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Assessing the coronary circulation with contrast-enhanced echocardiography has high clinical relevance. However, it is not being routinely performed in clinical practice because the current clinical tools generally cannot provide adequate image quality. The contrast agent's visibility in the myocardium is generally poor, impaired by motion and nonlinear propagation artifacts. The established multipulse contrast schemes (MPCSs) and the more experimental singular value decomposition (SVD) filter also fall short to solve these issues. Here, we propose a scheme to process amplitude modulation/amplitude-modulated pulse inversion (AM/AMPI) echoes with higher order SVD (HOSVD) instead of conventionally summing the complementary pulses. The echoes from the complementary pulses form a separate dimension in the HOSVD algorithm. Then, removing the ranks in that dimension with dominant coherent signals coming from tissue scattering would provide the contrast detection. We performed both in vitro and in vivo experiments to assess the performance of our proposed method in comparison with the current standard methods. A flow phantom study shows that HOSVD on AM pulsing exceeds the contrast-to-background ratio (CBR) of conventional AM and an SVD filter by 10 and 14 dB, respectively. In vivo porcine heart results also demonstrate that, compared to AM, HOSVD improves CBR in open-chest acquisition (up to 19 dB) and contrast ratio (CR) in closed-chest acquisition (3 dB).

Understanding and controlling the ultrasound contrast agent (UCA)'s response to an applied ultrasound pressure field are crucial when investigating ultrasound imaging sequences and therapeutic applications. The magnitude and frequency of the applied ultrasonic pressure waves affect the oscillatory response of the UCA. Therefore, it is important to have an ultrasound compatible and optically transparent chamber in which the acoustic response of the UCA can be studied. The aim of our study was to determine the in situ ultrasound pressure amplitude in the ibidi μ -slide I Luer channel, an optically transparent chamber suitable for cell culture, including culture under flow, for all microchannel heights (200, 400, 600, and [Formula: see text]). First, the in situ pressure field in the 800- [Formula: see text] high channel was experimentally characterized using Brandaris 128 ultrahigh-speed camera recordings of microbubbles (MBs) and a subsequent iterative processing method, upon insonification at 2 MHz, 45° incident angle, and 50-kPa peak negative pressure (PNP). Control studies in another cell culture chamber, the CLINIcell, were compared with the obtained results. The pressure amplitude was -3.7 dB with respect to the pressure field without the ibidi μ -slide. Second, using finite-element analysis, we determined the in situ pressure amplitude in the ibidi with the 800- [Formula: see text] channel (33.1 kPa), which was comparable to the experimental value (34 kPa). The simulations were extended to the other ibidi channel heights (200, 400, and [Formula: see text]) with either 35° or 45° incident angle, and at 1 and 2 MHz. The predicted in situ ultrasound pressure fields were between -8.7 and -1.1 dB of the incident pressure field depending on the listed configurations of ibidi slides with different channel heights, applied ultrasound frequencies, and incident angles. In conclusion, the determined ultrasound in situ pressures demonstrate the acoustic compatibility of the ibidi μ -slide I Luer for different channel heights, thereby showing its potential for studying the acoustic behavior of UCAs for imaging and therapy.

Two-dimensional (2-D) arrays offer volumetric imaging capabilities without the need for probe translation or rotation. A sparse array with elements seeded in a tapering spiral pattern enables one-to-one connection to an ultrasound machine, thus allowing flexible transmission and reception strategies. To test the concept of sparse spiral array imaging, we have designed, realized, and characterized two prototype probes designed at 2.5-MHz low-frequency (LF) and 5-MHz high-frequency (HF) center frequencies. Both probes share the same electronic design, based on piezoelectric ceramics and rapid prototyping with printed circuit board substrates to wire the elements to external connectors. Different center frequencies were achieved by adjusting the piezoelectric layer thickness. The LF and HF prototype probes had 88% and 95% of working elements, producing peak pressures of 21 and 96 kPa/V when focused at 5 and 3 cm, respectively. The one-way -3-dB bandwidths were 26% and 32%. These results, together with experimental tests on tissue-mimicking phantoms, show that the probes are viable for volumetric imaging.

Atrial fibrillation (AF) is the most common cardiac arrhythmia and is normally treated by RF ablation. Intracardiac echography (ICE) is widely employed during RF ablation procedures to guide the electrophysiologist in navigating the ablation catheter, although only 2-D probes are currently clinically used. A 3-D ICE catheter would not only improve visualization of the atrium and ablation catheter, but it might also provide the 3-D mapping of the electromechanical wave (EW) propagation pattern, which represents the mechanical response of cardiac tissue to electrical activity. The detection of this EW needs 3-D high-frame-rate imaging, which is generally only realizable in tradeoff with channel count and image quality. In this simulation-based study, we propose a high volume rate imaging scheme for a 3-D ICE probe design that employs 1-D micro-beamforming in the elevation direction. Such a probe can achieve a high frame rate while reducing the channel count sufficiently for realization in a 10-Fr catheter. To suppress the grating-lobe (GL) artifacts associated with micro-beamforming in the elevation direction, a limited number of fan-shaped beams with a wide azimuthal and narrow elevational opening angle are sequentially steered to insonify slices of the region of interest. An angular weighted averaging of reconstructed subvolumes further reduces the GL artifacts. We optimize the transmit beam divergence and central frequency based on the required image quality for EW imaging (EWI). Numerical simulation results show that a set of seven fan-shaped transmission beams can provide a frame rate of 1000 Hz and a sufficient spatial resolution to visualize the EW propagation on a large 3-D surface.

In a recent study, we proposed a technique to correct aberration caused by the skull and reconstruct a transcranial B-mode image with a refraction-corrected synthetic aperture imaging (SAI) scheme. Given a sound speed map, the arrival times were calculated using a fast marching technique (FMT), which solves the Eikonal equation and, therefore, is computationally expensive for real-time imaging. In this article, we introduce a two-point ray tracing method, based on Fermat's principle, for fast calculation of the travel times in the presence of a layered aberrator in front of the ultrasound probe. The ray tracing method along with the reconstruction technique is implemented on a graphical processing unite (GPU). The point spread function (PSF) in a wire phantom image reconstructed with the FMT and the GPU implementation was studied with numerical synthetic data and experiments with a bone-mimicking plate and a sagittally cut human skull. The numerical analysis showed that the error on travel times is less than 10% of the ultrasound temporal period at 2.5 MHz. As a result, the lateral resolution was not significantly degraded compared with images reconstructed with FMT-calculated travel times. The results using the synthetic, bone-mimicking plate, and skull dataset showed that the GPU implementation causes a lateral/axial localization error of 0.10/0.20, 0.15/0.13, and 0.26/0.32 mm compared with a reference measurement (no aberrator in front of the ultrasound probe), respectively. For an imaging depth of 70 mm, the proposed GPU implementation allows reconstructing 19 frames/s with full synthetic aperture (96 transmission events) and 32 frames/s with multiangle plane wave imaging schemes (with 11 steering angles) for a pixel size of [Formula: see text]. Finally, refraction-corrected power Doppler imaging is demonstrated with a string phantom and a bone-mimicking plate placed between the probe and the moving string. The proposed approach achieves a suitable frame rate for clinical scanning while maintaining the image quality.

