Toward Noninvasive Mapping of Diffuse Scattering in the Presence of Motion.

Ultrasonic coda wave analysis techniques localize defects in fields such as seismography and nondestructive testing. In medical ultrasound, these techniques might provide novel mapping of tissue properties in diseases characterized by local fibrosis. In this work, we present an approach for localizing variation in scattering properties in the diffuse regime with an array transducer in medical ultrasound. This approach estimates coda wave decorrelation as the array is displaced by 0.5 mm, allowing data acquisition at two slightly different spatial locations. An inverse problem is solved as in nondestructive testing based on coda wave decorrelation estimates and a locally-estimated diffusion constant. The developed approach is demonstrated in a tissue-mimicking phantom to assess sensitivity to variation in scattering properties. Next, the ability of the approach for localizing regions of increased multiple scattering in biological tissues is assessed with a large multiple scattering bead in an ex vivo porcine cardiac sample. Through these experiments, the ability to map variation in multiple scattering is demonstrated for the first time, with a mean localization error of 1.42 ± 3.5 mm for this low-resolution mapping technique. While the goal of this technique is to map defects in the diffuse regime rather than to develop a conventional image, contrast ratios in the resulting images were in good agreement with scattering concentrations in phantom studies: 1.98 ± 0.05 for a 2× scattering target, 1.37 ± 0.02 for a 1.4× scattering target, 0.65 ± 0.02 for a 0.7× scattering target, and 0.49 ± 0.03 for a 0.5× scattering targets.

Refraction correction in 3D transcranial ultrasound imaging.

We present the first correction of refraction in three-dimensional (3D) ultrasound imaging using an iterative approach that traces propagation paths through a two-layer planar tissue model, applying Snell's law in 3D. This approach is applied to real-time 3D transcranial ultrasound imaging by precomputing delays offline for several skull thicknesses, allowing the user to switch between three sets of delays for phased array imaging at the push of a button. Simulations indicate that refraction correction may be expected to increase sensitivity, reduce beam steering errors, and partially restore lost spatial resolution, with the greatest improvements occurring at the largest steering angles. Distorted images of cylindrical lesions were created by imaging through an acrylic plate in a tissue-mimicking phantom. As a result of correcting for refraction, lesions were restored to 93.6% of their original diameter in the lateral direction and 98.1% of their original shape along the long axis of the cylinders. In imaging two healthy volunteers, the mean brightness increased by 8.3% and showed no spatial dependency.

Dual-frequency piezoelectric transducers for contrast enhanced ultrasound imaging.

For many years, ultrasound has provided clinicians with an affordable and effective imaging tool for applications ranging from cardiology to obstetrics. Development of microbubble contrast agents over the past several decades has enabled ultrasound to distinguish between blood flow and surrounding tissue. Current clinical practices using microbubble contrast agents rely heavily on user training to evaluate degree of localized perfusion. Advances in separating the signals produced from contrast agents versus surrounding tissue backscatter provide unique opportunities for specialized sensors designed to image microbubbles with higher signal to noise and resolution than previously possible. In this review article, we describe the background principles and recent developments of ultrasound transducer technology for receiving signals produced by contrast agents while rejecting signals arising from soft tissue. This approach relies on transmitting at a low-frequency and receiving microbubble harmonic signals at frequencies many times higher than the transmitted frequency. Design and fabrication of dual-frequency transducers and the extension of recent developments in transducer technology for dual-frequency harmonic imaging are discussed.

High Frequency, 2 mm-diameter Forward-viewing 2D Array for 3D Intracoronary Blood Flow Imaging.

