Peak Negative Pressure Research Articles

Sonoporation of the Round Window Membrane on a Sheep Model: A Safety Study.

Sonoporation using microbubble-assisted ultrasound increases the permeability of a biological barrier to therapeutic molecules. Application of this method to the round window membrane could improve the delivery of therapeutics to the inner ear. The aim of this study was to assess the safety of sonoporation of the round window membrane in a sheep model. To achieve this objective, we assessed auditory function and cochlear heating, and analysed the metabolomics profiles of perilymph collected after sonoporation, comparing them with those of the control ear in the same animal. Six normal-hearing ewes were studied, with one sonoporation ear and one control ear for each. A mastoidectomy was performed on both ears. On the sonoporation side, Vevo MicroMarker® microbubbles (MBs; VisualSonics-Fujifilm, Amsterdam, The Netherlands) at a concentration of 2 × 108 MB/mL were locally injected into the middle ear and exposed to 1.1 MHz sinusoidal ultrasonic waves at 0.3 MPa negative peak pressure with 40% duty cycle and 100 μs interpulse period for 1 min; this was repeated three times with 1 min between applications. The sonoporation protocol did not induce any hearing impairment or toxic overheating compared with the control condition. The metabolomic analysis did not reveal any significant metabolic difference between perilymph samples from the sonoporation and control ears. The results suggest that sonoporation of the round window membrane does not cause damage to the inner ear in a sheep model.

Multi-Objective Airfoil Optimization Under Unsteady-Freestream Dynamic Stall Conditions

Aimed at alleviating dynamic stall, an optimization method for rotor airfoils is proposed considering the unsteady-freestream circumstance and pitching motion. The method is based on the unsteady Reynolds-averaged Navier-Stokes equations, kriging model, and non-dominated sorting genetic algorithm II (NSGA-II). Three objective functions are built for minimizing the area of lift hysteresis loop, value of peak drag, and peak pitching moment. An optimized airfoil with larger maximum thickness, maximum camber, and upper leading-edge radius is obtained based on the baseline SC1095 airfoil. Besides, the optimized airfoil shows smaller local thickness and camber near the trailing edge. The results show that the flow separation and dynamic stall are suppressed or alleviated under both design and off-design conditions, attributed to a significant reduction of negative pressure peak and adverse pressure gradient. The dynamic stall is also alleviated for the rotor configured with the optimized airfoil in forward flight. This indicates that the optimized airfoil performs well in a rotor environment.

Numerical analysis on the high-speed impulsive noise propagation characteristic of helicopter rotor in the presence of strong shear flow

Based on the Linearized Euler Equations (LEE) and the Computational Fluid Dynamics (CFD) technique, the propagation characteristics of helicopter rotor High-Speed Impulsive (HSI) noise in non-uniform flowfield are simulated and analyzed. A Hybrid Computational Aeroacoustics (HCAA) method for solving the sound field of rotor is first developed. The acoustic source region is simulated by solving Navier-Stokes equations, and the acoustic near-field is simulated by solving LEE based on the Runge-Kutta Discontinuous Galerkin (RKDG) method. The numerical analysis method is then validated through comparisons with experimental data, and the aeroacoustics characteristics of the UH-1H rotor are calculated. Afterwards, the propagation characteristics of HSI noise in the wind tunnel are calculated, and the “trap” effect of the shear layer on HSI noise is determined. Finally, the peak negative pressure, time-averaged acoustic energy, and instantaneous perturbed pressure field are analyzed in detail, and some conclusions are drawn. In jet flow, the HSI noise energy is reinforced, and the time of the peak negative pressure is significantly advanced. In still air, the HSI noise energy is attenuated, and the time of the peak negative pressure is slightly delayed. These investigations offer valuable data for developing advanced theoretical correction method to consider the effect of shear layer on rotating acoustic source.

Numerical investigation on vortex control effect of pump-jet propulsion via porous blade tips

Pump-Jet Propulsions (PJPs) are widely equipped on submarines, torpedoes and other underwater vehicles. The special structure of PJP leads to complex vortex system in the working process, especially the strong Tip Leakage Vortex (TLV) in the clearance between the duct and the rotor blade tips, which seriously affects the unsteady hydrodynamic performance and acoustic characteristics of PJP. The rotor blade tips of PJP are modified with porous materials, the control effect of the porous blade tip on the TLV is investigated, and the influence of the porous blade tips with different parameters on the vortex control effect is quantitatively analyzed. Large Eddy Simulation (LES) method is applied to the flow field observation. It is concluded that the porous blade tips can weaken the TLV intensity and inhibit the backflow at the blade tip clearance. The analysis results of fluctuating pressure indicate that the negative pressure peak and pressure gradient in tip clearance can be effectively reduced after installing porous blade tips, which is helpful to the vibration and noise reduction of the PJP. Through a series of optimization work, the porous blade tip scheme with minimal propulsion performance loss and obvious vortex control effect is determined.

