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Adaptive acoustic output selection in ultrasound imaging promises to improve adherence to the ALARA (as low as reasonably achievable) principle. Demonstrated imaging sequences have balanced image quality and safety considerations based on transducer channel lag-one coherence to select Mechanical Index (MI), a measure of acoustic output. In this study, data were collected with an adaptive output selection tool on 9 pregnant volunteers to explore factors affecting the recommended output. The placenta, fetal abdomen, and fetal heart in each volunteer were repeatedly scanned. A statistically significant difference in recommended ALARA MI was observed between target structures (p < 0.001). Each target's underlying channel data signal magnitude correlated with the recommended ALARA MI used for scanning, suggesting the brightness of a target affects the selected ALARA MI. These findings imply that continued observance of the ALARA principle during clinical examinations requires adaptive output selection be performed with each new target structure, or each time a transducer or acoustic window shift causes a change in the target brightness

Ultrasound (US) and cavitation agents such as microbubbles (MBs) have been demonstrated to decrease the barrier function of endothelial and epithelial layers. However, in vitro experiments that study this effect are often hindered by the inability to deliver buoyant contrast agents in proximity to cell monolayers in order to adequately control the decrease in barrier function whilst insonating a sufficiently large tissue area. We have addressed this by adapting a cell culture system and fabricating a bespoke high-power miniature unfocused US transducer. The setup was used to control the drop in barrier function and to determine how varying the mechanical index (MI) and the duty cycle affected the barrier function. It was found that buffer solution alone and buffer + MBs did not decrease the transepithelial electrical resistance (TEER) of the cell monolayer. Buffer + US decreased the TEER by ~40%, with 10% TEER recovery 9 min after switching US off. Buffer + MBs + US decreased the TEER by 80%, with little or no recovery following treatment. In the presence of MBs, the barrier function was decreased by a duty cycle = [1% - 50%] and by an MI = [0.25 - 0.5], without any recovery following treatment. Detectable amounts of fluorescent dextran were delivered across the Caco-2 monolayer only by a combination of US + MBs. These results suggest that our adapted setup and custom-built miniature transducer permits control of the decrease in barrier function for further therapeutic investigations.

A software-based processing approach for contrast-enhanced ultrasound (US) imaging is presented. Termed pulse-inversion spectral convolution (PISD), the main motivation here was to further evaluate the performance of this contrast-enhanced US imaging technique using a series of experimental studies. The PISD-based contrast-enhanced US approach is founded on a class of Gaussian derivative functions (GDFs). Two types of PISD pulses (one GDF and convolution of three GDF pulses) can be used to form two new inverted pulse sequences. These pulses are then used to filter backscattered US data for isolation of the nonlinear MB signal component. An US system (Vantage 256, Verasonics Inc) with a L11-4v linear array transducer was programmed and used for PISD-based contrast-enhanced US imaging. The receive data from all channels was shaped using a wide beamforming technique. In vitro US images were collected from a flow phantom perfused with a MB contrast agent using PISD and traditional pulse-inversion US (nonlinear, NL) for comparison. Further, role of the transmit aperture size ( $\text{TX}=32$ or 64) was also evaluated using a US pulse frequency of 6.25 MHz and a low mechanical index of 0.2. Contrast enhancement was measured using a contrast-to-noise ratio (CNR). Preliminary in vivo data was acquired from the hindlimb (femoral artery) of healthy rats after receiving a bolus injection of MBs. Overall, widebeam contrast-enhanced US imaging using the larger aperture size of 64 elements yielded improved CNR values. Using this widebeam US imaging approach, both in vitro and in vivo results demonstrated that the PISD-based contrast-enhanced US technique produced images with improved contrast compared to the more traditional B-mode and NL US imaging strategies.

This paper reports underestimation of peak compressional pressure (p(c)), peak rarefactional pressure (p(r)), and pulse intensity integral (pii) due to hydrophone spatial averaging of acoustic radiation force impulse (ARFI) beams generated by clinical linear and phased arrays. Although a method exists for correcting for hydrophone spatial averaging for circularly-symmetric beams, there is presently no analogous method for rectangularly-symmetric beams generated by linear and phased arrays. Consequently, pressure parameters (p(c), p(r), and pii) from clinical arrays are often not corrected for spatial averaging. This can lead to errors in Mechanical Index (MI) and Thermal Index (TI), which are derived from pressure measurements and are displayed in real-time during clinical ultrasound scans. ARFI beams were generated using three clinical linear array transducers. Output pressure waveforms for all three transducers were measured using five hydrophones with geometrical sensitive element sizes (d(g)) ranging from 85 to 1000 μm. Spatial averaging errors were found to increase with hydrophone sensitive element size. For example, if d(g) = 500 μm (typical membrane hydrophone), frequency = 2.25 MHz and F/# = 1.5, then average errors are approximately −20% (p(c)), −10% (p(r)), and −25% (pii). Therefore, due to hydrophone spatial averaging, typical membrane hydrophones can exhibit significant underestimation of ARFI pressure measurements, which likely compromises exposure safety indexes.

This paper reports underestimation of peak compressional pressure (pc), peak rarefactional pressure (pr), and pulse intensity integral (pii) due to hydrophone spatial averaging of pulsed Doppler beams generated by clinical linear and phased arrays. Although a method exists for correcting for hydrophone spatial averaging for circularly-symmetric beams, there is presently no analogous method for rectangularly-symmetric beams generated by linear and phased arrays. Consequently, pressure parameters (pc, pr and pii) from clinical arrays are often not corrected for spatial averaging. This can lead to errors in Mechanical Index (MI) and Thermal Index (TI), which are derived from pressure measurements and are displayed in realtime during clinical ultrasound scans. Pulsed Doppler beams were generated using three clinical linear array transducers. Output pressure waveforms for all three transducers were measured using five hydrophones with geometrical sensitive element sizes (d g ) ranging from 85 to 1000 µm. Spatial averaging errors were found to increase with hydrophone sensitive element size. For example, if d g = 500 µm (typical membrane hydrophone), frequency = 6 MHz and F /# = 2, then average errors are approximately -40% (pc), -20% (pr), and -50% (pii). Therefore, due to hydrophone spatial averaging, typical membrane hydrophones can exhibit significant underestimation of Doppler pressure measurements, which likely compromises exposure safety indexes.

Current localization-based super-resolution ultrasound imaging requires a low concentration of flowing microbubbles to visualize microvasculature beyond the diffraction limit and acquisition is slow. Recent studies have shown that Acoustic Wave Sparsely Activated Localization Microscopy (AWSALM) using phase change nanodroplets can generate fast or even real-time super-resolution imaging. However, the optimal experimental conditions to activate the droplets for generating the super-resolution images are still unknown, especially the activation ultrasound amplitude or mechanical index (MI). The aim of this study is to investigate the effect of the activation MI on the repeated activation of decafluorobutane nanodroplets in vivo . Noninvasive ultrasound data acquisition on a rabbit kidney using the AWSALM pulse sequence was repeated for different activation MIs. It was found that the droplet activation was not observed in the rabbit kidney at an MI of 1.1. The activation of droplet started at an activation MI of 1.3. The contrast of activated droplet signals is maximized at an MI of 1.5 and decreased when the activation MI was increased above 1.5. Such understanding of the effects of activation MI could help improve droplet-base fast super-resolution imaging.