Coronary artery disease (CAD) is one of the leading causes of death globally. Currently, diagnosis and intervention in CAD are typically performed via minimally-invasive cardiac catheterization procedures. Using current diagnostic technology such as angiography and FFR, interventional cardiologists must decide which patients require intervention and which can be deferred. 10% of patients with stable CAD are incorrectly deferred using current diagnostic best practices. By developing a forward-viewing intravascular ultrasound (FV-IVUS) 2D array capable of simultaneously evaluating morphology, hemodynamics, and plaque composition, physicians would be better able to stratify risk of major adverse cardiac events in patients with intermediate stenosis. For this application, a forward-viewing, 16 MHz 2D array transducer was designed and fabricated. A 2 mm-diameter aperture consisting of 140 elements, with element dimensions of 98 µm × 98 µm × 70 µm (w × h × t) and a nominal inter-element spacing of 120 µm was designed for this application based on simulations. The acoustic stack for this array was developed with a designed center frequency of 16 MHz. A novel via-less interconnect was developed to enable electrical connections to fan out from a 140-element 2D array with 120 µm inter-element spacing. The fabricated array transducer had 96/140 functioning elements operating at a center frequency of 16 MHz with a -6 dB fractional bandwidth of 62 ± 7%. Single element SNR was 23 ± 3 dB, and the measured electrical crosstalk was -33 ± 3 dB. In imaging experiments, the measured lateral resolution was 0.231 mm and the measured axial resolution was 0.244 mm at a depth of 5 mm. Finally, the transducer was used to perform 3D B-mode imaging of a 3 mm-diameter spring and 3D B-mode and power Doppler imaging of a tissue-mimicking phantom.

Dynamic Coronary Blood Flow Velocity and Wall Shear Stress Estimation Using Ultrasound in an Ex Vivo Porcine Heart.

PURPOSE: Wall shear stress (WSS) is a critically important physical factor contributing to atherosclerosis. Mapping the spatial distribution of local, oscillatory WSS can identify important mechanisms underlying the progression of coronary artery disease. METHODS: In this study, blood flow velocity and time-varying WSS were estimated in the left anterior descending (LAD) coronary artery of an ex vivo beating porcine heart using ultrasound with an 18 MHz linear array transducer aligned with the LAD in a forward-viewing orientation. A pulsatile heart loop with physiologically-accurate flow was created using a pulsatile pump. The coronary artery wall motion was compensated using a local block matching technique. Next, 2D and 3D velocity magnitude and WSS maps in the LAD coronary artery were estimated at different time points in the cardiac cycle using an ultrafast Doppler approach. The blood flow velocity estimated using the presented approach was compared with a commercially-available, calibrated single element blood flow velocity measurement system. RESULTS: The resulting root mean square error (RMSE) of 2D velocity magnitude acquired from a high frequency, linear array transducer was less than 8% of the maximum velocity estimated by the commercial system. CONCLUSION: When implemented in a forward-viewing intravascular ultrasound device, the presented approach will enable dynamic estimation of WSS, an indicator of plaque vulnerability in coronary arteries.

Effect of skull porosity on ultrasound transmission and wave mode conversion at large incidence angles.

BACKGROUND: Transcranial ultrasound imaging and therapy depend on the efficient transmission of acoustic energy through the skull. Multiple previous studies have concluded that a large incidence angle should be avoided during transcranial-focused ultrasound therapy to ensure transmission through the skull. Alternatively, some other studies have shown that longitudinal-to-shear wave mode conversion might improve transmission through the skull when the incidence angle is increased above the critical angle (i.e., 25° to 30°). PURPOSE: The effect of skull porosity on the transmission of ultrasound through the skull at varying incidence angles was investigated for the first time to elucidate why transmission through the skull at large angles of incidence is decreased in some cases but improved in other cases. METHODS: Transcranial ultrasound transmission at varying incidence angles (0°-50°) was investigated in phantoms and ex vivo skull samples with varying bone porosity (0% to 28.54% ± 3.36%) using both numerical and experimental methods. First, the elastic acoustic wave transmission through the skull was simulated using micro-computed tomography data of ex vivo skull samples. The trans-skull pressure was compared between skull segments having three levels of porosity, that is, low porosity (2.65% ± 0.03%), medium porosity (13.41% ± 0.12%), and high porosity (26.9%). Next, transmission through two 3D-printed resin skull phantoms (compact vs. porous phantoms) was experimentally measured to test the effect of porous microstructure alone on ultrasound transmission through flat plates. Finally, the effect of skull porosity on ultrasound transmission was investigated experimentally by comparing transmission through two ex vivo human skull segments having similar thicknesses but different porosities (13.78% ± 2.05% vs. 28.54% ± 3.36%). RESULTS: Numerical simulations indicated that an increase in transmission pressure occurs at large incidence angles for skull segments having low porosities but not for those with high porosity. In experimental studies, a similar phenomenon was observed. Specifically, for the low porosity skull sample (13.78% ± 2.05%), the normalized pressure was 0.25 when the incidence angle increased to 35°. However, for the high porosity sample (28.54% ± 3.36%), the pressure was no more than 0.1 at large incidence angles. CONCLUSIONS: These results indicate that the skull porosity has an evident effect on the transmission of ultrasound at large incidence angles. The wave mode conversion at large, oblique incidence angles could enhance the transmission of ultrasound through parts of the skull having lower porosity in the trabecular layer. However, for transcranial ultrasound therapy in the presence of highly porous trabecular bone, transmission at a normal incidence angle is preferable relative to oblique incidence angles due to the higher transmission efficiency.

