Rarefactional Pressure Research Articles

Quantitative evaluation of anti-biofilm cavitation activity seeded from microbubbles or protein cavitation nuclei by passive acoustic mapping

Bacterial biofilms represent a major challenge for effective antibiotic therapy as they confer physical and functional changes that protect bacteria from their surrounding environment. In this work, focused ultrasound in combination with cavitation nuclei was used to disrupt biofilms of Staphylococcus aureus and Pseudomonas aeruginosa, both of which are on the World Health Organization's priority list for new antimicrobial research. 
Approach: Single species biofilms were exposed to ultrasound (0.5 MHz centre frequency, 0.5-1.5 MPa peak rarefactional pressure, 200 cycle pulses, 5 Hz repetition frequency, 30 s duration), in the presence of two different types of cavitation nuclei. Quantitative passive acoustic mapping (PAM) was used to monitor cavitation emissions during treatment using a calibrated linear array. 
Main Results: It was observed that the cumulative energy of acoustic emissions during treatment was positively correlated with biofilm disruption, with differences between bacterial species attributed to differences in biofilm morphology. PCaN provided increased biofilm reduction compared to microbubbles due in large part to their persistence over the duration of ultrasound exposure. There was also good correlation between the spatial distribution of cavitation as characterized by PAM and the extent of biofilm disruption observed with microscopy. 
Significance: Collectively, the results from this work indicate the potential broad applicability of cavitation for eliminating biofilms of priority pathogens and the opportunity presented by Passive Acoustic Mapping for real-time monitoring of antimicrobial processes.

Characterisation of Gas Vesicles as Cavitation Nuclei for Ultrasound Therapy using Passive Acoustic Mapping.

Genetically encodable gas filled particles known as gas vesicles (GVs) have shown promise as a biomolecular contrast agent for ultrasound imaging and have the potential to be used as cavitation nuclei for ultrasound therapy. In this study, we used passive acoustic mapping techniques to characterize GV-seeded cavitation, utilizing 0.5 and 1.6 MHz ultrasound over peak rarefactional pressures ranging from 100 to 2200 kPa. We found that GVs produce cavitation for the duration of the first applied pulse, up to at least 5000 cycles, but that bubble activity diminishes rapidly over subsequent pulses. At 0.5 MHz the frequency content of cavitation emissions was predominantly broadband in nature, whilst at 1.6 MHz narrowband content at harmonics of the main excitation frequency dominated. Simulations and high-speed camera imaging suggest that the received cavitation emissions come not from individual GVs but instead from the coalescence of GV-released gas into larger bubbles during the applied ultrasound pulse. These results will aid the future development of GVs as cavitation nuclei in ultrasound therapy.

A spatiotemporal deconvolution approach for measurements of therapeutic ultrasound pressures, intensities, and beamwidths

Complete characterization of high intensity focused ultrasound (HIFU) systems includes measurements of transmitted pressure at the focal plane with a hydrophone. However, highly focused, nonlinear HIFU beams can result in considerable spatial averaging artifacts due to finite area of the hydrophone active element. Spatiotemporal deconvolution (STD) can correct for hydrophone spatial averaging (Wear, IEEE Trans. UFFC 69, 1243–1256 (2021)]. The objective of the present work is to extend validation of STD from diagnostic levels (6 MPa) to therapeutic levels (49 MPa). Three HIFU transducers (1.45 MHz F/1, 1.53 MHz F/1.5, and 3.91 MHz F/1) were driven in tone bursts (Agilent HP3314A function generator, ENI 240L amplifier) to generate HIFU fields in a degassed, deionized water tank with focal compressional pressures of 49, 16, and 29 MPa. Fields were measured in focal planes with two hydrophones (Onda HFO 100-μm fiber-optic; Onda HNA-0400 400-μm robust needle). STD reduced inter-hydrophone differences from −18 ± 11% to 0 ± 8% (peak compressional pressure), −8 ± 4% to −5 ± 5% (peak rarefactional pressure), −20% ± 7% to −3 ± 8% (pulse intensity integral), and 21 ± 12% to −2 ± 3% (beam FWHM). STD reduces dependence of measurements on hydrophone active element size. STD reduces reliance on fiber optic hydrophones, which can be expensive, difficult to use, and prone to radiation-force-induced sensor misalignment.

