Peak Negative Pressure Research Articles

The effects of ultrasound pressure and temperature fields in millisecond bubble nucleation

A phenomenological implementation of Classical Nucleation Theory (CNT) is employed to investigate the connection between high intensity focused ultrasound (HIFU) pressure and temperature fields with the energetic requirements of bubble nucleation. As a case study, boiling histotripsy in tissue-mimicking phantoms is modelled. The physics of key components in the implementation of CNT in HIFU conditions such as the derivation of nucleation pressure thresholds and approximations regarding the surface tension of the liquid are reviewed and discussed. Simulations show that the acoustic pressure is the ultimate trigger for millisecond bubble nucleation in boiling histotripsy, however, HIFU heat deposition facilitates nucleation by lowering nucleation pressure thresholds. Nucleation thus occurs preferentially at the regions of highest heat deposition within the HIFU field. This implies that bubble nucleation subsequent to millisecond HIFU heat deposition can take place at temperatures below 100 °C as long as the focal HIFU peak negative pressure exceeds the temperature-dependent nucleation threshold. It is also found that the magnitude of nucleation pressure thresholds decreases with decreasing frequencies. Overall, results indicate that it is not possible to separate thermal and mechanical effects of HIFU in the nucleation of bubbles for timescales of a few milliseconds. This methodology provides a promising framework for studying time and space dependencies of the energetics of bubble nucleation within a HIFU field.

Reynolds number dependence of turbulent structures associated with high-amplitude wall pressure peaks in channel flow

We investigate the turbulent structures associated with positive and negative high-amplitude wall pressure peaks in fully developed turbulent channel flows. The analysis is performed by conditional sampling of a channel flow dataset computed in direct numerical simulations. The Reynolds number was varied from 180 to 4000 based on the channel half-depth h and the friction velocity uτ. Positive and negative wall pressure events were associated with small-scale vortex structures identified by Q-criterion. When scaled in wall units, the overall size of the structure was independent of Reynolds number. Positive and negative wall pressure events were also associated with a large-scale sweep motion (of ) from the outer layer, which constitutes a shear layer in the near-wall region. In a statistical analysis of the instantaneous pressure field, a sequence of negative and positive pressure peaks was found to predominate at the wall. The relative contributions from the large- and small-scale structures were qualitatively assessed by investigating the rapid and slow pressure terms from Poisson’s equation. Both terms contributed nearly equally to the positive wall pressure peaks, but the slow term dominated the negative pressure peaks (with a relative contribution of approximately 60%).

Magnetic nanodroplets for targeted drug delivery

A limitation of microbubbles for both diagnostic and therapeutic applications is their relatively rapid clearance times, typically Notwithstanding their significant potential, the development of nanodroplets still poses some considerable challenges. The conversion efficiency, i.e., the proportion of droplets undergoing a phase change for a given set of ultrasound exposure conditions is often very low. Thus either very high concentrations of nanodroplets or potentially damaging ultrasound intensities are required. We therefore investigated the effect of loading perfluorocarbon nanodroplets with superparamagnetic solid nanoparticles to act as nucleation agents to promote phase transition thereby improving conversion efficiency. Using iron oxide particles also provides a means of imaging the droplets using magnetic resonance imaging (MRI) and manipulating the droplets using an external magnetic field which has been shown in previous work to be highly advantageous for drug delivery. We first determined the effect upon the physical properties of the nanodroplets in terms of their size, surface charge, and stability under physiological conditions. Their response to ultrasound exposure was then examined to determine conversion efficiency, change in size and potential for image contrast enhancement under both ultrasound and MRI. Finally, delivery of a small molecule chemotherapy drug, paclitaxel, and small interfering ribonucleic acid (siRNA) to different cancer cell lines was investigated. The nanodroplets were stable at 37°C over 10 days and showed a significantly higher conversion efficiency than a control droplet formulated without nanoparticles at 1 MHz and peak negative pressures Magnetic nanodroplets for targeted drug delivery

Effects of ultrasound pulse parameters on cavitation properties of flowing microbubbles under physiologically relevant conditions

