Inertial Cavitation Research Articles

Acoustic Detection of Retained Perfluoropropane Droplets Within the Developing Myocardial Infarct Zone.

Perfluoropropane droplets (PDs) cross endothelial barriers and can be acoustically activated for selective myocardial extravascular enhancement following intravenous injection (IVI). Our objective was to determine how to optimally activate extravascular PDs for transthoracic ultrasound-enhanced delineation of a developing scar zone (DSZ). Ultrafast-frame-rate microscopy was conducted to determine the effect of pulse sequence on the threshold of bubble formation from PDs. In vitro studies were subsequently performed at different flow rates to determine acoustic activation and inertial cavitation thresholds for a PD infusion using multipulse fundamental non-linear or single-pulse harmonic imaging. IVIs of PDs were given in 9 rats and 10 pigs following prolonged left anterior descending ischemia to detect and quantify PD kinetics within the DSZ. A multipulse sequence had a lower myocardial index threshold for acoustic activation by ultrafast-frame-rate microscopy. Acoustic activation was observed at a myocardial index ≥0.4 below the inertial cavitation threshold for both pulse sequences. In rats, confocal microscopy and serial acoustic activation imaging detected higher droplet presence (relative to remote regions) within the DSZ at 3 min post-IVI. Transthoracic high-mechanical-index impulses with fundamental non-linear imaging in pigs at this time post-IVI resulted in selective contrast enhancement within the DSZ.

Nanostructured Sonophotocatalysts for spatially controlled inertial cavitation towards energy‐efficient sonochemistry

AbstractCatalytic nanomaterials have been demonstrated to enhance sonochemical processing through interactions with inertial cavitation events. Typically, sonochemistry generates inertial cavitation events directly from the solvent, which results in spatially uncontrolled cavitation events with limited interaction with the catalytic active site. These high intensity acoustic fields also result in thermal effects and side reactions, which may further influence chemical yields and selectivity. Herein, we report on ultrasound‐responsive structured AuPd/TiO2 open nanoshells (TONs) to surface‐stabilize gas bubbles for promoting cavitation events in the vicinity of catalytic active site. These exogenous bubbles trapped on catalytic active sites readily cavitate to produce free radicals for chemical reactions. Our findings indicate a positive trend between cavitation and benzaldehyde production in the presence of our AuPd/TONs. In contrast, nanostructures without gas‐stabilization demonstrate reduced sonochemical conversion, suggesting the catalytic potential of nanostructuring photocatalytic materials to function as both cavitation agents and photo‐oxidative catalysts, or photocatalytic nanostructure (PCN).

Acoustic droplet vaporization for nonthermal ablation of brain tumors

Acoustic vaporization of perfluorobutane-based phase-shift nanoemulsions (PSNE) can be used to nucleate inertial cavitation (IC) in vivo. The acoustic pressure amplitude must exceed a threshold for vaporization of PFB-based nanoemulsions. Two focused ultrasound transducers with a center frequency of 837 kHz were oriented such that their focal volumes overlapped and the acoustic pressure amplitude was amplified. In this study, the dual transducer system was combined with circulating PSNE to nucleate IC in established brain tumors, leading to nonthermal ablation of the tumors. For comparison, microbubble ultrasound agents (UCA) were used as IC nuclei for ultrasound-mediated tumor ablation. The ablation volume was confined to focal volume when PSNE were used to nucleate IC, whereas pre-focal damage was observed when UCA were used as IC nuclei. Additionally, PSNE-nucleated IC ablated a larger percentage of the brain tumors on average than MB-nucleated IC (89.46.8% vs 11.17.7%, respectively). These results suggest that PFB-based PSNE may be used to significantly reduce the inertial cavitation threshold in the cerebrovasculature, and when combined with transcranial focused ultrasound, enable efficient focal intracranial nonthermal ablation.

Perfluorocarbon nanodroplet size, acoustic vaporization, and inertial cavitation affected by lipid shell composition in vitro.

