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Advances in magnetic materials have enabled the development of new therapeutic agents that can be localized by external magnetic fields. These agents offer a potential means of improving treatment targeting and reducing the toxicity-related side effects associated with systemic delivery. Achieving sufficiently high magnetic fields at clinically relevant depths in vivo, however, remains a challenge. Similarly, there is a need for techniques for real-time monitoring that do not rely on magnetic resonance imaging (MRI). Here, we present a hand-held device to meet these requirements, combining an array of permanent magnets and a thin 64-element capacitive micromachined ultrasonic transducer (CMUT) interfaced to a real-time imaging system. Drug carrier localization was assessed by measuring the terminal velocity of magnetic microbubbles in a column of fluid above the magnetic array. It was found that the magnetic pull force was sufficient to overcome buoyancy at equivalent tissue depths of at least 35 mm and that the median terminal velocity ranged from 0.7 to 20 $\mu \text{m}$ /s over the distances measured. A Monte Carlo study was performed to estimate capture effectiveness in tumor microvessels over a range of different tissue depths and flow rates. Finally, B-mode and contrast-enhanced ultrasound (CEUS) imaging were demonstrated using a gel flow phantom containing a 1.6-mm diameter vessel. Real-time monitoring provided visual confirmation of retention of magnetic microbubbles along the vessel wall at a flow rate of 0.5 mL/min. These results indicate that the system can successfully retain and image magnetic microbubbles at tissue depths and flow rates relevant for clinical applications such as molecular ultrasound imaging of atherosclerosis, sonodynamic and antimetabolite cancer therapy, and clot dissolution via sonothrombolysis. [ABSTRACT FROM AUTHOR]

Microbubbles (MBs) serve as contrast agents in diagnostic ultrasound (US) imaging. Contrast harmonic imaging (CHI) of MBs takes advantage of their nonlinear properties that generate additional harmonic frequencies in the received spectrum. However, CHI suffers from limitations in terms of contrast, the signal-to-noise ratio, and artifacts. This article presents an enhanced, real-time, nonlinear imaging technique based on the excitation of MBs with a dual frequency waveform. The MBs trigger a frequency mixing effect that generates additional frequency components in the received spectrum; i.e., difference and sum frequencies, in addition to the standard harmonics, thus amplifying the MB’s nonlinear response and enhancing image contrast. In this real-time approach, two single frequency waveforms are superpositioned into a dual frequency transmission. The dual frequency waveform is incorporated into a standard pulse-inversion (PI) sequence and is transmitted by an array transducer using an arbitrary waveform generator (AWG) in a programmable US system. Upon receive, standard dynamic receive beamforming is used, without additional post processing. Numerical simulations using the Marmottant model are used to confirm the generation of the difference frequency in the MB’s backscattered echoes. The resulting image quality enhancement is demonstrated in a tissue-mimicking phantom containing MBs’ suspension. A maximal contrast improvement of 3.43 dB compared to standard PI was achieved, along with a reduction by 4.5 fold in the mechanical index (MI). [ABSTRACT FROM AUTHOR]

Fiber Bragg gratings (FBGs) are a potential alternative to piezoelectric ultrasound sensors for applications that demand high sensitivity and immunity to electromagnetic interference (EMI). However, limited data exist on the quantitative performance characterization of FBG sensors in the MHz frequency range relevant to biomedical ultrasound. In this work, we evaluated an FBG to detect MHz-frequency ultrasound and tested the feasibility of measuring passive cavitation signals nucleated using a commercial contrast agent (SonoVue). The sensitivity, repeatability, and linearity of the measurements were assessed for ultrasound measurements at 1, 5, and 10 MHz. The bandwidth of the FBG sensor was measured and compared to that of a calibrated needle hydrophone. The FBG showed a sensitivity of 0.99, 0.769, and 0.818 V/MPa for 1, 5, and 10 MHz ultrasound, respectively. The sensor also exhibited linear response ($0.975\leq {R}$ -Squared ≤ 0.996) and good repeatability with a coefficient of variation (CV) less than 5.5%. A 2-MHz focused transducer was used to insonify SonoVue microbubbles at a peak negative pressure of 175 kPa and passive cavitation emissions were measured, in which subharmonic and ultraharmonic spectral peaks were observed. These results demonstrate the potential of FBGs for MHz-range ultrasound applications, including passive cavitation detection (PCD). [ABSTRACT FROM AUTHOR]

Due to the significant acoustic impedance contrast at cortical boundaries, highly inside attenuation, and the unknown sound velocity distribution, accurate ultrasound cortical bone imaging remains a challenge, especially for the traditional pulse-echo modalities using unique sound velocity. Moreover, the large amounts of data recorded by multielement probe results in a relatively time-consuming reconstruction process. To overcome these limitations, this article proposed an index-rotated fast ultrasound imaging method based on predicted velocity model (IR-FUI-VP) for cortical cross section ultrasound tomography (UST) imaging, utilizing ray-tracing synthetic aperture (RTSA). In virtue of ring probe, the sound velocity model was predicted in advance using bent-ray inversion (BRI). With the predicted velocity model, index-rotated fast ultrasound imaging (IR-FUI) was further applied to image the cortical cross sections in the sectors corresponding to the dynamic apertures (DAs) and ring center. The final result was merged by all sector images. One cortical bone phantom and two ex vivo bovine femurs were utilized to demonstrate the performance of the proposed method. Compared to the conventional synthetic aperture (SA) imaging, the method can not only accurately image the outer cortical boundary but also precisely reconstruct the inner cortical surface. The mean relative errors of the predicted sound velocity in the region of interest (ROI) were all smaller than 7%, and the mean errors of cortical thickness are all less than 0.31 mm. The reconstructed images of bovine femurs were in good agreement with the reference images scanned by micro-computed tomography ($\mu $ CT) with respect to the morphology and thickness. The speed of IR-FUI is about 3.73 times faster than the traditional SA. It is proved that the proposed IR-FUI-VP-based UST is an effective way for fast and accurate cortical bone imaging. [ABSTRACT FROM AUTHOR]

Lateral motion estimation has been a challenge in ultrasound elastography mainly due to the low resolution, low sampling frequency, and lack of phase information in the lateral direction. Synthetic transmit aperture (STA) can achieve high resolution due to two-way focusing and can beamform high-density image lines for improved lateral motion estimation with the disadvantages of low signal-to-noise ratio (SNR) and limited penetration depth. In this study, Hadamard-encoded STA (Hadamard-STA) is proposed for the improvement of lateral motion estimation in elastography, and it is compared with STA and conventional focused wave (CFW) imaging. Simulations, phantom, and in vivo experiments were conducted to make the comparison. The normalized root mean square error (NRMSE) and the contrast-to-noise ratio (CNR) were calculated as the evaluation criteria in the simulations. The results show that, at a noise level of −10 dB and an applied strain of −1% (compression), Hadamard-STA decreases the NRMSEs of lateral displacements by 46.92% and 35.35%, decreases the NRMSEs of lateral strains by 52.34% and 39.75%, and increases the CNRs by 9.70 and 9.75 dB compared with STA and CFW, respectively. In the phantom experiments performed on a heterogeneous tissue-mimicking phantom, the sum of squared differences (SSD) between the reference and the motion-compensated RF data, and the CNR were calculated as the evaluation criteria. At an applied strain of −1.80%, Hadamard-STA is found to decrease the SSDs by 20.91% and 30.99% and increase the CNRs by 14.15 and 24.66 dB compared with STA and CFW, respectively. In the experiments performed on a breast phantom, Hadamard-STA achieves better visualization of the breast inclusion with a clearer boundary between the inclusion and the background than STA and CFW. The in vivo experiments were performed on a patient with a breast tumor, and the tumor could also be better visualized with a more homogeneous background in the strain image obtained by Hadamard-STA than by STA and CFW. These results demonstrate that Hadamard-STA achieves a substantial improvement in lateral motion estimation and maybe a competitive method for quasi-static elastography. [ABSTRACT FROM AUTHOR]