Acoustic cavitation from ultrasound-driven microbubbles can induce diverse bioeffects that are useful in clinical therapy. However, lack of control over the cavitation activity of flowing microbubbles results in unwanted treatment regions in the targeted tissue, which influences the therapeutic efficacy and bio-safety. The aim of this study is to understand the relationship between the ultrasound pulse parameters and cavitation properties of flowing microbubbles, including the type (and transition between types), threshold, intensity and temporal distribution of cavitation. An in vitro physiological-flow phantom was fabricated, in which the microbubbles had a constant velocity, and were sonicated to a 1-MHz focused transducer at a wide range of peak negative pressures (PNPs) (0.10–1.28 MPa), pulse repetition frequencies (PRFs) (1–200 Hz) and pulse lengths (PLs) (10–400 μs). The signals from the flowing bubbles were passively detected by another 7.5-MHz plane transducer. From detailed time- and frequency-domain analysis, we found 1). The occurrence of stable cavitation (SC) and inertial cavitation (IC) depended on PNP and PL when the PRF was below a critical value (PRF threshold) that related to the fluid velocity and PNP full width at half maximum diameter of the transducer. 2) Below the PRF threshold, the PL had no influence on the temporal distribution of SC intensity; however, above the PRF threshold, the SC properties depended on the PL because of acoustically-driven diffusion. Specifically, at shorter PLs, the SC intensity had a uniform temporal distribution and was independent of the PRF; at longer PLs, the SC intensity correlated negatively with the PRF. 3) Below the PRF threshold, the IC properties were independent of the PRF. Increasing the PRF above the PRF threshold caused the IC intensity to decrease with a non-uniform temporal distribution. These results indicate that the fluid velocity and a pulsed acoustic field influence the number and properties of the replenished bubbles into the targeted region, resulting in the change of cavitation properties. In future therapeutic applications, the physiological fluid conditions must be taken into consideration to design reasonable pulse parameters and achieve desirable cavitation properties.

Numerical modelling of vented lean hydrogen deflagations in an ISO container

Hydrogen process equipment are often housed in 20-foot or 40-foot container either be at refueling stations or at the portable standalone power generation units. Shipping Container provide an easy to install, cost effective, all weather protective containment. Hydrogen has unique physical properties, it can quickly form an ignitable cloud for any accidental release or leakages in air, due to its wide flammability limits. Identifying the hazards associated with these kind of container applications are very crucial for design and safe operation of the container hydrogen installations. Recently both numerical studies and experiment have been performed to ascertain the level of hazards and its possible mitigation methods for hydrogen applications. This paper presents the numerical modelling and the simulations performed using the HyFOAM CFD solver for vented deflagrations processes. HyFOAM solver is developed in-house using the opensource CFD toolkit OpenFOAM libraries. The turbulent flame deflagrations are modelled using the flame wrinkling combustion model. This combustion model is further improved to account for flame instabilities dominant role in vented lean hydrogen-air mixtures deflagrations. The 20-foot ISO containers of dimensions 20′ × 8′ × 8′.6″ filled with homogeneous mixture of hydrogen-air at different concentration, with and without model obstacles are considered for numerical simulations. The numerical predictions are first validated against the recent experiments carried out by Gexcon as part of the HySEA project supported by the Fuel Cells and Hydrogen 2 Joint Undertaking (FCH 2 JU) under the Horizon 2020 Framework Programme for Research and Innovation. The effects of congestion within the containers on the generated overpressures are investigated. The preliminary CFD predictions indicated that the container walls deflections are having considerable effect on the trends of generated overpressures, especially the peak negative pressure generated within the container is overestimated. Hence to account for the container wall deflections, the fluid structure interactions (FSI) are also included in the numerical modelling. The final numerical predictions are presented with and without the FSI. The FSI modelling considerably improved the numerical prediction and resulted in better match of overpressure trends with the experimental results.