Perfluorocarbon nanodroplets (PFCnDs) are ultrasound contrast agents that phase-transition from liquid nanodroplets to gas microbubbles when activated by laser irradiation or insonated with an ultrasound pulse. The dynamics of PFCnDs can vary drastically depending on the nanodroplet composition, including the lipid shell properties. In this paper, we investigate the effect of varying the ratio of PEGylated to non-PEGylated phospholipids in the outer shell of PFCnDs on the acoustic nanodroplet vaporization (liquid to gas phase transition) and inertial cavitation (rapid collapse of the vaporized nanodroplets) dynamics in vitro when insonated with focused ultrasound. Nanodroplets with a high concentration of PEGylated lipids had larger diameters and exhibited greater variance in size distribution compared to nanodroplets with lower proportions of PEGylated lipids in the lipid shell. PFCnDs with a lipid shell composed of 50:50 PEGylated to non-PEGylated lipids yielded the highest B-mode image intensity and duration, as well as the greatest pressure difference between acoustic droplet vaporization onset and inertial cavitation onset. We demonstrate that slight changes in lipid shell composition of PFCnDs can significantly impact droplet phase transitioning and inertial cavitation dynamics. These findings can help guide researchers to fabricate PFCnDs with optimized compositions for their specific applications.

Passive cavitation imaging in fuel injector nozzles

Modern fuel injection systems operate at high pressures and flow velocities. Injectors can be pressurized in excess of 10 MPa, resulting in fuel velocities on the order of hundreds of meters/second in the mm and sub-mm internal confines of a fuel injector. Subsequent ejection velocities at the nozzle yield characteristic atomization droplet size distributions and spread angles. Studies have shown or inferred the presence of cavitation in such fuel injectors, typically beneficially decreasing ejection droplet sizes while increasing the spray spreading angle. While beneficial for fuel atomization, it is known that bubble collapse near a solid surface produces a strong jet which impinges on the surface and causes erosion. In this study, Fourier based image reconstruction is used to perform Passive Cavitation Imaging (PCI) in laboratory nozzles to detect, characterize, and most importantly localize inertial cavitation. [Work funded by DOE.]

Passive and active Doppler methods and metrics to quantify inertial cavitation induced by pulsed focused ultrasound

Inertial cavitation induced by pulses of nonlinearly distorted focused ultrasound (FUS) at moderate intensity can result in mild mechanical disruption of tissue, short of its complete mechanical disintegration—histotripsy. This effect can be used to enhance diffusion of subsequently systemically administered drugs or biologics. Previously, single-element passive cavitation detection (PCD) of broadband noise emissions was successfully used to quantify tissue disruption and enhancement in drug concentration. This metric, however, has limitations: minimal spatial resolution and challenges with calibration when used at large depths in acoustically variable tissue. To address this, we developed a combination of passive and active Doppler-based methods that relied on relative, rather than absolute signal metrics. Specifically, destructive cavitation behaviors were previously linked to substantial motion of the bubbles during the FUS pulse due to acoustic radiation force and shock scattering. This was reflected in the backscattered FUS harmonics as Doppler shift and measurable from PCD. The bubbles were observed to dissolve within milliseconds following each FUS pulse, thus their distribution could be visualized as an area of rapid change via fast plane wave Doppler ensemble following the FUS pulse. The Doppler power distribution was spatially correlated with the area of tissue disruption in the in vivo experiments. [Work supported by NIH R01CA154451, R01EB025187, and R01EB23910.]

Passive and Doppler-based assessment of cavitation activity induced by pulsed focused ultrasound

Pulsed focused ultrasound (pFUS) exposures utilizing short, nonlinearly distorted pulses at low duty cycle have been shown to enhance drug and gene delivery to targeted tissue through inertial cavitation activity. Passive cavitation detection (PCD) and mapping of broadband emissions are current conventional methods to monitor and quantify cavitation but provide limited spatial resolution. Here, plane-wave Doppler imaging was used with PCD to quantify pFUS-induced cavitation in ex vivo bovine tissues and in vivo surgically exposed porcine liver, kidney, and pancreas. A 1.5 MHz FUS transducer (aperture 75 mm, F-number 0.75) was used to deliver 60 pulses (duration 1 ms, 0.1% duty cycle, focal pressure p+ = 70i–110 MPa, p− = 13–20 MPa). A coaxially mounted ATL P7-4 ultrasound imaging probe was used for PCD during the FUS pulse, and Doppler and B-mode sequences. Disrupted tissue areas were collected for histology and compared to Doppler power images. Maximum Doppler power was found to correlate to broadband noise level for each FUS pulse. The Doppler power map integrated over the exposure was observed to correlate spatially with tissue disruption area from histology, which thus represents a promising real-time metric for quantifying cavitation activity induced by pFUS exposures. [Work supported by NIH R01CA154451, R01EB025187, and R01EB23910.]