Contrast-enhanced ultrasound (CEUS) imaging relies on distinguishing between microbubble and tissue echoes. Amplitude modulation (AM), a nonlinear pulsing scheme, has been developed to take advantage of the amplitude-dependent nonlinearity of microbubble echoes. However, with AM, tissue nonlinear propagation can also degrade the image contrast. Segmentation of CEUS images based on amplitude-dependent phase difference in the echoes, defined in this article as ${\sf \varDelta } {\sf \varPhi }_{\textit {AM}}$ , has been proposed as an additional method of enhancing contrast-to-tissue ratio as tissue is not expected to create the same degree of ${\sf \varDelta } {\sf \varPhi }_{\textit {AM}}$ ; however, this has not been robustly investigated. In this work, we evaluate the source of ${\sf \varDelta } {\sf \varPhi }_{\textit {AM}}$ through simulations of unshelled versus shelled microbubble oscillation and simulations of nonlinear propagation in tissue. We then validate the simulated ${\sf \varDelta } {\sf \varPhi }_{\textit {AM}}$ results with experimental ${\sf \varDelta } {\sf \varPhi }_{\textit {AM}}$ measurements during in vitro scattering and imaging in a flow phantom. We show that shelled and unshelled microbubbles resulted in a ${\sf \varDelta } {\sf \varPhi }_{\textit {AM}}$ with similar overall magnitude with some differences in trends, and that tissue echoes have a small yet detectable degree of ${\sf \varDelta } {\sf \varPhi }_{\textit {AM}}$ due to nonlinear propagation. The results from this work can help inform optimal parameter selection for phase segmentation and implementation on a clinical scanner. [ABSTRACT FROM AUTHOR]

The thrombolysis potential of low-boiling-point (−2 °C) perfluorocarbon phase-change nanodroplets (NDs) has previously been demonstrated on aged clots, and we hypothesized that this efficacy would extend to retracted clots. We tested this hypothesis by comparing sonothrombolysis of both unretracted and retracted clots using ND-mediated ultrasound (US+ND) and microbubble-mediated ultrasound (US+MB), respectively. Assessment data included clot mass reduction, cavitation detection, and cavitation cloud imaging in vitro. Acoustic parameters included a 7.9-MPa peak negative pressure and 180-cycle bursts with 5-Hz repetition (the corresponding duty cycle and time-averaged intensity of 0.09% and 1.87 W/cm2, respectively) based on prior studies. With these parameters, we observed a significantly reduced efficacy of US+MB in the retracted versus unretracted model (the averaged mass reduction rate from 1.83%/min to 0.54%/min). Unlike US+MB, US+ND exhibited less reduction of efficacy in the retracted model (from 2.15%/min to 1.04%/min on average). The cavitation detection results correlate with the sonothrombolysis efficacy results showing that both stable and inertial cavitation generated in a retracted clot by US+ND is higher than that by US+MB. We observed that ND-mediated cavitation shows a tendency to occur inside a clot, whereas MB-mediated cavitation occurs near the surface of a retracted clot, and this difference is more significant with retracted clots compared to unretracted clots. We conclude that ND-mediated sonothrombolysis outperforms MB-mediated therapy regardless of clot retraction, and this advantage of ND-mediated cavitation is emphasized for retracted clots. The primary mechanisms are hypothesized to be sustained cavitation level and cavitation clouds in the proximity of a retracted clot by US+ND. [ABSTRACT FROM AUTHOR]

Existing 3-D intravascular ultrasound (IVUS) systems that combine two electromagnetic (EM) motors to drive catheters are bulky and require considerable efforts to eliminate EM interference (EMI). Here, we propose a new scanning method to realize 3-D IVUS imaging using a helical ultrasonic motor to overcome the aforementioned issues. The ultrasonic motor with compact dimensions (7-mm outer diameter and 30-mm longitudinal length), lightweight (20.5 g), and free of EMI exhibits a great application potential in mobile imaging devices. In particular, it can simultaneously perform rotary and linear motions, facilitating precise 3-D scanning of an imaging catheter. Experimental results show that the signal-to-noise ratio (SNR) of raw images obtained using the ultrasonic motor is 5.3 dB better than that of an EM motor. Moreover, the proposed imaging device exhibits the maximum rotary speed of 12.3 r/s and the positioning accuracy of 2.6 $\mu \text{m}$ at a driving voltage of 240 Vp-p. The 3-D wire phantom imaging and 3-D tube phantom imaging are performed to evaluate the performance of the imaging device. Finally, the in vitro imaging of a porcine coronary artery demonstrates that the layered architecture of the vessel can be precisely identified while significantly increasing the SNR of the raw images. [ABSTRACT FROM AUTHOR]

Real-time, 3-D, passive acoustic mapping (PAM) of microbubble dynamics during transcranial focused ultrasound (FUS) is essential for optimal treatment outcomes. The angular spectrum approach (ASA) potentially offers a very efficient method to perform PAM, as it can reconstruct specific frequency bands pertinent to microbubble dynamics and may be extended to correct aberrations caused by the skull. Here, we experimentally assess the abilities of heterogeneous ASA (HASA) to perform trans-skull PAM. Our experimental investigations demonstrate that the 3-D PAMs of a known 1-MHz source, constructed with HASA through an ex vivo human skull segment, reduced both the localization error (from 4.7 ± 2.3 to 2.3 ± 1.6 mm) and the number, size, and energy of spurious lobes caused by aberration, with the modest additional computational expense. While further improvements in the localization errors are expected with arrays with denser elements and larger aperture, our analysis revealed that experimental constraints associated with the array pitch and aperture (here, 1.8 mm and 2.5 cm, respectively) can be ameliorated by interpolation and peak finding techniques. Beyond the array characteristics, our analysis also indicated that errors in the registration (translation and rotation of ±5 mm and ±5°, respectively) of the skull segment to the array can lead to peak localization errors of the order of a few wavelengths. Interestingly, errors in the spatially dependent speed of sound in the skull (±20%) caused only subwavelength errors in the reconstructions, suggesting that registration is the most important determinant of point source localization accuracy. Collectively, our findings show that HASA can address source localization problems through the skull efficiently and accurately under realistic conditions, thereby creating unique opportunities for imaging and controlling the microbubble dynamics in the brain. [ABSTRACT FROM AUTHOR]

Histotripsy is a focused ultrasound therapy for tissue ablation via the generation of bubble clouds. These effects can be achieved noninvasively, making sensitive and specific bubble imaging essential for histotripsy guidance. Plane-wave ultrasound imaging can track bubble clouds with an excellent temporal resolution, but there is a significant reduction in echoes when deep-seated organs are targeted. Chirp-coded excitation uses wideband, long-duration imaging pulses to increase signals at depth and promote nonlinear bubble oscillations. In this study, we evaluated histotripsy bubble contrast with chirp-coded excitation in scattering gel phantoms and a subcutaneous mouse tumor model. A range of imaging pulse durations were tested, and compared to a standard plane-wave pulse sequence. Received chirped signals were processed with matched filters to highlight components associated with either fundamental or subharmonic (bubble-specific) frequency bands. The contrast-to-tissue ratio (CTR) was improved in scattering media for subharmonic contrast relative to fundamental contrast (both chirped and standard imaging pulses) with the longest-duration chirped-pulse tested (7.4 $\mu \text{s}$ pulse duration). The CTR was improved for subharmonic contrast relative to fundamental contrast (both chirped and standard imaging pulses) by 4.25 dB ± 1.36 dB in phantoms and 3.84 dB ± 6.42 dB in vivo. No systematic changes were observed in the bubble cloud size or dissolution rate between sequences, indicating image resolution was maintained with the long-duration imaging pulses. Overall, this study demonstrates the feasibility of specific histotripsy bubble cloud visualization with chirp-coded excitation. [ABSTRACT FROM AUTHOR]

