Inertial Cavitation Behaviors Induced by Nonlinear Focused Ultrasound Pulses.

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% to 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, 1.5, 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 toward 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.

Phase-Aberration Correction for HIFU Therapy Using a Multielement Array and Backscattering of Nonlinear Pulses.

Phase aberrations induced by heterogeneities in body wall tissues introduce a shift and broadening of the high-intensity focused ultrasound (HIFU) focus, associated with decreased focal intensity. This effect is particularly detrimental for HIFU therapies that rely on shock front formation at the focus, such as boiling histotripsy (BH). In this article, an aberration correction method based on the backscattering of nonlinear ultrasound pulses from the focus is proposed and evaluated in tissue-mimicking phantoms. A custom BH system comprising a 1.5-MHz 256-element array connected to a Verasonics V1 engine was used as a pulse/echo probe. Pulse inversion imaging was implemented to visualize the second harmonic of the backscattered signal from the focus inside a phantom when propagating through an aberrating layer. Phase correction for each array element was derived from an aberration-correction method for ultrasound imaging that combines both the beamsum and the nearest neighbor correlation method and adapted it to the unique configuration of the array. The results were confirmed by replacing the target tissue with a fiber-optic hydrophone. Comparing the shock amplitude before and after phase-aberration correction showed that the majority of losses due to tissue heterogeneity were compensated, enabling fully developed shocks to be generated while focusing through aberrating layers. The feasibility of using a HIFU phased-array transducer as a pulse-echo probe in harmonic imaging mode to correct for phase aberrations was demonstrated.

A Prototype Therapy System for Boiling Histotripsy in Abdominal Targets Based on a 256-Element Spiral Array.

Boiling histotripsy (BH) uses millisecond-long ultrasound (US) pulses with high-amplitude shocks to mechanically fractionate tissue with potential for real-time lesion monitoring by US imaging. For BH treatments of abdominal organs, a high-power multielement phased array system capable of electronic focus steering and aberration correction for body wall inhomogeneities is needed. In this work, a preclinical BH system was built comprising a custom 256-element 1.5-MHz phased array (Imasonic, Besançon, France) with a central opening for mounting an imaging probe. The array was electronically matched to a Verasonics research US system with a 1.2-kW external power source. Driving electronics and software of the system were modified to provide a pulse average acoustic power of 2.2 kW sustained for 10 ms with a 1-2-Hz repetition rate for delivering BH exposures. System performance was characterized by hydrophone measurements in water combined with nonlinear wave simulations based on the Westervelt equation. Fully developed shocks of 100-MPa amplitude are formed at the focus at 275-W acoustic power. Electronic steering capabilities of the array were evaluated for shock-producing conditions to determine power compensation strategies that equalize BH exposures at multiple focal locations across the planned treatment volume. The system was used to produce continuous volumetric BH lesions in ex vivo bovine liver with 1-mm focus spacing, 10-ms pulselength, five pulses/focus, and 1% duty cycle.

Experimental observation of acoustic emissions generated by a pulsed proton beam from a hospital-based clinical cyclotron.

PURPOSE: To measure the acoustic signal generated by a pulsed proton spill from a hospital-based clinical cyclotron. METHODS: An electronic function generator modulated the IBA C230 isochronous cyclotron to create a pulsed proton beam. The acoustic emissions generated by the proton beam were measured in water using a hydrophone. The acoustic measurements were repeated with increasing proton current and increasing distance between detector and beam. RESULTS: The cyclotron generated proton spills with rise times of 18 µs and a maximum measured instantaneous proton current of 790 nA. Acoustic emissions generated by the proton energy deposition were measured to be on the order of mPa. The origin of the acoustic wave was identified as the proton beam based on the correlation between acoustic emission arrival time and distance between the hydrophone and proton beam. The acoustic frequency spectrum peaked at 10 kHz, and the acoustic pressure amplitude increased monotonically with increasing proton current. CONCLUSIONS: The authors report the first observation of acoustic emissions generated by a proton beam from a hospital-based clinical cyclotron. When modulated by an electronic function generator, the cyclotron is capable of creating proton spills with fast rise times (18 µs) and high instantaneous currents (790 nA). Measurements of the proton-generated acoustic emissions in a clinical setting may provide a method for in vivo proton range verification and patient monitoring.

Enhanced therapeutic anti-inflammatory effect of betamethasone on topical administration with low-frequency, low-intensity (20 kHz, 100 mW/cm(2)) ultrasound exposure on carrageenan-induced arthritis in a mouse model.