Lonidamine (LND) has been widely explored due to its ability to target metabolic glycolysis and mitochondrial respiration in tumors [4]. However, clinical translation has stalled due to poor bioavailability after oral administration. In this study, we explored three incubation time points of loading oxygen-filled microbubbles with LND (SE61O2-LND) for radiotherapy sensitization by modifying our published methods for creating surfactant-shelled oxygen microbubbles (SE61 O2). Acoustic enhancement and stability were quantified in vitro in a continuously insonated sample holder using a 5 MHz single element transducer which generated a peak positive pressure of 0.69 MPa and a peak negative pressure of 0.25 MP at a PRF of 100 Hz and in a pulsatile flow phantom insonated at a single point using a C1-6 transducer on a GE Logiq E9 system (GE Healthcare) operating at 4.0 MHz at a mechanical index of 0.12. Flow cytometry was performed to analyze the total bubble count for each incubation time point. Lonidamine encapsulation was determined using liquid chromatography-mass spectrometry (LC-MS), the loading approach consisted of incubating the LND and TPGS at 37°C at 0, 24, and 48 hours. Bubbles incubated for 24 hours had an average encapsulation of 2.64 ± 0.32 µg LND/ mL MB, and those incubated for 48 hours had an average of 2.97 ± 0.36 µg LND/ mL MB, while non-incubated micelles had an average of 1.51 ± 0.05 µg LND/ mL MB, both TPGS micelle methods that were incubated showed a statistically significant improvement p < 0.001 compared to non-incubated. This work demonstrates the feasibility of fabricating lonidamine-loaded microbubbles and an improved approach for increasing drug encapsulation. The microbubbles retained their acoustic properties, and by incubating the lonidamine with the TPGS to form micelles, drug loading was increased.

We previously showed in simulations that the Mechanical Index is inaccurate for estimating peak rarefaction pressure (PRP) and can overestimates PRP by more than 40%. In this work, we created a new experimental method to measure in situ pressures when accounting for propagation through the abdominal wall and liver. Our experimental results show concordance with the previous simulation work.

Dynamic contrast enhanced ultrasound (DCE-US) imaging has the potential to provide quantitative information which is sensitive to tumour perfusion, an indicator for tumour response to radiotherapy. To increase the reproducibility of time-intensity curve (TIC) characteristics, we are developing a 3 $D$ DCE-US imaging system. There are, however, many choices to be made in system design, such as whether to use plane wave (PWI) or focused imaging (FI), and the values to use for parameters such as focal depth (FD), F-number (F#), mechanical index (MI) and number of angles (NA) (for PWI). We evaluated the effect of such choices on TICs (we refer to time-amplitude curve (TAC) here), using a microvascular flow phantom containing $\sim 100, 000$ parallel microtubes, each $200\mu \text{m}$ in diameter. DCE-US 2D images were obtained using a Vantage (Verasonics Inc.) and a pulse-inversion algorithm. 800 frames were recorded at 10 Hz for PWI and FI. All measurements were repeated 3 times, injecting 0.4 ml of contrast agent (Sonozoid) and changing one parameter at a time, using the values: FD = 20, 40 mm; F# = 2, 4; MI = 0.11, 0.15, 0.25; NA = 3, 7, 11. For a large region of interest which included the periphery of the phantom, TACs were sharp and single-peaked for F2 but broader and double-peaked for F4, consistent with F4 averaging over a greater focal volume than F2. Choosing a smaller more central ROI reduced the effect but did not eliminate it completely. Placing the focus deeper than the center reduced the TAC amplitude due to attenuation but also resulted in a flatter TAC. PWI amplitude was greatest for 3 angles with evidence that this may be due to side lobe artefacts added to the contrast signal. TAC characteristics are thus expected to be highly sensitive to imaging parameters. This should be considered in longitudinal studies.

Ultrasound (US)and systemic administration of microbubbles (MBs)have been shown to improve the delivery of drugs and nanoparticles (NPs)to tumor tissue. A better understanding of the mechanisms is crucial for effective delivery of NPs and drugs. To elucidate the kinetics of extravasation events, and relate it to the vessel diameter and flow, we have performed real-time intravital multiphoton microscopy during US sonication of tumors growing in dorsal window chambers. We studied the effects of four different mechanical index (MI)levels (0.2 to 0.8)while injecting SonoVue or in-house made MBs with NPs in the shell (NPMB). We found that high MI of 0.8 induced a violent extravasation of both NPs and dextrans. Using lower MIs (0.2-0.6), less extravasation was detected and it occurred in vessels with larger diameters compared to sonication at MI 0.8. The rate of extravasation of both NPs and dextrans, and the displacement of NPs and dextrans from the vessel into the tumor tissue, correlated with MI. The observed extravasation events happened within milliseconds to minutes after the US exposure started. Moreover, we have observed a change of blood flow rate and direction with all the MIs tested © 2018 IEEE. Personal use of this material is permitted. Permission from IEEE must be obtained for all other uses, in any current or future media, including reprinting/republishing this material for advertising or promotional purposes, creating new collective works, for resale or redistribution to servers or lists, or reuse of any copyrighted component of this work in other works.

The current standard for evaluating breast tumor response to neoadjuvant treatment remains the assessment of a tumor size change several weeks after therapy begins. However, the tumor microenvironment (including microvasculature) is known to change drastically before any detectable change in physical size manifests. To that end, we have developed a new high-resolution ultrasound (US) imaging modality in our laboratory, termed super-resolution ultrasound (SR-US), for improved visualization of the tumor angiogenic network. A clinical US scanner (Acuson Sequoia 512, Siemens Healthcare) equipped with a 15L8-S linear array transducer was used for our study. Operation of this system was done using a nonlinear harmonic imaging. A low transmit power (mechanical index < 0.2) was used to minimize any MB destruction during imaging. After a slow injection of a MB contrast via a tail vein catheter placed in breast cancer-bearing mice (N = 10), each tumor was US imaged for 10 min at baseline and again at 1 and 2 h after dosing with an antiangiogenic drug (bevacizumab, Genentech Inc) or sham control drug. After collecting a stack of US images, images corrupted by respiratory motion were removed using curve fit-based filtering. A singular value decomposition (SVD)-based spatiotemporal filter was then used to localize individual MBs. Subsequently, a SR-US image (i.e., MB density map) was generated by mapping the cumulative MB localizations. SR-US images were reviewed and longitudinal changes in the tumor microvascular network in response to treatment were evaluated. Overall, an acute microvascular response to bevacizumab was found within 2 h of drug dosing. This observation was consistent with immunohistologic findings and suggests that in vivo SR-US imaging has enormous potential in monitoring the early tumor response to drug treatment.