Characterization and monitoring of cavitation behavior induced by a dual-mode pulsed high-intensity focused ultrasound array

Pulsed high-intensity focused ultrasound (pHIFU) is capable of inducing cavitation in tissue without the need for contrast agents, thereby enhancing permeability and passive drug penetration in tissue with poor perfusion. We have developed and characterized the performance of a 64-element linear ultrasound array for image-guided therapy, capable of generating sufficient levels of inertial cavitation at 1 MHz, along with B-mode and Doppler imaging for targeting and cavitation assessment, respectively. Cavitation behaviors induced by different pHIFU exposures were investigated using high-speed imaging in agarose and polyacrylamide phantoms in conjunction with passive cavitation detection (PCD) and plane wave Doppler imaging. Image quality assessment was performed on in vivo porcine models, and cavitation monitoring was demonstrated on ex vivo tissues. High-speed images of the induced cavitation behavior while steering the beam focus both axially and laterally (within ±1.2 cm) were in agreement with Doppler power distributions and broadband noise emissions from PCD. Destructive cavitation behaviors in both gels and tissue were induced at relatively low peak-negative pressures (3–4 MPa), provided that the pHIFU focal waveform was nonlinearly distorted. B-mode image quality is sufficient for recognizing the relative position of anatomic landmarks and targeting cm-sized regions. [Work supported by NIH grants R01EB023910 and R01EB025187.]

Effect of acoustic output on fetal ultrasound color Doppler performance

Increasing transmit acoustic output in color Doppler ultrasound imaging improves the received data temporal signal-to-noise ratio (SNR), but such elevated acoustic pressures increase the potential for inertial cavitation and tissue heating. Safety regulations constrain maximum acoustic output to mitigate bioeffects, but lower output is encouraged following the ALARA (As Low As Reasonably Achievable) principle. In this study, color Doppler imaging with a Siemens ACUSON Sequoia and 10L4 transducer was performed on the placenta umbilical cord insertion site of 10 pregnant volunteers. Flow data were collected at five acoustic output levels and four frequency settings to assess each parameter’s effect. The output Thermal Index (TI) ranged from 0.001 to 0.7 and frequency ranged from 4.0 to 7.3 MHz. Increased temporal SNR in the receive signals at high output levels was linked to lower pulse-to-pulse phase variance and velocity bias. These metrics changed most dramatically across low output levels, before converging towards constant phase variance and velocity bias at high temporal SNR. The output levels approaching stable phase variance and velocity were specific to each volunteer and frequency. This result provides a framework for future automated Doppler ALARA implementations that calculate performance metrics and adjust acoustic power in accordance with ALARA principles.

Investigation of Inertial Cavitation Induced by Modulated Focused Ultrasound Stimuli

Abstract A passive cavitation detection setup is used to assess and verify the capability of frequency- and amplitudemodulated ultrasound burst signals on the generation of inertial cavitation. The measurements were conducted with a flowthrough tissue-mimicking phantom with a canal of dc = 1mm in diameter simulating a fine blood vessel. By means of a flow velocity of vf= 50mm/s circulating blood in the cardiovascular system is imitated. Applying signal frequencies from f = 550 − 950 kHz and peak rarefaction pressures in a range from ˆpPRFP ≈ 0.17 − 1.81 MPa, various ultrasound stimuli with alternating signal parameters were investigated in the absence and presence of a talcum-water mixture acting as cavitation nuclei. By evaluating the broadband emissions in the frequency domain and calculating the voltage spectral density Srm, the results can be compared. The findings of the present study demonstrate that each ultrasound stimulus triggers a similar strength of cavitation noise at the same Mechanical Index, representing a certain pressure. Over the whole frequency and Mechanical Index (pressure) range, each ultrasound signal type generates a voltage spectral density from Srm= 0.25 − 2.25 V/ √ Hz.