Therapeutic ultrasound and microbubble technologies seek to drive systemically administered microbubbles into oscillations that safely manipulate tissue or release drugs. Such procedures often detect the unique acoustic emissions from microbubbles with the intention of using this feedback to control the microbubble activity. However, most sensor systems reported introduce distortions to the acoustic signal. Acoustic shockwaves, a key emission from microbubbles, are largely absent in reported recording, possibly due to the sensors being too large or too narrowband, or having strong phase distortions. Here, we built a sensor array that countered such limitations with small, broadband sensors and a low-phase distorting material. We built eight needle hydrophones with polyvinylidene fluoride (PVDF, diameter: 2 mm) then fit them into a 3-D-printed scaffold in a two-layered, staggered arrangement. Using this array, we monitored microbubbles exposed to therapeutically relevant ultrasound pulses (center frequency: 0.5 MHz, peak-rarefactional pressure: 130–597 kPa, pulselength: four cycles). Our tests revealed that the hydrophones were broadband with the best having a sensitivity of −224.8 dB ± 3.2 dB re 1 V/ $\boldsymbol \mu $ Pa from 1 to 15 MHz. The array was able to capture shockwaves generated by microbubbles. The signal-to-noise ratio (SNR) of the array was approximately two times higher than individual hydrophones. Also, the array could localize microbubbles (−3 dB lateral resolution: 2.37 mm) and determine the cavitation threshold (between 161 and 254 kPa). Thus, the array accurately monitored and localized microbubble activities, and may be an important technological step toward better feedback control methods and safer and more effective treatments. [ABSTRACT FROM AUTHOR]

Ultrasound contrast agent microbubbles are considered promising sensors to measure portal vein pressure noninvasively. In this study, we investigated the subharmonic scattering power and optimal incident acoustic pressure of SonoVue microbubbles (concentration: $1~\mu \text{L}$ /mL 0.9% NaCl solution) in the ambient pressure range of 10–40 mmHg with 10-mmHg increments at a temperature of 25 °C. The results demonstrated that the subharmonic response of the SonoVue microbubbles existed in three stages: the first growth stage (40–300 kPa), saturation (300–400 kPa), and the second growth stage (400–540 kPa). In the first growth stage, the subharmonic amplitude increased with ambient pressure. However, while the ambient pressure increased, the subharmonic amplitude decreased in the second growth stage. The best correlation of the subharmonic amplitudes with the ambient pressures was obtained at a high incident acoustic pressure of 520 kPa (sensitivity: 0.15 dB/mmHg, ${r}^{{{2}}} =0.99$ , and root-mean-square error = 0.49 mmHg), which indicated that the subharmonic signals in the second growth stage might be suitable for estimating low ambient pressures. The results presented in our study may pave the way for portal vein pressure estimation using SonoVue microbubbles as sensors in clinical applications. [ABSTRACT FROM AUTHOR]

Increasing the local concentration of microbubbles (MBs) within the blood flow plays a crucial role in several medical applications, but there are few imaging modalities available for volumetric tracking of the aggregated MBs in real time. Here we describe a device integrating acoustic vortex tweezers (AVTs) and ultrasound plane-wave imaging (PWI) to achieve the goal of controlling the spatial distribution of MBs in blood vessels and simultaneously monitoring this process using the same probe. Experiments were conducted using a 5-MHz 2-D array ultrasound probe (with three cycles of excitation at an acoustic pressure of 2000 kPa) and 1.2- $\mu \text{m}$ -diameter MBs at a flow rate of 20 mm/s. The AVT waveform was produced by modulating the repetition frequency of the transmitted pulse asymmetrically (4 and 8 kHz at the inflow and outflow ends, respectively). In order to simultaneously capture MBs and carry out imaging with the same probe, the asymmetric AVT pulse signal and the ultrasound-imaging pulse signal were arranged in a staggered series, and the imaging was carried out using plane-wave pulses at nine angles (−7° to 7°) in compounded PWI (volume rate: 200 Hz). Microscopy observations showed that freely suspended MBs could indeed be gathered by the asymmetric AVT in the flow field to form an MBs cluster with a spot size of about $4022~\mu \text{m}^{{2}}$ , which could resist the flow to remain at a fixed location for about 22 s. After the asymmetric AVT signal and the ultrasound-imaging pulse signal were turned on for 1 s, the ultrasound 3-D image showed that the signal intensity of the MB clusters increased by 13.1 dB ± 2.9 dB in relation to the background area. These results show that the proposed strategy can be used to accumulate flowing MBs at a desired location and to simultaneously observe this phenomenon. This tool could be used in the future to improve the outcomes of MB-related treatments for various diseases. [ABSTRACT FROM AUTHOR]

Cavitation is the fundamental physical mechanism of various focused ultrasound (FUS)-mediated therapies in the brain. Accurately knowing the three-dimensional (3-D) location of cavitation in real-time can improve the targeting accuracy and avoid off-target tissue damage. Existing techniques for 3-D passive transcranial cavitation detection require the use of expensive and complicated hemispherical phased arrays with 128 or 256 elements. The objective of this study was to investigate the feasibility of using four sensors for transcranial 3-D localization of cavitation. Differential microbubble cavitation detection combined with the time difference of arrival algorithm was developed for the localization using the four sensors. Numerical simulation using k-Wave toolbox was performed to validate the proposed method for transcranial cavitation source localization. The sensors with a center frequency of 2.25 MHz and a 6 dB bandwidth of 1.39 MHz were used to locate cavitation generated by FUS (500 kHz) sonication of microbubbles that were injected into a tube positioned inside an ex vivo human skullcap. Cavitation emissions from the microbubbles were detected transcranially using the four sensors. Both simulation and experimental studies found that the proposed method achieved accurate 3-D cavitation localization. When the cavitation source was located within 30 mm from the geometric center of the sensor network, the accuracy of the localization method with the skull was measured to be 1.9±1.0 mm, which was not significantly different from that without the skull (1.7 ± 0.5 mm). The accuracy decreased as the cavitation source was away from the geometric center of the sensor network. It also decreased as the pulse length increased. Its accuracy was not significantly affected by the sensor position relative to the skull. In summary, four sensors combined with the proposed localization algorithm offer a simple approach for 3-D transcranial cavitation localization. [ABSTRACT FROM AUTHOR]

The coronary flow reserve (CFR), relating to the volumetric flow rate, is an effective functional parameter to assess the stenosis in the left anterior descending (LAD) coronary artery. We have recently proposed to use high-frame-rate (HFR) contrast-enhanced ultrasound (CEUS) to estimate the volumetric flow rate using ultrasound (US) speckle decorrelation (SDC) without any assumptions about the velocity profile. However, this method still has challenges in imaging deep and small vessels, such as LAD. In this study, we proposed to address the challenges and demonstrate the feasibility of volumetric flow rate measurement in a coronary mimicking phantom with pulsatile flow using a 1-D array cardiac probe, vector Doppler, and an optimal probe rotation/tilting for flow direction detection. Both simulations and in vitro experiments were conducted to validate the proposed method. It is shown that in-plane velocities estimated by vector Doppler under a 10° probe tilting resulted in smaller percentage error (+5.2%) in flow rate estimates than that in US imaging velocimetry (−20.2%) although their relative standard deviations were very close, being 2.6 and 2.8 ml/min, respectively. The flow rate estimated by SDC without direction detection had an error higher than 70%. A 10° tilting of the probe had the best results in flow rate estimation compared to the 5° or 15° tilting. Realistic global motions in the LAD increased the flow rate estimation error from 5.2% to 14.2%. It is concluded that it is feasible to measure the volumetric flow rate in a coronary artery flow phantom with a conventional cardiac probe, using HFR acquisition, Doppler, and SDC analysis. Potentially, this technique could also be applied to investigate the volumetric flow rate in other small vessels similar to the LAD. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Acoustic angiography is a superharmonic contrast-enhanced ultrasound imaging method that produces high-resolution, 3-D maps of the microvasculature. Previous acoustic angiography studies have used twoelement, annular,mechanicallyactuated transducers(called “wobblers”) to image microvasculature in preclinical tumor models with high contrast-to-tissue ratio and resolution, but these earlywobbler transducerscould not achieve the depth and sensitivity required for clinical acoustic angiography. In this work, we present a system for performing acoustic angiography with a novel dual-frequency(DF) transducer—a coaxially stacked DF array (DFA). We evaluate the DFA system bothin vitro andin vivo and demonstrate improvements in sensitivity and imaging depth up to 13.1 dB and 10 mm, respectively, compared with previous wobbler probes. [ABSTRACT FROM AUTHOR]

