Publications by authors named "V A Khokhlova"

110 Publications

Ultrastructural Analysis of Volumetric Histotripsy Bio-effects in Large Human Hematomas.

Ultrasound Med Biol 2021 Jun 8. Epub 2021 Jun 8.

Laboratory for Industrial and Medical Ultrasound, Physics Faculty, M. V. Lomonosov Moscow State University, Moscow, Russian Federation; Center for Industrial and Medical Ultrasound, Applied Physics Laboratory, University of Washington, Seattle, Washington, USA.

Large-volume soft tissue hematomas are a serious clinical problem, which, if untreated, can have severe consequences. Current treatments are associated with significant pain and discomfort. It has been reported that in an in vitro bovine hematoma model, pulsed high-intensity focused ultrasound (HIFU) ablation, termed histotripsy, can be used to rapidly and non-invasively liquefy the hematoma through localized bubble activity, enabling fine-needle aspiration. The goals of this study were to evaluate the efficiency and speed of volumetric histotripsy liquefaction using a large in vitro human hematoma model. Large human hematoma phantoms (85 cc) were formed by recalcifying blood anticoagulated with citrate phosphate dextrose/saline-adenine-glucose-mannitol solution. Typical boiling histotripsy pulses (10 or 2 ms) or hybrid histotripsy pulses using higher-amplitude and shorter pulses (0.4 ms) were delivered at 1% duty cycle while continuously translating the HIFU focus location. Histotripsy exposures were performed under ultrasound guidance with a 1.5-MHz transducer (8-cm aperture, F# = 0.75). The volume of liquefied lesions was determined by ultrasound imaging and gross inspection. Untreated hematoma samples and samples of the liquefied lesions aspirated using a fine needle were analyzed cytologically and ultrastructurally with scanning electron microscopy. All exposures resulted in uniform liquid-filled voids with sharp edges; liquefaction speed was higher for exposures with shorter pulses and higher shock amplitudes at the focus (up to 0.32, 0.68 and 2.62 mL/min for 10-, 2- and 0.4-ms pulses, respectively). Cytological and ultrastructural observations revealed completely homogenized blood cells and fibrin fragments in the lysate. Most of the fibrin fragments were less than 20 μm in length, but a number of fragments were up to 150 μm. The lysate with residual debris of that size would potentially be amenable to fine-needle aspiration without risk for needle clogging in clinical implementation.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2021.05.002DOI Listing
June 2021

Partial Respiratory Motion Compensation for Abdominal Extracorporeal Boiling Histotripsy Treatments with a Robotic Arm.

IEEE Trans Ultrason Ferroelectr Freq Control 2021 Apr 27;PP. Epub 2021 Apr 27.

Extracorporeal boiling histotripsy (BH), a noninvasive method for mechanical tissue disintegration, is getting closer to clinical applications. However, motion of the targeted organs, mostly resulting from the respiratory motion, reduces the efficiency of the treatment. Here, a practical and affordable unidirectional respiratory motion compensation method for BH is proposed and evaluated in ex vivo tissues. The BH transducer is fixed on a robotic arm following the motion of the skin, which is tracked using an inline ultrasound imaging probe. In order to compensate for system lags and obtain a more accurate compensation, an autoregressive motion prediction model is implemented. BH pulse gating is also implemented to ensure targeting accuracy. The system is then evaluated with ex vivo BH treatments of tissue samples undergoing motion simulating breathing with movement of amplitudes between 5 to 10 mm, frequency between 16 to 18 breaths per minute, and a maximum speed of 14.2 mm/s. Results show a reduction of at least 89% of the value of the targeting error during treatment, while only increasing the treatment time by no more than 1%. The lesions obtained by treating with the motion compensation were close in size and affected area to the no-motion case, whereas lesions obtained without the compensation were often incomplete and had larger affected area. This approach to motion compensation could benefit extracorporeal BH and other histotripsy methods in clinical translation.
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http://dx.doi.org/10.1109/TUFFC.2021.3075938DOI Listing
April 2021

"HIFU beam": a Simulator for Predicting Axially Symmetric Nonlinear Acoustic Fields Generated by Focused Transducers in a Layered Medium.

IEEE Trans Ultrason Ferroelectr Freq Control 2021 Apr 20;PP. Epub 2021 Apr 20.