Enhanced microbubble contrast agent oscillation following 250\u2009kHz insonation

Microbubble contrast agents are widely used in ultrasound imaging and therapy, typically with transmission center frequencies in the MHz range. Currently, an ultrasound center frequency near 250 kHz is proposed for clinical trials in which ultrasound combined with microbubble contrast agents is applied to open the blood brain barrier, since at this low frequency focusing through the human skull to a predetermined location can be performed with reduced distortion and attenuation compared to higher frequencies. However, the microbubble vibrational response has not yet been carefully evaluated at this low frequency (an order of magnitude below the resonance frequency of these contrast agents). In the past, it was assumed that encapsulated microbubble expansion is maximized near the resonance frequency and monotonically decreases with decreasing frequency. Our results indicated that microbubble expansion was enhanced for 250 kHz transmission as compared with the 1 MHz center frequency. Following 250 kHz insonation, microbubble expansion increased nonlinearly with increasing ultrasonic pressure, and was accurately predicted by either the modified Rayleigh–Plesset equation for a clean bubble or the Marmottant model of a lipid-shelled microbubble. The expansion ratio reached 30-fold with 250 kHz at a peak negative pressure of 400 kPa, as compared to a measured expansion ratio of 1.6 fold for 1 MHz transmission at a similar peak negative pressure. Further, the range of peak negative pressure yielding stable cavitation in vitro was narrow (~100 kPa) for the 250 kHz transmission frequency. Blood brain barrier opening using in vivo transcranial ultrasound in mice followed the same trend as the in vitro experiments, and the pressure range for safe and effective treatment was 75–150 kPa. For pressures above 150 kPa, inertial cavitation and hemorrhage occurred. Therefore, we conclude that (1) at this low frequency, and for the large oscillations, lipid-shelled microbubbles can be approximately modeled as clean gas microbubbles and (2) the development of safe and successful protocols for therapeutic delivery to the brain utilizing 250 kHz or a similar center frequency requires consideration of the narrow pressure window between stable and inertial cavitation.

Nanoparticle-Mediated Acoustic Cavitation Enables High Intensity Focused Ultrasound Ablation Without Tissue Heating.

While thermal ablation of various solid tumors has been demonstrated using high intensity focused ultrasound (HIFU), the therapeutic outcomes of this technique are still unsatisfactory because of common recurrence of thermally ablated cancers and treatment side effects due to the high ultrasound intensity and acoustic pressure requirements. More precise ablation of tumors can be achieved by generating cavitating bubbles in the tissue using shorter pulses with higher acoustic pressures, which induce mechanical damage rather than thermal. However, it has remained as a challenge to safely deliver the acoustic pressures required for mechanical ablation of solid tumors. Here, we report a method to achieve mechanical ablation at lower acoustic pressures by utilizing phospholipid-stabilized hydrophobic mesoporous silica nanoparticles (PL-hMSN). The PL-hMSNs act as seeds for nucleation of cavitation events and thus significantly reduce the peak negative pressures and spatial-average temporal-average HIFU intensities needed to achieve mechanical ablation. Substantial mechanical damage was observed in the red blood cell or tumor spheroid containing tissue mimicking phantoms at PL-hMSN concentrations as low as 10 μg mL-1, after only 5 s of HIFU treatment with peak negative pressures ∼11 MPa and duty cycles ∼0.01%. Even the application of HIFU (peak negative pressure of 16.8 MPa and duty cycle of 0.017%) for 1 min in the presence of PL-hMSN (200 μg mL-1) did not cause any detectable temperature increase in tissue-mimicking phantoms. In addition, the mechanical effects of cavitation promoted by PL-hMSNs were observed up to 0.5 mm from the center of the cavitation events. This method may thus also improve delivery of therapeutics or nanoparticles to tumor environments with limited macromolecular transport.

Testing Different Combinations of Acoustic Pressure and Doses of Quinolinic Acid for Induction of Focal Neuron Loss in Mice Using Transcranial Low-Intensity Focused Ultrasound

The goal of this study was to test different combinations of acoustic pressure and doses of quinolinic acid (QA) for producing a focal neuronal lesion in the murine hippocampus without causing unwanted damage to adjacent brain structures. Sixty male CD-1 mice were divided into 12 groups that underwent magnetic resonance-guided focused ultrasound at high (0.67 MPa), medium (0.5 MPa) and low (0.33 MPa) acoustic peak negative pressures and received QA at high (0.012 mmol), medium (0.006 mmol) and low (0.003 mmol) dosages. Neuronal loss occurred only when magnetic resonance-guided focused ultrasound with adequate acoustic power (0.67 or 0.5 MPa) was combined with QA. The animals subjected to the highest acoustic power had larger lesions than those treated with medium acoustic power, but two mice had evidence of bleeding. When the intermediate acoustic power was used, medium and high dosages of QA produced lesions larger than those produced by the low dosage.