Magnetomotive Ultrasound (MMUS) is an emerging imaging modality, in which magnetic nanoparticles (MNPs) are used as contrast agents. MNPs are driven by a time-varying magnetic force, and the resulting movement of the surrounding tissue is detected with a signal processing algorithm. However, there is currently no analytical model to quantitatively predict this magnetically-induced displacement. Toward the goal of predicting motion due to forces on the distribution of MNPs, in this work, a model originally derived from the Navier–Stokes equation for the motion of a single magnetic particle subject to a magnetic gradient force is presented and validated. Displacement amplitudes for a spatially inhomogeneous and temporally sinusoidal force were measured as a function of force amplitude and Young’s modulus, and the predicted linear and inverse relationships were confirmed in gelatin phantoms, respectively, with three out of four data sets exhibiting ${R}^{{2}} \ge {0.88}$. The mean absolute uncertainty between the predicted displacement magnitude and experimental results was 14%. These findings provide a means by which the performance of MMUS systems may be predicted to verify that systems are working to theoretical limits and to compare results across laboratories. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Therapeutic ultrasound technologies using microbubbles require a feedback control system to perform the treatment in a safe and effective manner. Current feedback control technologies utilize the microbubble’s acoustic emissions to adjust the treatment acoustic parameters. Typical systems use two separated transducers: one for transmission and the other for reception. However, separating the transmitter and receiver leads to foci misalignment. This limitation could be resolved by arranging the transmitter and receiver in a stacked configuration. Taking advantage of an increasing number of short-pulse-based therapeutic methods, we have constructed a lead zirconate titanate–polyvinylidene fluoride (PZT–PVDF) stacked transducer design that allows the transmission and reception of short-pulse ultrasound from the same location. Our design had a piston transmitter composed of a PZT disk (1 MHz, 12.7 mm in diameter), a backing layer, and two matching layers. A layer of PVDF (28 μm in thickness, 12.7 mm in diameter) was placed at the front surface of the transmitter for reception. Transmission and reception from the same location were demonstrated in pulse-echo experiments where PZT transmitted a pulse and both PZT and PVDF received the echo. The echo signal received by the PVDF was 0.43 μs shorter than the signal received by the PZT. Reception of broadband acoustic emissions using the PVDF was also demonstrated in experiments where microbubbles were exposed to ultrasound pulses. Thus, we have shown that our PZT–PVDF stack design has unique transmission and reception features that could be incorporated into a multielement array design that improves focal superimposing, transmission efficiency, and reception sensitivity. [ABSTRACT FROM AUTHOR]

The utility of ultrasound imaging and therapy with microbubbles may be greatly enhanced by determining their impulse-response dynamics as a function of size and composition. Prior methods for microbubble characterization utilizing high-speed cameras, acoustic transducers and laser-based techniques typically scan a limited frequency range. Here, we report on the use of a novel photoacoustic technique to measure the impulse response of single microbubbles. Individual microbubbles are driven with a broadband photoacoustic wave generated by a nanosecond-pulse laser illuminating an optical absorber. The resulting microbubble oscillations were detected by following transmission of a second laser as it passes twice through the microbubble. The system could even resolve oscillations resulting from a single-shot. As a proof-of-concept study, the size-dependent, linear impulse response of lipid-coated microbubbles was characterized using this technique. This unique method of microbubble characterization with exceptional spatiotemporal resolution opens new avenues for capturing and analyzing microbubble system dynamics. [ABSTRACT FROM AUTHOR]

Contrast agents are routinely used in ultrasound examinations. Nonlinear ultrasound imaging techniques have been developed over decades to enhance the contrast between the tissue and the blood pool after the injection of ultrasound contrast agents (UCAs). In this study, we introduce a new contrast pulse sequence, CPS4. The CPS4 combines pulse inversion (PI), subharmonic (SH), and ultraharmonic (UH) techniques to remove propagation distortion while capturing the unique SH and UH responses from UCAs. The novel CPS4 and conventional PI, SH, and UH techniques were used to detect the presence of a research-grade, thick-shell, polymer microbubble in a tissue-mimicking flow phantom. The contrast-to-tissue ratios (CTRs) obtained from the applications of all techniques were compared. The results show that the highest CTR of approximately 16 dB was obtained using CPS4, which was superior to the individual reference techniques: PI, SH, and UH techniques, in all scenarios considered in this study. [ABSTRACT FROM AUTHOR]

Contrast-enhanced ultrasound (CEUS) is a real-time imaging technique that allows the visualization of organ and tumor microcirculation by utilizing the nonlinear response of microbubbles. Nonlinear pulsing schemes are used exclusively in CEUS imaging modes in modern scanners. One important aspect of nonlinear pulsing schemes is the near-complete elimination of the linear signals that originate from tissue. Up until now, no study has investigated the performance of Verasonics scanners in eliminating the linear signals during CEUS and, by extension, the optimal pulsing sequences for performing CEUS. The aim of this article was to investigate linear signal cancellation of the Verasonics scanner performing nonlinear pulsing schemes with two different probes (L7-4 linear array and C5-2 convex array). We have considered two pulsing schemes: pulse inversion (PI) and amplitude modulation (AM). We have also compared our results from the Verasonics scanner with a clinical scanner (Philips iU22). We found that the linear signal cancellation of the transmitted pulse by Verasonics scanner was ~40 dB in AM mode and ~30 dB in PI mode when operated at 0.06 MI. The linear signal cancellation performance of Verasonics scanner was comparable with Philips iU22 scanner in focused AM mode and on average 3 dB better than Philips iU22 scanner in focused PI mode. [ABSTRACT FROM AUTHOR]

Thisstudy focuses on evaluating the real-time functionality of a customized interface and investigating the optimal parameters for intracardiac subharmonic-aided pressure estimation (SHAPE) utilizing Definity (Lantheus Medical Imaging Inc., North Billerica, MA, USA) and Sonazoid (GE Healthcare, Oslo, Norway) microbubbles. Pressure measurements within the chambers of the heart yield critical information for managing cardiovascular diseases. An alternative to current, invasive, clinical cardiac catheterization procedures is utilizing ultrasound contrast agents and SHAPE to noninvasively estimate intracardiac pressures. Therefore, this work developed a customized interface (on a SonixTablet, BK Ultrasound, Peabody, MA, USA) for real-time intracardiac SHAPE. In vitro, a Doppler flow phantom was utilized to mimic the dynamic pressure changes within the heart. Definity (15.0– $22.5~\mu \text{L}$ microspheres corresponding to 0.1–0.15 mL) and Sonazoid (GE Healthcare; 0.4– $1.2~\mu \text{L}$ microspheres corresponding to 0.05–0.15 mL) microbubbles were used. Data were acquired for varying transmit frequencies (2.5–4.0 MHz), and pulse shaping options (square wave and chirp down) to determine optimal transmit parameters. Simultaneously obtained radio frequency data and ambient pressure data were compared. For Definity, the chirp down pulse at 3.0 MHz yielded the highest correlation ($r = - 0.77\,\,\pm \,\,0.2$) between SHAPE and pressure catheter data. For Sonazoid, the square wave pulse at 2.5 MHz yielded the highest correlation (${r} = - 0.72\,\,\pm \,\,0.2$). In conclusion, the real-time functionality of the customized interface has been verified, and the optimal parameters for utilizing Definity and Sonazoid for intracardiac SHAPE have been determined. [ABSTRACT FROM AUTHOR]