Comparison of frequency domain and time domain methods for the numerical simulation of contactless ultrasonic cavitation

The use of a top-mounted electromagnetic induction coil has been demonstrated as a contactless alternative to traditional ultrasonic treatment (UST) techniques that use an immersed mechanical sonotrode for the treatment of metals in the liquid state. This method offers similar benefits to existing UST approaches, including degassing, grain refinement, and dispersion of nanoparticles, while also preventing contact contamination due to erosion of the sonotrode. Contactless treatment potentially extends UST to high temperature or reactive melts. Generally, the method relies on acoustic resonance to reach pressure levels suitable for inertial cavitation and as a result the active cavitation volume tends to lie deep in the melt rather than in the small volume surrounding the immersed sonotrode probe. Consequently, (i) with suitable tuning of the coil supply frequency for resonance, the treatment volume can be made arbitrarily large, (ii) the problem of shielding and pressure wave attenuation suffered by the immersed sonotrode is avoided. However, relying on acoustic resonance presents problems: (i) the emergence of bubbles alters the speed of sound, resonance is momentarily lost, and cavitation becomes intermittent, (ii) as sound waves travel through and reflect on all the materials surrounding the melt, the sound characteristics of the crucible and supporting structures need to be carefully considered. The physics of cavitation coupled with this intermittent behaviour poses a challenge to sonotrode modelling orthodoxy, a problem we are trying to address in this publication. Two alternative approaches will be discussed, one of which is in the time domain and one in the frequency domain, which couple the solution of a bubble dynamics solver with that of an acoustics solver, to give an accurate prediction of the acoustic pressure generated by the induction coil. The time domain solver uses a novel algorithm to improve simulation time, by detecting an imminent bubble collapse and prescribing its subsequent behaviour, rather than directly solving a region that would normally require extremely small time steps. This way, it is shown to predict intermittent cavitation. The frequency domain solver for the first time couples the nonlinear Helmholtz model used for studying cavitation, with a background source term for the contribution of Lorentz forces. It predicts comparable RMS pressures to the time domain solver, but not the intermittent behaviour due to the underlying harmonic assumption. As further validation, the frequency domain method is also used to compare the generated acoustic pressure with that of traditional UST using a mechanical sonotrode.

Developing high intensity ultrasonic cleaning (HIUC) for post-processing additively manufactured metal components

The high energy phenomenon of cavitation bubble collapses has enabled numerous applications, including cleaning. In ultrasonic cleaning, cavitation intensity is typically lower than in other applications, such as sonochemistry and material processing. However, there has been an emerging application in intense cleaning of metal additively manufactured (AM) components. The presence of partially melted powders on AM surfaces is undesirable, contributing to high surface roughness and posing contamination risks during usage. We designed a high-intensity cavitation cleaning process that has significantly higher inertial cavitation intensity – i.e., erosion potential – than a conventional ultrasonic cleaning tank. Through acoustic signal characterisation, we showed that placing transducer sets on four sides of the tank could effectively focus and generate high-amplitude pressure waves directed towards the central region. Strong subharmonic signals indicate intensely inertial cavitation throughout the tank. Cavitation intensities were measured at various locations to understand the wave transmission characteristics and distribution patterns. Our results show that the cavitation intensity distribution is highly dependent on the height position. Finally, we demonstrated that the high intensity ultrasonic cleaning (HIUC) process could remove partially melted powders from an AM surface – which was not possible through conventional ultrasonic cleaning. HIUC could lead to higher cleaning efficiency and enhanced AM specimen cleanliness.

Stable Cavitation Interferes with Aβ16-22 Oligomerization.