The purpose of this work was to investigate whether low-frequency, low-intensity (20 kHz, <100 mW/cm(2), spatial-peak, temporal-peak intensity) ultrasound, delivered with a lightweight (<100 g), tether-free, fully wearable, battery-powered applicator, is capable of reducing inflammation in a mouse model of rheumatoid arthritis. The therapeutic, acute, anti-inflammatory effect was estimated from the relative swelling induced in mice hindlimb paws. In an independent, indirect approach, the inflammation was bio-imaged by measuring glycolytic activity with near-infrared labeled 2-deoxyglucose. The outcome of the experiments indicated that the combination of ultrasound exposure and topical application of 0.1% (w/w) betamethasone gel resulted in statistically significantly (p < 0.05) enhanced anti-inflammatory activity in comparison with drug or ultrasound treatment alone. The present study underscores the potential benefits of low-frequency, low-intensity ultrasound-assisted drug delivery. However, the proof of concept presented indicates the need for additional experiments to systematically evaluate and optimize the potential of, and the conditions for, tolerable low-frequency, low-intensity ultrasound-promoted non-invasive drug delivery.

Ultrasound-induced modulation of cardiac rhythm in neonatal rat ventricular cardiomyocytes.

Isolated neonatal rat ventricular cardiomyocytes were used to study the influence of ultrasound on the chronotropic response in a tissue culture model. The beat frequency of the cells, varying from 40 to 90 beats/min, was measured based upon the translocation of the nuclear membrane captured by a high-speed camera. Ultrasound pulses (frequency = 2.5 MHz) were delivered at 300-ms intervals [3.33 Hz pulse repetition frequency (PRF)], in turn corresponding to 200 pulses/min. The intensity of acoustic energy and pulse duration were made variable, 0.02-0.87 W/cm(2) and 1-5 ms, respectively. In 57 of 99 trials, there was a noted average increase in beat frequency of 25% with 8-s exposures to ultrasonic pulses. Applied ultrasound energy with a spatial peak time average acoustic intensity (Ispta) of 0.02 W/cm(2) and pulse duration of 1 ms effectively increased the contraction rate of cardiomyocytes (P < 0.05). Of the acoustic power tested, the lowest level of acoustic intensity and shortest pulse duration proved most effective at increasing the electrophysiological responsiveness and beat frequency of cardiomyocytes. Determining the optimal conditions for delivery of ultrasound will be essential to developing new models for understanding mechanoelectrical coupling (MEC) and understanding novel nonelectrical pacing modalities for clinical applications.

Low-frequency (<100 kHz), low-intensity (<100 mW/cm(2)) ultrasound to treat venous ulcers: a human study and in vitro experiments.

The purpose of this study was to examine whether low frequency (<100 kHz), low intensity (<100 mW/cm(2), spatial peak temporal peak) ultrasound can be an effective treatment of venous stasis ulcers, which affect 500 000 patients annually costing over $1 billion per year. Twenty subjects were treated with either 20 or 100 kHz ultrasound for between 15 and 45 min per session for a maximum of four treatments. Healing was monitored by changes in wound area. Additionally, two in vitro studies were conducted using fibroblasts exposed to 20 kHz ultrasound to confirm the ultrasound's effects on proliferation and cellular metabolism. Subjects receiving 20 kHz ultrasound for 15 min showed statistically faster (p < 0.03) rate of wound closure. All five of these subjects fully healed by the fourth treatment session. The in vitro results indicated that 20 kHz ultrasound at 100 mW/cm(2) caused an average of 32% increased metabolism (p < 0.05) and 40% increased cell proliferation (p < 0.01) after 24 h when compared to the control, non-treated cells. Although statistically limited, this work supports the notion that low-intensity, low-frequency ultrasound is beneficial for treating venous ulcers.

Influence of shell composition on the resonance frequency of microbubble contrast agents.