In therapeutic ultrasound using microbubbles, it is essential to drive the microbubbles into the correct type of activity and the correct location to produce the desired biological response. Although passive acoustic mapping (PAM) is capable of locating where microbubble activities are generated, it is well known that microbubbles rapidly move within the ultrasound beam. We propose a technique that can image microbubble movement by estimating their velocities within the focal volume. Microbubbles embedded within a wall-less channel of a tissue-mimicking material were sonicated using 1-MHz focused ultrasound. The acoustic emissions generated by the microbubbles were captured with a linear array (L7-4). PAM with robust Capon beamforming was used to localize the microbubble acoustic emissions. We spectrally analyzed the time trace of each position and isolated the higher harmonics. Microbubble velocity maps were constructed from the position-dependent Doppler shifts at different time points during sonication. Microbubbles moved primarily away from the transducer at velocities on the order of 1 m/s due to primary acoustic radiation forces, producing a time-dependent velocity distribution. We detected microbubble motion both away and toward the receiving array, revealing the influence of acoustic radiation forces and fluid motion due to the ultrasound exposure. High-speed optical images confirmed the acoustically measured microbubble velocities. Doppler PAM enables passive estimation of microbubble motion and may be useful in therapeutic applications, such as drug delivery across the blood–brain barrier, sonoporation, sonothrombolysis, and drug release. [ABSTRACT FROM AUTHOR]

This study demonstrates, in detail, the potential of using capacitive micromachined ultrasonic transducers (CMUTs) for acoustic angiography of the microvasculature. It is known that when ultrasound contrast agents (microbubbles) are excited with moderate acoustic pressure around their resonance (2–4 MHz), they produce higher order harmonics (greater than third harmonic) due to their nonlinear behavior. To date, the fundamental challenge has been the availability of a transducer that can generate the transmit signals to excite the microbubbles at low frequencies and, in the same cycle, confocally detect harmonics in the higher frequencies. We present a novel device structure and dual-mode operation of a CMUT that operates with a center frequency of 4.3 MHz and 150% bandwidth in the conventional mode for transmitting and a center frequency of 9.8 MHz and a 125.5% bandwidth in collapse mode for receiving. Output pressure of 1.7 MPapp is achieved on the surface of a single unfocused transducer. The mechanical index at the transducer surface is 0.56. FEM simulations are performed first to show the functionality of the proposed device, and then, the device fabrication is described in detail. Finally, we experimentally demonstrate the ability to detect the microbubble signals with good contrast, and the background reflection is adequately suppressed, indicating the feasibility of the presented approach for acoustic angiography. [ABSTRACT FROM AUTHOR]

Current methods for in vivo microvascular imaging (<1 mm) are limited by the tradeoffs between the depth of penetration, resolution, and acquisition time. Ultrasound Doppler approaches combined at elevated frequencies (<7.5 MHz) are able to visualize smaller vasculature and, however, are still limited in the segmentation of lower velocity blood flow from moving tissue. Contrast-enhanced ultrasound (CEUS) has been successful in visualizing changes in microvascular flow at conventional diagnostic ultrasound imaging frequencies (<7.5 MHz). However, conventional CEUS approaches at elevated frequencies have met with limited success, due, in part, to the diminishing microbubble response with frequency. We apply a plane-wave acquisition combined with the non-linear Doppler processing of ultrasound contrast agents at 15 MHz to improve the resolution of microvascular blood flow while compensating for reduced microbubble response. This plane-wave Doppler approach of imaging ultrasound contrast agents also enables simultaneous detection and separation of blood flow in the microcirculation and higher velocity flow in the larger vasculature. We apply singular value decomposition filtering on the nonlinear Doppler signal to orthogonally separate the more stationary lower velocity flow in the microcirculation and higher velocity flow in the larger vasculature. This orthogonal separation was also utilized to improve time-intensity curve analysis of the microcirculation, by removing higher velocity flow corrupting bolus kinetics. We demonstrate the utility of this imaging approach in a rat spinal cord injury model, requiring submillimeter resolution. [ABSTRACT FROM AUTHOR]

We report the time kinetics of fluorescently labeled microbubbles (MBs) in capillary-level microvasculature as measured via confocal microscopy and compare these results to ultrasound localization microscopy (ULM). The observed 19.4 ± 4.2 MBs per confocal field-of-view ($212\,\,\mu \text{m}\,\,\times 212\,\,\mu \text{m}$) are in excellent agreement with the expected count of 19.1 MBs per frame. The estimated time to fully perfuse this capillary network was 193 s, which corroborates the values reported in the literature. We then modeled the capillary network as an empirically determined discrete-time Markov chain with adjustable MB transition probabilities though individual capillaries. The Monte Carlo random walk simulations found perfusion times ranging from 24.5 s for unbiased Markov chains up to 182 s for heterogeneous flow distributions. This pilot study confirms a probability-derived explanation for the long acquisition times required for super-resolution ULM. [ABSTRACT FROM AUTHOR]

Blind source separation (BSS) refers to a number of signal processing techniques that decompose a signal into several “source” signals. In recent years, BSS is increasingly employed for the suppression of clutter and noise in ultrasonic imaging. In particular, its ability to separate sources based on measures of independence rather than their temporal or spatial frequency content makes BSS a powerful filtering tool for data in which the desired and undesired signals overlap in the spectral domain. The purpose of this work was to review the existing BSS methods and their potential in ultrasound imaging. Furthermore, we tested and compared the effectiveness of these techniques in the field of contrast-ultrasound super-resolution, contrast quantification, and speckle tracking. For all applications, this was done in silico, in vitro, and in vivo. We found that the critical step in BSS filtering is the identification of components containing the desired signal and highlighted the value of a priori domain knowledge to define effective criteria for signal component selection. [ABSTRACT FROM AUTHOR]

One of the main challenges that impede cavitation-mediated imaging in the brain is restricted opening of the blood–brain barrier (BBB) making it difficult to locate cavitating microbubbles (MBs). Passive cavitation imaging (PCI) has received attention due to the possibility of performing real-time monitoring by listening to acoustic cavitation. However, the long excitation pulses associated with PCI degrade its axial resolution. The present study combined a coded excitation technique with a dual-frequency chirp (DFC) excitation method to prevent interference from the nonlinear components of MBs’ cavitation. The use of DFC excitation generates a low-frequency (0.4, 0.5, or 0.6 MHz) chirp component as the envelope of the signal-driving MBs’ cavitation with a dual-frequency pulse ($\omega {1} = {1.35}$ MHz and $\omega {2} = {1.65}$ MHz, $\omega {1} = {1.3}$ MHz and $\omega {2} = {1.7}$ MHz, and $\omega {1} = {1.25}$ MHz and $\omega {2} = {1.75}$ MHz). The cavitation of MBs was passively imaged utilizing a chirp component with pulse compression to maintain abundant insonation energy without any reduction in the axial imaging resolution. In vitro experiments showed that the DFC method improved the signal-to-noise ratio by 42.2% and the axial resolution by 4.1-fold compared with using a conventional long-pulse waveform. Furthermore, the cavitating MBs driven by different ultrasound (US) energy (0, 0.3, 0.6, and 0.9 MPa, ${N}= {3}$ for each group) in the rat brain with an intact skull still could be mapped by DFC. Our successful demonstration of using the DFC method to image cavitation-induced BBB opening affords an alternative tool for assessing cavitation-dependent drug delivery to the brain, with the benefit of real-time and high convenient integration with current US imaging devices. [ABSTRACT FROM AUTHOR]

