focused ultrasound (HIFU) is a treatment modality that relies on the delivery of acoustic energy to remote tissue sites to induce thermal and/or mechanical tissue ablation. To ensure the safety and efficacy of this medical technology, standard approaches are needed for accurately characterizing the acoustic pressures generated by clinical ultrasound sources under operating conditions. Characterization of HIFU fields is complicated by nonlinear wave propagation and the complexity of phased-array transducers. Previous work has described aspects of an approach that combines measurements and modeling, and here we demonstrate this approach for a clinical phased-array transducer. First, low amplitude hydrophone measurements were performed in water over a scan plane between the array and the focus. Second, these measurements were used to holographically reconstruct the surface vibrations of the transducer and to set a boundary condition for a 3-D acoustic propagation model. Finally, nonlinear simulations of the acoustic field were carried out over a range of source power levels. Simulation results were compared with pressure waveforms measured directly by hydrophone at both low and high power levels, demonstrating that details of the acoustic field, including shock formation, are quantitatively predicted.
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http://dx.doi.org/10.1109/TUFFC.2013.2750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4130294PMC
August 2013

Ultrasound-guided tissue fractionation by high intensity focused ultrasound in an in vivo porcine liver model.

Proc Natl Acad Sci U S A 2014 Jun 19;111(22):8161-6. Epub 2014 May 19.

Center for Industrial and Medical Ultrasound, Applied Physics Laboratory, University of Washington, Seattle, WA 98105; andDepartment of Acoustics, Physics Faculty, Moscow State University, Leninskie Gory, Moscow 119991, Russia.

The clinical use of high intensity focused ultrasound (HIFU) therapy for noninvasive tissue ablation has been recently gaining momentum. In HIFU, ultrasound energy from an extracorporeal source is focused within the body to ablate tissue at the focus while leaving the surrounding organs and tissues unaffected. Most HIFU therapies are designed to use heating effects resulting from the absorption of ultrasound by tissue to create a thermally coagulated treatment volume. Although this approach is often successful, it has its limitations, such as the heat sink effect caused by the presence of a large blood vessel near the treatment area or heating of the ribs in the transcostal applications. HIFU-induced bubbles provide an alternative means to destroy the target tissue by mechanical disruption or, at its extreme, local fractionation of tissue within the focal region. Here, we demonstrate the feasibility of a recently developed approach to HIFU-induced ultrasound-guided tissue fractionation in an in vivo pig model. In this approach, termed boiling histotripsy, a millimeter-sized boiling bubble is generated by ultrasound and further interacts with the ultrasound field to fractionate porcine liver tissue into subcellular debris without inducing further thermal effects. Tissue selectivity, demonstrated by boiling histotripsy, allows for the treatment of tissue immediately adjacent to major blood vessels and other connective tissue structures. Furthermore, boiling histotripsy would benefit the clinical applications, in which it is important to accelerate resorption or passage of the ablated tissue volume, diminish pressure on the surrounding organs that causes discomfort, or insert openings between tissues.
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http://dx.doi.org/10.1073/pnas.1318355111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4050569PMC
June 2014

Acoustic field characterization of the Duolith: measurements and modeling of a clinical shock wave therapy device.

J Acoust Soc Am 2013 Aug;134(2):1663-74

Center for Industrial and Medical Ultrasound, Applied Physics Laboratory, University of Washington, 1013 NE 40th Street, Seattle, Washington 98105, USA.

Extracorporeal shock wave therapy (ESWT) uses acoustic pulses to treat certain musculoskeletal disorders. In this paper the acoustic field of a clinical portable ESWT device (Duolith SD1) was characterized. Field mapping was performed in water for two different standoffs of the electromagnetic head (15 or 30 mm) using a fiber optic probe hydrophone. Peak positive pressures at the focus ranged from 2 to 45 MPa, while peak negative pressures ranged from -2 to -11 MPa. Pulse rise times ranged from 8 to 500 ns; shock formation did not occur for any machine settings. The maximum standard deviation in peak pressure at the focus was 1.2%, indicating that the Duolith SD1 generates stable pulses. The results compare qualitatively, but not quantitatively with manufacturer specifications. Simulations were carried out for the short standoff by matching a Khokhlov-Zabolotskaya-Kuznetzov equation to the measured field at a plane near the source, and then propagating the wave outward. The results of modeling agree well with experimental data. The model was used to analyze the spatial structure of the peak pressures. Predictions from the model suggest that a true shock wave could be obtained in water if the initial pressure output of the device were doubled.
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http://dx.doi.org/10.1121/1.4812885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3745538PMC
August 2013

Infrared mapping of ultrasound fields generated by medical transducers: feasibility of determining absolute intensity levels.