Ultrasound and microbubbles are used for many medical applications nowadays. Scanning ultrasound can remove amyloid-β (Aβ) aggregates in the mouse brain and restores memory in an Alzheimer's disease mouse model. In vitro studies showed that amyloid fibrils are fragmented due to the ultrasound-induced bubble inertial cavitation, and ultrasonic pulses accelerate the depolymerization of Aβ fibrils into monomers at 1 μM of concentration. Under applied ultrasound, microbubbles can be in a stable oscillating state or unstable inertial cavitation state. The latter occurs when ultrasound causes a dramatic change of bubble sizes above a certain acoustic pressure. We have developed and implemented a nonequilibrium molecular dynamics simulation algorithm to the AMBER package, to facilitate the investigation of the molecular mechanism of Aβ oligomerization under stable cavitation. Our results indicated that stable cavitation not only inhibited oligomeric formation, but also prevented the formation of β-rich oligomers. The network analysis of state transitions revealed that stable cavitation altered the oligomerization pathways of Aβ16-22 peptides. Our simulation tool may be applied to optimize the experimental conditions to achieve the best therapeutical effect.

A new animal femoral artery model of localized intermediate stage of atherosclerosis using focused ultrasound- mediated inertial cavitation- induced injury and high- cholesterol diet injury

Background and Aims : The use of animal models in atherosclerotic lesions has improved our understanding of atherosclerosis pathophysiology. We sought to develop an easily reproducible and inexpensive experimental rabbit femoral artery model of intermediate stage atherosclerosis with moderate stenosis (< 40%).

Regression of advanced atherosclerosis with neovessels using inertial cavitation effect of collapsed microbubbles- mediated pulsed- focused ultrasound antivascular therapy

Background and Aims : Atherosclerosis is the leading cause of infarction. Atherosclerotic lesions are considered to be advanced when the accumulation of lipid is associated with the disorganization and deformity of the arterial wall. In this study, we investigated focused ultrasound effectiveness on destruction of neovessles in advanced atherosclerotic plaque.

Investigation of hardware and software techniques to enhance the characteristics of focused ultrasound (FUS) spectra

Objective. Microbubble cavitation generated by focused ultrasound (FUS) can induce safe blood-brain-barrier (BBB) opening allowing therapeutic drug passage. Spectral changes in the hydrophone sensor signal are currently used to distinguish stable cavitation from inertial cavitation that can damage the BBB. Gibbs’ ringing, peak intensity loss and peak width increase are well-known distortions evident when using the discrete Fourier transform (DFT) to transform data containing a few hundred points. We investigate overcoming the fact that FUS time signals (10 ms providing 312 500 points sampled at 32 ns intervals) can generate such sharp spectral peaks that variations in their DFT-related distortions can significantly impact the values of the key metrics used for cavitation characterization. Approach. We introduce low-pass filter hardware to improve how the analogue to digital convertor handles high-frequency noise components and the orders of magnitude differences between FUS harmonic intensities. We investigate the enhanced FUS spectral stability and resolution obtained from a new technique, physical sparsification (PH-SP), customized to the a-priori information that all key FUS components are harmonically related. Results are compared with standard DFT optimizations involving time data windowing and Fourier interpolation. Main results. A new simulation model showed peak intensity, widths and metrics modified by small changes in the transformed signal’s length when removing the noisy starting transient of the FUS hydrophone signal or following minor excitation frequency or sampling rate adjustments. 25%–60% area-under-the-curve changes occurred in phantom studies at different pressure levels. Spectral peak sharpness was best optimized and stabilized with PH-SP. Significance. Special FUS characteristics mean starting transients and minor variations in experimental procedures lead to significant changes in the spectral metrics used to monitor cavitation levels. Customizing PH-SP to these characteristics led to sharper, more stable spectra with the potential to track the impact of microbubble environment changes.