Low intensity pulsed ultrasound (LIPUS) is a therapy used clinically for bone fracture and soft tissue healing LIPUS induces functional alterations in cell behavior and has shown potential for cancer therapy. In order to understand the underlying biophysical mechanisms, the ability to control acoustic exposure parameters and elimination of unwanted effects such as the formation of standing wave patterns, heating, and cavitation, is vital. In this study, we designed an in-vitro focused ultrasound setup (FUS) with repeatable exposure conditions where the cells or spheroids are surrounded by an agar substrate with sufficient absorption to eliminate unwanted reflections and cell culture medium which acts as an effective coolant. The measured maximum temperature rise with the presence of coolant was 1°C and the estimated mechanical index was 1.28. The shear wave propagation induced by acoustic radiation force was monitored and no reflection was observed. We propose an in-vitro FUS cell stimulation setup which can induce non-thermal and non-cavitation biological response with no unwanted artifacts.

We have previously reported increases in diagnostic shearwave and harmonic SNR using pressures that exceed the US FDA guideline for the Mechanical Index (MI). The MI is calculated using peak rarefaction pressure (PRP) measured in water with linear derating to account for tissue attenuation. However, acoustic propagation through water is a highly nonlinear process that inherently differs in attenuation, nonlinearity, and path heterogeneity from propagation in tissue. We hypothesize that MI overestimates the in situ acoustic output for many clinical scenarios and that PRP can occur in spatially offset locations when imaging through heterogeneous media such as the abdominal wall. Herein we demonstrate how these parameters affect in situ PRP as compared to that predicted by linear derating.

Harmonic imaging techniques are widely used in B-mode abdominal imaging and motion tracking in shear wave elasticity imaging (SWEI) to reduce clutter and improve data quality. Harmonic imaging can be both signal-to-noise (SNR) and penetration depth (PD) limited, resulting in decreased diagnostic utility. This work evaluates B-mode harmonic imaging and SWEI harmonic tracking data quality between imaging sequences using a Mechanical Index (MI) within the FDA guideline of 1.9 and an elevated MI (1.9 < MI < 2.6), to determine if there is clinical benefit in exceeding the current FDA guideline for MI in the context of hepatic imaging.

Contrast-enhanced ultrasound (CEUS) imaging offers great opportunities for new ultrasound applications by improving the contrast between blood and tissue using microbubbles. However, the low signal-to-noise ratio (SNR) due to the low mechanical index (MI) requirement can sometimes be an issue in practice. Multiplane wave (MW) imaging is a technique recently proposed to increase the SNR for compounding plane wave imaging. In this study, we propose to combine CEUS with MW imaging to improve SNR without elevating MI in plane-wave-based CEUS imaging. The MW-CEUS method emits multiple Hadamard-coded CEUS pulses in each transmission events (i.e., pulse-echo events). The received echo signals first undergoes fundamental bandpass filtering (i.e., filter centered on transmit frequency) to eliminate the microbubble 2nd harmonic signals as they cannot be encoded by pulse inversion. The filtered signals are then Hadamard decoded and re-aligned in fast time to recover the signals as they would have been obtained from classic CEUS pulses, followed by designed recombination to cancel the linear tissue responses. The MW-CEUS method significantly improves contrast-to-tissue ratio (CTR) of CEUS imaging by transmitting longer coded pulses with preserved image spatial resolutions. The microbubble disruption ratio in MW-CEUS is also comparable with classic CEUS imaging. In addition, the MW-CEUS sequence can be readily adapted to other transmission coding formats. These properties of MW-CEUS can potentially facilitate CEUS imaging for a wide spectrum of clinical applications, especially for deep abdominal organs or heart.

In this paper, we report the development of miniaturized forward-looking transducers for microbubble-mediated intravascular ultrasound-enhanced thrombolysis (UET). UET has shown its efficacy for thrombo-occlusive disease by enhancing penetration of thrombolytic drugs into clots, reducing the required dose. In this study, we adopted a previously-developed forward-looking, stacked type transducer for thrombolysis treatment with low dose (approximately 0.4 μg/ml)-recombinant tissue-plasminogen activator (rt-PA). The 650 kHz-prototype transducer with a concave lens enabled a confined ultrasound beam despite the small aperture (diameter

Microembolization during PCI for acute myocardial infarction can cause microvascular obstruction (MVO). MVO severely limits the success of reperfusion therapies and is linked to worse prognosis, including death. A recent clinical trial showed that adjunct short pulse MB+US therapy prior to and following PCI in first STEMI patients, improved angiographic recanalization prior to PCI and ejection fraction at 1 month (Mathias et al. JACC. 2016;67:2506-15). This study demonstrated the clinical potential of short pulse high mechanical index MB+US as an adjunct therapy for STEMI. Based on our historical success with using long tone burst US for sonoreperfusion (SRP) therapy in a rat hindlimb model of MVO (Pacella et al. UMB. 2015;41:456-64), we sought to compare the use of short (5 cycles) and long (5000 cycles) US pulsing schemes for SRP.

We present a novel class of ultrasound (US) contrast agents, which enable de novo production of echogenic O 2 microbubbles (MBs) in vivo in regions with elevated hydrogen peroxide (H 2 O 2 ). The agent is a 200 nm silica shell nanoparticle loaded with catalase (catSHEL) that catalyzes H 2 O 2 into water (H 2 O) and oxygen (O 2 ). Importantly, this reactive process produces O 2 MBs visible during US imaging. We have shown that this agent can detect elevated levels of H 2 O 2 in kidneys with acute kidney injury (AKI). The purpose of this in vitro study is to further characterize the US properties of these O 2 MBs. When exposed to US energy (mechanical index, MI = 0.07), a marked increase in the 2nd harmonic signal was recorded after the addition of H 2 O 2 when the catSHELs were suspended in 25% plasma + phosphate buffered saline (PBS) versus PBS alone (13.1 vs. 1.7 dB). This harmonic gain abated at higher plasma concentrations (6.0 dB at 100% plasma) and higher (MI = 0.10) and lower (MI = 0.03) US transmit powers (8.8 and 5.7 dB, respectively). The harmonic signal also increased with increasing surfactant concentration. Again, the response was greatest at moderate acoustic power. O 2 MBs produced in PBS alone were transient and relatively large, while those produced at increasing plasma and surfactant concentrations were smaller and longer lasting, suggesting that they are stabilized in plasma or surfactant. Overall, nonlinear US imaging may be suitable for the local visualization of O 2 MBs produced in response to AKI.