J Acoust Soc Am 2013 Aug;134(2):1586-97

University of Washington, Center for Industrial and Medical Ultrasound, Seattle, Washington 98105, USA.

Considerable progress has been achieved in the use of infrared (IR) techniques for qualitative mapping of acoustic fields of high intensity focused ultrasound (HIFU) transducers. The authors have previously developed and demonstrated a method based on IR camera measurement of the temperature rise induced in an absorber less than 2 mm thick by ultrasonic bursts of less than 1 s duration. The goal of this paper was to make the method more quantitative and estimate the absolute intensity distributions by determining an overall calibration factor for the absorber and camera system. The implemented approach involved correlating the temperature rise measured in an absorber using an IR camera with the pressure distribution measured in water using a hydrophone. The measurements were conducted for two HIFU transducers and a flat physiotherapy transducer of 1 MHz frequency. Corresponding correction factors between the free field intensity and temperature were obtained and allowed the conversion of temperature images to intensity distributions. The system described here was able to map in good detail focused and unfocused ultrasound fields with sub-millimeter structure and with local time average intensity from below 0.1 W/cm(2) to at least 50 W/cm(2). Significantly higher intensities could be measured simply by reducing the duty cycle.
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http://dx.doi.org/10.1121/1.4812878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3745508PMC
August 2013

Introduction to the special issue on therapeutic ultrasound.

J Acoust Soc Am 2013 Aug;134(2):1441

Moscow State University, Leninskie Gory, Moscow, 119991, Russia.

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http://dx.doi.org/10.1121/1.4813105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3745487PMC
August 2013

Ultrasonic Atomization: A Mechanism of Tissue Fractionation.

Proc Meet Acoust 2013 May 6;133(5). Epub 2013 May 6.

Ctr. for Industrial and Medical Ultrasound, Appl. Phys. Lab., Univ. of Washington, Seattle, WA, USA.

High intensity focused ultrasound (HIFU) can be used to atomize liquid by creating a fountain on the surface exposed to air. The mechanism of atomization can be most accurately described by the cavitation-wave hypothesis wherein a combination of capillary waves excited on the liquid surface with cavitation beneath the surface produces a fine spray. Here, we show experimentally that a free tissue surface can also be atomized resulting in erosion of tissue from the surface. A 2-MHz spherically focused transducer operating at linearly predicted intensities up to 14,000 W/cm was focused at bovine liver and porcine liver tissue surfaces without the capsule. The end result for both and tissues was erosion from the surface. In bovine liver at the maximum intensity, the erosion volume reached 25.7±10.9 mm using 300 10-ms pulses repeated at 1 Hz. Jet velocities for all tissues tested here were on the order of 10 m/s. Besides providing a mechanism for how HIFU can mechanically disrupt tissue, atomization may also explain how tissue is fractionated in boiling histotripsy.
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http://dx.doi.org/10.1121/1.4805524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8315039PMC
May 2013

The role of acoustic nonlinearity in tissue heating behind a rib cage using a high-intensity focused ultrasound phased array.

Phys Med Biol 2013 Apr 26;58(8):2537-59. Epub 2013 Mar 26.

Physics Faculty, Moscow State University, Moscow 119991, Russia.

The goal of this study was to investigate theoretically the effects of nonlinear propagation in a high-intensity focused ultrasound (HIFU) field produced by a therapeutic phased array and the resultant heating of tissue behind a rib cage. Three configurations of focusing were simulated: in water, in water with ribs in the beam path and in water with ribs backed by a layer of soft tissue. The Westervelt equation was used to model the nonlinear HIFU field, and a 1 MHz phased array consisting of 254 circular elements was used as a boundary condition to the model. The temperature rise in tissue was modelled using the bioheat equation, and thermally necrosed volumes were calculated using the thermal dose formulation. The shapes of lesions predicted by the modelling were compared with those previously obtained in in vitro experiments at low-power sonications. Intensity levels at the face of the array elements that corresponded to the formation of high-amplitude shock fronts in the focal region were determined as 10 W cm(-2) in the free field in water and 40 W cm(-2) in the presence of ribs. It was shown that exposures with shocks provided a substantial increase in tissue heating, and its better spatial localization in the main focal region only. The relative effects of overheating ribs and splitting of the focus due to the periodic structure of the ribs were therefore reduced. These results suggest that utilizing nonlinear propagation and shock formation effects can be beneficial for inducing confined HIFU lesions when irradiating through obstructions such as ribs. Design of compact therapeutic arrays to provide maximum power outputs with lower intensity levels at the elements is necessary to achieve shock wave regimes for clinically relevant sonication depths in tissue.
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http://dx.doi.org/10.1088/0031-9155/58/8/2537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3661952PMC
April 2013

Histological and biochemical analysis of mechanical and thermal bioeffects in boiling histotripsy lesions induced by high intensity focused ultrasound.