A Transverse Velocity Spectral Estimation Method for Ultrafast Ultrasound Doppler Imaging.

A novel transverse velocity spectral estimation method is proposed to estimate the velocity component in the direction transverse to the beam axis for ultrafast imaging. The transverse oscillation was introduced by filtering the envelope data after the axial oscillation was removed. The complex transverse oscillated signal was then used to estimate the transverse velocity spectrum and mean velocity. In simulations, both steady flow with a parabolic flow profile and temporally varying flow were simulated to investigate the performance of the proposed method. Next, the proposed approach was used to estimate the flow velocity in a phantom with pulsatile flow, and finally, this method was applied in vivo in a small animal model. Results of the simulation study indicate that the proposed method provided an accurate velocity spectrogram for beam-to-flow angles from 45° to 90°, without significant performance degradation as the angle decreased. For the simulation of temporally varying flow, the proposed method had a reduced bias ( % versus 73.3%) and higher peak-to-background ratio (PBR) (>15.6 versus 10.5 dB) compared to previous methods. Results in a vessel phantom show that the temporally varying flow velocity can be estimated in the transverse direction obtained using the spectrogram produced by the proposed method operating on the envelope data. Finally, the proposed method was used to map the microvascular blood flow velocity in the mouse spinal cord, demonstrating the estimation of pulsatile blood flow in both the axial and transverse directions in vivo over several cardiac cycles.

Supervised segmentation for guiding peripheral revascularization with forward-viewing, robotically steered ultrasound guidewire.

BACKGROUND: Approximately 500 000 patients present with critical limb ischemia (CLI) each year in the U.S., requiring revascularization to avoid amputation. While peripheral arteries can be revascularized via minimally invasive procedures, 25% of cases with chronic total occlusions are unsuccessful due to inability to route the guidewire beyond the proximal occlusion. Improvements to guidewire navigation would lead to limb salvage in a greater number of patients. PURPOSE: Integrating ultrasound imaging into the guidewire could enable direct visualization of routes for guidewire advancement. In order to navigate a robotically-steerable guidewire with integrated imaging beyond a chronic occlusion proximal to the symptomatic lesion for revascularization, acquired ultrasound images must be segmented to visualize the path for guidewire advancement. METHODS: The first approach for automated segmentation of viable paths through occlusions in peripheral arteries is demonstrated in simulations and experimentally-acquired data with a forward-viewing, robotically-steered guidewire imaging system. B-mode ultrasound images formed via synthetic aperture focusing (SAF) were segmented using a supervised approach (U-net architecture). A total of 2500 simulated images were used to train the classifier to distinguish the vessel wall and occlusion from viable paths for guidewire advancement. First, the size of the synthetic aperture resulting in the highest classification performance was determined in simulations (90 test images) and compared with traditional classifiers (global thresholding, local adaptive thresholding, and hierarchical classification). Next, classification performance as a function of the diameter of the remaining lumen (0.5 to 1.5 mm) in the partially-occluded artery was tested using both simulated (60 test images at each of 7 diameters) and experimental data sets. Experimental test data sets were acquired in four 3D-printed phantoms from human anatomy and six ex vivo porcine arteries. Accuracy of classifying the path through the artery was evaluated using microcomputed tomography of phantoms and ex vivo arteries as a ground truth for comparison. RESULTS: An aperture size of 3.8 mm resulted in the best-performing classification based on sensitivity and Jaccard index, with a significant increase in Jaccard index (p < 0.05) as aperture diameter increased. In comparing the performance of the supervised classifier and traditional classification strategies with simulated test data, sensitivity and F1 score for U-net were 0.95 ± 0.02 and 0.96 ± 0.01, respectively, compared to 0.83 ± 0.03 and 0.41 ± 0.13 for the best-performing conventional approach, hierarchical classification. In simulated test images, sensitivity (p < 0.05) and Jaccard index both increased with increasing artery diameter (p < 0.05). Classification of images acquired in artery phantoms with remaining lumen diameters ≥ 0.75 mm resulted in accuracies > 90%, while mean accuracy decreased to 82% when artery diameter decreased to 0.5 mm. For testing in ex vivo arteries, average binary accuracy, F1 score, Jaccard index, and sensitivity each exceeded 0.9. CONCLUSIONS: Segmentation of ultrasound images of partially-occluded peripheral arteries acquired with a forward-viewing, robotically-steered guidewire system was demonstrated for the first-time using representation learning. This could represent a fast, accurate approach for guiding peripheral revascularization.