Common clamp-on ultrasonic flow meters consist of two single-element transducers placed on the pipe wall. Flow speed is measured noninvasively, i.e., without interrupting the flow and without perforating the pipe wall, which also minimizes safety risks and avoids pressure drops inside the pipe. However, before metering, the transducers have to be carefully positioned along the pipe axis to correctly align the acoustic beams and obtain a well-calibrated flowmeter. This process is done manually, is dependent on the properties of the pipe and the liquid, does not account for pipe imperfections, and becomes troublesome on pipelines with an intricate shape. Matrix transducer arrays are suitable to dynamically steer acoustic beams and realize self-alignment upon reception, without user input. In this work, the design of a broadband 37×17 matrix array (center frequency of 1 MHz) to perform clamp-on ultrasonic flow measurements over a wide range of liquids ( c=1000-2000 m/s, α ≤ 1 dB/MHz · cm) and pipe sizes is presented. Three critical aspects were assessed: efficiency, electronic beam steering, and wave mode conversion in the pipe wall. A prototype of a proof-of-concept flowmeter consisting of two 36-element linear arrays (center frequency of 1.1 MHz) was fabricated and placed on a 1-mm-thick, 40-mm inner diameter stainless steel pipe in a custom-made flow loop filled with water. At resonance, simulated and measured efficiencies in water of the linear arrays compared well: 0.88 and 0.81 kPa/V, respectively. Mean flow measurements were achieved by electronic beam steering of the acoustic beams and using both compressional and shear waves generated in the pipe wall. Correlation coefficients of between measured and reference flow speeds were obtained, thus showing the operational concept of an array-based clamp-on ultrasonic flowmeter.

Suppressing tissue clutter is an essential step in blood flow estimation and visualization, even when using ultrasound contrast agents. Blind source separation (BSS)-based clutter filter for high-framerate ultrasound imaging has been reported to perform better in tissue clutter suppression than the conventional frequency-based wall filter and nonlinear contrast pulsing schemes. The most notable BSS technique, singular value decomposition (SVD) has shown compelling results in cases of slow tissue motion. However, its performance degrades when the tissue motion is faster than the blood flow speed, conditions that are likely to occur when imaging the small vessels, such as in the myocardium. Independent component analysis (ICA) is another BSS technique that has been implemented as a clutter filter in the spatiotemporal domain. Instead, we propose to implement ICA in the spatial domain where motion should have less impact. In this work, we propose a clutter filter with the combination of SVD and ICA to improve the contrast-to-background ratio (CBR) in cases where tissue velocity is significantly faster than the flow speed. In an in vitro study, the range of fast tissue motion velocity was 5-25 mm/s and the range of flow speed was 1-12 mm/s. Our results show that the combination of ICA and SVD yields 7-10 dB higher CBR than SVD alone, especially in the tissue high-velocity range. The improvement is crucial for cardiac imaging where relatively fast myocardial motions are expected.

Superheated nanodroplet (ND) vaporization by proton radiation was recently demonstrated, opening the door to ultrasound-based in vivo proton range verification. However, at body temperature and physiological pressures, perfluorobutane nanodroplets (PFB-NDs), which offer a good compromise between stability and radiation sensitivity, are not directly sensitive to primary protons. Instead, they are vaporized by infrequent secondary particles, which limits the precision for range verification. The radiation-induced vaporization threshold (i.e., sensitization threshold) can be reduced by lowering the pressure in the droplet such that ND vaporization by primary protons can occur. Here, we propose to use an acoustic field to modulate the pressure, intermittently lowering the proton sensitization threshold of PFB-NDs during the rarefactional phase of the ultrasound wave. Simultaneous proton irradiation and sonication with a 1.1 MHz focused transducer, using increasing peak negative pressures (PNPs), were applied on a dilution of PFB-NDs flowing in a tube, while vaporization was acoustically monitored with a linear array. Sensitization to primary protons was achieved at temperatures between [Formula: see text] and 40 °C using acoustic PNPs of relatively low amplitude (from 800 to 200 kPa, respectively), while sonication alone did not lead to ND vaporization at those PNPs. Sensitization was also measured at the clinically relevant body temperature (i.e., 37 °C) using a PNP of 400 kPa. These findings confirm that acoustic modulation lowers the sensitization threshold of superheated NDs, enabling a direct proton response at body temperature.

Transcranial ultrasound imaging (TUI) is a diagnostic modality with numerous applications, but unfortunately, it is hindered by phase aberration caused by the skull. In this article, we propose to reconstruct a transcranial B-mode image with a refraction-corrected synthetic aperture imaging (SAI) scheme. First, the compressional sound velocity of the aberrator (i.e., the skull) is estimated using the bidirectional headwave technique. The medium is described with four layers (i.e., lens, water, skull, and water), and a fast marching method calculates the travel times between individual array elements and image pixels. Finally, a delay-and-sum algorithm is used for image reconstruction with coherent compounding. The point spread function (PSF) in a wire phantom image and reconstructed with the conventional technique (using a constant sound speed throughout the medium), and the proposed method was quantified with numerical synthetic data and experiments with a bone-mimicking plate and a human skull, compared with the PSF achieved in a ground truth image of the medium without the aberrator (i.e., the bone plate or skull). A phased-array transducer (P4-1, ATL/Philips, 2.5 MHz, 96 elements, pitch = 0.295 mm) was used for the experiments. The results with the synthetic signals, the bone-mimicking plate, and the skull indicated that the proposed method reconstructs the scatterers with an average lateral/axial localization error of 0.06/0.14 mm, 0.11/0.13 mm, and 1.0/0.32 mm, respectively. With the human skull, an average contrast ratio (CR) and full-width-half-maximum (FWHM) of 37.1 dB and 1.75 mm were obtained with the proposed approach, respectively. This corresponds to an improvement of CR and FWHM by 7.1 dB and 36% compared with the conventional method, respectively. These numbers were 12.7 dB and 41% with the bone-mimicking plate.

Current ultrasonic clamp-on flow meters consist of a pair of single-element transducers that are carefully positioned before use. This positioning process consists of manually finding the distance between the transducer elements, along the pipe axis, for which maximum signal-to-noise ratio (SNR) is achieved. This distance depends on the sound speed, thickness, and diameter of the pipe and on the sound speed of the liquid. However, these parameters are either known with low accuracy or completely unknown during positioning, making it a manual and troublesome process. Furthermore, even when sensor positioning is done properly, uncertainty about the mentioned parameters, and therefore on the path of the acoustic beams, limits the final accuracy of flow measurements. In this research, we address these issues using an ultrasonic clamp-on flow meter consisting of two matrix arrays, which enables the measurement of pipe and liquid parameters by the flow meter itself. Automatic parameter extraction, combined with the beam-steering capabilities of transducer arrays, yields a sensor capable of compensating for pipe imperfections. Three parameter extraction procedures are presented. In contrast to similar literature, the procedures proposed here do not require that the medium be submerged nor do they require a priori information about it. First, axial Lamb waves are excited along the pipe wall and recorded with one of the arrays. A dispersion curve-fitting algorithm is used to extract bulk sound speeds and wall thickness of the pipe from the measured dispersion curves. Second, circumferential Lamb waves are excited, measured, and corrected for dispersion to extract the pipe diameter. Third, pulse-echo measurements provide the sound speed of the liquid. The effectiveness of the first two procedures has been evaluated using simulated and measured data of stainless steel and aluminum pipes, and the feasibility of the third procedure has been evaluated using simulated data.

Volumetric ultrasound imaging of blood flow with microbubbles enables a more complete visualization of the microvasculature. Sparse arrays are ideal candidates to perform volumetric imaging at reduced manufacturing complexity and cable count. However, due to the small number of transducer elements, sparse arrays often come with high clutter levels, especially when wide beams are transmitted to increase the frame rate. In this study, we demonstrate with a prototype sparse array probe and a diverging wave transmission strategy, that a uniform transmission field can be achieved. With the implementation of a spatial coherence beamformer, the background clutter signal can be effectively suppressed, leading to a signal to background ratio improvement of 25 dB. With this approach, we demonstrate the volumetric visualization of single microbubbles in a tissue-mimicking phantom as well as vasculature mapping in a live chicken embryo chorioallantoic membrane.