Ultrasound Med Biol 2013 Mar 11;39(3):424-38. Epub 2013 Jan 11.

Center for Industrial and Medical Ultrasound, Applied Physics Laboratory, University of Washington, Seattle, WA, USA.

Recent studies have shown that shockwave heating and millisecond boiling in high-intensity focused ultrasound fields can result in mechanical fractionation or emulsification of tissue, termed boiling histotripsy. Visual observations of the change in color and contents indicated that the degree of thermal damage in the emulsified lesions can be controlled by varying the parameters of the exposure. The goal of this work was to examine thermal and mechanical effects in boiling histotripsy lesions using histologic and biochemical analysis. The lesions were induced in ex vivo bovine heart and liver using a 2-MHz single-element transducer operating at duty factors of 0.005-0.01, pulse durations of 5-500 ms and in situ shock amplitude of 73 MPa. Mechanical and thermal damage to tissue was evaluated histologically using conventional staining techniques (hematoxylin and eosin, and nicotinamide adenine dinucleotide-diaphorase). Thermal effects were quantified by measuring denaturation of salt soluble proteins in the treated region. According to histologic analysis, the lesions that visually appeared as a liquid contained no cellular structures larger than a cell nucleus and had a sharp border of one to two cells. Both histologic and protein analysis showed that lesions obtained with short pulses (<10 ms) did not contain any thermal damage. Increasing the pulse duration resulted in an increase in thermal damage. However, both protein analysis and nicotinamide adenine dinucleotide-diaphorase staining showed less denaturation than visually observed as whitening of tissue. The number of high-intensity focused ultrasound pulses delivered per exposure did not change the lesion shape or the degree of thermal denaturation, whereas the size of the lesion showed a saturating behavior suggesting optimal exposure duration. This study confirmed that boiling histotripsy offers an effective, predictable way to non-invasively fractionate tissue into sub-cellular fragments with or without inducing thermal damage.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2012.10.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3570648PMC
March 2013

Rectified growth of histotripsy bubbles.

Proc Meet Acoust 2013;19(1)

Histotripsy treatments use high-amplitude shock waves to fractionate tissue. Such treatments have been demonstrated using both cavitation bubbles excited with microsecond-long pulses and boiling bubbles excited for milliseconds. A common feature of both approaches is the need for bubble growth, where at 1 MHz cavitation bubbles reach maximum radii on the order of 100 microns and boiling bubbles grow to about 1 mm. To explore how histotripsy bubbles grow, a model of a single, spherical bubble that accounts for heat and mass transport was used to simulate the bubble dynamics. Results suggest that the asymmetry inherent in nonlinearly distorted waveforms can lead to rectified bubble growth, which is enhanced at elevated temperatures. Moreover, the rate of this growth is sensitive to the waveform shape, in particular the transition from the peak negative pressure to the shock front. Current efforts are focused on elucidating this behavior by obtaining an improved calibration of measured histotripsy waveforms with a fiber-optic hydrophone, using a nonlinear propagation model to assess the impact on the focal waveform of higher harmonics present at the source's surface, and photographically observing bubble growth rates.
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http://dx.doi.org/10.1121/1.4800326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4579538PMC
January 2013

Ultrasonic atomization of tissue and its role in tissue fractionation by high intensity focused ultrasound.

Phys Med Biol 2012 Dec 16;57(23):8061-78. Epub 2012 Nov 16.

Center for Industrial and Medical Ultrasound, Applied Physics Laboratory, University of Washington, 1013 NE 40th Street, Seattle, WA 98105, USA.