Recent advances in high frame rate biomedical ultrasound have led to the development of ultrasound localization microscopy (ULM), a method of imaging microbubble (MB) contrast agents beyond the diffraction limit of conventional coherent imaging techniques. By localizing and tracking the positions of thousands of individual MBs, ultrahigh resolution vascular maps are generated which can be further analyzed to study disease. Isolating bubble echoes from tissue signal is a key requirement for super-resolution imaging which relies on the spatiotemporal separability and localization of the bubble signals. To date, this has been accomplished either during acquisition using contrast imaging sequences or post-beamforming by applying a spatiotemporal filter to the B-mode images. Superharmonic imaging (SHI) is another contrast imaging method that separates bubbles from tissue based on their strongly nonlinear acoustic properties. This approach is highly sensitive, and, unlike spatiotemporal filters, it does not require decorrelation of contrast agent signals. Since this superharmonic method does not rely on bubble velocity, it can detect completely stationary and moving bubbles alike. In this work, we apply SHI to ULM and demonstrate an average improvement in SNR of 10.3-dB in vitro when compared with the standard singular value decomposition filter approach and an increase in SNR at low flow (0.27 μm/frame) from 5 to 16.5 dB. Additionally, we apply this method to imaging a rodent kidney in vivo and measure vessels as small as 20 μm in diameter after motion correction. [ABSTRACT FROM AUTHOR]

Multipulse (MP) ultrasound contrast agent (UCA) imaging is a method to increase the contrast-to-background (CBR) ratio in regions of blood flow. Plane-wave imaging allows high frame rates, and with high-frequency ultrasound, fine-spatial and temporal resolution. MP and plane-wave imaging have not been applied to high-frequency ultrasound. Here, an 18-MHz linear array was employed to implement the MP methods of pulse inversion (PI) and amplitude modulation (AM) using high-speed, multiangle, compound plane-wave imaging. A flow of the UCA DEFINITY© at a dilution ratio of 2000:1 circulating through a 2-mm-diameter flow channel in a tissue-mimicking phantom was used to characterize CBR and compared with cases of standard, multiangle compound plane-wave imaging. The relative improvement of PI and AM versus standard plane-wave imaging ranged from 5 to 10 dB. The CBR was observed to be stable over a 60-min time duration for a 2000:1 dilution ratio and a 2000:1 dilution ratio provided an optimal CBR. [ABSTRACT FROM AUTHOR]

Three-dimensional (3-D) ultrasound elastography can provide 3-D tissue stiffness information that may be used during clinical diagnoses. In the framework of strain elastography, motion tracking plays an important role. In this study, an improved 3-D region-growing motion tracking (RGMT) algorithm based on a concept of exterior boundary points was developed. In principle, the proposed method first determines displacement at some seed points by strictly checking the local correlation and continuity in the neighborhood of those seeds. Subsequent displacement estimation is then conducted from these initial seeds to obtain displacements associated with other locations. This RGMT algorithm is designed to use more known information—including displacements and correlation values of all known-displacement neighboring points—to estimate the displacement of an unknown-displacement point, whereas previous RGMT methods employed information from only one such point. The algorithm was tested on 3-D ultrasound volumetric data acquired from a simulation, a tissue-mimicking phantom, and five human subjects. Motion-compensated cross correlations (MCCCs), strain contrast, and displacement Laplacian values (representing smoothness of an estimated displacement field) were calculated and used to evaluate the merits of the proposed RGMT method. Compared with a previously published RGMT method, the results show that the proposed RGMT method can provide smaller displacement errors and smoother displacements and improve strain contrast while maintaining reasonably high MCCC values, indicating good motion tracking quality. The proposed method is also computationally more efficient. In summary, our preliminary results demonstrated that the proposed RGMT algorithm is capable of obtaining high-quality 3-D strain elastographic data using modified clinical equipment. [ABSTRACT FROM AUTHOR]

Radial modulation imaging improves the detection of microbubbles at high frequency using a dual ultrasonic excitation. However, the synchronization between the imaging pulses is nontrivial because microbubbles need to be interrogated in the compression and the rarefaction phase, and the time-delay difference from dispersion has to be corrected. To address these issues, we propose the use of ultrafast radial modulation imaging (uRMI). In this technique, a beat frequency between the modulation pulse (around 1 MHz) and the ultrafast pulse-repetition frequency was exploited to separate microbubbles from tissue phantom in vitro. This led to a modulated images’ set in the spectral domain of the slow time that may then be demodulated through a digital lock-in amplifier to retrieve the contrast image. Ultrafast RMI, applied on a flow phantom with microbubbles, provided a contrast-to-tissue ratio from 7.2 to 14.8 dB at 15 MHz. For flow speed lower than 0.05 mL/min, uRMI (16 dB) provided a better contrast-to-tissue ratio than other techniques: singular value decomposition spatiotemporal filter (11 dB), amplitude modulation (9 dB), or microbubbles disruption (6 dB). This technique may then be suitable to improve the detection of targeted microbubbles, in ultrasound molecular imaging applications, and the detection of extremely slow microbubbles moving in the finest vessels in ultrasound localization microscopy. [ABSTRACT FROM AUTHOR]

The measurement of cardiac and aortic pressures enables diagnostic insight into cardiac contractility and stiffness. However, these pressures are currently assessed invasively using pressure catheters. It may be possible to estimate these pressures less invasively by applying microbubble ultrasound contrast agents as pressure sensors. The aim of this study was to investigate the subharmonic response of the microbubble ultrasound contrast agent SonoVue (Bracco Spa, Milan, Italy) at physiological pressures using a static pressure phantom. A commercially available cell culture cassette with Luer connections was used as a static pressure chamber. SonoVue was added to the phantom, and radio frequency data were recorded on the ULtrasound Advanced Open Platform (ULA-OP). The mean subharmonic amplitude over a 40% bandwidth was extracted at 0–200-mmHg hydrostatic pressures, across 1.7–7.0-MHz transmit frequencies and 3.5%–100% maximum scanner acoustic output. The Rayleigh–Plesset equation for single-bubble oscillations and additional hysteresis experiments were used to provide insight into the mechanisms underlying the subharmonic pressure response of SonoVue. The subharmonic amplitude of SonoVue increased with hydrostatic pressure up to 50 mmHg across all transmit frequencies and decreased thereafter. A decreasing microbubble surface tension may drive the initial increase in the subharmonic amplitude of SonoVue with hydrostatic pressure, while shell buckling and microbubble destruction may contribute to the subsequent decrease above 125-mmHg pressure. In conclusion, a practical operating regime that may be applied to estimate cardiac and aortic blood pressures from the subharmonic signal of SonoVue has been identified. [ABSTRACT FROM AUTHOR]

High-frame-rate 3-D ultrasound imaging technology combined with super-resolution processing method can visualize 3-D microvascular structures by overcoming the diffraction-limited resolution in every spatial direction. However, 3-D super-resolution ultrasound imaging using a full 2-D array requires a system with a large number of independent channels, the design of which might be impractical due to the high cost, complexity, and volume of data produced. In this study, a 2-D sparse array was designed and fabricated with 512 elements chosen from a density-tapered 2-D spiral layout. High-frame-rate volumetric imaging was performed using two synchronized ULA-OP 256 research scanners. Volumetric images were constructed by coherently compounding nine-angle plane waves acquired at a pulse repetition frequency of 4500 Hz. Localization-based 3-D super-resolution images of two touching subwavelength tubes were generated from 6000 volumes acquired in 12 s. Finally, this work demonstrates the feasibility of 3-D super-resolution imaging and super-resolved velocity mapping using a customized 2-D sparse array transducer. [ABSTRACT FROM AUTHOR]