Theranostics in the vasculature: bioeffects of ultrasound and microbubbles to induce vascular shutdown.

Ultrasound-triggered microbubbles destruction leading to vascular shutdown have resulted in preclinical studies in tumor growth delay or inhibition, lesion formation, radio-sensitization and modulation of the immune micro-environment. Antivascular ultrasound aims to be developed as a focal, targeted, non-invasive, mechanical and non-thermal treatment, alone or in combination with other treatments, and this review positions these treatments among the wider therapeutic ultrasound domain. Antivascular effects have been reported for a wide range of ultrasound exposure conditions, and evidence points to a prominent role of cavitation as the main mechanism. At relatively low peak negative acoustic pressure, predominantly non-inertial cavitation is most likely induced, while higher peak negative pressures lead to inertial cavitation and bubbles collapse. Resulting bioeffects start with inflammation and/or loose opening of the endothelial lining of the vessel. The latter causes vascular access of tissue factor, leading to platelet aggregation, and consequent clotting. Alternatively, endothelium damage exposes subendothelial collagen layer, leading to rapid adhesion and aggregation of platelets and clotting. In a pilot clinical trial, a prevalence of tumor response was observed in patients receiving ultrasound-triggered microbubble destruction along with transarterial radioembolization. Two ongoing clinical trials are assessing the effectiveness of ultrasound-stimulated microbubble treatment to enhance radiation effects in cancer patients. Clinical translation of antivascular ultrasound/microbubble approach may thus be forthcoming.

Nanobubble-mediated cancer cell sonoporation using low-frequency ultrasound.

Ultrasound insonation of microbubbles can form transient pores in cell membranes that enable the delivery of non-permeable extracellular molecules to the cells. Reducing the size of microbubble contrast agents to the nanometer range could facilitate cancer sonoporation. This size reduction can enhance the extravasation of nanobubbles into tumors after an intravenous injection, thus providing a noninvasive sonoporation platform. However, drug delivery efficacy depends on the oscillations of the bubbles, the ultrasound parameters and the size of the target compared to the membrane pores. The formation of large pores is advantageous for the delivery of large molecules, however the small size of the nanobubbles limit the bioeffects when operating near the nanobubble resonance frequency at the MHz range. Here, we show that by coupling nanobubbles with 250 kHz low frequency ultrasound, high amplitude oscillations can be achieved, which facilitate low energy sonoporation of cancer cells. This is beneficial both for increasing the uptake of a specific molecule and to improve large molecule delivery. The method was optimized for the delivery of four fluorescent molecules ranging in size from 1.2 to 70 kDa to breast cancer cells, while comparing the results to targeted microbubbles. Depending on the fluorescent molecule size, the optimal ultrasound peak negative pressure was found to range between 300 and 500 kPa. Increasing the pressure to 800 kPa reduced the fraction of fluorescent cells for all molecules sizes. The optimal uptake for the smaller molecule size of 4 kDa resulted in a fraction of 19.9 ± 1.8% of fluorescent cells, whereas delivery of 20 kDa and 70 kDa molecules yielded 14 ± 0.8% and 4.1 ± 1.1%, respectively. These values were similar to targeted microbubble-mediated sonoporation, suggesting that nanobubbles can serve as noninvasive sonoporation agents with a similar potency, and at a reduced bubble size. The nanobubbles effectively reduced cell viability and may thus potentially reduce the tumor burden, which is crucial for the success of cancer treatment. This method provides a non-invasive and low-energy tumor sonoporation theranostic platform, which can be combined with other therapies to maximize the therapeutic benefits of cancer treatment or be harnessed in gene therapy applications.

MRI-guided focused ultrasound blood-brain barrier opening increases drug delivery and efficacy in a diffuse midline glioma mouse model.