Dynamics of large cavity induced by valve closure in an undulating pipeline

The dynamics of large cavity and the accompanied water column separation and rejoining induced by fast closing of a butterfly valve in an undulating pipeline system are investigated in this study. The three-dimensional computational fluid dynamics numerical simulations are performed using a newly developed interfacial surface tension-based model (ISTM) that accounts for the surface tension effect on large cavities. The applicability of the ISTM model is validated with the experimental data, showing better accuracy in predicting pressure fluctuations and cavity evolutions than three typical cavitation models. Differences in cavitation characteristics are observed between upstream and downstream of the valve. Upstream the valve, cavitation primarily appears at the pipe top, with the vapor volume fraction varying sharply due to the rarefaction pressure waves (maximum value of 0.0073). Downstream the valve, the complete water-column separation occurs, and vapor volume fraction changes slowly correspond with the growth and collapse of the large cavity (maximum value of 0.647). The maximum length of the large cavity can reach about six times the pipe diameter, with a minimum water vapor interface angle of 16°. The cavitation evolution displays a transition from a clustered inception to a sheet-like growth and collapse pattern. These findings contribute to the design and operation guidance for complex hydraulic systems during transient processes.

Quantifying the Effect of Acoustic Parameters on Temporal and Spatial Cavitation Activity: Gauging Cavitation Dose.

Cavitation-enhanced delivery of therapeutic agents is under development for the treatment of cancer and neurodegenerative and cardiovascular diseases, including sonothrombolysis for deep vein thrombosis. The objective of this study was to quantify the spatial and temporal distribution of cavitation activity nucleated by Definity infused through the EKOS catheter over a range of acoustic parameters controlled by the EKOS endovascular system. Three insonation protocols were compared in an in vitro phantom mimicking venous flow to measure the effect of peak rarefactional pressure, pulse duration and pulse repetition frequency on cavitation activity energy, location and duration. Inertial and stable cavitation activity was quantified using passive cavitation imaging, and a metric of cavitation dose based on energy density was defined. For all three insonation protocols, cavitation was sustained for the entire 30min Definity infusion. The evolution of cavitation energy during each pulse duration was similar for all three protocols. For insonation protocols with higher peak rarefactional acoustic pressures, inertial and stable cavitation doses also increased. A complex relationship between the temporal behavior of cavitation energy within each pulse and the pulse repetition frequency affected the cavitation dose for the three insonation protocols. The relative predominance of stable or inertial cavitation dose varied according to insonation schemes. Passive cavitation images revealed the spatial distribution of cavitation activity. Our cavitation dose metric based on energy density enabled the impact of different acoustic parameters on cavitation activity to be measured. Depending on the type of cavitation to be promoted or suppressed, particular pulsing schemes could be employed in future studies, for example, to correlate cavitation dose with sonothrombolytic efficacy.

Acoustic droplet vaporization for on-demand modulation of microporosity in smart hydrogels.

Microporosity in hydrogels is critical for directing tissue formation and function. We have developed a fibrin-based smart hydrogel, termed an acoustically responsive scaffold (ARS), which responds to focused ultrasound in a spatiotemporally controlled, user-defined manner. ARSs are highly flexible platforms due to the inclusion of phase-shift droplets and their tunable response to ultrasound through a mechanism termed acoustic droplet vaporization (ADV). Here, we demonstrated that ADV enabled consistent generation of micropores in ARSs, throughout the entire thickness (∼5.5 mm), utilizing perfluorooctane phase-shift droplets. Size characteristics of the generated micropores were quantified in response to critical parameters including acoustic properties, droplet size, and shear elastic modulus of fibrin using confocal microscopy. The findings showed that the length of the generated micropores correlated directly with excitation frequency, peak rarefactional pressure, pulse duration, droplet size, and indirectly with the shear elastic modulus of the fibrin matrix. The ADV-generated micropores in ARSs were further compared with cavitation-mediated micropores in fibrin gels without droplets. Additionally, the Keller-Miksis equation was used to predict an upper bound for micropore formation in ARSs at varying driving frequencies and droplet sizes. Finally, our in vivo studies showed that host cell migration following ADV-induced micropore formation was frequency-dependent, with up to 2.6 times higher cell migration at lower frequencies. Overall, these findings demonstrate a new potential application of ADV in hydrogels. STATEMENT OF SIGNIFICANCE: Interconnected micropores within a hydrogel can facilitate many cell-mediated processes. Most techniques for generating micropores are typically not biocompatible or do not enable controlled, in situ micropore formation. We used an ultrasound-based technique, termed acoustic droplet vaporization, to generate microporosity in smart hydrogels termed acoustically responsive scaffolds (ARSs). ARSs contain a fibrin matrix doped with a phase-shift droplet. We demonstrate that unique acoustic properties of phase-shift droplets can be tailored to yield spatiotemporally controlled, on-demand micropore formation. Additionally, the size characteristics of the ultrasound-generated micropores can be modulated by tuning ultrasound parameters, droplet properties, and bulk elastic properties of fibrin. Finally, we demonstrate significant, frequency-dependent host cell migration in subcutaneously implanted ARSs in mice following ultrasound-induced micropore formation in situ.