Study of ultrasound contrast imaging is of great importance in recent years thanks to its wide application in ultrasonic diagnosis. Plane wave imaging has been considered as a good method with high frame rate and low mechanical index. High frame rate can improve the temporal resolution of contrast imaging. Meanwhile, low mechanical index is essential to contrast imaging since high mechanical index in traditional B-mode imaging could break micro-bubbles easily. However, plane wave contrast imaging suffers from low signal-to-noise ratio (SNR) and contrast (CR) which leads to poor image quality. In this paper, adaptive beamformer and pulse inversion (PI) technique were combined to solve the shortcomings of the plane wave contrast imaging. For the adaptive beamformer, eigenspace based minimum variance (ESBMV) with coherence factor (ESBMVCF) was proposed. Experimental results show that ESBMVCF offers an enhancement of 1.1dB, 13dB and 0.8dB in CR, contrast-to-tissue ratio (CTR) and contrast-to-noise ratio (CNR) respectively compared with minimum variance and coherence factor (MVCF). Besides, PI offers 1.5dB, 15dB and 15dB enhancement in CR, CTR and CNR compared with traditional pulse-echo imaging.

Calibration of ultrasonic hydrophone probes in the frequency range from 250 kHz to 1 MHz is required to sufficiently assess the peak rarefactional pressure (pr) and the Mechanical Index (MI) of medical ultrasound imaging devices. However, the ultrasonic hydrophone calibration in this low frequency is barely conducted. Therefore, the objective of this research was to develop a calibration technique for ultrasonic hydrophone probes in the frequency range from 250 kHz to 1 MHz. Two ultrasonic hydrophone probes, one membrane hydrophone and one needle hydrophone, were calibrated using a substitution method combined with time-delay spectrometry (TDS). The calibration results are presented in term of end-of-cable voltage sensitivity as a function of frequency. The calibration data show that the membrane hydrophone exhibit a very flat frequency response, to within ±1 dB for the entire investigated frequency range, whereas the needle hydrophone demonstrates a relative large variations in sensitivity of about 5 dB. These results are in good agreement with the limited data previously reported. Therefore, the substitution calibration technique with Time Delay Spectrometry (TDS) is capable of calibrating the ultrasonic hydrophone probes in the frequency range from 250 kHz to 1 MHz.

Tissue harmonic imaging (THI) has been widely used in abdominal imaging due to its significant reduction in acoustic noise compared to fundamental imaging. However, THI can be both signal-to-noise ratio (SNR) and penetration-depth limited during clinical imaging, resulting in decreased diagnostic utility. A logical approach is to increase the source pressure, but the in situ pressures used in diagnostic imaging have been subject to a de facto upper limit based upon the Food and Drug Administration (FDA) guideline for the Mechanical Index (MI < 1.9) since 1992. A recent AIUM report concluded that exceeding MI of 1.9 up to an estimated in situ value of 4.0, could be warranted without concern for increased risk of cavitation in non-fetal tissues without gas bodies. This work quantifies the benefit of elevated acoustic output in hepatic harmonic imaging. Increasing MI values were shown to be associated with increases in harmonic signal content, penetration depth, and vessel Contrast-to-noise ratio in THI images. Obese patients who suffer from poor ultrasound image quality are more likely to benefit from elevated acoustic output to enable better THI performance.

We have investigated the feasibility of in vivo high resolution imaging of blood perfusion in the rat brain tissue using a dual-mode ultrasound array (DMUA). The DMUA is capable of generating therapeutic transcranial focused ultrasound (tFUS) beams as well as forming images of the target in synthetic-aperture (SA) mode. Low mechanical index (MI) SA frames are used to estimate the dynamic changes in perfusion, which could be used for guidance, monitoring, or damage assessment. We have previously demonstrated the advantages of the post-beamforming third-order Volterra filter in imaging nonlinear echo components due to UCA oscillations using diagnostic probes. In this study, we decompose the beamformed transcranial DMUA SA data into its linear, quadratic, and cubic components and evaluate a temporal perfusion index (TPI) to characterize perfusion. The data collection used a 3.2-MHz, concave (40-mm ROC) DMUA operating in SA mode at a frame rate of approximately 23 fps and in the low MI setting (about 0.05 to 0.11). The experiment was performed on healthy rats (250-300 grams). Targestar-P UCA (60 µL in 140 µL of sterile saline) was injected through the animal tail vein. Images from the linear, quadratic, and cubic components were formed as LB-mode, QB-mode and CB-mode, respectively. TPI image frames were computed from each image component after limiting the dynamic range appropriately. The results clearly show separation of TPI values and demonstrate the feasibility of high-resolution estimation of blood perfusion in rat brain transcranially.

Shear wave elasticity imaging (SWEI) has found success in liver fibrosis staging. However, technical failure and unreliable shear wave speed (SWS) estimation have been reported to increase both with elevated patient body mass index (BMI) and in the presence of significant hepatic fibrosis. Elevated BMI results in a significant amount of subcutaneous fat which attenuates acoustic radiation force (ARF) and abberates tracking beams. Advanced fibrosis results in small displacement amplitudes in stiff livers. This work evaluates hepatic SWEI measurement success as a function of push pulse energy using 2 Mechanical Index (MI) values (1.6 and 2.2) over a range of pulse durations. The rate of successful SWS estimation for 8 repeated measurements is linearly proportional to the push energy level. As expected, elevated push energy in SWEI measurements results in higher displacement signal-to-noise ratio (SNR). SWEI measurements with elevated push energy are successful in patients for whom standard push energy levels failed. Deep liver capsule is shown to be an indicator for lower yield of SWS estimation. Patients with deep liver capsules are likely to benefit from elevated push energies. We conclude that there is clinical benefit to using elevated acoustic output for hepatic SWS measurement in “difficult to image” patients.

Light-absorbing nanorods can be used to improve the signal-to-noise ratio of the thermoelastic emissions from tissue that are used in photoacoustic imaging. As nanorods can be functionalised to selectively target cancer cells, which could then be used to identify and/or destroy them through the formation of ultrasonically driven vapour bubbles. Heating the nanorods with a laser whilst they are simultaneously under tension from a ultrasound field results in a significant reduction in the fluence and pressure thresholds required for bubble formation. A custom build 96-channel diagnostic ultrasound system (4 MHz) was used in conjunction with a nanosecond pulse laser (850 nm) to B-mode image both transparent and turbid tissue-mimicking phantoms, which have been doped with gold nanorods (surface plasmon resonance 850 nm). For a mechanical index of 0.93 (1.86 MPa) and laser fluence of 16 mJ/cm2, which are both below safety limits for diagnostic exposures, broadband emissions from the nanorod nucleated vapour bubbles were generated in both phantom types. For the turbid phantom type un-beamformed RF data was filtered using a narrowband filter to remove both the fundamental and second harmonic components of the ultrasound to show only the broadband emissions generated by the inertial collapse of the vapour bubbles. This demonstrates how this technique could be used for the diagnostic imaging of molecular-targeted nanorods.