Diffuse intrinsic pontine glioma (DIPG) is the most common and deadliest pediatric brainstem tumor and is difficult to treat with chemotherapy in part due to the blood-brain barrier (BBB). Focused ultrasound (FUS) and microbubbles (MBs) have been shown to cause BBB opening, allowing larger chemotherapeutics to enter the parenchyma. Panobinostat is an example of a promising in vitro agent in DIPG with poor clinical efficacy due to low BBB penetrance. In this study, we hypothesized that using FUS to disrupt the BBB allows higher concentrations of panobinostat to accumulate in the tumor, providing a therapeutic effect. Mice were orthotopically injected with a patient-derived diffuse midline glioma (DMG) cell line, BT245. MRI was used to guide FUS/MB (1.5 MHz, 0.615 MPa peak negative pressure, 1 Hz pulse repetition frequency, 10-ms pulse length, 3 min treatment time)/(25 µL/kg, i.v.) targeting to the tumor location. In animals receiving panobinostat (10 mg/kg, i.p.) in combination with FUS/MB, a 3-fold increase in tumor panobinostat concentration was observed, without significant increase of the drug in the forebrain. In mice receiving 3 weekly treatments, the combination of panobinostat and FUS/MB led to a 71% reduction of tumor volumes (P = .01). Furthermore, we showed the first survival benefit from FUS/MB improved delivery increasing the mean survival from 21 to 31 days (P < .0001). Our study demonstrates that FUS-mediated BBB disruption can increase the delivery of panobinostat to an orthotopic DMG tumor, providing a strong therapeutic effect and increased survival.

Faster calcium recovery and membrane resealing in repeated sonoporation for delivery improvement.

In sonoporation-based macromolecular delivery, repetitive microbubble cavitation in the bloodstream results in repeated sonoporation of cells or sonoporation of non-sonoporated neighboring cells (i.e., adjacent to the sonoporated host cells). The resealing and recovery capabilities of these two types of sonoporated cells affect the efficiency and biosafety of sonoporation-based delivery. Therefore, an improved understanding of the preservation of viability in these sonoporated cells is necessary. Using a customized platform for single-pulse ultrasound exposure (pulse length 13.33μs, peak negative pressure 0.40MPa, frequency 1.5MHz) and real-time recording of membrane perforation and intracellular calcium fluctuations (using propidium iodide and Fluo-4 fluorescent probes, respectively), spatiotemporally controlled sonoporation was performed to administer first and second single-site sonoporations of a single cell or single-site sonoporation of a neighboring cell. Two distinct intracellular calcium changes, reversible and irreversible calcium fluctuations, were identified in cells undergoing repeat reversible sonoporation and in neighboring cells undergoing reversible sonoporation. In addition to an increased proportion of reversible calcium fluctuations that occurred with repeated sonoporation compared with that in the initial sonoporation, repeated sonoporation resulted in significantly shorter calcium fluctuation durations and faster membrane resealing than that produced by initial sonoporation. Similarly, compared with those in sonoporated host cells, the intracellular calcium fluctuation recovery and membrane perforation resealing times were significantly shorter in sonoporated neighboring cells. These results demonstrated that the function recovery and membrane resealing capabilities after a second sonoporation or sonoporation of neighboring cells were potentiated in the short term. This could aid in sustaining the long-term viability of sonoporated cells, therefore improving delivery efficiency and biosafety. This investigation provides new insight into the resealing and recovery capabilities in re-sonoporation of sonoporated cells and sonoporation of neighboring cells and can help develop safe and efficient strategies for sonoporation-based drug delivery.

The effects of elastic modulus and impurities on bubble nuclei available for acoustic cavitation in polyacrylamide hydrogels.

Safety of biomedical ultrasound largely depends on controlling cavitation bubbles in vivo, yet bubble nuclei in biological tissues remain unexplored compared to water. This study evaluates the effects of elastic modulus (E) and impurities on bubble nuclei available for cavitation in tissue-mimicking polyacrylamide (PA) hydrogels. A 1.5 MHz focused ultrasound transducer with f# = 0.7 was used to induce cavitation in 17.5%, 20%, and 22.5% v/v PA hydrogels using 10-ms pulses with pressures up to peak negative pressure (p-) = 35 MPa. Cavitation was monitored at 0.075 ms through high-speed photography at 40 000 fps. At p- = 29 MPa for all hydrogels, cavitation occurred at random locations within the -6 dB focal area [9.4 × 1.2 mm (p-)]. Increasing p- to 35 MPa increased bubble location consistency and caused shock scattering in the E = 282 MPa hydrogels; as the E increased to 300 MPa, bubble location consistency decreased (p = 0.045). Adding calcium phosphate or cholesterol at 0.25% w/v or bovine serum albumin at 5% or 10% w/v in separate 17.5% PA as impurities decreased the cavitation threshold from p- = 13.2 MPa for unaltered PA to p- = 11.6 MPa, p- = 7.3 MPa, p- = 9.7 MPa, and p- = 7.5 MPa, respectively. These results suggest that both E and impurities affect the bubble nuclei available for cavitation in tissue-mimicking hydrogels.