Very Low Frequency Radial Modulation for Deep Penetration Contrast-Enhanced Ultrasound Imaging.

Contrast-enhanced ultrasound imaging allows vascular imaging in a variety of diseases. Radial modulation imaging is a contrast agent-specific imaging approach for improving microbubble detection at high imaging frequencies (≥7.5 MHz), with imaging depth limited to a few centimeters. To provide high-sensitivity contrast-enhanced ultrasound imaging at high penetration depths, a new radial modulation imaging strategy using a very low frequency (100 kHz) ultrasound modulation wave in combination with imaging pulses ≤5 MHz is proposed. Microbubbles driven at 100 kHz were imaged in 10 successive oscillation states by manipulating the pulse repetition frequency to unlock the frame rate from the number of oscillation states. Tissue background was suppressed using frequency domain radial modulation imaging (F-RMI) and singular value decomposition-based radial modulation imaging (S-RMI). One hundred-kilohertz modulation resulted in significantly higher microbubble signal magnitude (63-88 dB) at the modulation frequency relative to that without 100-kHz modulation (51-59 dB). F-RMI produced images with high contrast-to-tissue ratios (CTRs) of 15 to 22 dB in a stationary tissue phantom, while S-RMI further improved the CTR (19-26 dB). These CTR values were significantly higher than that of amplitude modulation pulse inversion images (11.9 dB). In the presence of tissue motion (1 and 10 mm/s), S-RMI produced high-contrast images with CTR up to 18 dB; however, F-RMI resulted in minimal contrast enhancement in the presence of tissue motion. Finally, in transcranial ultrasound imaging studies through a highly attenuating ex vivo cranial bone, CTR values with S-RMI were as high as 23 dB. The proposed technique demonstrates successful modulation of microbubble response at 100 kHz for the first time. The presented S-RMI low-frequency radial modulation imaging strategy represents the first demonstration of real-time (20 frames/s), high-penetration-depth radial modulation imaging for contrast-enhanced ultrasound imaging.

A Thin Transducer With Integrated Acoustic Metamaterial for Cardiac CT Imaging and Gating.

Coronary artery disease (CAD) is a leading cause of death globally. Computed tomography coronary angiography (CTCA) is a noninvasive imaging procedure for diagnosis of CAD. However, CTCA requires cardiac gating to ensure that diagnostic-quality images are acquired in all patients. Gating reliability could be improved by utilizing ultrasound (US) to provide a direct measurement of cardiac motion; however, commercially available US transducers are not computed tomography (CT) compatible. To address this challenge, a CT-compatible 2.5-MHz cardiac phased array transducer is developed via modeling, and then, an initial prototype is fabricated and evaluated for acoustic and radiographic performance. This 92-element piezoelectric array transducer is designed with a thin acoustic backing (6.5 mm) to reduce the volume of the radiopaque acoustic backing that typically causes arrays to be incompatible with CT imaging. This thin acoustic backing contains two rows of air-filled, triangular prism-shaped voids that operate as an acoustic diode. The developed transducer has a bandwidth of 50% and a single-element SNR of 9.9 dB compared to 46% and 14.7 dB for a reference array without an acoustic diode. In addition, the acoustic diode reduces the time-averaged reflected acoustic intensity from the back wall of the acoustic backing by 69% compared to an acoustic backing of the same composition and thickness without the acoustic diode. The feasibility of real-time echocardiography using this array is demonstrated in vivo, including the ability to image the position of the interventricular septum, which has been demonstrated to effectively predict cardiac motion for prospective, low radiation CTCA gating.