SPIO labeling of endothelial cells using ultrasound and targeted microbubbles at diagnostic pressures.

In vivo cell tracking of therapeutic, tumor, and endothelial cells is an emerging field and a promising technique for imaging cardiovascular disease and cancer development. Site-specific labeling of endothelial cells with the MRI contrast agent superparamagnetic iron oxide (SPIO) in the absence of toxic agents is challenging. Therefore, the aim of this in vitro study was to find optimal parameters for efficient and safe SPIO-labeling of endothelial cells using ultrasound-activated CD31-targeted microbubbles for future MRI tracking. Ultrasound at a frequency of 1 MHz (10,000 cycles, repetition rate of 20 Hz) was used for varying applied peak negative pressures (10–160 kPa, i.e. low mechanical index (MI) of 0.01–0.16), treatment durations (0–30 s), time of SPIO addition (-5 min– 15 min with respect to the start of the ultrasound), and incubation time after SPIO addition (5 min– 3 h). Iron specific Prussian Blue staining in combination with calcein-AM based cell viability assays were applied to define the most efficient and safe conditions for SPIO-labeling. Optimal SPIO labeling was observed when the ultrasound parameters were 40 kPa peak negative pressure (MI 0.04), applied for 30 s just before SPIO addition (0 min). Compared to the control, this resulted in an approximate 12 times increase of SPIO uptake in endothelial cells in vitro with 85% cell viability. Therefore, ultrasound-activated targeted ultrasound contrast agents show great potential for effective and safe labeling of endothelial cells with SPIO.

Effect of high intensity focused ultrasound transducer F-number and waveform non-linearity on inertial cavitation activity

Enhanced chemotherapeutic drug delivery has been shown using pulsed high intensity focused ultrasound (pHIFU) without contrast agents. The threshold of these inertial cavitation effects has recently been correlated to the formation of shocks at the focus. The shock amplitude and corresponding peak negative pressure (p-) are primarily determined by the transducers F-number with less focused (higher F-number) transducers producing shocks at lower p-. Here, the dependence of inertial cavitation activity on F-number was investigated in gel phantoms using passive cavitation detection (PCD) and high-speed photography. HIFU transducers with the same aperture but different F-numbers (0.77, 1.02, and 1.52), operable at three driving frequencies (1 MHz, 1.5 MHz, and 1.9 MHz), were utilized with driving conditions consisting of 1 ms pulses delivered every second and p- from 1 to 15 MPa. Broadband noise emissions recorded by PCD were batch-processed to extract cavitation probability and persistence while concurrent imaging was performed in the focal pHIFU region. At the same p-, both PCD metrics and the imaging revealed enhanced cavitation activity at higher F-numbers. These results support the use of less focused, smaller-footprint transducers for achieving desired cavitation-aided drug delivery. [Work supported by NIH R01EB023910, K01DK104854, R01EB007643, and RFBR 17-54-33034.]

Impact of stone characteristics on cavitation in burst wave lithotripsy

Non-invasive kidney stone treatments such as shock wave lithotripsy (SWL) and burst wave lithotripsy (BWL) rely on the delivery of pressure waves through tissue to the stone. In both SWL and BWL, the potential to hinder comminution by exciting cavitation proximal to the stone has been reported. To elucidate how different stones alter prefocal cavitation in BWL, different natural and synthetic stones were treated in vitro using a therapy transducer operating at 350 kHz (peak negative pressure 7 MPa, pulse length 20 cycles, pulse repetition frequency 10 Hz). Stones were held in a confined volume of water designed to mimic the geometry of a kidney calyx, with the water filtered and degassed to maintain conditions for which the cavitation threshold (in the absence of a stone) matches that from in vivo observations. Stone targeting and cavitation monitoring were performed via ultrasound imaging using a diagnostic probe aligned coaxially with the therapy transducer. Quantitative differences in the extent and location of cavitation activity were observed for different stone types—e.g., “softer” stones (natural and synthetic) that disintegrate into dusty fragments produced larger prefocal cavitation clouds. Future work will focus on correlation of such cavitation metrics with stone fragmentation. [Funding support by NIH P01-DK043881, K01-DK104854.]