Development of an ultrasound guided focused ultrasound system for 3D volumetric low energy nanodroplet-mediated histotripsy

Low pressure histotripsy is likely to facilitate current treatments that require extremely high pressures. An ultrasound guided focused ultrasound system was designed to accommodate a rotating imaging transducer within a low frequency therapeutic transducer that operates at a center frequency of 105 kHz. The implementation of this integrated system provides real-time therapeutic and volumetric imaging functions, that are used here for low-cost, low-energy 3D volumetric ultrasound histotripsy using nanodroplets. A two-step approach for low pressure histotripsy is implemented with this dual-array. Vaporization of nanodroplets into gaseous microbubbles was performed via the 1D rotating imaging probe. The therapeutic transducer is then used to detonate the vaporized nanodroplets and trigger potent mechanical effects in the surrounding tissue. Rotating the imaging transducer creates a circular vaporized nanodroplet shape which generates a round lesion upon detonation. This contrasts with the elongated lesion formed when using a standard 1D imaging transducer for nanodroplet activation. Optimization experiments show that maximal nanodroplet activation can be achieved with a 2-cycle excitation pulse at a center frequency of 3.5 MHz, and a peak negative pressure of 3.4 MPa (a mechanical index of 1.84). Vaporized nanodroplet detonation was achieved by applying a low frequency treatment at a center frequency of 105 kHz and mechanical index of 0.9. In ex-vivo samples, the rotated nanodroplet activation method yielded the largest lesion area, with a mean of 4.7 ± 0.5 mm2, and a rounded shape. In comparison, standard fixed transducer nanodroplet activation resulted in an average lesion area of 2.6 ± 0.4 mm2, and an elongated shape. This hybrid system enables to achieve volumetric low energy histotripsy, and thus facilitates the creation of precise, large-volume mechanical lesions in tissues, while reducing the pressure threshold required for standard histotripsy by over an order of magnitude.

On nonlinear effects in holographic-modulated ultrasound

Holographic acoustic lenses (HALs), also known as acoustic holograms, are used for generating unprecedented complex focused ultrasound (FU) fields. HALs store the phase profile of the desired wavefront, which is used to reconstruct the acoustic pressure field when illuminated by a single acoustic source. Nonlinear effects occur as the sound intensity increases, leading to distorted and asymmetric waveforms. Here, the k-space pseudospectral method is used to perform homogeneous three-dimensional nonlinear acoustic simulations with power law absorption. An in-depth analysis is performed to study the evolution of holographic-modulated FU fields produced by HALs as the excitation amplitude increases. It is shown that nonlinear waveform distortion significantly affects the reconstruction of the pressure pattern when compared to the linear condition. Diffraction and nonlinear effects result in an asymmetric waveform with distinct positive and negative pressure patterns at the target plane. Peak positive pressure distribution becomes more localized around the areas with the highest nonlinear distortion. The peak signal-to-distortion ratio (PSDR) at the target plane falls while the nonuniformity index (NUI) rises. As a result of harmonic generation, the heat deposition distribution becomes highly localized with a significant increase in the NUI. Nonlinear effects have also been shown to flatten the peak negative pressure distribution while having minimal effect on the PSDR or NUI. However, nonlinear effects are shown to be critical for accurately predicting cavitation zones. Findings will pave the way for HALs implementation in high-intensity applications and prompt the incorporation of nonlinear acoustics into the notion of computer-generated holography.