Delayed subharmonic response of a phospholipid-shelled ultrasound contrast agent: Effect of temperature and protein concentration

The subharmonic response of ultrasound contrast agents (UCAs) is important for imaging and therapy. Therefore, factors influencing the temporal evolution of subharmonic signals should be elucidated. We evaluated the influence of temperature (25°C and 37°C) and protein concentration in the fluid (0.5% w/v at 25°C and 37°C) on the subharmonic response of Definity, a phospholipid-shelled UCA. Definity was diluted to 106 microbubbles/ml and sonicated at 2 MHz frequency, 50 cycles, and 470 kPa peak rarefactional pressure. The subharmonic response demonstrated striking qualitative and quantitative changes with time. At 25°C, a delayed subharmonic onset was observed. The subharmonic signal appeared after 28 min, peaking at 18dB above the baseline. At 37°C, the subharmonic signal appeared immediately but it peaked (5 dB increase) after 52 min. In the presence of dissolved protein, the subharmonic signal appeared at 16 min at 25°C and at 4min at 37°C. The signal peaked at 24 dB and 10 dB above the baseline at 25°C and 37°C, respectively. These observations underscore the need to standardize acoustic measurements and may have implications for subharmonic imaging, non-invasive pressure sensing, and cavitation detection.

Acoustic radiation force impulse-induced lung hemorrhage: investigating the relationship with peak rarefactional pressure amplitude and mechanical index in rabbits

PurposeThe safety of acoustic radiation force impulse (ARFI) elastography, which applies higher acoustic power with a longer pulse duration (PD) than conventional diagnostic ultrasound, is yet to be verified. We assessed the ARFI-induced lung injury risk and its relationship with peak rarefactional pressure amplitude (PRPA) and mechanical index (MI).MethodsEighteen and two rabbits were included in the ARFI (0.3-ms push pulses) and sham groups, respectively. A 5.2-MHz linear probe was applied to the subcostal area and aimed at both lungs through the liver for 30 ARFI emissions. The derated PRPA varied among the six ARFI groups—0.80 MPa, 1.13 MPa, 1.33 MPa, 1.70 MPa, 1.91 MPa, and 2.00 MPa, respectively.ResultsThe occurrence of lung hemorrhage and the mean lesion area among all samples in the seven groups were 0/6, 0/6, 1/6 (1.7 mm2), 4/6 (8.0 mm2), 4/6 (11.2 mm2), 5/6 (23.8 mm2), and 0/4 (sham), respectively. Logistic regression analysis showed that derated PRPA was significantly associated with lung injury occurrence (odds ratio: 207, p < 0.01), with the threshold estimated to be 1.1 MPa (MI, 0.5). Spearman’s rank correlation showed a positive correlation between derated PRPA and lesion area (r = 0.671, p < 0.01).ConclusionThis study demonstrated that the occurrence and severity of ARFI-induced lung hemorrhage increased with a rise in PRPA under clinical conditions in rabbits. This indicates a potential risk of lung injury due to ARFI elastography, especially when ARFI is unintentionally directed to the lungs during liver, heart, or breast examinations.

Spatio-temporal evaluation of anti-biofilm cavitation activity by passive acoustic mapping

Bacterial biofilms present a major challenge to achieving effective antibiotic therapy, as these sessile communities of microbes confer protection to bacteria by decreasing antibiotic efficacy. Focused ultrasound can mechanically disrupt biofilms, offering a new ‘drug-free’ antibiotic paradigm. The goal of this work is to validate, quantify, and optimize the role of acoustic cavitation in the biofilm disruption process through spatiotemporal monitoring of cavitation activity. A clinical isolate strain of Staphylococcus aureus from native valve endocarditis was cultured for 72 hours within a flow channel to form a biofilm. A 1.1 MHz spherically focused transducer was used to expose the biofilm from below at a 45° angle. The in situ acoustic field was characterized with a fibre-optic hydrophone. A calibrated 5–11 MHz linear array was placed 25 mm above the biofilm in order to record acoustic emissions during biofilm disruption from which passive acoustic maps of cavitation could be derived. Biofilms were exposed to 4.5 MPa peak rarefactional pressure (derated), 10,000 cycles, at a 1 Hz PRF. Qualitative reduction of biofilms was assessed by live/dead staining with Syto 9/propidium iodide, which was correlated with cavitation activity observed in the passive acoustic maps.