High-frame-rate (HFR) echo-particle image velocimetry (echoPIV) is a promising tool for measuring intracardiac blood flow dynamics. In this study, we investigate the optimal ultrasound contrast agent (UCA: SonoVue) infusion rate and acoustic output to use for HFR echoPIV (PRF = 4900 Hz) in the left ventricle (LV) of patients. Three infusion rates (0.3, 0.6, and 1.2 ml/min) and five acoustic output amplitudes (by varying transmit voltage: 5, 10, 15, 20, and 30 V-corresponding to mechanical indices of 0.01, 0.02, 0.03, 0.04, and 0.06 at 60-mm depth) were tested in 20 patients admitted for symptoms of heart failure. We assess the accuracy of HFR echoPIV against pulsed-wave Doppler acquisitions obtained for mitral inflow and aortic outflow. In terms of image quality, the 1.2-ml/min infusion rate provided the highest contrast-to-background ratio (CBR) (3-dB improvement over 0.3 ml/min). The highest acoustic output tested resulted in the lowest CBR. Increased acoustic output also resulted in increased microbubble disruption. For the echoPIV results, the 1.2-ml/min infusion rate provided the best vector quality and accuracy; mid-range acoustic outputs (corresponding to 15-20-V transmit voltages) provided the best agreement with the pulsed-wave Doppler. Overall, the highest infusion rate (1.2 ml/min) and mid-range acoustic output amplitudes provided the best image quality and echoPIV results.

In the above article [1], the authors regret that there was a mistake in calculating the mol% of the microbubble coating composition used. For all experiments, the unit in mg/mL was utilized and the conversion mistake only came when converting to mol% in order to define the ratio between the coating formulation components. The correct molecular weight of PEG-40 stearate is 2046.54 g/mol [2], [3], not 328.53 g/mol. On page 556, Table I should read as shown here.

In the above article [1], the authors regret that there was a mistake in calculating the mol% of the microbubble coating composition. For all experiments, the unit in mg/mL was utilized and the conversion mistake only came when converting to mol% in order to define the ratio between the coating formulation components. The correct molecular weight of PEG-40 stearate is 2046.54 g/mol [2], [3], not 328.53 g/mol. On page 786, paragraph II-A, it should read "The coating was composed of 84.8 mol% DSPC (P6517, Sigma-Aldrich, Zwijndrecht, The Netherlands) or DPPC (850355, Avanti Polar Lipids, Alabaster, AL, USA); 8.2 mol% polyoxyethylene-40-stearate (PEG-40 stearate, P3440, Sigma-Aldrich); 5.9 mol% 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[carboxy(polyethylene glycol)-2000] (DSPE-PEG(2000), 880125, Avanti Polar Lipids); and 1.1 mol% 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[biotinyl(polyethylene glycol)-2000] (DSPE-PEG(2000)-biotin, 880129, Avanti Polar Lipids)."

Phase aberration in transcranial ultrasound imaging (TUI) caused by the human skull leads to an inaccurate image reconstruction. In this article, we present a novel method for estimating the speed of sound and an adaptive beamforming technique for phase aberration correction in a flat polyvinylchloride (PVC) slab as a model for the human skull. First, the speed of sound of the PVC slab is found by extracting the overlapping quasi-longitudinal wave velocities of symmetrical Lamb waves in the frequency-wavenumber domain. Then, the thickness of the plate is determined by the echoes from its front and back side. Next, an adaptive beamforming method is developed, utilizing the measured sound speed map of the imaging medium. Finally, to minimize reverberation artifacts caused by strong scatterers (i.e., needles), a dual probe setup is proposed. In this setup, we image the medium from two opposite directions, and the final image can be the minimum intensity projection of the inherently co-registered images of the opposed probes. Our results confirm that the Lamb wave method estimates the longitudinal speed of the slab with an error of 3.5% and is independent of its shear wave speed. Benefiting from the acquired sound speed map, our adaptive beamformer reduces (in real time) a mislocation error of 3.1, caused by an 8 mm slab, to 0.1 mm. Finally, the dual probe configuration shows 7 dB improvement in removing reverberation artifacts of the needle, at the cost of only 2.4-dB contrast loss. The proposed image formation method can be used, e.g., to monitor deep brain stimulation procedures and localization of the electrode(s) deep inside the brain from two temporal bones on the sides of the human skull.

In our paper titled "Lamb Waves and Adaptive Beamforming for Aberration Correction in Medical Ultrasound Imaging" [1], we mentioned that the superposition of the different symmetric (S) modes in the frequency-wavenumber (f-k) domain results in a high intensity region where its slope corresponds to the longitudinal wave speed in the slab. However, we have recently understood that this high intensity region belongs to the propagation of a wave called lateral wave or head wave [2-5]. It is generated if the longitudinal sound speed of the aberrator (i.e. the PVC slab) is larger than that of water and if the incident wavefront is curved. When the incidence angle at the interface between water and PVC is near the critical angle, the refracted wave in PVC re-radiates a small part of its energy into the fluid (i.e. the head wave). As discussed in [4], if the thickness of the waveguide is larger than the wavelength, the first arriving signal is the head wave. This is also the case in our study [1] where the ultrasound wavelength of a compressional wave in PVC was close to 1 mm, and a PVC slab with a thickness of 8 mm was used.

Shear wave speed measurements can potentially be used to noninvasively measure myocardial stiffness to assess the myocardial function. Several studies showed the feasibility of tracking natural mechanical waves induced by aortic valve closure in the interventricular septum, but different echocardiographic views have been used. This article systematically studied the wave propagation speeds measured in a parasternal long-axis and in an apical four-chamber view in ten healthy volunteers. The apical and parasternal views are predominantly sensitive to longitudinal or transversal tissue motion, respectively, and could, therefore, theoretically measure the speed of different wave modes. We found higher propagation speeds in apical than in the parasternal view (median of 5.1 m/s versus 3.8 m/s, , n = 9 ). The results in the different views were not correlated ( r = 0.26 , p = 0.49 ) and an unexpectedly large variability among healthy volunteers was found in apical view compared with the parasternal view (3.5-8.7 versus 3.2-4.3 m/s, respectively). Complementary finite element simulations of Lamb waves in an elastic plate showed that different propagation speeds can be measured for different particle motion components when different wave modes are induced simultaneously. The in vivo results cannot be fully explained with the theory of Lamb wave modes. Nonetheless, the results suggest that the parasternal long-axis view is a more suitable candidate for clinical diagnosis due to the lower variability in wave speeds.

This article quantitatively analyzes the impact of bit errors in digitized RF data on ultrasound image quality. The quality of B-mode images in both linear array and phased array imaging is evaluated by means of three objective image quality metrics: peak signal-to-noise ratio, structural similarity index, and contrast-to-noise ratio, when bit errors are introduced to the RF data with different bit-error rates (BERs). The effectiveness of coding schemes for forward error detection and correction to improve the image quality is also studied. The results show that ultrasound imaging is inherently resilient to high BER. The image quality suffers unnoticeable degradation for BER lower than 1E-6. Simple 1-bit parity coding with 9% added redundancy helps to retain similar image quality for BER up to 1E-4, and Hamming coding with 33.3% added redundancy allows the BER to increase to 1E-3. These results can serve as a guideline in the datalink design for ultrasound probes with in-probe receive digitization. With much more relaxed BER requirements than in typical datalinks, the design can be optimized by allowing fewer cables with higher data rate per cable or lower power consumption with the same cable count.