Dependence of inertial cavitation induced by high intensity focused ultrasound on transducer F-number and nonlinear waveform distortion.

Pulsed high intensity focused ultrasound was shown to enhance chemotherapeutic drug uptake in tumor tissue through inertial cavitation, which is commonly assumed to require peak rarefactional pressures to exceed a certain threshold. However, recent studies have indicated that inertial cavitation activity also correlates with the presence of shocks at the focus. The shock front amplitude and corresponding peak negative pressure (p -) in the focal waveform are primarily determined by the transducer F-number: less focused transducers produce shocks at lower p -. Here, the dependence of inertial cavitation activity on the transducer F-number was investigated in agarose gel by monitoring broadband noise emissions with a coaxial passive cavitation detector (PCD) during pulsed exposures (pulse duration 1 ms, pulse repetition frequency 1 Hz) with p- varying within 1-15 MPa. Three 1.5 MHz transducers with the same aperture, but different focal distances (F-numbers 0.77, 1.02, 1.52) were used. PCD signals were processed to extract cavitation probability, persistence, and mean noise level. At the same p -, all metrics indicated enhanced cavitation activity at higher F-numbers; specifically, cavitation probability reached 100% when shocks formed at the focus. These results provide further evidence supporting the excitation of inertial cavitation at reduced p - by waveforms with nonlinear distortion and shocks.

Burst wave lithotripsy: An in vivo demonstration of efficacy and acute safety using a porcine model

Burst wave lithotripsy (BWL) is a new non-invasive method for stone comminution using bursts of sub-megahertz ultrasound. A porcine model of urolithiasis and techniques to implement BWL treatment have been developed to evaluate its effectiveness and acute safety. Five human calcium oxalate monohydrate stones (6–7 mm) were hydrated, weighed, and surgically implanted into the kidneys of three pigs. Transcutaneous stone treatments were performed with a BWL transducer coupled to the skin via an external water bath. Stone targeting and treatment monitoring were performed with a co-aligned ultrasound imaging probe. Treatment exposures were applied in three 10-minute intervals for each stone. If sustained cavitation in the parenchyma was observed by ultrasound imaging feedback, treatment was paused and the pressure amplitude was decreased for the remaining time. Peak negative focal pressures between 6.5 and 7 MPa were applied for all treatments. After treatment, stone fragments were removed from the kidneys. At least 50% of each stone was reduced to <2 mm fragments. 100% of four stones were reduced to <4 mm fragments. Magnetic resonance imaging showed minimal injury to the functional renal volume. This study demonstrated that BWL can be used to effectively fragment kidney stones with minimal injury. [Funding support: NIH P01-DK043881, NIH K01-DK104854.]

Development of a freely available simulator with graphical interface for modeling nonlinear focused ultrasound fields with shocks

Measurement-based modeling is gaining acceptance as a standard tool for characterizing the nonlinear fields of existing therapeutic ultrasound devices and designing new ones. Here, a freely available simulation tool is presented for modeling axially symmetric, strongly nonlinear HIFU beams with shocks in a layered propagation medium such as water and different types of tissue. Two nonlinear wave equations are included in the simulator: the KZK equation generalized to include an equivalent source boundary condition for strongly focused beams and the Westervelt equation in a nonlinear wide-angle parabolic representation. Both equations are solved in the frequency domain and permit definition of the HIFU transducer as an annular array. The geometrical parameters and power output of the array, electronic focus steering along the beam axis, and acoustic properties of the layered propagation medium can be configured via graphical interface. Visualization and output of various acoustic field parameters such as peak positive and negative pressures, shock amplitude, intensity, heat deposition rate, and total power of a beam are also provided. The simulator can be used for transducers without ideal symmetry through definition of an equivalent radially symmetric source. Widespread availability of such simulation tools will help advance standardized utilization of measurement-based modeling and facilitate the adoption of such approaches for HIFU treatment planning. [Work supported by NIH R01EB7643, R01EB025187, and RSF №14-12-00974.]