Amplitude and phase relation of harmonics in nonlinear focused ultrasound

High intensity focused ultrasound has gained rapid clinical acceptance as a noninvasive treatment for solid tumors. As implied by the name, the intensity of sound at the focus is generally large. In a nonlinear ultrasound field, where the acoustic spectrum contains a considerable spread of harmonics, the pressure waveform is asymmetrically distorted, with a discrepancy between the peak compressional pressure and the peak rarefactional pressure, which are required in FDA and IEC regulations. Therefore, the amplitude and phase of the harmonics matter. In order to better understand nonlinear focused ultrasound, the amplitude and phase relation of the harmonics are investigated through both numerical simulations and measurements. The first three harmonics are extracted from the distorted wave by a zero-phase band-pass filter. It is demonstrated that, as the source pressure increases, the focusing gain for the fundamental component tends to decrease while the focusing gains for the second and third harmonics rise. The relative phases show very little change. There is a substantive agreement between the simulated and measured results for the focusing gain of the harmonics. The relative phase of the harmonics needs to be further verified after the calibration of the phase response of the hydrophone is well-developed.

Spatiotemporal Deconvolution of Hydrophone Response for Linear and Nonlinear Beams-Part I: Theory, Spatial-Averaging Correction Formulas, and Criteria for Sensitive Element Size.

This article reports spatiotemporal deconvolution methods and simple empirical formulas to correct pressure and beamwidth measurements for spatial averaging across a hydrophone sensitive element. Readers who are uninterested in hydrophone theory may proceed directly to Appendix A for an easy method to estimate spatial-averaging correction factors. Hydrophones were modeled as angular spectrum filters. Simulations modeled nine circular transducers (1-10 MHz; F/1.4-F/3.2) driven at six power levels and measured with eight hydrophones (432 beam/hydrophone combinations). For example, the model predicts that if a 200- [Formula: see text] membrane hydrophone measures a moderately nonlinear 5-MHz beam from an F/1 transducer, spatial-averaging correction factors are 33% (peak compressional pressure or pc ), 18% (peak rarefactional pressure or p ), and 18% (full width half maximum or FWHM). Theoretical and experimental estimates of spatial-averaging correction factors to were in good agreement (within 5%) for linear and moderately nonlinear signals. Criteria for maximum appropriate hydrophone sensitive element size as functions of experimental parameters were derived. Unlike the oft-cited International Electrotechnical Commission (IEC) criterion, the new criteria were derived for focusing rather than planar transducers and can accommodate nonlinear signals in addition to linear signals. Responsible reporting of hydrophone-based pressure and beamwidth measurements should always acknowledge spatial-averaging considerations.

Investigation of the Effects of Cardiovascular Therapeutic Ultrasound Applied in Female and Male Rats' Hearts of Different Ages.

This study investigates the role of age and sex on the cardiovascular effects of 3.5-MHz pulsed ultrasound (US) in a rat model. Ultrasonic bursts of 2.0-MPa peak rarefactional pressure amplitude (equivalent to an in vitro spatial-peak temporal-peak intensity of ~270 W/cm2 and a mechanical index of 1.1) were delivered in five consecutive 10-s intervals, one interval for each pulse repetition frequency (PRF) (6, 5, 4, 5, and 6 Hz; always the same order) for a total exposure duration of 50 consecutive seconds. Sixty F344 rats were split into 12 groups in a 3 × 2 × 2 factorial design (three ages, male versus female, and US application versus control). This study is the first study on US-induced cardiac effects that contains data across three age groups of rats (premenopause, fertile, and postmenopause) to mimic the fertile and nonfertile human window. US was applied transthoracically, while heart rate, stroke volume, ejection fraction, temperature, and other physiologic parameters were recorded at baseline and after exposure. Significant decreases in cardiac output compared to respective control groups were observed in multiple experimental groups, spanning both females and males. A negative chronotropic effect was observed in young male (~7%) and female (~16%) rats, in five-month-old male (~9%) and female (~15%) rats, and in old rats where the effect was not statistically significant. Younger groups and, to a lesser extent, lower weight groups generally had more significant effects. The pathophysiology of US-induced cardiovascular effects appears to be multifactorial and not strictly related to hormones, menopause, weight, sex, or age, individually.