An ultrasound scan generates a huge amount of data. To form an image, this data has to be transferred to the imaging system. This is an issue for applications where the data transfer capacity is limited such as hand-held systems, wireless probes, and miniaturized array probes. Two-stage beamforming methods can be used to significantly reduce the data transfer requirements. In the first stage, which is applied in-probe, the amount of data is reduced from channel to scanline data. In the imaging system, the data are then beamformed to obtain images, which are synthetically focused over the entire image. Currently, two approaches exist for the second stage. The first approach is a time-of-flight (TOF) approach called synthetic aperture sequential beamforming (SASB), which has been developed for both linear and phased arrays. SASB does, however, introduce artifacts in the image that can be reduced by tapering the first-stage scanlines at the cost of lateral resolution. The second approach is based on the wave equation, but a computationally efficient method for phased arrays that is producing sector scan data is lacking. Here, we propose an algorithm that uses the fast Hankel transform to obtain a fast algorithm. The imaging performance of this method is evaluated with simulations and experiments. Compared with PSASB, which is an adaption of SASB for phased arrays, our method requires a similar amount of operations to construct the entire image and there is no tradeoff between resolution and artifacts. These results show the advantage of using the wave equation instead of a TOF approach.

Ultrasound contrast agents consist of gas-filled coated microbubbles that oscillate upon ultrasound insonification. Their characteristic oscillatory response provides contrast enhancement for imaging and has the potential to locally enhance drug delivery. Since microbubble response depends on the local acoustic pressure, an ultrasound compatible chamber is needed to study their behavior and the underlying drug delivery pathways. In this study, we determined the amplitude of the acoustic pressure in the CLINIcell, an optically transparent chamber suitable for cell culture. The pressure field was characterized based on microbubble response recorded using the Brandaris 128 ultrahigh-speed camera and an iterative processing method. The results were compared to a control experiment performed in an OptiCell, which is conventionally used in microbubble studies. Microbubbles in the CLINIcell responded in a controlled manner, comparable to those in the OptiCell. For frequencies from 1 to 4 MHz, the mean pressure amplitude was -5.4 dB with respect to the externally applied field. The predictable ultrasound pressure demonstrates the potential of the CLINIcell as an optical, ultrasound, and cell culture compatible device to study microbubble oscillation behavior and ultrasound-mediated drug delivery.

Echocardiographic determination of multicomponent blood flow dynamics in the left ventricle remains a challenge. In this paper, we compare contrast enhanced, high frame rate (HFR) (1000 frames/s) echo-particle image velocimetry (ePIV) against optical particle image velocimetry (oPIV, gold standard), in a realistic left ventricular (LV) phantom. We find that ePIV compares well to oPIV, even for the high velocity inflow jet (normalized RMSE = 9% ± 1%). In addition, we perform the method of proper orthogonal decomposition, to better qualify and quantify the differences between the two modalities. We show that ePIV and oPIV resolve very similar flow structures, especially for the lowest order mode with a cosine similarity index of 86%. The coarser resolution of ePIV does result in increased variance and blurring of smaller flow structures when compared to oPIV. However, both modalities are in good agreement with each other for the modes that constitute the bulk of the kinetic energy. We conclude that HFR ePIV can accurately estimate the high velocity diastolic inflow jet and the high energy flow structures in an LV setting.

Treatment of abdominal aortic (AA) aneurysms and stenotic lesions may be improved by analyzing their associated blood-flow patterns. Angle-independent blood-flow patterns in the AA can be obtained by combining echo-particle image velocimetry (ePIV) with high-frame-rate (HFR) contrast-enhanced ultrasonography. However, ePIV performance is affected by ultrasound contrast agent (UCA) concentration, microbubble stability, and tissue clutter. In this study, we assessed the influence of acoustic pressure and UCA concentration on image quality for ePIV analysis. We also compared amplitude modulation (AM) and singular value decomposition (SVD) as tissue suppression strategies for ePIV. Fourteen healthy volunteers were imaged in the region of the distal AA. We tested four different UCA bolus volumes (0.25, 0.5, 0.75, and 1.5 mL) and four different acoustic output pressures (mechanical indices: 0.01, 0.03, 0.06, and 0.09). As image quality metrics, we measured contrast-to-background ratio, bubble disruption ratio, and maximum normalized cross-correlation value during ePIV. At mechanical indices ≥ 0.06, we detected severe bubble destruction, suggesting that very low acoustic pressures should be used for ePIV. SVD was able to suppress tissue clutter better than AM. The maximum tracking correlation was affected by both UCA concentration and flow rate, where at high flow rates, lower UCA concentrations resulted in slightly higher correlation values but more signal drop-outs during late diastole. HFR ePIV was successfully performed in the AA of healthy volunteers and shows promise for future studies in patients.

Intravascular ultrasound (IVUS) is an imaging modality used to visualize atherosclerosis from within the inner lumen of human arteries. Complex lesions like chronic total occlusions require forward-looking IVUS (FL-IVUS), instead of the conventional side-looking geometry. Volumetric imaging can be achieved with 2-D array transducers, which present major challenges in reducing cable count and device integration. In this work, we present an 80-element lead zirconium titanate matrix ultrasound transducer for FL-IVUS imaging with a front-end application-specific integrated circuit (ASIC) requiring only four cables. After investigating optimal transducer designs, we fabricated the matrix transducer consisting of 16 transmit (TX) and 64 receive (RX) elements arranged on top of an ASIC having an outer diameter of 1.5 mm and a central hole of 0.5 mm for a guidewire. We modeled the transducer using finite-element analysis and compared the simulation results to the values obtained through acoustic measurements. The TX elements showed uniform behavior with a center frequency of 14 MHz, a -3-dB bandwidth of 44%, and a transmit sensitivity of 0.4 kPa/V at 6 mm. The RX elements showed center frequency and bandwidth similar to the TX elements, with an estimated receive sensitivity of /Pa. We successfully acquired a 3-D FL image of three spherical reflectors in water using delay-and-sum beamforming and the coherence factor method. Full synthetic-aperture acquisition can be achieved with frame rates on the order of 100 Hz. The acoustic characterization and the initial imaging results show the potential of the proposed transducer to achieve 3-D FL-IVUS imaging.

Ultrasound in the presence of gas-filled microbubbles can be used to enhance local uptake of drugs and genes. To study the drug delivery potential and its underlying physical and biological mechanisms, an in vitro vessel model should ideally include 3-D cell culture, perfusion flow, and membrane-free soft boundaries. Here, we propose an organ-on-a-chip microfluidic platform to study ultrasound-mediated drug delivery: the OrganoPlate. The acoustic propagation into the OrganoPlate was determined to assess the feasibility of controlled microbubble actuation, which is required to study the microbubble-cell interaction for drug delivery. The pressure field in the OrganoPlate was characterized non-invasively by studying experimentally the well-known response of microbubbles and by simulating the acoustic wave propagation in the system. Microbubble dynamics in the OrganoPlate were recorded with the Brandaris 128 ultrahigh-speed camera (17 million frames/s) and a control experiment was performed in an OptiCell, an in vitro monolayer cell culture chamber that is conventionally used to study ultrasound-mediated drug delivery. When insonified at frequencies between 1 and 2 MHz, microbubbles in the OrganoPlate experienced larger oscillation amplitudes resulting from higher local pressures. Microbubbles responded similarly in both systems when insonified at frequencies between 2 and 4 MHz. Numerical simulations performed with a 3-D finite-element model of ultrasound propagation into the OrganoPlate and the OptiCell showed the same frequency-dependent behavior. The predictable and homogeneous pressure field in the OrganoPlate demonstrates its potential to develop an in vitro 3-D cell culture model, well suited to study ultrasound-mediated drug delivery.