High-resolution transcranial ultrasound imaging in humans has been a persistent challenge for ultrasound due to the imaging degradation effects from aberration and reverberation. These mechanisms depend strongly on skull morphology and have high variability across individuals. Here, we demonstrate the feasibility of human transcranial super-resolution imaging using a geometrical focusing approach to efficiently concentrate energy at the region of interest, and a phase correction focusing approach that takes the skull morphology into account. It is shown that using the proposed focused super-resolution method, we can image a 208- $\mu \text{m}$ microtube behind a human skull phantom in both an out-of-plane and an in-plane configuration. Individual phase correction profiles for the temporal region of the human skull were calculated and subsequently applied to transmit–receive a custom focused super-resolution imaging sequence through a human skull phantom, targeting the 208- $\mu \text{m}$ diameter microtube at 68.5 mm in depth and at 2.5 MHz. Microbubble contrast agents were diluted to a concentration of $1.6\times 10^{6}$ bubbles/mL and perfused through the microtube. It is shown that by correcting for the skull aberration, the RF signal amplitude from the tube improved by a factor of 1.6 in the out-of-plane focused emission case. The lateral registration error of the tube’s position, which in the uncorrected case was 990 $\mu \text{m}$ , was reduced to as low as 50 $\mu \text{m}$ in the corrected case as measured in the B-mode images. Sensitivity in microbubble detection for the phase-corrected case increased by a factor of 1.48 in the out-of-plane imaging case, while, in the in-plane target case, it improved by a factor of 1.31 while achieving an axial registration correction from an initial 1885- $\mu \text{m}$ error for the uncorrected emission, to a 284- $\mu \text{m}$ error for the corrected counterpart. These findings suggest that super-resolution imaging may be used far more generally as a clinical imaging modality in the brain. [ABSTRACT FROM AUTHOR]

Due to the primary radiation force, microbubble displacement has been observed previously in the focal region of single-element and array ultrasound probes. This effect has been harnessed to increase the contact between the microbubbles and targeted endothelium for drug delivery and ultrasound molecular imaging. In this study, microbubble displacements associated with plane-wave (PW) transmission are thoroughly investigated and compared to those obtained in focused-wave (FW) transmission over a range of pulse repetition frequencies, burst lengths (BLs), peak negative pressures, and transmission frequencies. In PW mode, the displacements, depending upon the experimental conditions, are in some cases consistently higher (e.g., by 28%, when the longest BL was used at PRF = 4 kHz), and the axial displacements are spatially more uniform compared to FW mode. Statistical analysis on the measured displacements reveals a slightly different frequency dependence of statistical quantities compared to transient peak microbubble displacements, which may suggest the need to consider the size range within the tested microbubble population. [ABSTRACT FROM AUTHOR]

Ultrasound (US) localization microscopy offers new radiation-free diagnostic tools for vascular imaging deep within the tissue. Sequential localization of echoes returned from inert microbubbles (MBs) with low concentration within the bloodstream reveals the vasculature with capillary resolution. Despite its high spatial resolution, low MB concentrations dictate the acquisition of tens of thousands of images, over the course of several seconds to tens of seconds, to produce a single superresolved image. Such long acquisition times and stringent constraints on MB concentration are undesirable in many clinical scenarios. To address these restrictions, sparsity-based approaches have recently been developed. These methods reduce the total acquisition time dramatically, while maintaining good spatial resolution in settings with considerable MB overlap. Here, we further improve the spatial resolution and visual vascular reconstruction quality of sparsity-based superresolution US imaging from low-frame rate acquisitions, by exploiting the inherent flow of MBs and utilize their motion kinematics. We also provide quantitative measurements of MB velocities and show that our approach achieves higher MB recall rate than the state-of-the-art techniques, while increasing contrast agents concentration. Our method relies on simultaneous tracking and sparsity-based detection of individual MBs in a frame-by-frame manner, and as such, may be suitable for real-time implementation. The effectiveness of the proposed approach is demonstrated on both simulations and an in vivo contrast-enhanced human prostate scan, acquired with a clinically approved scanner operating at a 10-Hz frame rate. [ABSTRACT FROM AUTHOR]

A number of acoustic super-resolution techniques have recently been developed to visualize microvascular structure and flow beyond the diffraction limit. A crucial aspect of all ultrasound (US) super-resolution (SR) methods using single microbubble localization is time-efficient detection of individual bubble signals. Due to the need for bubbles to circulate through the vasculature during acquisition, slow flows associated with the microcirculation limit the minimum acquisition time needed to obtain adequate spatial information. Here, a model is developed to investigate the combined effects of imaging parameters, bubble signal density, and vascular flow on SR image acquisition time. We find that the estimated minimum time needed for SR increases for slower blood velocities and greater resolution improvement. To improve SR from a resolution of $\lambda $ /10 to $\lambda $ /20 while imaging the microvasculature structure modeled here, the estimated minimum acquisition time increases by a factor of 14. The maximum useful imaging frame rate to provide new spatial information in each image is set by the bubble velocity at low blood flows (<150 mm/s for a depth of 5 cm) and by the acoustic wave velocity at higher bubble velocities. Furthermore, the image acquisition procedure, transmit frequency, localization precision, and desired super-resolved image contrast together determine the optimal acquisition time achievable for fixed flow velocity. Exploring the effects of both system parameters and details of the target vasculature can allow a better choice of acquisition settings and provide improved understanding of the completeness of SR information. [ABSTRACT FROM AUTHOR]

Temporal- and spatial-resolved observations of microbubble cavitation generated through high-intensity ultrasound irradiation are key in improving both the efficiency and efficacy of ultrasound-assisted drug delivery systems. A method of measuring bubble cavitation applying an image-reconstruction technique of back-propagation of an acoustic cavitation emission (ACE) signal is proposed. A high-intensity focused ultrasound wave (pump wave) irradiates the bubble synchronously using ultrasound recording equipment to acquire the timing of the RF signal, which is produced when the bubble radiates a secondary wave during bubble cavitation. The ACE signal source is reconstructed through ultrasound-wave back-propagation followed by amplitude deconvolution. The proposed method was applied to microbubbles of an ultrasound contrast agent by changing the sound pressure of the pump wave. The method reliability of the temporal resolution was verified by simulating the amplitude-modulated signal of the virtual sound source. The temporal transition of the ACE signal exhibited sub-microsecond-order fluctuations in the signal intensity. From the amplitude signal image and the instantaneous frequency image reconstruction of the proposed method, two different ACE phenomena were visualized. One is the periodic pattern by the beat signals from the harmonic and ultraharmonic component of nonlinear oscillation under low-intensity ultrasound conditions. The other is the nonperiodic temporal and spatial distributions of this irradiation under high-intensity ultrasound conditions. [ABSTRACT FROM AUTHOR]

Phase-change perfluorohexane nanodroplets (PFHnDs) are a new class of recondensable submicrometer-sized contrast agents that have potential for contrast-enhanced and super-resolution ultrasound imaging with an ability to reach extravascular targets. The PFHnDs can be optically triggered to undergo vaporization, resulting in spatially stationary, temporally transient microbubbles. The vaporized PFHnDs are hyperechoic in ultrasound imaging for several to hundreds of milliseconds before recondensing to their native, hypoechoic, liquid nanodroplet state. The decay of echogenicity, i.e., the dynamic behavior of the ultrasound signal from optically triggered PFHnDs in ultrasound imaging, can be captured using high-frame-rate ultrasound imaging. We explore the possibility to manipulate the echogenicity dynamics of optically triggered PFHnDs in ultrasound imaging by changing the phase of the ultrasound imaging pulse. Specifically, the ultrasound imaging system was programmed to transmit two imaging pulses with inverse polarities. We show that the imaging pulse phase can affect the amplitude and the temporal behavior of PFHnD echogenicity in ultrasound imaging. The results of this study demonstrate that the ultrasound echogenicity is significantly increased (about 78% improvement) and the hyperechoic timespan of optically triggered PFHnDs is significantly longer (about four times) if the nanodroplets are imaged by an ultrasound pulse starting with rarefactional pressure versus a pulse starting with compressional pressure. Our finding has direct and significant implications for contrast-enhanced ultrasound imaging of droplets in applications such as super-resolution imaging and molecular imaging where detection of individual or low-concentration PFHnDs is required. [ABSTRACT FROM AUTHOR]