Atomization and fountain formation is a well-known phenomenon that occurs when a focused ultrasound wave in liquid encounters an air interface. High intensity focused ultrasound (HIFU) has been shown to fractionate a tissue into submicron-sized fragments in a process termed boiling histotripsy, wherein the focused ultrasound wave superheats the tissue at the focus, producing a millimetre-sized boiling or vapour bubble in several milliseconds. Yet the question of how this millimetre-sized boiling bubble creates submicron-sized tissue fragments remains. The hypothesis of this work is that the tissue can behave as a liquid such that it atomizes and forms a fountain within the vapour bubble produced in boiling histotripsy. We describe an experiment, in which a 2 MHz HIFU transducer (maximum in situ intensity of 24 000 W cm(-2)) was aligned with an air-tissue interface meant to simulate the boiling bubble. Atomization and fountain formation was observed with high-speed photography and resulted in tissue erosion. Histological examination of the atomized tissue showed whole and fragmented cells and nuclei. Air-liquid interfaces were also filmed. Our conclusion was that HIFU can fountain and atomize tissue. Although this process does not entirely mimic what was observed in liquids, it does explain many aspects of tissue fractionation in boiling histotripsy.
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http://dx.doi.org/10.1088/0031-9155/57/23/8061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3535451PMC
December 2012

Characterization of nonlinear ultrasound fields of 2D therapeutic arrays.

IEEE Int Ultrason Symp 2012 Oct;2012:1-4

Center for Industrial and Medical Ultrasound University of Washington Seattle, USA ; Physics Faculty Moscow State University Moscow, Russia.

A current trend in high intensity focused ultrasound (HIFU) technologies is to use 2D focused phased arrays that enable electronic steering of the focus, beamforming to avoid overheating of obstacles (such as ribs), and better focusing through inhomogeneities of soft tissue using time reversal methods. In many HIFU applications, the acoustic intensity can reach thousands of W/cm leading to nonlinear propagation effects. At high power outputs, shock fronts develop in the focal region and significantly alter the bioeffects induced. Clinical applications of HIFU are relatively new and challenges remain for ensuring their safety and efficacy. A key component of these challenges is the lack of standard procedures for characterizing nonlinear HIFU fields under operating conditions. Methods that combine low-amplitude pressure measurements and nonlinear modeling of the pressure field have been proposed for axially symmetric single element transducers but have not yet been validated for the much more complex 3D fields generated by therapeutic arrays. Here, the method was tested for a clinical HIFU source comprising a 256-element transducer array. A numerical algorithm based on the Westervelt equation was used to enable 3D full-diffraction nonlinear modeling. With the acoustic holography method, the magnitude and phase of the acoustic field were measured at a low power output and used to determine the pattern of vibrations at the surface of the array. This pattern was then scaled to simulate a range of intensity levels near the elements up to 10 W/cm. The accuracy of modeling was validated by comparison with direct measurements of the focal waveforms using a fiber-optic hydrophone. Simulation results and measurements show that shock fronts with amplitudes up to 100 MPa were present in focal waveforms at clinically relevant outputs, indicating the importance of strong nonlinear effects in ultrasound fields generated by HIFU arrays.
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http://dx.doi.org/10.1109/ULTSYM.2012.0231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4507577PMC
October 2012

Tissue Atomization by High Intensity Focused Ultrasound.

IEEE Int Ultrason Symp 2012 Oct 18;2012:1003-1006. Epub 2013 Jul 18.

Center for Industrial and Medical Ultrasound, University of Washington, Seattle, WA, USA.

Liquid atomization and fountain formation by focused ultrasound was first published by Wood and Loomis [1]. Since then, the cavitation-wave hypothesis emerged to explain atomization in a fountain, which states atomization arises from a combination of surface capillary waves and the collapse of cavitation bubbles. More recently, high intensity focused ultrasound (HIFU) has been shown to fractionate tissue through either pulsed-cavitation or millisecond boiling histotripsy therapies; however it is unclear how millimeter-size boiling bubbles or cavitation bubble clouds fractionate tissue into submicron-size fragments. The objective of this work is to test the hypothesis experimentally that atomization and fountain formation occurs similarly in liquids and tissues and results in tissue erosion. A 2-MHz HIFU transducer operating at peak pressures of 50 MPa and -11 MPa (linear intensity = 14,000 W/cm) was focused at the interface between a liquid or tissue and air. A high-speed camera was used to monitor atomization and fountain formation in water, ethanol, glycerol, bovine liver, and porcine blood clots. The linear intensity threshold for consistent atomization in one 10-ms pulse increased in the order: ethanol (180 W/cm) < blood clot (250 W/cm) < water (350 W/cm) < liver (6200 W/cm); glycerol did not atomize. Average jet velocities for the initial spray at the maximum acoustic intensity were similar for all materials and on the order of 20 m/s. The tissue erosion rate of liver approached saturation at around 300 10-ms pulses repeated at 1 Hz, which had an average erosion volume of 25.7±10.9 mm. While tissue atomization and fountain formation does not completely mimic what is observed in liquids, atomization provides a plausible explanation of how tissue is fractionated in millisecond boiling and possibly even cavitation cloud histotrispy therapies.
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http://dx.doi.org/10.1109/ultsym.2012.0251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8320307PMC
October 2012

Random focusing of nonlinear acoustic N-waves in fully developed turbulence: laboratory scale experiment.