Assessment of bubble activity generated by histotripsy combined with echogenic liposomes

Objective. Histotripsy is a form of focused ultrasound therapy that uses the mechanical activity of bubbles to ablate tissue. While histotripsy alone degrades the cellular content of tissue, recent studies have demonstrated it effectively disrupts the extracellular structure of pathologic conditions such as venous thrombosis when combined with a thrombolytic drug. Rather than relying on standard administration methods, associating thrombolytic drugs with an ultrasound-triggered echogenic liposome vesicle will enable targeted, systemic drug delivery. To date, histotripsy has primarily relied on nano-nuclei inherent to the medium for bubble cloud generation, and microbubbles associated with echogenic liposomes may alter the histotripsy bubble dynamics. The objective of this work was to investigate the interaction of histotripsy pulse with echogenic liposomes. Approach. Bubble clouds were generated using a focused source in an in vitro model of venous flow. Acoustic emissions generated during the insonation were passively acquired to assess the mechanical activity of the bubble cloud. High frame rate, pulse inversion imaging was used to track the change in echogenicity of the liposomes following histotripsy exposure. Main results. For peak negative pressures less than 20 MPa, acoustic emissions indicative of stable and inertial bubble activity were observed. As the peak negative pressure of the histotripsy excitation increased, harmonics of the excitation were observed in OFP t-ELIP solutions and plasma alone. Additional observations with high frame rate imaging indicated a transition of bubble behavior as the pulse pressure transitioned to shock wave formation. Significance. These observations suggest that a complex interaction between histotripsy pulses and echogenic liposomes that may be exploited for combination treatment approaches.

Mechanical damage thresholds for hematomas near gas-containing bodies in pulsed HIFU fields

Objective. Boiling histotripsy (BH) is a novel high intensity focused ultrasound (HIFU) application currently being developed for non-invasive mechanical fractionation of soft tissues and large hematomas. In the context of development of BH treatment planning approaches for ablating targets adjacent to gas-containing organs, this study aimed at investigation of the ultrasound pressure thresholds of atomization-induced damage to the tissue-air interface and correlation of the danger zone dimensions with spatial structure of nonlinear HIFU field parameters. Approach. A flat interface with air of freshly clotted bovine blood was used as an ex vivo model due to its homogenous structure and higher susceptibility to ultrasound-induced mechanical damage compared to soft tissues. Three 1.5 MHz transducers of different F-numbers (0.77, 1 and 1.5) were focused at various distances before or beyond a flat clot surface, and a BH exposure was delivered either at constant, high-amplitude output level, or at gradually increasing level until a visible damage to the clot surface occurred. The HIFU pressure field parameters at the clot surface were determined through a combination of hydrophone measurements in water, forward wave propagation simulation using ‘HIFU beam’ software and an image source method to account for the wave reflection from the clot surface and formation of a standing wave. The iso-levels of peak negative pressure in the resulting HIFU field were correlated to the outlines of surface erosion to identify the danger zone around the BH focus. Main results. The outline of the danger zone was shown to differ from that of a typical BH lesion produced in a volume of clot material. In the prefocal area, the zone was confined within the 4 MPa contour of the incident peak-to-peak pressure; within the main focal lobe it was determined by the maximum BH lesion width, and in the postfocal area—by the transverse size of the focal lobe and position of the first postfocal pressure axial null. Significance. The incident HIFU pressure-based danger zone boundaries were outlined around the BH focus and can be superimposed onto in-treatment ultrasound image to avoid damage to adjacent gas-containing bodies.

Symptom Localization May Differentiate Subtypes of Eustachian Tube Dysfunction.

To evaluate the predictive ability of symptom self-localization to distinguish obstructive eustachian tube dysfunction from non-obstructive salpingitis. Adult (age ≥18 years) patients with a primary complaint of aural discomfort who underwent diagnostic nasal endoscopy and tympanometry at a tertiary academic center were enrolled. Symptoms were self-localized by using a single finger on the affected side. All patients completed the 7-item Eustachian Tube Dysfunction Questionnaire (ETDQ-7) and underwent scoring of eustachian tube inflammation using the Endoscopic Evaluation of the Eustachian Tube (3ET) system. Seventy-three patients were included in the study. Symptoms were localized to the external auditory canal (EAC) in 28 (38.4%), to the infratemporal fossa (ITF) below the lobule in 37 (50.7%), and to the preauricular region in 8 (11.0%). Demographics and medical history were similar between groups. The EAC group had significantly more negative tympanometric peak pressure (TPP) (median, -92.0 daPa; IQR, 95.5) and higher 3ET scores. In contrast, the ITF group had normal TPP (median, -2.0 daPa; IQR, 7.0) and higher 3ET scores. The preauricular group was more likely to have temporomandibular joint or pterygoid muscle pain. ETDQ-7 scores did not differ significantly between groups. Symptom localization is associated with specific objective findings in the evaluation of aural discomfort. Patients with pain localizing to the ITF are more likely to have findings of eustachian tube salpingitis without obstruction whereas patients with symptoms deep in the EAC are more likely to have findings consistent with obstructive eustachian tube dysfunction. 3 Laryngoscope, 133:1818-1823, 2023.