Combining diverging ultrasound waves and microbubbles could improve contrast-enhanced echocardiography (CEE), by providing enhanced temporal resolution for cardiac function assessment over a large imaging field of view. However, current image formation techniques using coherent summation of echoes from multiple steered diverging waves (DWs) are susceptible to tissue and microbubble motion artifacts, resulting in poor image quality. In this study, we used correlation-based 2-D motion estimation to perform motion compensation for CEE using DWs. The accuracy of this motion estimation method was evaluated with Field II simulations. The root-mean-square velocity errors were 5.9% ± 0.2% and 19.5% ± 0.4% in the axial and lateral directions, when normalized to the maximum value of 62.8 cm/s which is comparable to the highest speed of blood flow in the left ventricle (LV). The effects of this method on image contrast ratio (CR) and contrast-to-noise ratio (CNR) were tested in vitro using a tissue mimicking rotating disk with a diameter of 10 cm. Compared against the control without motion compensation, a mean increase of 12 dB in CR and 7 dB in CNR were demonstrated when using this motion compensation method. The motion correction algorithm was tested in vivo on a CEE data set acquired with the Ultrasound Array Research Platform II performing coherent DW imaging. Improvement of the B-mode and contrast-mode image quality with cardiac motion and blood flow-induced microbubble motion was achieved. The results of motion estimation were further processed to interpret blood flow in the LV. This allowed for a triplex cardiac imaging technique, consisting of B mode, contrast mode, and 2-D vector flow imaging with a high frame rate of 250 Hz. [ABSTRACT FROM AUTHOR]

Being able to measure 3-D flow velocity and volumetric flow rate effectively in the cardiovascular system is valuable but remains a significant challenge in both clinical practice and research. Currently, there has not been an effective and practical solution to the measurement of volume flow using ultrasound imaging systems due to challenges in existing 3-D imaging techniques and high system cost. In this study, a new technique for quantifying volumetric flow rate from the cross-sectional imaging plane of the blood vessel was developed by using speckle decorrelation (SDC), 2-D high-frame-rate imaging with a standard 1-D array transducer, microbubble contrast agents, and ultrasound imaging velocimetry (UIV). Through SDC analysis of microbubble signals acquired with a very high frame rate and by using UIV to estimate the two in-plane flow velocity components, the third and out-of-plane velocity component can be obtained over time and integrated to estimate volume flow. The proposed technique was evaluated on a wall-less flow phantom in both steady and pulsatile flow. UIV in the longitudinal direction was conducted as a reference. The influences of frame rate, mechanical index (MI), orientation of imaging plane, and compounding on velocity estimation were also studied. In addition, an in vivo trial on the abdominal aorta of a rabbit was conducted. The results show that the new system can estimate volume flow with an averaged error of 3.65% ± 2.37% at a flow rate of 360 mL/min and a peak velocity of 0.45 m/s, and an error of 5.03% ± 2.73% at a flow rate of 723 mL/min and a peak velocity of 0.8 m/s. The accuracy of the flow velocity and volumetric flow rate estimation directly depend on the imaging frame rate. With a frame rate of 6000 Hz, a velocity up to 0.8 m/s can be correctly estimated. A higher mechanical index (MI = 0.42) is shown to produce greater errors (up to 21.78±0.49%, compared to 3.65±2.37% at MI = 0.19). An in vivo trial, where velocities up to 1 m/s were correctly measured, demonstrated the potential of the technique in clinical applications. [ABSTRACT FROM AUTHOR]

Three-dimensional contrast-enhanced ultrasound (CEUS) imaging presents a clear advantage over its 2-D counterpart in detecting and characterizing suspicious lesions as it properly surveys the inherent heterogeneity of tumors. However, 3-D CEUS is also slow compared to 2-D CEUS and tends to undersample the microbubble wash-in. This makes it difficult to resolve the feeding vessels, an important oncogenic marker, from the background perfusion cloud. Contrast-enhanced Doppler is helpful in isolating this conduit flow, but requires too many pulses in conventional line-by-line beamforming design. Recent breakthroughs in plane-wave imaging have greatly accelerated the volumetric imaging frame rate, but volumetric Doppler angiography still remains challenging when considering real-time limitations on the Doppler ensemble length. In this work, we demonstrate the feasibility of volumetric CEUS angiography subjected to real-time imaging constraints. Namely, we show how principal curvature detection can significantly improve 3-D rendering of relatively noisy ultrasound angiograms without degrading the spatial resolution while subjected to a reasonable Doppler ensemble size. Singular value decomposition is also shown to be capable of identifying the quasi-stationary capillary perfusion. [ABSTRACT FROM AUTHOR]

Radiation force is known to produce microbubble axial displacements by an amount that depends on the transmit burst frequency, amplitude, and length, as well as the pulse repetition frequency (PRF). In the standard focused-imaging mode, the actual PRF experienced by each microbubble is low, because it is of the order of the frame rate (i.e., usually tens of Hertz). In the plane-wave imaging mode, however, the actual PRF is considerably higher, as it is equivalent to the transmit PRF (kiloHertz range). Furthermore, the radiation pressure is expected to be almost uniform over the field of view, and typically lower than the peak pressure experienced in the focused transmit (TX) mode. We have experimentally investigated the possible effects of radiation force in the plane-wave mode. Here, we report on preliminary findings that show that the acoustic radiation force is negligible only at lower TX levels. At higher TX amplitudes, the bubble displacements due to radiation force are comparable to those obtained for focused waves at the same PRF. In addition, the radiation force is nearly uniform over the field of view and increases as the TX burst central frequency approaches the resonance frequency of size-isolated microbubbles. [ABSTRACT FROM AUTHOR]

Contrast-enhanced ultrasound (CEUS) imaging has great potential for use in many new ultrasound clinical applications. We recently proposed a novel CEUS imaging sequence, Hadamard-encoded multipulses (HEM), to improve the signal-to-noise ratio (SNR) and the contrast-to-tissue ratio (CTR) as compared to other classic CEUS methods. HEM increases microbubble responses by using longer coded transmit pulses and the fast polarity change between coded pulses. In this study, we propose to combine the HEM pulse with multiplane wave (MW) imaging technique to further improve CEUS imaging SNR and contrast-to-noise ratio. During MW-HEM transmissions, the microbubbles undergo multiple fast pulse polarity changes, leading to significantly improved microbubble nonlinear responses, and thus further enhanced SNR and CTR as compared to HEM alone or other CEUS sequences. This improvement may facilitate more robust CEUS imaging for deep abdominal organs and the heart. [ABSTRACT FROM AUTHOR]

Because it drives the compromise between resolution and penetration, the diffraction limit has long represented an unreachable summit to conquer in ultrasound imaging. Within a few years after the introduction of optical localization microscopy, we proposed its acoustic alter ego that exploits the micrometric localization of microbubble contrast agents to reconstruct the finest vessels in the body in-depth. Various groups now working on the subject are optimizing the localization precision, microbubble separation, acquisition time, tracking, and velocimetry to improve the capacity of ultrasound localization microscopy (ULM) to detect and distinguish vessels much smaller than the wavelength. It has since been used in vivo in the brain, the kidney, and tumors. In the clinic, ULM is bound to improve drastically our vision of the microvasculature, which could revolutionize the diagnosis of cancer, arteriosclerosis, stroke, and diabetes. [ABSTRACT FROM AUTHOR]

The structure of microvasculature cannot be resolved using conventional ultrasound (US) imaging due to the fundamental diffraction limit at clinical US frequencies. It is possible to overcome this resolution limitation by localizing individual microbubbles through multiple frames and forming a superresolved image, which usually requires seconds to minutes of acquisition. Over this time interval, motion is inevitable and tissue movement is typically a combination of large- and small-scale tissue translation and deformation. Therefore, super-resolution (SR) imaging is prone to motion artifacts as other imaging modalities based on multiple acquisitions are. This paper investigates the feasibility of a two-stage motion estimation method, which is a combination of affine and nonrigid estimation, for SR US imaging. First, the motion correction accuracy of the proposed method is evaluated using simulations with increasing complexity of motion. A mean absolute error of 12.2 \mu \textm was achieved in simulations for the worst-case scenario. The motion correction algorithm was then applied to a clinical data set to demonstrate its potential to enable in vivo SR US imaging in the presence of patient motion. The size of the identified microvessels from the clinical SR images was measured to assess the feasibility of the two-stage motion correction method, which reduced the width of the motion-blurred microvessels to approximately 1.5-fold. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM PUBLISHER]