Dual-Resonance (16/32 MHz) Piezoelectric Transducer With a Single Electrical Connection for Forward-Viewing Robotic Guidewire.

Peripheral artery disease (PAD) affects more than 200 million people globally. Minimally invasive endovascular procedures can provide relief and salvage limbs while reducing injury rates and recovery times. Unfortunately, when a calcified chronic total occlusion is encountered, ~25% of endovascular procedures fail due to the inability to advance a guidewire using the view provided by fluoroscopy. To enable a sub-millimeter, robotically steerable guidewire to cross these occlusions, a novel single-element, dual-band transducer is developed that provides simultaneous multifrequency, forward-viewing imaging with high penetration depth and high spatial resolution while requiring only a single electrical connection. The design, fabrication, and acoustic characterization of this device are described, and proof-of-concept imaging is demonstrated in an ex vivo porcine artery after integration with a robotically steered guidewire. Measured center frequencies of the developed transducer were 16 and 32 MHz, with -6 dB fractional bandwidths of 73% and 23%, respectively. When imaging a 0.2-mm wire target at a depth of 5 mm, measured -6 dB target widths were 0.498 ± 0.02 and 0.268 ± 0.01 mm for images formed at 16 and 32 MHz, respectively. Measured SNR values were 33.3 and 21.3 dB, respectively. The 3-D images of the ex vivo artery demonstrate high penetration for visualizing vessel morphology at 16 MHz and ability to resolve small features close to the transducer at 32 MHz. Using images acquired simultaneously at both frequencies as part of an integrated forward-viewing, guidewire-based imaging system, an interventionalist could visualize the best path for advancing the guidewire to improve outcomes for patients with PAD.

Effect of Skull Porous Trabecular Structure on Transcranial Ultrasound Imaging in the Presence of Elastic Wave Mode Conversion at Varying Incidence Angle.

With the advancement of aberration correction techniques, transcranial ultrasound imaging has exhibited great potential in applications such as imaging neurological function and guiding therapeutic ultrasound. However, the feasibility of transcranial imaging varies among individuals because of the differences in skull acoustic properties. To better understand the fundamental mechanisms underlying the variation in imaging performance, the effect of the structure of the porous trabecular bone on transcranial imaging performance (i.e., target localization errors and resolution) was investigated for the first time through the use of elastic wave simulations and experiments. Simulation studies using high-resolution computed tomography data from ex vivo skull samples revealed that imaging at large incidence angles reduced the target localization error for skulls having low porosity; however, as skull porosity increased, large angles of incidence resulted in degradation of resolution and increased target localization errors. Experimental results indicate that imaging at normal incidence introduced a localization error of 1.85 ± 0.10 mm, while imaging at a large incidence angle (40°) resulted in an increased localization error of 6.54 ± 1.33 mm and caused a single point target to no longer appear as a single, coherent target in the resulting image, which is consistent with simulation results. This first investigation of the effects of skull microstructure on transcranial ultrasound imaging indicates that imaging performance is highly dependent on the porosity of the skull, particularly at non-normal angles of incidence.

Forward-viewing estimation of 3D blood flow velocity fields by intravascular ultrasound: Influence of the catheter on velocity estimation in stenoses.