It is investigated how linear simulation can be used to predict both the magnitude of the intensities as well as the placement of the peak values. An ultrasound sequence is defined through the normal setup routines for the experimental SARUS scanner, and Field II is then used automatically on the sequence to simulate both intensity and mechanical index (MI) according to FDA rules. A 3 MHz BK Medical 8820e convex array transducer is used with the SARUS scanner. An Onda HFL-0400 hydrophone and the Onda AIMS III system measures the pressure field for three imaging schemes: a fixed focus, single emission scheme, a duplex vector flow scheme, and finally a vector flow imaging scheme. The hydrophone is connected to a receive channel in SARUS, which automatically measures the emitted pressure for the complete imaging sequence. MI can be predicted with an accuracy of 16.4 to 38 %. The accuracy for the intensity is from −17.6 to 9.7 %, although the measured fields are highly non-linear (several MPa) and linear simulation is used. Linear simulation can, thus, be used to accurately predict intensity levels for any advanced imaging sequence and is an efficient tool in predicting the energy distribution.

Intravascular ultrasound imaging is a powerful tool in assessing cardiovascular diseases, and contrast enhanced ultrasound imaging has the ability to generate high signal to noise ratio images and can provide information such as degree of plaque vascularization and molecular function. Currently, however, contrast enhanced intravascular ultrasound (CE-IVUS) imaging has not been used clinically. Design, fabrication, and characterization of a small aperture (0.6 × 3 mm), dual frequency ultrasound transducer were performed, followed by microbubble tests for viability study of CE-IVUS imaging. Results show that more than 1.23 MPa (mechanical index: 0.48) was generated by the 6.5 MHz transmission component at the imaging area, where nonlinear response of microbubbles was detected by the 30 MHz broadband (-6dB bandwidth: 58.6%) receiving component. Nonlinear echo response from microbubbles flowing through a micro-tube with diameter of 0.2 mm was clearly detected with a signal to noise ratio higher than 12 dB. These promising results show that small aperture, dual frequency transducers are capable of detecting contrast agents using split frequency detection methods and suggest they are a reasonable platform for CE-IVUS imaging.

Microbubble ultrasound contrast agent (UCA) has been well recognized as a potential noninvasive tool for the blood pressure measurement. A decrease in subharmonic amplitude of 9 to 12 dB has been reported for Levovist, Optison, Definity, Sonazoid, and SonoVue for ambient overpressure values around 180 mmHg. However, a pressure resolution of 3 mmHg is desirable in medical diagnostics, it is still necessary to enhance the pressure sensitivity for the method based on the subharmonic amplitude as a function of local pressure. The purpose of this study was to improve the ambient pressure sensitivity of the subharmonic amplitude by optimizing acoustic parameters in in vitro experiments. The acoustic scattering measurement was carried out at different acoustic parameters, and it was demonstrated for SonoVue by us that the subharmonic amplitude reduced by 10.9 dB at the driving frequency of 4 MHz and the acoustic pressure of 450 kPa (mechanical index MI = 0.225), 19.8 dB at 4 MHz and 500 kPa (MI = 0.25), and 17.6 dB at 1.33 MHz and 350 kPa (MI = 0.3), respectively, when the overpressure increased to 180 mmHg. The results showed the effect of the mechanical index on the ambient pressure sensitivity of subharmonic amplitude, and indicated the existence of a MI threshold ( ≈ 0.23) at which the sensitivity can be enhanced significantly.

Low frequency ultrasound has a diverse set of industrial and medical applications ranging from high power industrial ultrasound equipment through to various therapeutic medical applications. In recent years, several speech interface applications have also been developed which exploit the low ultrasonic frequency region to augment human-computer interfacing. These devices tend to operate just above the threshold of human hearing where signals can be generated and detected using off-the-shelf audio hardware components. Mechanical index has long been one of the main criteria used for determining safety limits for human exposure to ultrasound, however it is known to be inaccurate below about 500 kHz. This paper revisits the mathematical and physical foundations of the mechanical index, in particular transient cavitation, and applies these to the low-frequency ultrasound region. Simulations are performed to evaluate the effects on both blood and water. From the results, a new mechanical index formulation is proposed, which extends down to significantly lower frequencies. The aim is to provide a gauge for determining bio-effects of emerging and future low frequency ultrasonic applications operating around 20 kHz to 100 kHz.

The mechanical index (MI) quantifies the likelihood that exposure to diagnostic ultrasound will produce an adverse biological effect by a nonthermal mechanism. The current formulation of the MI is based on inertial cavitation thresholds in two liquids, water and blood, as calculated by a formalism assuming very short pulse durations. Although tissue contains a high proportion of water, it is not a liquid but a viscoelastic solid. Further, acoustic radiation force impulse imaging employs high-intensity pulses up to several hundred acoustic periods long. The effect of these differences was studied in water, blood and five representative tissues.

This study is focused on cellular uptake (in vitro) and microdistribution (in vivo) using a novel multifunctional drug delivery system consisting of microbubbles (MBs) stabilized by polymeric nanoparticles (NPs). Prostate cancer cells in suspension were incubated with NP-loaded MBs and then exposed to focused ultrasound (US, 300 kHz). Cellular uptake was measured by flow cytometry. To study microdistribution of the NPs in prostate tumors, particles were injected intravenously into mice bearing subcutaneous prostate xenografts. The tumors were exposed to focus US 5 min or 24 h after the injection using 300 kHz or 5 MHz US. Tumors were frozen and sections were analyzed by confocal laser scanning microscope (CLSM). Fluorescent labeled lectin was used to stain the blood vessels. The in vitro study shows enhancement of cellular uptake in the presence of US compared to untreated cells. Cellular uptake of NPs increased with increase in mechanical index. Analysis of confocal images of tumor slices showed an enhanced uptake and improved penetration of NPs after US exposure. These effects might be due to cavitation and radiation forces. The results show the potential of the novel multifunctional drug delivery system to improve cancer therapy.

This work examines clinical feasibility of using noninvasive transthoracic echocardiography techniques to visualize temporal variations of stiffness through the cardiac cycle using acoustic radiation force impulse (ARFI) imaging. Custom M-mode ARFI sequences were implemented on a Verasonics Research Platform using a Philips/ATL P4-2 phased-array echocardiography transducer. The research systems robust power supply, full parallel-receive capability, and programmable interface enabled sustained excitations, rapid data acquisition, and real-time processing and display of images in the clinic. An extended radiation force pulse length of 480 μs was used to produce tissue displacements up to 12μm around a region of excitation focused at 3 cm. Quadratic motion filters were used to separate ARFI excitation-induced displacements from intrinsic cardiac and respiratory physiological motion artifacts. Acoustic intensity and face heating measurements, as well as finite element method tissue focal heating simulations, were completed. These measurements and simulations calibrated the sequences with respect to the FDA acoustic exposure limits for intensity, mechanical index (MI) and tissue heating. Tests were conducted in phantom and animal models in preparation for the clinical trial. A series of 7 healthy volunteers were scanned in accordance with an approved Duke University Medical Center Institutional Review Board (IRB) protocol. Measurements were acquired from the apical 4 chamber view of the apex, at power levels with MI's ranging from 1.9-3.0. During each M-mode ARFI acquisition, the matched ECG signal was acquired, enabling registration with cardiac cycle. The M-mode ARFI displacement images reflect the expected myocardial stiffness changes through the cardiac cycle, with greatest displacements in diastole and lowest in systole. In the 7 volunteers, the mean displacements throughout the cardiac cycle rose with increasing transmit power level. The ratio of diastolic-to-systolic displacement was examined as a possible indicator of myocardial health. In this study, the measured ratios were in range up to 3.1:1 for the 7 patients, showing agreement with previous ratios reported by an animal studies using transthoracic, intracardiac and epicardial imaging methods. These preliminary clinical results support the feasibility of real-time imaging of cardiac stiffness in vivo using transthoracic ARFI imaging.