One of the main challenges for ultrasound molecular imaging is acoustically distinguishing nonbound microbubbles from those bound to their molecular target. In this in vitro study, we compared two types of in-house produced targeted lipid-coated microbubbles, either consisting of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, C16:0 (DPPC) or 1,2-distearoyl-sn-glycero-3-phosphocholine, C18:0 (DSPC) as the main lipid, using the Brandaris 128 ultrahigh-speed camera to determine vibrational response differences between bound and nonbound biotinylated microbubbles. In contrast to previous studies that studied vibrational differences upon binding, we used a covalently bound model biomarker (i.e., streptavidin) rather than physisorption, to ensure binding of the biomarker to the membrane. The microbubbles were insonified at frequencies between 1 and 4 MHz at pressures of 50 and 150 kPa. This paper shows lower acoustic stability of bound microbubbles, of which DPPC-based microbubbles deflated most. For DPPC microbubbles with diameters between 2 and [Formula: see text] driven at 50 kPa, resonance frequencies of bound microbubbles were all higher than 1.8 MHz, whereas those of nonbound microbubbles were significantly lower. In addition, the relative radial excursions at resonance were also higher for bound DPPC microbubbles. These differences did not persist when the pressure was increased to 150 kPa, except for the acoustic stability which further decreased. No differences in resonance frequencies were observed between bound and nonbound DSPC microbubbles. Nonlinear responses in terms of emissions at the subharmonic and second harmonic frequencies were similar for bound and nonbound microbubbles at both pressures. In conclusion, we identified differences in vibrational responses of bound DPPC microbubbles with diameters between 2 and [Formula: see text] that distinguish them from nonbound ones.

Although high-frequency ultrasound imaging is gaining attention in various applications, hardly any ultrasound contrast agents (UCAs) dedicated to such frequencies (>15 MHz) are available for contrast-enhanced ultrasound (CEUS) imaging. Moreover, the composition of the limited commercially available UCAs for high-frequency CEUS (hfCEUS) is largely unknown, while shell properties have been shown to be an important factor for their performance. The aim of our study was to produce UCAs in-house for hfCEUS. Twelve different UCA formulations A-L were made by either sonication or mechanical agitation. The gas core consisted of C 4 F 10 and the main coating lipid was either 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC; A-F formulation) or 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC; G-L formulation). Mechanical agitation resulted in UCAs with smaller microbubbles (number weighted mean diameter ~1 [Formula: see text]) than sonication (number weighted mean diameter ~2 [Formula: see text]). UCA formulations with similar size distributions but different main lipid components showed that the DPPC-based UCA formulations had higher nonlinear responses at both the fundamental and subharmonic frequencies in vitro for hfCEUS using the Vevo2100 high-frequency preclinical scanner (FUJIFILM VisualSonics, Inc.). In addition, UCA formulations F (DSPC-based) and L (DPPC-based) that were made by mechanical agitation performed similar in vitro to the commercially available Target-Ready MicroMarker (FUJIFILM VisualSonics, Inc.). UCA formulation F also performed similar to Target-Ready MicroMarker in vivo in pigs with similar mean contrast intensity within the kidney ( n = 7 ), but formulation L did not. This is likely due to the lower stability of formulation L in vivo. Our study shows that DSPC-based microbubbles produced by mechanical agitation resulted in small microbubbles with high nonlinear responses suitable for hfCEUS imaging.

The high efficiency with which gas microbubbles can scatter ultrasound compared with the surrounding blood pool or tissues has led to their widespread employment as contrast agents in ultrasound imaging. In recent years, their applications have been extended to include super-resolution imaging and the stimulation of localized bio-effects for therapy. The growing exploitation of contrast agents in ultrasound and in particular these recent developments have amplified the need to characterize and fully understand microbubble behavior. The aim in doing so is to more fully exploit their utility for both diagnostic imaging and potential future therapeutic applications. This paper presents the key characteristics of microbubbles that determine their efficacy in diagnostic and therapeutic applications and the corresponding techniques for their measurement. In each case, we have presented information regarding the methods available and their respective strengths and limitations, with the aim of presenting information relevant to the selection of appropriate characterization methods. First, we examine methods for determining the physical properties of microbubble suspensions and then techniques for acoustic characterization of both suspensions and single microbubbles. The next section covers characterization of microbubbles as therapeutic agents, including as drug carriers for which detailed understanding of their surface characteristics and drug loading capacity is required. Finally, we discuss the attempts that have been made to allow comparison across the methods employed by various groups to characterize and describe their microbubble suspensions and promote wider discussion and comparison of microbubble behavior.

In medical ultrasound transducer design, the geometry of the individual elements is crucial since it affects the vibration mode of each element and its radiation impedance. For a fixed frequency, optimal vibration (i.e., uniform surface motion) can be achieved by designing elements with very small width-to-thickness ratios. However, for optimal radiation impedance (i.e., highest radiated power), the width should be as large as possible. This leads to a contradiction that can be solved by subdicing wide elements. To systematically examine the effect of subdicing on the performance of a 1-D ultrasound transducer array, we applied finite-element simulations. We investigated the influence of subdicing on the radiation impedance, on the time and frequency response, and on the directivity of linear arrays with variable element widths. We also studied the effect of varying the depth of the subdicing cut. The results show that, for elements having a width greater than 0.6 times the wavelength, subdicing improves the performance compared with that of nonsubdiced elements: the emitted pressure may be increased up to a factor of three, the ringing time may be reduced by up to 50%, the bandwidth increased by up to 77%, and the sidelobes reduced by up to 13 dB. Moreover, this simulation study shows that all these improvements can already be achieved by subdicing the elements to a depth of 70% of the total element thickness. Thus, subdicing can improve important transducer parameters and, therefore, help in achieving images with improved signal-to-noise ratio and improved resolution.

This paper presents the design, fabrication, and experimental evaluation of a prototype lead zirconium titanate (PZT) matrix transducer with an integrated receive ASIC, as a proof of concept for a miniature three-dimensional (3-D) transesophageal echocardiography (TEE) probe. It consists of an array of 9 ×12 piezoelectric elements mounted on the ASIC via an integration scheme that involves direct electrical connections between a bond-pad array on the ASIC and the transducer elements. The ASIC addresses the critical challenge of reducing cable count, and includes front-end amplifiers with adjustable gains and micro-beamformer circuits that locally process and combine echo signals received by the elements of each 3 ×3 subarray. Thus, an order-of-magnitude reduction in the number of receive channels is achieved. Dedicated circuit techniques are employed to meet the strict space and power constraints of TEE probes. The ASIC has been fabricated in a standard 0.18-μm CMOS process and consumes only 0.44 mW/channel. The prototype has been acoustically characterized in a water tank. The ASIC allows the array to be presteered across ±37° while achieving an overall dynamic range of 77 dB. Both the measured characteristics of the individual transducer elements and the performance of the ASIC are in good agreement with expectations, demonstrating the effectiveness of the proposed techniques.

Detection methods implemented in present clinical ultrasound scanners for contrast-enhanced ultrasound imaging show high sensitivity but a rather poor specificity due to pseudo-enhancement (false detection of contrast agent) produced by nonlinear wave propagation. They all require linear ultrasound propagation to detect nonlinear scattering of contrast agent microbubbles. Even at low transmit pressure, nonlinear wave propagation occurs in regions perfused with contrast agent because contrast agent microbubbles can dramatically enhance the nonlinear elastic behavior of the medium. This image artifact hinders further development of contrast-enhanced ultrasound imaging toward reliable quantitative measurement of local concentration of contrast agent and blood perfusion kinetics. We propose in this manuscript a new detection method, with specific beamforming and pulsing scheme, that produces contrast images with highly reduced pseudo-enhancement. It is based on the interaction of two diverging wavefronts broadcasted by two single elements of a conventional probe array. The contrast image is formed line by line; one single image line is the line segment bisector defined by the centers of the two transmitting elements. Each image line is formed by a three-step pulse sequence: (1) transmission with one element, (2) transmission with the other element, and (3) transmission with both elements. The proof of principle is shown with numerical simulations and in vitro experiments. The method is implemented in a programmable ultrasound system and tested in a tissue-mimicking phantom containing a vessel filled with diluted contrast agent. At a given depth, increasing the distance between the two transmitting elements increases the angle describing the propagation directions of the two wavefronts. As a result, the nonlinear interaction between the two broadcasted waves is reduced. We show experimentally that increasing the distance between the transmitting elements from 0.6 to 24 mm reduces the amplitude of the pseudoenhancement at the far wall of the vessel relative to true contrast signal amplitude in the vessel by 12 dB, therefore improving specificity in the contrast-enhanced image.