Enhanced shock scattering histotripsy with pseudo-monopolar ultrasound pulses

Shock scattering histotripsy (SSH) involves a complex interaction between positive and negative phases of an acoustic burst to initiate a robust cavitation bubble cloud. To more precisely study these effects and optimize SSH therapy, we constructed a frequency compounding transducer to generate pseudo-monopolar ultrasound pulses. The transducer consisted of 113 individual piezoelectric elements with various resonant frequencies (250 kHz, 500 kHz, 750 kHz, 1 MHz, 1.5 MHz, 2 MHz, and 3 MHz). For each resonant frequency, a nearly 1.5-cycle pulse could be generated. Pseudo-monopolar peak positive pulses were generated by aligning the principal peak positive pressures of individual frequency components temporally so that they added constructively, and destructive interference occurred outside the peak-positive-overlapped temporal window. After inverting the polarity of the excitation signals, pseudo-monopolar peak negative pulses were generated similarly by aligning principal peak negative pressures. Decoupling the positive and negative acoustic phases could have significant advantages for therapeutic applications enhancing precision, avoiding cavitation at tissue interfaces, and reducing the acoustic aperture required for effective therapy. For example, we show that 16 SSH bubble clouds can be generated using only peak positive pulses following a single peak negative pulse. This results in a precise elongated lesion within red-blood-cell phantoms.

Update on clinical trials results of kidney stone repositioning and preclinical results of stone breaking with one ultrasound system

Our goal is an office-based, handheld ultrasound system to target, detach, break, and/or expel stones and stone fragments from the urinary space to facilitate natural clearance. Repositioning of stones in humans (maximum 2.5 MPa, and 3-second bursts) and breaking of stones in a porcine model (maximum 50 cycles, 20 Hz repetition, 30 minutes, and 7 MPa peak negative pressure) have been demonstrated using the same 350-kHz probe. Repositioning in humans was conducted during surgery with a ureteroscope in the kidney to film stone movement. Independent video review confirmed stone movements (≥ 3 mm) in 14 of 15 kidneys (93%). No serious or unanticipated adverse events were reported. Experiments of burst wave lithotripsy (BWL) effectiveness on breaking human stones implanted in the porcine bladder and kidney demonstrated fragmentation of 4 of 4 stones on post mortem dissection. All clinical pathology, hematology, and urinalysis for a 1-week survival study with the BWL exposures in 10 specific pathogen free pigs were within normal limits. These results demonstrate that repositioning of stones with ultrasonic propulsion and breaking of stones with BWL are safe and effective. [Work supported by NIH P01 DK043881, K01 DK104854, and R44 DK109779.]

Experimental and numerical analyses of multi-DBD plasma actuators to reduce wind loads and modify local flow on the roofs of low-rise buildings

The present study experimentally and numerically investigates the feasibility of applying multiple dielectric barrier discharge (multi-DBD) plasma actuators to reduce wind loads and modify local flow field on the roofs of low-rise buildings. Four arrangements of multi-DBD plasma actuators are placed on the roofs and induce four directions of wall jets. The results show that mean and peak negative pressure coefficients are negative no matter the plasma actuation is on or off. These wall jets decrease the absolute values of these pressure coefficients in different roof regions and succeed in modifying the local flow around the roof. The wall jet blowing from the trailing edge to the leading edge has the best effect on wind loads, since the absolute values of mean and peak negative pressure coefficients are respectively reduced by about 20% and 12% near the leading edge. The different variations of wind loads and the local flow for all arrangements are due to the compact of the directionality of the wall jets. The wall jet produces a strong suction region at the beginning of the wall jet, which leads to an obvious enhancement of wind loads in this region. Meanwhile, the wall jet induces a strong pressure region at the back of the wall jet, resulting in an apparent decline of wind loads.