Reversible increase in the EKG of rats using transthoracic pulsed ultrasound

This study showed the ability to increase inotropy in a rat heart while maintaining hemodynamic stability. A total of fourteen rats were used in this experiment. They were divided into four group including a control group (no ultrasound exposure). 3-month-old female rats were transthoracically to 3.5 MHz ultrasonic pulses of 2.0-MPa peak rarefactional pressure amplitude, ∼0.5% duty cycle and an increase pulse repetition frequency (PRF) sequence (4–5–6, 5–6–7, and 6–7–8 Hz). All rats underwent the same anesthesia, preparation, measurement, and positioning with only experimental rats being exposed to the turned-on transthoracic ultrasound. Rats were positioned in dorsal recruitment position and cardiac parameters were monitored using EKG and echocardiography. An increase in the heart rate was observed followed by each PRF sequence with increased heart rates. A mean of 550 + -50, 563 ± 45, and 712 ± 61 bpm at the conclusion of ultrasound for 4–5–6 Hz, 5–6–7 Hz, and 6–7–8 Hz sequences versus the control baseline of 248 ± 19 bpm was achieved. Other cardiac parameters were normal or had a compensatory decrease by 3- and 15-min post-ultrasound compared to control. EKG data of the experimental group of rats showed areas of rapid peaks outside of sinus rhythm during ultrasound pulsing while the control group-maintained sinus rhythm throughout the experiment.

Positive chronotropic effect caused by transthoracic ultrasound in heart of rats.

Pulsed ultrasound can produce chronotropic and inotropic effects on the heart with potential therapeutic applications. Fourteen 3-month-old female rats were exposed transthoracically to 3.5-MHz 2.0-MPa peak rarefactional pressure amplitude ultrasonic pulses of increasing 5-s duration pulse repetition frequency (PRF) sequences. An increase in the heart rate was observed following each PRF sequence: an ∼50% increase after the 4-5-6 Hz sequence, an ∼57% increase after the 5-6-7 Hz sequence, and an ∼48% increase after the 6-7-8 Hz sequence. Other cardiac parameters showed a normal or indicated a compensatory decrease at 3 and 15 min post-ultrasound compared to control.

On the Relationship between Spatial Coherence and In Situ Pressure for Abdominal Imaging

Tissue harmonic signal quality has been shown to improve with elevated acoustic pressure. The peak rarefaction pressure (PRP) for a given transmit, however, is limited by the Food and Drug Administration guidelines for mechanical index. We have previously demonstrated that the mechanical index overestimates in situ PRP for tightly focused beams in vivo, due primarily to phase aberration. In this study, we evaluate two spatial coherence-based image quality metrics—short-lag spatial coherence and harmonic short-lag spatial coherence—as proxy estimates for phase aberration and assess their correlation with in situ PRP in simulations and experiments when imaging through abdominal body walls. We demonstrate strong correlation between both spatial coherence-based metrics and in situ PRP (R2 = 0.77 for harmonic short-lag spatial coherence, R2 = 0.67 for short-lag spatial coherence), an observation that could be leveraged in the future for patient-specific selection of acoustic output.

The Influence of Xylazine and Clonidine on Lung Ultrasound–Induced Pulmonary Capillary Hemorrhage in Spontaneously Hypertensive Rats

Induction of pulmonary capillary hemorrhage (PCH) by lung ultrasound (LUS) depends not only on physical exposure parameters but also on physiologic conditions and drug treatment. We studied the influence of xylazine and clonidine on LUS-induced PCH in spontaneously hypertensive and normotensive rats using diagnostic B-mode ultrasound at 7.3 MHz. Using ketamine anesthesia, rats receiving saline, xylazine, or clonidine treatment were tested with different pulse peak rarefactional pressure amplitudes in 5 min exposures. Results with xylazine or clonidine in spontaneously hypertensive rats were not significantly different at the three exposure pulse peak rarefactional pressure amplitudes, and thresholds were lower (2.2 MPa) than with saline (2.6 MPa). Variations in LUS PCH were not correlated with mean systemic blood pressure. Similar to previous findings for dexmedetomidine, the clinical drug clonidine tended to increase susceptibility to LUS PCH.