Measuring the magnitude and direction of tissue displacement provides the basis for the assessment of tissue motion or tissue stiffness. Using conventional displacement tracking by ultrasound delay estimation, only one direction of tissue displacement can be estimated reliably. In this paper, we describe a new technique for estimating the complete two-dimensional displacement vector using high-frame-rate ultrasound imaging. We compute the displacement vector using phase delays that can be measured between pairs of elements within an array. By combining multiple element-pair solutions, we find a new robust estimate for the displacement vector. In this paper, we provide experimental proof that this method permits measurement of the displacement vector for isolated scatterers and diffuse scatterers with high (submicrometer) precision, without the need for beam steering. We also show that we can measure the axial and lateral distension of a carotid artery in a transverse view.

Molecular markers associated with diseases can be visualized and quantified noninvasively with targeted ultrasound contrast agent (t-UCA) consisting of microbubbles (MBs) that can bind to specific molecular targets. Techniques used for quantifying t-UCA assume that all unbound MBs are taken out of the blood pool few minutes after injection and only MBs bound to the molecular markers remain. However, differences in physiology, diseases, and experimental conditions can increase the longevity of unbound MBs. In such conditions, unbound MBs will falsely be quantified as bound MBs. We have developed a novel technique to distinguish and classify bound from unbound MBs. In the post-processing steps, first, tissue motion was compensated using block-matching (BM) techniques. To preserve only stationary contrast signals, a minimum intensity projection (MinIP) or 20th-percentile intensity projection (PerIP) was applied. The after-flash MinIP or PerIP was subtracted from the before-flash MinIP or PerIP. In this way, tissue artifacts in contrast images were suppressed. In the next step, bound MB candidates were detected. Finally, detected objects were tracked to classify the candidates as unbound or bound MBs based on their displacement. This technique was validated in vitro, followed by two in vivo experiments in mice. Tumors (n = 2) and salivary glands of hypercholesterolemic mice (n = 8) were imaged using a commercially available scanner. Boluses of 100 μL of a commercially available t-UCA targeted to angiogenesis markers and untargeted control UCA were injected separately. Our results show considerable reduction in misclassification of unbound MBs as bound ones. Using our method, the ratio of bound MBs in salivary gland for images with targeted UCA versus control UCA was improved by up to two times compared with unprocessed images.

This work describes the fracturing mechanism of air-filled microbubbles (MBs) encapsulated by a cross-linked poly(vinyl alcohol) (PVA) shell. The radial oscillation and fracturing events following the ultrasound exposure were visualized with an ultrahigh-speed camera, and backscattered timedomain signals were acquired with the acoustic setup specific for harmonic detection. No evidence of gas emerging from defects in the shell with the arrival of the first insonation burst was found. In optical recordings, more than one shell defect was noted, and the gas core was drained without any sign of air extrusion when several consecutive bursts of 1 MPa amplitude were applied. In acoustic tests, the backscattered peak-to-peak voltage gradually reached its maximum and exponentially decreased when the PVA-based MB suspension was exposed to approximately 20 consecutive bursts arriving at pulse repetition frequencies of 100 and 500 Hz. Taking into account that the PVA shell is porous and possibly contains large air pockets between the cross-linked PVA chains, the aforementioned acoustic behavior might be attributed to pumping gas from these pockets in combination with gas release from the core through shell defects. We refer to this fracturing mechanism as pumping-out behavior, and this behavior could have potential use for the local delivery of therapeutic gases, such as nitric oxide.

Intraplaque neovascularization (IPN) is an important biomarker of atherosclerotic plaque vulnerability. As IPN can be detected by contrast enhanced ultrasound (CEUS), imaging-biomarkers derived from CEUS may allow early prediction of plaque vulnerability. To select the best quantitative imaging-biomarkers for prediction of plaque vulnerability, a systematic analysis of IPN with existing and new analysis algorithms is necessary. Currently available commercial contrast quantification tools are not applicable for quantitative analysis of carotid IPN due to substantial motion of the carotid artery, artifacts, and intermittent perfusion of plaques. We therefore developed a specialized software package called Carotid intraplaque neovascularization quantification software (CINQS). It was designed for effective and systematic comparison of sets of quantitative imaging biomarkers. CINQS includes several analysis algorithms for carotid IPN quantification and overcomes the limitations of current contrast quantification tools and existing carotid IPN quantification approaches. CINQS has a modular design which allows integrating new analysis tools. Wizard-like analysis tools and its graphical-user-interface facilitate its usage. In this paper, we describe the concept, analysis tools, and performance of CINQS and present analysis results of 45 plaques of 23 patients. The results in 45 plaques showed excellent agreement with visual IPN scores for two quantitative imaging-biomarkers (The area under the receiver operating characteristic curve was 0.92 and 0.93).

Ultrasound contrast agents as drug-delivery systems are an emerging field. Recently, we reported that targeted microbubbles are able to sonoporate endothelial cells in vitro. In this study, we investigated whether targeted microbubbles can also induce sonoporation of endothelial cells in vivo, thereby making it possible to combine molecular imaging and drug delivery. Live chicken embryos were chosen as the in vivo model. αvß3-targeted microbubbles attached to the vessel wall of the chicken embryo were insonified at 1 MHz at 150 kPa (1 × 10,000 cycles) and at 200 kPa (1 × 1000 cycles) peak negative acoustic pressure. Sonoporation was studied by intravital microscopy using the model drug propidium iodide (PI). Endothelial cell PI uptake was observed in 48% of microbubble-vessel-wall complexes at 150 kPa (n = 140) and in 33% at 200 kPa (n = 140). Efficiency of PI uptake depended on the local targeted microbubble concentration and increased up to 80% for clusters of 10 to 16 targeted microbubbles. Ultrasound or targeted microbubbles alone did not induce PI uptake. This intravital microscopy study reveals that sonoporation can be visualized and induced in vivo using targeted microbubbles.

Drugs will be delivered to diseased tissue more efficiently if the vascular endothelial permeability is increased. Ultrasound in combination with an ultrasound contrast agent is known to increase the permeability of the endothelial layer, but the mechanism is not known. The goal of this study was to elucidate whether intracellular calcium ions, [Ca(2+)]i, and reactive oxygen species (ROS) are part of the mechanism that leads to an increased endothelial layer permeability following ultrasound and microbubble treatment. Human umbilical vein endothelial cells (HUVECs) treated for 2 min with ultrasound-activated microbubbles (1 MHz, 210 kPa, 10 000 cycles, 20 Hz repetition rate) had an increased permeability that lasted up to 12 h. Recovery of permeability after 2 h was only found when HUVECs were preincubated with the [Ca(2+)]i chelator BAPTA-AM or the antioxidant butylated hydroxytoluene (BHT). This suggests that both [Ca(2+)]i and ROS play an important role in the mechanism of increased permeability following ultrasound in combination with microbubble treatment.