A Modular, Kerf-Minimizing Approach for Therapeutic Ultrasound Phased Array Construction.

A novel method for fabricating a modular, kerf-minimizing histotripsy phased array was developed and tested. The method utilizes arbitrarily shaped elements, 3-D printing, water jet cutting, and a thin, 125- [Formula: see text] electrically insulating epoxy coating to maximize aperture utilization while allowing for replacement of individual transducer modules. The method was used to fabricate a 750-kHz truncated circular aperture array (165 mm ×234 mm) transducer with a focal length of 142 mm. The aperture was segmented into 260 arc-shaped modular elements, each approximately 11.5 mm ×11.5 mm, arranged in concentric rings. The resulting aperture utilization was 92%. The full-width-half-maximum (FWHM) focal zone of the array was measured to be 1.6 mm ×1.1 mm ×4.5 mm, and the FWHM electrical steering range was measured to be 38.5 mm ×33 mm 40 mm. The array was estimated to be capable of generating approximately 120-MPa peak negative pressure at the geometric focus. In addition, the array was used to ablate a 5-cm3 volume of tissue with electric focal steering.

Ultrasound-activated perfluorocarbon nanodroplets in ophthalmology

Glaucoma, a leading cause of blindness, can result from increased intraocular pressure resulting from elevated outflow resistance. In this preliminary study, we consider the potential of ultrasound-activated perfluorocarbon nanodroplets (NDs) to increase the permeability of the outflow pathway. 100nm diameter NDs with a perfluoropentane core and lipid shell were introduced into the anterior chamber (AC) of ex vivo pig and in vivo rat eyes. Imaging (18 and 28 MHz) was performed with a weakly focused (F = 2.9) beam. Activation was induced by increasing the array sub-aperture to tighten the focus to F = 0.62 centrally. Images showed NDs to be distributed widely within the AC, from which they could enter the outflow pathway by virtue of their small dimension. At 28 MHz, NDs were activated at a peak negative pressure of 5 MPa, corresponding to a mechanical index of 1.8.Two days after treatment, rat eyes showed no sign of inflammation, but a few small gas bubbles were present in the AC. In this application, NDs are advantageous as cavitation nuclei with respect to conventional microbubble contrast agents because of their higher density and smaller diameter (&amp;lt;1/10th that of microbubble agents), which facilitate entry into the outflow channels. Future preclinical in vivo studies will assess the effect of treatment on IOP and outflow facility.

The effects of varying ultrasound parameters on oxygen scavenging via acoustic droplet vaporization

Acoustic droplet vaporization (ADV) is a process that phase transitions liquid droplets into gas microbubbles via ultrasound. ADV results in oxygen scavenging from the surrounding fluid into the microbubbles. The objective of this study was to determine the effect of ultrasound parameters on oxygen scavenging. A microfluidic device was used to produce perfluoropentane droplets with a modal diameter of 1.14 ± 0.04 μm and a polydispersity index of 0.08 ± 0.02. Droplets were diluted to a concentration of 4.7 × 10−4 ± 0.4 × 10−5 ml/ml in 95% oxygenated water. The oxygen partial pressure (pO2) of the water was measured before and during ADV. An EkoSonic ultrasound catheter (2.35 MHz, 1.5 MPa peak negative pressure, 47 W pulse average power) nucleated ADV while either varying burst period or pulse duration (n = 5). Pre-ADV pO2 was 558 ± 5 mm Hg for all experiments. Peri-ADV pO2 dropped to 294 ± 6, 316 ± 10, and 356 ± 12 mmHg for a pulse duration of 17 μs and burst periods of 0.450 ms, 0.725 ms, and 1.000 ms, respectively. The peri-ADV pO2 dropped to 331 ± 14, 342 ± 10, 313 ± 10 mmHg for a burst period of 1.000 ms and pulse durations of 17.0, 23.4, and 37.9 μs, respectively. A significant difference was seen between the amount of oxygen scavenging for the lowest and highest burst periods (p = 0.0012) and pulse durations (p = 0.027).

Unfocused Field Analysis of a Density-Tapered Spiral Array for High-Volume-Rate 3-D Ultrasound Imaging.