"HIFU beam" is a freely available software tool that comprises a MATLAB toolbox combined with a user-friendly interface and binary executable compiled from FORTRAN source code HIFU beam. (2021). Available: http://limu.msu.ru/node/3555?language=en. It is designed for simulating high-intensity focused ultrasound (HIFU) fields generated by single-element transducers and annular arrays with propagation in flat-layered media that mimic biological tissues. Numerical models incorporated in the simulator include evolution-type equations, either the Khokhlov-Zabolotskaya-Kuznetsov (KZK) equation or one-way Westervelt equation, for radially symmetric ultrasound beams in homogeneous and layered media with thermoviscous or power law acoustic absorption. The software uses shock-capturing methods that allow for simulating strongly nonlinear acoustic fields with high-amplitude shocks. In this paper, a general description of the software is given along with three representative simulation cases of ultrasound transducers and focusing conditions typical for therapeutic applications. The examples illustrate major nonlinear wave effects in HIFU fields including shock formation. Two examples simulate propagation in water, involving a single-element source (1 MHz frequency, 100 mm diameter, 90 mm radius of curvature) and a 16-element annular array (3 MHz frequency, 48 mm diameter, and 35 mm radius of curvature). The third example mimics the scenario of a HIFU treatment in a 'water-muscle-kidney' layered medium using a source typical for abdominal HIFU applications (1.2 MHz frequency, 120 mm diameter and radius of curvature). Linear, quasi-linear, and shock-wave exposure protocols are considered. It is intended that "HIFU beam" can be useful in teaching nonlinear acoustics; designing and characterizing high-power transducers; and developing exposure protocols for a wide range of therapeutic applications such as shock-based HIFU, boiling histotripsy, drug delivery, immunotherapy, and others.
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http://dx.doi.org/10.1109/TUFFC.2021.3074611DOI Listing
April 2021

Inertial Cavitation Behaviors Induced by Nonlinear Focused Ultrasound Pulses.

IEEE Trans Ultrason Ferroelectr Freq Control 2021 Apr 16;PP. Epub 2021 Apr 16.

Inertial cavitation induced by pulsed high intensity focused ultrasound (pHIFU) has previously been shown to successfully permeabilize tumor tissue and enhance chemotherapeutic drug uptake. In addition to HIFU frequency, peak rarefactional pressure (p-), and pulse duration, the threshold for cavitation-induced bioeffects has recently been correlated with asymmetric distortion caused by nonlinear propagation, diffraction and formation of shocks in the focal waveform, and therefore with the transducer F-number. To connect previously observed bioeffects with bubble dynamics and their attendant physical mechanisms, the dependence of inertial cavitation behavior on shock formation was investigated in transparent agarose gel phantoms using high-speed photography and passive cavitation detection (PCD). Agarose phantoms with concentrations ranging from 1.5-5% were exposed to 1-ms pulses using three transducers of the same aperture but different focal distances (F-numbers of 0.77, 1.02, and 1.52). Pulses had central frequencies of 1 MHz, 1.5 MHz, or 1.9 MHz and a range of p-at the focus varying within 1-18 MPa. Three distinct categories of bubble behavior were observed as the acoustic power increased: stationary near-spherical oscillation of individual bubbles, proliferation of multiple bubbles along the pHIFU beam axis, and fanned-out proliferation towards the transducer. Proliferating bubbles were only observed under strongly nonlinear or shock-forming conditions regardless of frequency, and only where the bubbles reached a certain threshold size range. In stiffer gels with higher agarose concentrations, the same pattern of cavitation behavior was observed, but the dimensions of proliferating clouds were smaller. These observations suggest mechanisms that may be involved in bubble proliferation: enhanced growth of bubbles under shock-forming conditions, subsequent shock scattering from the gel-bubble interface, causing an increase in the repetitive tension created by the acoustic wave and the appearance of a new growing bubble in the proximal direction. Different behaviors corresponded to specific spectral characteristics in the PCD signals: broadband noise in all cases, narrow peaks of backscattered harmonics in the case of stationary bubbles, and broadened, shifted harmonic peaks in the case of proliferating bubbles. The shift in harmonic peaks can be interpreted as a Doppler shift from targets moving at speeds of up to 2 m/s, which correspond to the observed bubble proliferation speeds.
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http://dx.doi.org/10.1109/TUFFC.2021.3073347DOI Listing
April 2021

Dual-Use Transducer for Ultrasound Imaging and Pulsed Focused Ultrasound (pFUS) Therapy.

IEEE Trans Ultrason Ferroelectr Freq Control 2021 Apr 1;PP. Epub 2021 Apr 1.

Pulsed focused ultrasound (pFUS) uses short acoustic pulses delivered at low duty cycle and moderate intensity to non-invasively apply mechanical stress or introduce disruption to tissue. Ultrasound-guided pFUS has primarily been used for inducing cavitation at the focus, with or without contrast agents, to promote drug delivery to tumors. When applied in tandem with contrast agents, pFUS is often administered using an ultrasound imaging probe, which has a small footprint and does not require a large acoustic window. The use of nonlinear pFUS without contrast agents was recently shown to be beneficial for localized tissue disruption, but required higher ultrasound pressure levels than a conventional ultrasound imaging probe could produce. In this work, we present the design of a compact dual-use 1 MHz transducer for ultrasound-guided pFUS without contrast agents. Nonlinear pressure fields that could be generated by the probe, under realistic power input, were simulated using the Westervelt equation. In water, fully developed shocks of 42 MPa amplitude and peak negative pressure of 8 MPa were predicted to form at the focus at 458 W acoustic power or 35% of the maximum reachable power of the transducer. In absorptive soft tissue, fully developed shocks formed at higher power (760 W or 58% of the maximum reachable power) with the shock amplitude of 33 MPa and peak negative pressure of 7.5 MPa. The electronic focus steering capabilities of the array were evaluated and found to be sufficient to cover a target with dimensions of 19 mm in axial direction and 44 mm in transversal direction.
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http://dx.doi.org/10.1109/TUFFC.2021.3070528DOI Listing
April 2021