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.

Quantifying the Effect of Abdominal Body Wall on In Situ Peak Rarefaction Pressure During Diagnostic Ultrasound Imaging

In this study, 3-D non-linear ultrasound simulations and experimental measurements were used to estimate the range of in situ pressures that can occur during transcutaneous abdominal imaging and to identify the sources of error when estimating in situ peak rarefaction pressures (PRPs) using linear derating, as specified by the mechanical index (MI) guideline. Using simulations, it was found that, for a large transmit aperture (F/1.5), MI consistently over-estimated in situ PRP by 20%–48% primarily owing to phase aberration. For a medium transmit aperture (F/3), the MI accurately estimated the in situ PRP to within 8%. For a small transmit aperture (F/5), MI consistently underestimated the in situ PRP by 32%–50%, with peak locations occurring 1–2 cm before the focal depth, often within the body wall itself. The large variability across body wall samples and focal configurations demonstrates the limitations of the simplified linear derating scheme. The results suggest that patient-specific in situ PRP estimation would allow for increases in transmit pressures, particularly for tightly focused beams, to improve diagnostic image quality while ensuring patient safety.

Hydrophone Spatial Averaging Correction for Acoustic Exposure Measurements From Arrays-Part II: Validation for ARFI and Pulsed Doppler Waveforms.

This article reports the experimental validation of a method for correcting underestimates of peak compressional pressure ( pc) , peak rarefactional pressure ( pr) , and pulse intensity integral (pii) due to hydrophone spatial averaging effects that occur during output measurement of clinical linear and phased arrays. Pressure parameters ( pc , pr , and pii), which are used to compute acoustic exposure safety indexes, such as mechanical index (MI) and thermal index (TI), are often not corrected for spatial averaging because a standardized method for doing so does not exist for linear and phased arrays. In a companion article (Part I), a novel, analytic, inverse-filter method was derived to correct for spatial averaging for linear or nonlinear pressure waves from linear and phased arrays. In the present article (Part II), the inverse filter is validated on measurements of acoustic radiation force impulse (ARFI) and pulsed Doppler waveforms. Empirical formulas are provided to enable researchers to predict and correct hydrophone spatial averaging errors for membrane-hydrophone-based acoustic output measurements. For example, for a 400- [Formula: see text] membrane hydrophone, inverse filtering reduced errors (means ± standard errors for 15 linear array/hydrophone pairs) from about 34% ( pc) , 22% ( pr) , and 45% (pii) down to within 5% for all three parameters. Inverse filtering for spatial averaging effects significantly improves the accuracy of estimates of acoustic pressure parameters for ARFI and pulsed Doppler signals.

Quantification of microbubble‐induced sonothrombolysis in an ex vivo non‐human primate model

BackgroundIn vitro studies with ultrasound (US) and microbubbles (MB) have reported that sono‐thrombolysis can be achieved at high peak rarefactional acoustic pressure amplitudes (PRAPAs) using 0.25 and 1.05 MHz US frequencies. ObjectiveThe aim of the current study was to determine if these parameters work on an ex vivo physiological model of thrombosis. MethodsA thrombogenic device was placed in an ex vivo chronic arteriovenous shunt in juvenile baboons. Platelet accumulation was measured by dynamic imaging of the device and the 10 cm thrombus tail with 111In‐labeled platelets. After 15 minutes of thrombus formation, treatment with either low‐dose recombinant tissue plasminogen activator (rtPA) or low‐dose rtPA + MB+US was performed for 20 minutes. Four US settings at 0.25% duty cycle were used: 0.25 MHz at PRAPAs of 1.20 and 2.20 MPa, and 1.05 MHz at 1.75 and 4.75 MPa. ResultsPlatelet accumulation was not inhibited by low‐dose rtPA or MB with US alone. Platelet accumulation was significantly reduced with 0.25 MHz US at 2.20 PRAPA (P < .001) and with 1.05 MHz at 1.75 MPa and 4.75 MPa (P < .05) when used with MB and low‐dose rtPA. Although this approach prevented platelet accumulation it did not cause thrombolysis on the device. ConclusionsrtPA + MB + US (0.25 and 1.05 MHz) resulted in inhibition of platelet accumulation on the thrombogenic device when moderately high PRAPAs (≥1.75 MPa) were used. These results taken in context with lytic effects of US on myocardial microthrombi and direct effect on myocardial blood flow and function provide direction for the use of therapeutic US in acute coronary syndromes.