The effect of variations in microbubble shell composition on microbubble resonance frequency is revealed through experiment. These variations are achieved by altering the mole fraction and molecular weight of functionalized polyethylene glycol (PEG) in the microbubble phospholipid monolayer shell and measuring the microbubble resonance frequency. The resonance frequency is measured via a chirp pulse and identified as the frequency at which the pressure amplitude loss of the ultrasound wave is the greatest as a result of passing through a population of microbubbles. For the shell compositions used herein, we find that PEG molecular weight has little to no influence on resonance frequency at an overall PEG mole fraction (0.01) corresponding to a mushroom regime and influences the resonance frequency markedly at overall PEG mole fractions (0.050-0.100) corresponding to a brush regime. Specifically, the measured resonance frequency was found to be 8.4, 4.9, 3.3 and 1.4 MHz at PEG molecular weights of 1000, 2000, 3000 and 5000 g/mol, respectively, at an overall PEG mole fraction of 0.075. At an overall PEG mole fraction of just 0.01, on the other hand, resonance frequency exhibited no systematic variation, with values ranging from 5.7 to 4.9 MHz. Experimental results were analyzed using the Sarkar bubble dynamics model. With the dilatational viscosity held constant (10(-8) N·s/m) and the elastic modulus used as a fitting parameter, model fits to the pressure amplitude loss data resulted in elastic modulus values of 2.2, 2.4, 1.6 and 1.8 N/m for PEG molecular weights of 1000, 2000, 3000 and 5000 g/mol, respectively, at an overall PEG mole fraction of 0.010 and 4.2, 1.4, 0.5 and 0.0 N/m, respectively, at an overall PEG mole fraction of 0.075. These results are consistent with theory, which predicts that the elastic modulus is constant in the mushroom regime and decreases with PEG molecular weight to the inverse 3/5 power in the brush regime. Additionally, these results are consistent with inertial cavitation studies, which revealed that increasing PEG molecular weight has little to no effect on inethe rtial cavitation threshold in the mushroom regime, but that increasing PEG molecular weight decreases inertial cavitation markedly in the brush regime. We conclude that the design and synthesis of microbubbles with a prescribed resonance frequency is attainable by tuning PEG composition and molecular weight.

Finite element static displacement optimization of 20-100 kHz flexural transducers for fully portable ultrasound applicator.

This paper focuses on the development of a finite-element model and subsequent stationary analysis performed to optimize individual flexural piezoelectric elements for operation in the frequency range of 20-100kHz. These elements form the basic building blocks of a viable, un-tethered, and portable ultrasound applicator that can produce intensities on the order of 100mW/cm(2) spatial-peak temporal-peak (I(SPTP)) with minimum (on the order of 15V) excitation voltage. The ultrasound applicator can be constructed with different numbers of individual transducer elements and different geometries such that its footprint or active area is adjustable. The primary motivation behind this research was to develop a tether-free, battery operated, fully portable ultrasound applicator for therapeutic applications such as wound healing and non-invasive transdermal delivery of both naked and encapsulated drugs. It is shown that careful selection of the components determining applicator architecture allows the displacement amplitude to be maximized for a specific frequency of operation. The work described here used the finite-element analysis software COMSOL to identify the geometry and material properties that permit the applicator's design to be optimized. By minimizing the excitation voltage required to achieve the desired output (100mW/cm(2)I(SPTP)) the power source (rechargeable Li-Polymer batteries) size may be reduced permitting both the electronics and ultrasound applicator to fit in a wearable housing.

Optimization of un-tethered, low voltage, 20-100kHz flexural transducers for biomedical ultrasonics applications.

This paper describes optimization of un-tethered, low voltage, 20-100kHz flexural transducers for biomedical ultrasonics applications. The goal of this work was to design a fully wearable, low weight (<100g), battery operated, piezoelectric ultrasound applicator providing maximum output pressure amplitude at the minimum excitation voltage. Such implementation of ultrasound applicators that can operate at the excitation voltages on the order of only 10-25V is needed in view of the emerging evidence that spatial-peak temporal-peak ultrasound intensity (I(SPTP)) on the order of 100mW/cm(2) delivered at frequencies below 100kHz can have beneficial therapeutic effects. The beneficial therapeutic applications include wound management of chronic ulcers and non-invasive transdermal delivery of insulin and liposome encapsulated drugs. The early prototypes of the 20 and 100kHz applicators were optimized using the maximum electrical power transfer theorem, which required a punctilious analysis of the complex impedance of the piezoelectric disks mounted in appropriately shaped metal housings. In the implementation tested, the optimized ultrasound transducer applicators were driven by portable, customized electronics, which controlled the excitation voltage amplitude and facilitated operation in continuous wave (CW) or pulsed mode with adjustable (10-90%) duty cycle. The driver unit was powered by remotely located rechargeable lithium (Li) polymer batteries. This was done to further minimize the weight of the applicator unit making it wearable. With DC voltage of approximately 15V the prototypes were capable of delivering pressure amplitudes of about 55kPa or 100mW/cm(2) (I(SPTP)). This level of acoustic output was chosen as it is considered safe and side effects free, even at prolonged exposure.