In medical applications, the amplitude of ultrasonic pulses is often constrained by mechanical considerations summarized by a mechanical index. We apply the ideal observer approach in a simulation environment to evaluating the role of mechanical index limits on task performance in b-mode ultrasonic imaging. We simulate a linear array operating at 15 MHz and 60% fractional bandwidth, and consider three tasks related to breast sonography at a depth of 4 cm. The ideal observer suggests that there are gains in performance--and hence the quantity of diagnostic information--as the limit on mechanical index is raised. However these gains are almost completely erased after computation of a standard b-mode envelope.

This study intends to identify the best pulse sequences for ultrasound contrast imaging of the carotid artery by comparing a fairly exhaustive list of pulse sequences reported in literature. A good candidate must provide sensitive detection of contrast microbubbles, efficient suppression of tissue echoes and prevent artifacts. Especially the far wall artifact caused by nonlinear propagation through contrast agent dramatically impairs the detection of microbubbles in any region located behind a vessel. Pulse inversion, amplitude modulation, chirp reversal, subharmonic imaging, pulse subtraction time delay, radial modulation and ring-down imaging are investigated in vitro. A focused single-element transducer used in pulse-echo mode transmits ultrasound waves and receive backscattered signals in the frequency range of 3 MHz to 8 MHz. Transmitted waveforms are designed with a low mechanical index between 0.1 and 0.2. In a water tank, the transducer acquires a single line through a thin-wall tube containing diluted (1:5000) contrast agent (SonoVue, Bracco). A thin metallic wire is placed in front of the tube and a piece of rubber is positioned behind the tube to evaluate the contrast-to-tissue ratio (CTR) and the contrast-to-artifact ratio (CAR), respectively. The contrast-to-noise ratio (CNR) is determined by comparing backscattered signals from contrast agent with that of pure water. Only subharmonic imaging and ring-down imaging are free from the far wall artifact. Summing CNR, CAR and CTR, ring-down imaging (Hansen et al., IEEE Trans. UFFC, vol. 58(2), 2011) turns out to be the best candidate (CNR+CAR+CTR = 18 dB).

Therapeutic ultrasound has been used in the brain for thrombolysis and high intensity focused ultrasound (HIFU) therapy. A low-frequency clinical study of sonothrombolysis, called the transcranial low-frequency ultrasound-mediated thrombolysis in brain ischemia (TRUMBI), has revealed an increased incidence of hemorrhage, which may have been caused by cavitation. The goal of this study is to determine if there is a comparable risk of generating cavitation during HIFU brain therapy at different frequencies.Two approaches are used to transmit acoustic energy through the skull to the brain: low-frequency ultrasound, with a wavelength that is larger than the skull thickness, and high frequency ultrasound, that is sensitive to aberrations and must use corrective techniques. At high frequency, the mechanical index (MI) is lower, which translates to a higher cavitation threshold. In addition to the nonfocused geometry of the 300 kHz sonothrombolysis treatment device, two types of focused therapeutic transducers were modeled: a low frequency 220 kHz transducer and a 1 MHz transducer that required aberration correction with a time-reversal approach, representing the lowest and highest frequencies currently used. The acoustic field was modeled with a finite difference fullwave acoustic code developed for large scale computations, that is, capable of simulating the entire brain volume. Various MI thresholds and device geometries were considered to determine the regions of the brain that have an increased probability of cavitation events.For an equivalent energy deposition rate, it is shown that at a low frequency there is a significant volume of the brain that is above the MI thresholds. At a high frequency, the volume is over 3 orders of magnitude smaller, and it is entirely confined to a compact focal spot.The significant frequency dependence of the volumes with an increased probability of cavitation can be attributed to two factors: First, the volume encompassed by the focal region depends on the cube of the frequency. Second, the heat deposition increases with frequency. In conclusion, according to these simulations, the acoustic environment during HIFU brain therapy at 1 MHz is not conducive to a high probability of cavitation in extended regions of the brain.

Ultrasound and intravenous microbubbles have been used in recanalizing intravascular thrombi which cause ischemic stroke, myocardial infarction, and other vascular thrombo-embolic events. In previous studies, inertial cavitation (IC) produced by high mechanical index (MI) ultrasound has been shown to be effective in dissolving acute thrombi. However, IC is more likely to cause adverse bioeffects than stable cavitation (SC). This study indicates that SC induced by intermediate MI ultrasound (1.6 MHz, 0.35 MI, 50 cycles) is as effective for acute thrombus dissolution as IC by high MI ultrasound (1.6 MHz, 1.1 MI, 2.5 cycles).

The development of targeted ultrasound contrast agents has brought ultrasound imaging into the arena of molecular imaging. In particular, targeted microbubbles are now utilized to detect angiogenesis in the early phase of tumor development. The detection of bound agents in a low mechanical index imaging scheme is desirable for clinical application. Here, we present a novel quantitative ultrasound contrast imaging method using the 2D Fourier transform for such targeted contrast agents. In this study, microbubbles coated with RGD peptides were used to target αvβ3-bearing endothelial cells. The quantitative imaging method was based on the low mechanical-index contrast pulse sequencing (CPS) technology (Siemens Medical Solutions) and employed time-domain averaging to suppress echoes from freely circulating microbubbles, thus enhancing echoes from bound microbubbles. Intensity normalization over the ROI was employed to compensate for variations encountered during in vivo studies, such as differences in injected microbubble dose and vascular morphology. The spatial Fourier transform of the time-averaged images was calculated to assess image smoothness. Then, we compared the spatial Fourier spectra of the images and calculated the −6 dB Fourier width with and without high amplitude microbubble destruction. The proposed imaging method was verified in vitro. Images were acquired from Met-1 syngeneic tumors in mice after injection, 7 minutes later, and after a destructive sequence. The normalized intensity of bound microbubbles in the tumor region was 0.8±0.1, compared with a normalized intensity of 0.02±0.02 in the same region for a control (non-targeted) microbubble and 0.1±0.1 for a scrambled peptide. The normalized intensity of bound microbubbles in the surrounding vessels and tissues was negligible. The −6 dB Fourier width was 2.7±0.2 cycles/mm for targeted and 0.8±0.1 cycles/mm for freely circulating control microbubbles. With the application of image averaging, subtraction of the microbubble-image intensity after a destructive pulse was not required for bound bubble discrimination. The quantitative strategy using the spatial Fourier Transform was successfully implemented and is independent of attenuation.