J Acoust Soc Am 2011 Dec;130(6):3595-607

Faculty of Physics, Moscow State University, 119991 Moscow, Russia.

A laboratory experiment was conducted to study the propagation of short duration (25 μs) and high amplitude (1000 Pa) acoustic N-waves in turbulent flow. Turbulent flows with a root-mean-square value of the fluctuating velocity up to 4 m/s were generated using a bidimensional nozzle (140 × 1600 mm(2)). Energy spectra of velocity fluctuations were measured and found in good agreement with the modified von Kármán spectrum for fully developed turbulence. Spherical N-waves were generated by an electric spark source. Distorted waves were measured by four 3 mm diameter microphones placed beyond the turbulent jet. The presence of turbulence resulted in random focusing of the pulse; more than a threefold increase of peak pressures was occasionally observed. Statistics of the acoustic field parameters were evaluated as functions of the propagation distance and the level of turbulence fluctuations. It is shown that random inhomogeneities decrease the mean peak positive pressure up to 30% at 2 m from the source, double the mean rise time, and cause the arrival time about 0.3% earlier than that for corresponding conditions in still air. Probability distributions of the pressure amplitude possess autosimilarity properties with respect to the level of turbulence fluctuations.
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http://dx.doi.org/10.1121/1.3652869DOI Listing
December 2011

[Analysis of the spectrum of bacterial pathogens isolated from patients with complicated skin and soft tissue infections presumably due to grampositive or mixed flora in the countries of the Central and East Europe].

Antibiot Khimioter 2011 ;56(5-6):19-29

The data on the microbiological investigation of clinical materials from patients with complicated skin and soft tissue infections in 6 European countries were analysed. The analysis of the bacterial pathogens spectrum provided the microbial view and efficient use of novel antimicrobials in clinical trials.
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February 2012

Controlled tissue emulsification produced by high intensity focused ultrasound shock waves and millisecond boiling.

J Acoust Soc Am 2011 Nov;130(5):3498-510

Center for Industrial and Medical Ultrasound, Applied Physics Laboratory, University of Washington, 1013 NE 40th Street, Seattle, Washington 98105, USA.

In high intensity focused ultrasound (HIFU) applications, tissue may be thermally necrosed by heating, emulsified by cavitation, or, as was recently discovered, emulsified using repetitive millisecond boiling caused by shock wave heating. Here, this last approach was further investigated. Experiments were performed in transparent gels and ex vivo bovine heart tissue using 1, 2, and 3 MHz focused transducers and different pulsing schemes in which the pressure, duty factor, and pulse duration were varied. A previously developed derating procedure to determine in situ shock amplitudes and the time-to-boil was refined. Treatments were monitored using B-mode ultrasound. Both inertial cavitation and boiling were observed during exposures, but emulsification occurred only when shocks and boiling were present. Emulsified lesions without thermal denaturation were produced with shock amplitudes sufficient to induce boiling in less than 20 ms, duty factors of less than 0.02, and pulse lengths shorter than 30 ms. Higher duty factors or longer pulses produced varying degrees of thermal denaturation combined with mechanical emulsification. Larger lesions were obtained using lower ultrasound frequencies. The results show that shock wave heating and millisecond boiling is an effective and reliable way to emulsify tissue while monitoring the treatment with ultrasound.
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http://dx.doi.org/10.1121/1.3626152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3259668PMC
November 2011

SIMULATION OF THREE-DIMENSIONAL NONLINEAR FIELDS OF ULTRASOUND THERAPEUTIC ARRAYS.

Acoust Phys 2011 May;57(3):334-343

Moscow State University, Moscow, 119991, Russia.

A novel numerical model was developed to simulate three-dimensional nonlinear fields generated by high intensity focused ultrasound (HIFU) arrays. The model is based on the solution to the Westervelt equation; the developed algorithm makes it possible to model nonlinear pressure fields of periodic waves in the presence of shock fronts localized near the focus. The role of nonlinear effects in a focused beam of a two-dimensional array was investigated in a numerical experiment in water. The array consisting of 256 elements and intensity range on the array elements of up to 10 W/cm(2) was considered. The results of simulations have shown that for characteristic intensity outputs of modern HIFU arrays, nonlinear effects play an important role and shock fronts develop in the pressure waveforms at the focus.
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http://dx.doi.org/10.1134/S1063771011030213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3145364PMC
May 2011
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