In diagnostic medicine, microbubbles are used as contrast agents to image blood flow and perfusion in large and small vessels. The small vessels (the capillaries) have diameters from a few hundred micrometers down to less than 10 μ m. The effect of such microvessels surrounding the oscillating microbubbles is currently unknown, and is important for increased sensitivity in contrast diagnostics and manipulation of microbubbles for localized drug release. Here, oscillations of microbubbles in tubes with inner diameters of 25 μm and 160 ¿m are investigated using an ultra-high-speed camera at frame rates of ~12 million frames/s. A reduction of up to 50% in the amplitude of oscillation was observed for microbubbles in the smaller 25-μm tube, compared with those in a 160-μm tube. In the 25-μm tube, at 50 kPa, a 48% increase of microbubbles that did not oscillate above the noise level of the system was observed, indicating increased oscillation damping. No difference was observed between the resonance frequency curves calculated for microbubbles in 25-μm and 160-μm tubes. Although previous investigators have shown the effect of microvessels on microbubble oscillation at high ultrasound pressures, the present study provides the first optical images of low-amplitude microbubble oscillations in small tubes.

The merits of ultrasound contrast agents (UCAs) were already known in the 1960s. It was, however, not until the 1990s that UCAs were clinically approved and marketed. In these years, it was realized that the UCAs are not just efficient ultrasound scatterers, but that their main constituent, the coated gas microbubble, acts as a nonlinear resonator and, as such, is capable of generating harmonic energy. Subharmonic, ultraharmonic, and higher harmonic frequencies of the transmitted ultrasound frequency have been reported. This opened up new prospects for their use and several detection strategies have been developed to exploit this harmonic energy to discriminate the contrast bubbles from surrounding tissue. This insight created a need for tools to study coated bubble behavior in an ultrasound field and the first models were developed. Since then, 20 years have elapsed, in which a broad range of UCAs and UCA models have been developed. Although the models have helped in understanding the responses of coated bubbles, the influence of the coating has not been fully elucidated to date and UCA models are still being improved. The aim of this review paper is to offer an overview in these developments and indicate future directions for research.

Beamforming of plane-wave ultrasound echo signals in the Fourier domain provides fast and accurate image reconstruction. Conventional implementations perform a k-space interpolation from the uniform sampled grid to a nonuniform acoustic dispersion grid. In this paper, we demonstrate that this step can be replaced by a nonuniform Fourier transform. We study the performance of the nonuniform fast Fourier transform (NUFFT) in terms of signal-to-noise ratio and computational cost, and show that the NUFFT offers an advantage in the trade-off between speed and accuracy, compared with other frequency-domain beamforming strategies.

There is a clear clinical need for creating 3-D images of the heart. One promising technique is the use of transesophageal echocardiography (TEE). To enable 3-D TEE, we are developing a miniature ultrasound probe containing a matrix piezoelectric transducer with more than 2000 elements. Because a gastroscopic tube cannot accommodate the cables needed to connect all transducer elements directly to an imaging system, a major challenge is to locally reduce the number of channels, while maintaining a sufficient signal-to-noise ratio. This can be achieved by using front-end receiver electronics bonded to the transducers to provide appropriate signal conditioning in the tip of the probe. This paper presents the design of such electronics, realizing time-gain compensation (TGC) and micro-beamforming using simple, low-power circuits. Prototypes of TGC amplifiers and micro-beamforming cells have been fabricated in 0.35-μm CMOS technology. These prototype chips have been combined on a printed circuit board (PCB) to form an ultrasound-receiver system capable of reading and combining the signals of three transducer elements. Experimental results show that this design is a suitable candidate for 3-D TEE.

Tissue second-harmonic imaging is currently the default mode in commercial diagnostic ultrasound systems. A new modality, superharmonic imaging (SHI), combines the third through fifth harmonics originating from nonlinear wave propagation through tissue. SHI could further improve the resolution and quality of echographic images. The superharmonics have gaps between the harmonics because the transducer has a limited bandwidth of about 70% to 80%. This causes ghost reflection artifacts in the superharmonic echo image. In this work, a new dual-pulse frequency compounding (DPFC) method to eliminate these artifacts is introduced. In the DPFC SHI method, each trace is constructed by summing two firings with slightly different center frequencies. The feasibility of the method was established using a single-element transducer. Its acoustic field was modeled in KZK simulations and compared with the corresponding measurements obtained with a hydrophone apparatus. Subsequently, the method was implemented on and optimized for a setup consisting of an interleaved phased-array transducer (44 elements at 1 MHz and 44 elements at 3.7 MHz, optimized for echocardiography) and a programmable ultrasound system. DPFC SHI effectively suppresses the ghost reflection artifacts associated with imaging using multiple harmonics. Moreover, compared with the single-pulse third harmonic, DPFC SHI improved the axial resolution by 3.1 and 1.6 times at the -6-dB and -20-dB levels, respectively. Hence, DPFC offers the possibility of generating harmonic images of a higher quality at a cost of a moderate frame rate reduction.

This study investigates the use of an acoustic parametric array as a means for microbubble excitation. The excitation wave is generated during propagation in a nonlinear medium of two high-frequency carrier waves, whereby the frequency of the excitation wave is the difference frequency of the carrier waves. Carrier waves of around 10 and 25 MHz are used to generate low-frequency waves between 0.5 and 3.5 MHz at amplitudes in the range of 25 to 80 kPa in water. We demonstrate with high-speed camera observations that it is possible to induce microbubble oscillations with the low frequency signal arising from the nonlinear propagation process. As an application, we determined the resonance frequency of Definity contrast agent microbubbles with radius ranging from 1.5 to 5 μm by sweeping the difference frequency in the range from 0.5 to 3.5 MHz.

Second-harmonic imaging is currently one of the standards in commercial echographic systems for diagnosis, because of its high spatial resolution and low sensitivity to clutter and near-field artifacts. The use of nonlinear phenomena mirrors is a great set of solutions to improve echographic image resolution. To further enhance the resolution and image quality, the combination of the 3rd to 5th harmonics--dubbed the superharmonics--could be used. However, this requires a bandwidth exceeding that of conventional transducers. A promising solution features a phased-array design with interleaved low- and high-frequency elements for transmission and reception, respectively. Because the amplitude of the backscattered higher harmonics at the transducer surface is relatively low, it is highly desirable to increase the sensitivity in reception. Therefore, we investigated the optimization of the number of elements in the receiving aperture as well as their arrangement (topology). A variety of configurations was considered, including one transmit element for each receive element (1/2) up to one transmit for 7 receive elements (1/8). The topologies are assessed based on the ratio of the harmonic peak pressures in the main and grating lobes. Further, the higher harmonic level is maximized by optimization of the center frequency of the transmitted pulse. The achievable SNR for a specific application is a compromise between the frequency-dependent attenuation and nonlinearity at a required penetration depth. To calculate the SNR of the complete imaging chain, we use an approach analogous to the sonar equation used in underwater acoustics. The generated harmonic pressure fields caused by nonlinear wave propagation were modeled with the iterative nonlinear contrast source (INCS) method, the KZK, or the Burger's equation. The optimal topology for superharmonic imaging was an interleaved design with 1 transmit element per 6 receive elements. It improves the SNR by ~5 dB compared with the interleaved (1/2) design reported in literature. The optimal transmit frequency for superharmonic echocardiography was found to be 1.0 to 1.2 MHz. For superharmonic abdominal imaging this frequency was found to be 1.7 to 1.9 MHz. For 2nd-harmonic echocardiography, the optimal transmit frequency of 1.8 MHz reported in the literature was corroborated with our simulation results.

Drug delivery to a diseased tissue will be more efficient if the vascular endothelial permeability is increased. Recent studies have shown that the permeability of single cell membranes is increased by ultrasound in combination with contrast agents. It is not known whether this combination can also increase the permeability of an endothelial layer in the absence of cell damage. To investigate the feasibility of controlled increased endothelial layer permeability, we treated monolayers of human umbilical vein endothelial cells with ultrasound and the contrast agent BR14. Barrier function was assessed by measuring transendothelial electrical resistance (TEER). Ultrasound-activated BR14 significantly decreased TEER by 40.3% +/- 3.7% ( p < 0.01). After treatment, no cell detachment or damage was observed. In conclusion, ultrasound-activated BR14 microbubbles increased the endothelial layer permeability. This feature can be used for future ultrasound-guided drug delivery systems.