Ultrasound exposure parameters that maximize drug release from liposomes were studied using two ultrasound transducers (300 kHz and 1 MHz). Variations in acoustic peak negative pressure (260–2037 kPa), temporary average intensity (0.05–6.08 W/cm2), mechanical index (MI) (0.4–3.0), insonation time (0.5–20 minutes), pulse repetition frequency (PRF) (100–1000 Hz) and pulse length (0.05–0.4 ms) were studied. Drug release was more efficient at 300 kHz compared to 1 MHz. A certain threshold in peak negative pressure had to be overcome to obtain drug release, and the pressure needed was lower at 300 kHz (0.72 MPa) than at 1 MHz (1. 39 MPa) which corresponds to MI values of 1.30 and 1.39 respectively. Above the threshold the release increased with increasing temporal average intensity, peak negative pressure, MI and duty cycle (i.e PRF and pulse length). The release was found to increase with exposure time, where the profile followed a first-order kinetics. The first-order rate constant for the release increased linearly with MI. This indicates that the release of the drug from liposomes was caused by mechanical rather than thermal effects. The results demonstrate that ultrasound has a potential in enhancing drug release from liposomes and can potentially improve cancer therapy.

This research aims to assess the safety of 300 kHz ultrasound (300 kHz) for disruption of the blood brain barrier (BBB) to enable drug delivery to the brain of non-human primates (NHP). The approach is to measure in-situ acoustic pressure (ISAP) in an ex-vivo cadaver skull model to predict acoustic pressure in the brains of live NHP subjects. Two dual-transducer therapeutic ultrasound systems were built: an in-vivo system to expose live NHP subjects to 300 kHz, and an ex-vivo system to expose NHP cadaver skulls to 300 kHz and map ISAP within the skulls. The highest acoustic pressure sites (hot spots) were found in the center of the skulls between the two transducers. The average ISAP was a mechanical index (MI) of 0.2. MI is defined as the in-situ peak rarefactional acoustic pressure divided by the square root of frequency. MI values ranged from 0.01 to 0.98 MI. Histology from 300-kHz exposed NHP subjects showed evidence of delivery of BBB markers with no evidence of bleeding or other harmful bioeffects. Feasibility was demonstrated for safe 300 kHz enabled BBB disruption, in a treatment range below 1.0 MI.

The response of the rigid shelled contrast agent biSphere® has been previously studied optically and acoustically over a range of mechanical index (MI). Free bubble models have been used to model the behaviour of rigid shelled microbubbles (MBs). In this work a new theoretical model is proposed and is compared with available ones in terms of agreement with experimental acoustic responses from single MBs.

In this study, we investigated the feasibility of dual-mode intracranial catheter transducers for visualization and treatment of tumors in the brain. Feasibility is demonstrated in two ways: 1) by developing a 12 Fr, integrated matrix and linear array catheter transducer prototype for combined real-time 3D imaging and heating, and 2) by testing 3.5 Fr IVUS-catheter-packageable transducers for therapeutic potential. The 3.6 MHz, 12 Fr catheter acquired real-time 3D images of canine brain structures in vivo while placed in the superior sagittal sinus via a burr hole in the skull, and achieved a 3.5°C temperature rise in tissue-mimicking material at a 2 cm focus in vitro. The IVUS-sized prototype transducers were tested for maximum intensity and mechanical index, and a thermal model was used to extrapolate and estimate each transducer's maximum potential temperature rise in brain tissue.

The ability to localize, both spatially and temporally, a chemotherapeutic agent could be used to reduce the systemic toxicity associated with conventional chemotherapy regimens. Ultrasound (US)-triggered drug delivery systems, such as microbubbles or emulsions, present the ability to localize the effect of chemotherapy agents. In the case of phase-shift emulsions, the activation by US results in the production of gas bubbles - a process known as acoustic droplet vaporization (ADV). Here, the ability of ADV to selectively release chlorambucil (CHL), a clinically-used chemotherapeutic agent, from an emulsion is tested in vitro. A micron-sized emulsion, stabilized by bovine serum albumin, was made using perfluoropentane, soybean oil, and CHL. A linear array (6.3 MHz, mechanical index = 0.7) was used to vaporize the CHL-laden emulsion after introduction into chambers containing adherent Chinese hamster ovary (CHO) cells. An 84.3±3.8% growth inhibition was observed with ultrasound, compared to 46.7±7.6% growth inhibition without ultrasound. Therefore, ADV has the potential to localize the release of an agent encapsulated within the triggered emulsion.

Cavitation bubbles have aroused mush attention for their significant promise in ultrasonic contrast imaging, targeted therapy and monitoring of high-intensity focused ultrasound (HIFU) therapy. In this paper, a model using a dual-frequency driving pressure for subharmonics generation from cavitation bubbles is constructed. By calculation of the Fourier transformation to the Keller-Milksis equation, we show that bubbles with appropriate radii produce significant subharmonic components within backscatter spectrum. In contrast to the case of single-frequency driving pressure, subharmonics at dual- frequency driving pressure can be generated for higher value of mechanical index (MI) and wider range of initial radii of bubbles. The subharmonic wave is not easy to be absorbed by soft tissues during its propagation compared with higher harmonic wave, and thus subharmonic mode-imaging method for monitoring HIFU therapy maybe has a potential application in providing proper signal-to-noise ratio.

The use of ultrasound contrast agents for gene and drug delivery has shown much promise in many recent studies, while simultaneously raising questions regarding the safety of methods used. There is currently no consensus on the optimal safe operating regime, since the mechanisms for contrast- enhanced drug delivery are not well-understood. Here, the mechanisms for increased permeability are investigated by using high-speed microscopy to directly observe microbubbles in a vessel phantom and ex vivo preparation. The vessel phantom was a small block (30 mm times 20 mm times 3 mm) of 0.75% agarose gel with a 200-mum diameter cylindrical channel along the length of the block. For ex vivo work, the preparation used was an excised rat cecum with a cannulated ileocolic vein to allow for microbubble perfusion. Images of microbubble oscillation were acquired using a strobe imaging system with a 30 nsec flash provided by a copper vapor laser. Images of vessel wall disruption and tunnels formed in the wall were acquired with 1, 2.25, and 5 MHz center frequencies using microbubble concentration, duty cycle, and rarefactional pressures that were similar to those used for in vivo drug delivery experiments. Observations from in vitro and ex vivo studies indicate that expansion of microbubbles within small vessels is smaller than in an infinite fluid and that bubbles persist over many transmitted cycles and pulses. In vitro studies over a long pulse train indicate that microbubbles create pores within the tissue phantom and travel long distances along the beam axis. The width and depth of tunnels created by microbubbles at varied frequencies indicate a stronger dependence on insonation frequency than suggested by mechanical index.