GPU-accelerated study of the inertial cavitation threshold in viscoelastic soft tissue using a dual-frequency driving signal

Inertial cavitation thresholds under two forms of ultrasonic excitation (the single- and dual-frequency ultrasound modes) are studied numerically. The Gilmore–Akulichev model coupled with the Zener viscoelastic model is used to model the bubble dynamics. The threshold pressures are determined with two criteria, one based on the bubble radius and the other on the bubble collapse speed. The threshold behavior is investigated for different initial bubble sizes, acoustic signal modes, frequencies, tissue viscosities, tissue elasticities, and all their combinations. Due to the large number of parameters and their many combinations (around 1.5 billion for each threshold criterion), all simulations were executed on graphics processing units to speed up the calculations. We used our own code written in the C++ and CUDA C languages. The results obtained demonstrate that using the dual-frequency signal mode can help to reduce the inertial cavitation threshold (in comparison to the single-frequency mode). The criterion based on the bubble size gives a lower threshold than the criterion using the bubble collapse speed. With an increase of the elasticity, the threshold pressure also increases, whereas changing the viscosity has a very small impact on the optimal threshold, unlike the elasticity. A detailed analysis of the optimal ultrasound frequencies for a dual-frequency driving signal found that for viscosities less than 0.02 Pa·s, the first optimal frequency, in general, is much smaller than the second optimal frequency, which can reach 1 MHz. However, for high viscosities, both optimal frequencies are similar and varied in the range 0.01–0.05 MHz. Overall, this study presents a detailed analysis of inertial cavitation in soft tissue under dual-frequency signal excitation. It may be helpful for the further development of different applications of biomedical ultrasound.

Particle-Assisted Laser-Induced Inertial Cavitation for High Strain-Rate Soft Material Characterization

Particle-Assisted Laser-Induced Inertial Cavitation for High Strain-Rate Soft Material Characterization

Dosimetric assessment of antitumor treatment by enhanced bleomycin delivery via electroporation and sonoporation

Targeted and controlled techniques of intratumoral delivery of chemotherapeutic agents are under extensive development, since they diminish detrimental side-effects of conventional anticancer drugs.We investigated the effectiveness of chemotherapy using bleomycin (1 mg/ml) and Sonovue microbubbles combined with: electroporation (EP), mainly designed for subcutaneous tumor therapy, and sonoporation (SP) - for deeper localized tumors. Research was performed on hepatoma MH-22A tumors in murine models, exposed to EP or SP and combined (EP + SP) treatment.Animal survival time and the rate/ speed of tumor growth reduction were examined. Study demonstrated that both EP or SP and their combination (EP + SP) were able to induce the reduction of tumor volume from the 3rd day after treatment. The employment of EP before SP allowed to significantly reduce the values of inertial cavitation dose (ICD), necessary to induce complete tumor reduction and prolong animal survival.The analysis of ultrasound (US) side-scattered signals and B-scan imaging indicated the occurrence of inertial cavitation at our experimental conditions. Strong (R2 = 0.88; p < 0.0001) correlation of ICD with the survival time of corresponding unrecovered mice indicates the option for the dosimetric control and standardization of cavitation activities for in vivo practice.

Boron Imidazolate Framework‐Derived Porous Carbon Nanospheres for Dual‐Mode Bioimaging‐Guided Photothermal/Sonodynamic Synergistic Cancer Therapy

AbstractDevelopment of efficient nanotherapeutic agents to enhance anticancer therapeutic effects is challenging. In this study, photo/sono‐dual‐responsive boron imidazolate framework‐derived single‐component porous carbon nanospheres (PCNSs) are successfully developed for dual‐mode bioimaging‐guided photothermal/sonodynamic (PTT/SDT) synergistic therapy for triple‐negative breast cancer. The PCNS not only exhibits satisfactory and excellent photothermal conversion ability under near‐infrared laser irradiation but also demonstrates a promising capability as an efficient sonosensitizer to generate cytotoxic reactive oxygen species through inertial cavitation in response to low‐intensity ultrasound stimulation. The outstanding photothermal effect enhances the blood flow in tumor tissues and thus improves the oxygen supply, helping to achieve a remarkable synergistic therapeutic effect in the PTT/SDT synergistic therapy without any tumor recurrence or systemic toxicity. Interestingly, the PCNS enables the precise visualization of solid tumors using contrast‐enhanced ultrasound and photothermal dual‐modal bioimaging techniques. Overall, this study provides valuable insights in developing all‐in‐one theranostic nanoplatforms for the clinical treatment of triple‐negative breast cancer.