Investigating the role of lipid transfer in sonoporation

The permeabilisation of cell membranes following exposure to microbubbles and ultrasound has considerable potential for therapeutic delivery. Recent studies have demonstrated that transfer of material takes place between phospholipid-coated microbubbles and cell membranes. The aim of this study was to investigate the impact of this transfer on membrane properties and cell permeability. Microbubbles were prepared with matched concentrations and size distributions from a series of formulations utilising phospholipids with differing molecular characteristics. Quantitative fluorescence microscopy techniques were used to quantify changes in the molecular packing, viscosity, and permeability to model drugs of cancer cells under mild ultrasound exposure (15 s of 1 MHz centre frequency, 125 kPa peak negative pressure, 1 kHz pulse repetition frequency, and 10% duty cycle). The molecular “packing” of cancer cell membranes was found to be significantly affected by the transfer of both phospholipids and other microbubble coating constituents. This was particularly pronounced in the case of microbubbles containing a specific class of lipids, which promoted a ~4-fold increase in model drug uptake following ultrasound exposure. Similar results were observed in an investigation of permeability in an in vitro blood brain barrier model suggesting that microbubble composition may play a key role in the efficacy of ultrasound mediated delivery.

Ultrasound-Mediated Gene Therapy in Swine Livers Using Single-Element, Multi-lensed, High-Intensity Ultrasound Transducers

We have achieved significant enhancement of gene delivery into livers of large animals using ultrasound (US)-targeted microbubble (MB) destruction methods. An infusion of pGL4 (encoding a luciferase reporter gene) plasmid DNA (pDNA) and MBs into a portal-vein segmental branch of a porcine liver was exposed to US for 4 min. Therapeutic US induced cavitation of MBs to temporarily permeabilize the vascular endothelium and cell membranes, allowing entry of pDNA. We obtained a 64-fold enhancement in luciferase expression in pig livers compared to control without US using an unfocused, dual-element transducer (H105, center frequency [fc] = 1.10 MHz) at 2.7 MPa peak negative pressure (PNP). However, input electrical energy was limited, and modified transducers were designed to have spherical (H185A, fc = 1.10 MHz) or cylindrical foci (H185B, fc = 1.10 MHz; H185D, fc = 1.05 MHz) to enhance PNP output. The revised transducers required less electrical input to achieve 2.7 MPa PNP compared to H105, thereby allowing PNP outputs of up to 6.2 MPa without surpassing the piezo-material limitations. Subsequently, luciferase expression significantly improved up to 9,000-fold compared to controls with minor liver damage. These advancements will allow us to modify our current protocols toward minimally invasive US gene therapy.

A convenient, reliable, and fast acoustic pressure field measurement method for magnetic resonance-guided high-intensity focused ultrasound systems with phased array transducers

BackgroundWith the expanding applications of magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU), there is an urgent need for a convenient, reliable, and fast acoustic pressure field measurement method to aid treatment protocol design, ensure consistent and safe operation of the transducer, and facilitate regulatory approval of new techniques. Herein, we report a method for acoustic pressure field characterization of MR-HIFU systems with multi-element phased array transducers. This method integrates fiber-optic hydrophone measurements and electronic steering of the ultrasound beam with MRI-assisted HIFU focus alignment to the fiber tip.MethodsA clinical MR-HIFU system (Sonalleve V2, Profound Medical Inc., Mississauga, Canada) was used to assess the proposed method. A fiber-optic hydrophone was submerged in a degassed water bath, and the fiber tip location was traced using MRI. Subsequently, the nominal transducer focal point indicated on the MR-HIFU therapy planning software was positioned at the fiber tip, and the HIFU focus was electronically steered around the fiber tip within a 3D volume for 3D pressure field mapping, eliminating the need for an additional, expensive, and MRI-compatible 3D positioning stage. The peak positive and negative pressures were measured at the focus and validated using a standard hydrophone measurement setup outside the MRI magnet room.ResultsWe found that the initial MRI-assisted HIFU focus alignment had an average offset of 2.23 ± 1.33 mm from the fiber tip as identified by the 3D pressure field mapping. MRI guidance and electronic beam steering allowed 3D focus localization within ~ 1 h, i.e., faster than the typical time required using the standard laboratory setup (~ 3–4 h). Acoustic pressures measured using the proposed method were not significantly different from those obtained with the standard laboratory hydrophone measurements.ConclusionsIn conclusion, our method offers a convenient, reliable, and fast acoustic pressure field characterization tool for MR-HIFU systems with phased array transducers.