For several years, the standard in ultrasound imaging has been second-harmonic imaging. A new imaging technique dubbed "super-harmonic imaging" (SHI) was recently proposed. It takes advantage of the higher - third to fifth - harmonics arising from nonlinear propagation or ultrasound-contrast-agent (UCA) response. Next to its better suppression of near-field artifacts, tissue SHI is expected to improve axial and lateral resolutions resulting in clearer images than second-harmonic imaging. When SHI is used in combination with UCAs, a better contrast-to-tissue ratio can be obtained. The use of SHI implies a large dynamic range and requires a sufficiently sensitive array over a frequency range from the transmission frequency up to its fifth harmonic (bandwidth > 130%). In this paper, we present the characteristics and performance of a new interleaved dual frequency array built chiefly for SHI. We report the rationale behind the design choice, frequencies, aperture, and piezomaterials used. The array is efficient both in transmission and reception with well-behaved transfer functions and a combined -6-dB bandwidth of 144%. In addition, there is virtually no contamination of the harmonic components by spurious transducer transmission, due to low element-to-element crosstalk (< 30 dB) and a low transmission efficiency of the odd harmonics (< 46 dB). The interleaved array presented in this article possesses ideal characteristics for SHI and is suitable for other methods like second-harmonic, subharmonic, and second-order ultrasound field (SURF) imaging.

Ultrasound contrast agents (UCA) populations are typically polydisperse and contain microbubbles with radii over a given range. Although the behavior of microbubbles of certain sizes might be masked by the behavior of others, the acoustic characterization of UCA is typically made on full populations. In this paper, we have combined acoustic and optical methods to investigate the response of isolated lipid-shelled microbubbles to low-pressure (49 and 62 kPa peak negative pressure) ultrasound tone bursts. These bursts induced slow deflation of the microbubbles. The experimental setup included a microscope connected to a fast camera acquiring one frame per pulse transmitted by a single-element transducer. The behavior of each bubble was measured at multiple frequencies, by cyclically changing the transmission frequency over the range of 2 to 4 MHz during subsequent pulse repetition intervals. The bubble echoes were captured by a second transducer and coherently recorded. More than 50 individual microbubbles were observed. Microbubbles with radii larger than 3 mum did not experience any size reduction. Smaller bubbles slowly deflated, generally until the radius reached a value around 1.4 microm, independent of the initial microbubble size. The detected pressure amplitude backscattered at 2.5 cm distance was very low, decreasing from about 5 Pa down to 1 Pa at 2 MHz as the bubbles deflated. The resonant radius was evaluated from the echo amplitude normalized with respect to the geometrical cross section. At 2-MHz excitation, deflating microbubbles showed highest normalized echo when the radius was 2.2 microm while at higher excitation frequencies, the resonant radius was lower. The relative phase shift of the echo during the deflation process was also measured. It was found to exceed pi/2 in all cases. A heuristic procedure based on the analysis of multiple bubbles of a same population was used to estimate the undamped natural frequency. It was found that a microbubble of 1.7 microm has an undamped natural frequency of 2 MHz. The difference between this size and the resonant radius is discussed as indicative of significant damping.

Radial modulation imaging is a new promising technique to improve contrast-enhanced ultrasound images. The method is based on dual-frequency insonation of contrast agent microbubbles. A low-frequency (LF) pulse is used to modulate the responses of the microbubbles to a high-frequency (HF) imaging pulse. Inverting the LF pulse induces amplitude and phase differences in the HF response of contrast agent microbubbles, which can be detected using Doppler techniques. Although the technique has been successfully implemented, no consensus persists on parameter choice and resulting effects. In a separate study, "compression-only" behavior of coated microbubbles was observed. Compression-only behavior could be beneficial for radial modulation imaging. This was investigated using high-speed camera recordings and simulations. We recorded the vibrations of 78 single microbubbles in a dual-frequency ultrasound field. The results showed that the LF pulse induced significant compression-only behavior, which for microbubble sizes below and at HF resonance resulted in high radial amplitude modulation. It, however, also appeared that, for radial modulation imaging, microbubble size is more important than resonance and compression-only effects.

Active response of a microbubble is characterized by its resonance behavior where the microbubble might oscillate after the excitation waveform has been turned off. We investigate in this paper an excitation approach based on this resonance phenomenon using chirps. The technique, called chirp reversal, consists in transmitting a first excitation signal, the up-sweep chirp (UPF) of increasing frequency with time, and a second excitation signal, the down-sweep (DNF) that is a replica of the first signal, but time reversed with a sweep of decreasing frequency with time. Simulations using a modified Rayleigh-Plesset equation were carried out to determine bubble response to chirp reversal. In addition, optical observations and acoustical measurements were carried out to corroborate the theoretical findings. Results of simulations show differences between bubbles' oscillations in response to up-sweep and down-sweep chirps mainly for transmitted center frequencies above the bubble's resonance frequency. Bubbles that are at resonance or far away from resonance engender identical responses. From the optical data, the larger bubbles showed different dynamics when up-sweep or down-sweep chirps were transmitted. Smaller bubbles (< 2 microm diameter) appear to be less sensitive to frequency sweep at 1.7 MHz center frequency. However, driven at a higher center frequency, smaller bubbles tend to be more sensitive. These results were confirmed through the acoustical measurements. We concluded that simulations and experimental data show that significant differences might be observed between bubbles' responses to UPF and DNF chirps. We demonstrate in this study that, for an optimal use of chirp reversal, the transmit frequency should be higher than the resonance frequency of the contrast microbubbles.

Detection of contrast agent in perfused tissues has been an important research topic for many years. Currently available methods are mostly based on the strong nonlinear scattering of contrast agent microbubbles. These methods selectively extract those parts of the spectrum that show the largest difference in nonlinearity between contrast agent and tissue. The method introduced in this paper expands this extraction approach in that it additionally exploits differences in system behavior between tissue and contrast bubbles. The resonant nature of contrast bubbles implies that the response of a contrast bubble is stateful, i.e., the response not only depends on the current input, but also on all previous inputs. Tissue does not show this dependence on previous inputs. Our method is based on a 3 pulse design in which the echoes from 2 nonoverlapping pulses are subtracted from a third pulse. With this method we aim to separate and suppress those parts in an echo signal that originate from tissue while leaving the part originating from contrast bubbles relatively undisturbed. Simulation results show increases up to 30 dB in contrast-to-tissue ratio (CTR) with this method relative to single pulse echoes. This was confirmed in an in vitro experiment that showed an increase of approximately 12 dB in CTR.

Three-dimensional (3-D) stress echocardiography is a novel technique for diagnosing cardiac dysfunction. It involves evaluating wall motion of the left ventricle, by visually analyzing ultrasound images obtained in rest and in different stages of stress. Since the acquisitions are performed minutes apart, variabilities may exist in the visualized cross-sections. To improve anatomical correspondence between rest and stress, aligning the images is essential. We developed a new intensity-based, sparse registration method to retrieve standard anatomical views from 3-D stress images that were equivalent to the manually selected views in the rest images. Using sparse image planes, the influence of common image artifacts could be reduced. We investigated different similarity measures and different levels of sparsity. The registration was tested using data of 20 patients and quantitatively evaluated based on manually defined anatomical landmarks. Alignment was best using sparse registration with two long-axis and two short-axis views; registration errors were reduced significantly, to the range of interobserver variabilities. In 91% of the cases, the registration result was qualitatively assessed as better than or equal to the manual alignment. In conclusion, sparse registration improves the alignment of rest and stress images, with a performance similar to manual alignment. This is an important step towards objective quantification in 3-D stress echocardiography.