Spiral array transducers with a sparse 2-D aperture have demonstrated their potential in realizing 3-D ultrasound imaging with reduced data rates. Nevertheless, their feasibility in high-volume-rate imaging based on unfocused transmissions has yet to be established. From a metrology standpoint, it is essential to characterize the acoustic field of unfocused transmissions from spiral arrays not only to assess their safety but also to identify the root cause of imaging irregularities due to the array's sparse aperture. Here, we present a field profile analysis of unfocused transmissions from a density-tapered spiral array transducer (256 hexagonal elements, 220- [Formula: see text] element diameter, and 1-cm aperture diameter) through both simulations and hydrophone measurements. We investigated plane- and diverging-wave transmissions (five-cycle, 7.5-MHz pulses) from 0° to 10° steering for their beam intensity characteristics and wavefront arrival time profiles. Unfocused firings were also tested for B-mode imaging performance (ten compounded angles, -5° to 5° span). The array was found to produce unfocused transmissions with a peak negative pressure of 93.9 kPa at 2 cm depth. All transmissions steered up to 5° were free of secondary lobes within 12 dB of the main beam peak intensity. All wavefront arrival time profiles were found to closely match the expected profiles with maximum root-mean-squared errors of [Formula: see text] for plane wave (PW) and [Formula: see text] for diverging wave. The B-mode images showed good spatial resolution with a penetration depth of 22 mm in PW imaging. Overall, these results demonstrate that the density-tapered spiral array can facilitate unfocused transmissions below regulatory limits (mechanical index: 0.034; spatial-peak, pulse-average intensity: 0.298 W/cm2) and with suppressed secondary lobes while maintaining smooth wavefronts.

Thrombolytic efficacy of histotripsy combined with thrombolytic-loaded echogenic liposomes

Deep vein thrombosis (DVT) is a substantial burden to the American public. Thrombolytics drugs are the front-line approach to treat the most egregious forms of DVT. Histotripsy is a bubble-based focused ultrasound therapy that enhances thrombolytic activity while simultaneously breaking down erythrocytes within the thrombus mechanically. Loading thrombolytics inside echogenic liposomes may accentuate the action of histotripsy via site-specific thrombolytic release and prompt bubble nuclei. The objective of this study was to assess clot degradation under the action of histotripsy and echogenic liposomes in an in vitro venous flow model. Histotripsy pulses were applied along the length of the clot at pulse peak negative pressures of 0 (control) or 42 MPa. Echogenic liposomes were diluted into the perfusate such that the thrombolytic concentration was 0 or 2.68 μg/ml. The combination of histotripsy and echogenic liposomes displayed increased clot mass loss, thrombolytic activity, hemolysis, and intact erythrocytes in the perfusate relative to echogenic liposomes alone (ANOVA p &amp;lt; 0.05, n = 6–8/group). Expect for hemolysis, markers of clot degradation were increased for histotripsy and echogenic liposome arms relative to histotripsy exposure alone. Together, these data indicate histotripsy combined with thrombolytics is a promising approach for the treatment of DVT.

Power Doppler-based ultrasound detection of cavitation for burst wave lithotripsy

Burst wave lithotripsy (BWL) is a noninvasive method to fragment urinary stones with pulsed focused ultrasound. Cavitation activity produced by ultrasound pulses in BWL can cause multiple effects including stone fragmentation, acoustic shielding, and tissue injury. Monitoring cavitation activity and spatial extent is therefore important to evaluating these effects and determining parameters that maximize effectiveness and safety. In vivo experiments in a porcine model were conducted using a Verasonics ultrasound system to detect the onset and spatial extent of cavitation through synchronized power Doppler ultrasound imaging during 350-kHz BWL exposures to stones and kidney tissue. Kidneys (n = 15) were exposed in vivo to transcutaneous BWL at multiple pressure levels, and cavitation in tissue was found to be detected as an increase in the measured Doppler power by an average of 28.6 dB (range 11–51 dB) over the background. Cavitation occurred at average levels between 5.8 and 8.0 MPa peak negative pressure, depending on targeting location, stone presence, and exposure parameters. Cavitation presence further correlated with gross observation of injury. These studies demonstrate suggest filtered power Doppler imaging can sensitively detect presence of sustained cavitation during burst wave lithotripsy exposures. [Work supported by NIDDK K01 DK104854 and P01 DK043881.]