A simulation study is performed to present results concerning 3D aberration correction for harmonic imaging. Two different correction schemes (a pure time-delay correction and a time-delay and amplitude correction) are employed along with estimation based on either the received first- or second-harmonic frequency. An aberrating body wall is implemented as a 20 mm delay-screen body wall using eight screens, and is tuned to match human abdominal wall characteristics. The transmit pressure of the first harmonic is set to not succeed a mechanical index of 1.1 for the uncorrected case and a pure time-delay correction. Using a time-delay and amplitude correction, the total acoustic energy transmitted is equal to that of the uncorrected case. The total amount of generated second-harmonic energy increases with approximately 1 dB for a pure time-delay correction and about 2 dB for a time-delay and amplitude correction, both estimated at the received first-harmonic frequency. The general side-lobe level of the first- and second-harmonic focal point beam profile averaged over circles around the transducer axis is lowered with 2-10 dB for both correction schemes relative to the uncorrected case.

Introduction of a temporally periodic pressure field within a fluid can induce forced oscillations to bubbles present therein. The resultant [radial] bubble dynamics are a complex function of several parameters, including the driving pressure amplitude, and proximity to nearby boundaries, such as vessel walls, or indeed, other bubbles. Recently, experimentation gauged towards the development of a quantitative understanding of [acoustically] driven bubbles of micrometer dimensions, especially when close to boundaries, has become a challenge of heightened academic and industrial interest. In pursuit of this, the present authors pioneered a new approach to such measurements that exploits optical trapping to locate microbubbles at prescribed displacements from a boundary [1,2]. Here, we extend our previous method and report the first comprehensive study that has observed the dynamical behavior of isolated single micro-bubbles (the commercially available ultrasound contrast agent: SonoVue) that had been optically trapped over a range of well-defined displacements from a rigid boundary. All of the measurements were conducted at a mechanical index (MI) > 3. We noted a distinct variance in micro-bubble behavior across all quiescent radii and stand-off parameter, and also correlated bubble outcome statistics with measured radial dynamics. Finally, we suggest that the procedure outlined can be exploited to design ‘next-generation’ microbubbles with specific response characteristics.

Experimental studies of the dynamics of ultrasound contrast agents (UCAs) both in vitro and in vivo indicate that UCA oscillation can enhance vascular permeability and increase extravasation of drugs and genes at a target site. For improving local drug and gene delivery efficiency and minimizing any permanent damage to small blood vessels, it is essential to examine the mechanism whereby vascular permeability is enhanced and vascular injuries in small blood vessels are produced. In this work, we proposed a theoretical model to study the dynamics of the oscillation of UCAs and microvessels with MHz-frequency ultrasound (US) with emphasis on the potential application of drug and gene delivery. Numerical results demonstrate that the presence of UCAs with ultrasound can substantially increase the transmural pressure through the blood vessel and thus enhance the vascular permeability. For a microbubble within an 8 to 40-micron vessel with a low peak negative pressure such as 0.1 MPa and a center frequency of 1 MHz, small changes in the microbubble oscillation frequency and maximum diameter are observed. Strong nonlinear oscillation occurs and the induced circumferential stress in the vessel increases as the ultrasound pressure increases. For the compliable vessels considered in this work, 0.2 MPa PNP at 1 MHz is predicted to be sufficient for microbubble fragmentation. However, for a rigid vessel 0.5 MPa PNP at 1 MHz may not be sufficient to fragment the bubbles. For a center frequency of 1 MHz, a peak negative pressure of 0.5 MPa is predicted to be sufficient to induce the stress in the vessel which exceeds the vascular rupture limit in a small (diameter less than 15 mum) compliant vessel. As vasculature becomes more rigid, the UCA oscillation and vessel dilation decrease, however the circumferential stress is predicted to increase. The circumferential stress in the vessel increases as the vessel size decreases or the center frequency increases. For the two frequencies considered in this work, the circumferential stress does not scale as the inverse of the square root of the acoustic frequency va in the Mechanical Index, but rather has a stronger frequency dependence, 1/va

Characterization of ultrasonic contrast agents (UCAs) destruction provides important information for the design of contrast-assisted perfusion imaging. In this paper, we proposed an acoustical method to demonstrate the relationship between different acoustic exposure conditions and the degree of UCAs destruction. The method also provides a simple and convenient way to determine the bubble destruction threshold. The insonation parameters include transmission pressure, pulse frequency and pulse cycles. The term of destruction percentage (DP) represented the ratio of backscattered power with and without acoustic insonation. The results showed that the DP increased with decreasing pulse frequency, but with increasing transmission acoustic pressure and pulse cycle. Over 90% UCAs could be destroyed at 0.15, 0.4, 0.7 and 0.8 MPa in 1, 2.25, 5 and 7.5 MHz pulse under 10-cycle pulses condition, respectively. In addition, there was an exponential relationship between DP and acoustic pressure, pulse cycle and thus the UCAs destruction threshold parameters could be predicted by the exponential curve. The UCAs destruction threshold is not related to the mechanical index. Potential applications of this method include UCAs high resolution destruction/replenishment imaging model, microbubble cavitation, sonoporation in drug delivery and gene therapy

The paper introduces a simulator of echo contrast imaging (SECI) which simulates the entire process of echographic imaging with a contrast agent. It gives the possibility, through a GUI (graphical user interface), to choose simulation parameters such as the contrast agent, the probe (especially size, geometry and central frequency), the imaging modality or the echoscanner tuning. The aim of SECI is to simulate the image, considering a particular configuration. The simulator was validated by a set of in-vitro experiments using a tissue mimicking phantom (ATS Lab) and a solution of Sonovue/spl trade/ (Bracco Research). Concentrations and mechanical index (MI) were the variable parameters. In both the experimental and simulated data, two regions of interest (ROI) at the same depth were selected, one inside the bubbles cloud, the other in the tissue. The agent-to-tissue ratios (ATR) were then calculated in those ROI. The ratio was computed using first the gray level of the image and then the power spectrum over a particular frequency window of the RF signal.

Our laboratory previously has demonstrated the ability of liquid perfluoro-carbon (PFC) nanoparticles to serve as site-targeted contrast and therapeutic agents by specifically binding molecular markers. In this study, we sought to enhance the delivery of targeted PFC nanoparticles to cells expressing the integrin /spl alpha//sub v//spl beta//sub 3/ using clinical levels of ultrasound energy. Using an Acuson Sequoia imager, we demonstrate that ultrasound applied at 2MHz and 1.9 mechanical index (MI) for a five minute duration enhances the cellular interaction of targeted perfluorocarbon nanoparticles by melanoma cancer cells in vitro without any untoward effect from the ultrasound energy itself upon either the cells or the perfluorocarbon nanoparticles. Employing a custom designed specimen chamber, we have visualized a fundamental physical mechanism for this effect, that of acoustic radiation force (primary and secondary) on the particles, that may contribute to enhanced delivery. Accordingly, our study shows that enhancement of cellular interaction with targeted nanoparticles is feasible by noncavitational mechanisms. Ultrasonically-enhanced delivery of tracers or drugs to a wide variety of pathologic tissues may be useful for augmenting drug delivery after targeting, while limiting untoward effects on other tissues.