Coronary artery disease is the most common type of cardiovascular disease, affecting > 18 million adults, and is responsible for > 365 k deaths per year in the U.S. alone. Wall shear stress (WSS) is an emerging indicator of likelihood of plaque rupture in coronary artery disease, however, non-invasive estimation of 3-D blood flow velocity and WSS is challenging due to the requirement for high spatial resolution at deep penetration depths in the presence of significant cardiac motion. Thus we propose minimally-invasive imaging with a catheter-based, 3-D intravascular forward-viewing ultrasound (FV US) transducer and present experiments to quantify the effect of the catheter on flow disturbance in stenotic vessel phantoms with realistic velocities and luminal diameters for both peripheral (6.33 mm) and coronary (4.74 mm) arteries. An external linear array ultrasound transducer was used to quantify 2-D velocity fields in vessel phantoms under various conditions of catheter geometry, luminal diameter, and position of the catheter relative to the stenosis at a frame rate of 5000 frames per second via a particle imaging velocimetry (PIV) approach. While a solid catheter introduced an underestimation of velocity measurement by > 20% relative to the case without a catheter, the hollow catheter introduced < 10% velocity overestimation, indicating that a hollow catheter design allowing internal blood flow reduces hemodynamic disturbance. In addition, for both peripheral and coronary arteries, the hollow catheter introduced < 3% deviation in flow velocity at the minimum luminal area compared to the control case. Finally, an initial comparison was made between velocity measurements acquired using a low frequency, catheter-based, 3-D intravascular FV US transducer and external linear array measurements, with relative error < 12% throughout the region of interest for a flow rate of 150 mL/min. While further system development is required, results suggest intravascular ultrasound characterization of blood flow velocity fields in stenotic vessels could be feasible with appropriate catheter design.

Ultrasound-gated computed tomography coronary angiography: Development of ultrasound transducers with improved computed tomography compatibility.

PURPOSE: Cardiovascular disease (CVD) is a leading cause of death worldwide, with coronary artery disease (CAD) accounting for nearly half of all CVD deaths. The current gold standard for CAD diagnosis is catheter coronary angiography (CCA), an invasive, expensive procedure. Computed tomography coronary angiography (CTCA) represents an attractive non-invasive alternative to CCA, however, CTCA requires gated acquisition of CT data during periods of minimal cardiac motion (quiescent periods) to avoid non-diagnostic scans. Current gating methods either expose patients to high levels of radiation (retrospective gating) or lead to high rates of non-diagnostic scans (prospective gating) due to the challenge of predicting cardiac quiescence based on ECG alone. Alternatively, ultrasound (US) imaging has been demonstrated as an effective indicator of cardiac quiescence, however, ultrasound transducers produce prominent streak artifacts that disrupt CTCA scans. In this study, a proof-of-concept array transducer with improved CT-compatibility was developed for utilization in an integrated US-CTCA system. METHODS: Alternative materials were tested radiographically and acoustically to replace the radiopaque acoustic backings utilized in low frequency (1-4 MHz) cardiac US transducers. The results of this testing were used to develop alternative acoustic backings consisting of varying concentrations of aluminum oxide in an epoxy matrix via simulations. On the basis of these simulations, single element test transducers designed to operate at 2.5 MHz were fabricated, and the performance of these devices was characterized via acoustic and radiographic testing with micro-computed tomography (micro-CT). Finally, a first proof-of-concept cardiac phased array transducer was developed and its US imaging performance was evaluated. Micro-CT images of the developed US array with improved CT-compatibility were compared with those of a conventional array. RESULTS: Materials testing with micro-CT identified an acoustic backing with a measured radiopacity of 1008 HU, more than an order of magnitude lower than that of the acoustic backing (24,000 HU) typically used in cardiac transducers operating in the 1-4 MHz range. When utilized in a simulated transducer design, this acoustic backing yielded a -6-dB fractional bandwidth of 57%, similar to the 54% bandwidth of the transducer with the radiopaque acoustic backing. The developed 2.5 MHz, single element transducer based on these simulations exhibited a fractional bandwidth of 51% and signal-to-noise ratio (SNR) of 14.7 dB. Finally, the array transducer developed with the acoustic backing having decreased radiopacity exhibited a 56% fractional bandwidth and 10.4 dB single channel SNR, with penetration depth >10 cm in phantom and in vivo imaging using the full array. CONCLUSIONS: The first attempt at developing a CT-compatible ultrasound transducer is described. The developed CT-compatible transducer exhibits improved radiographic compatibility relative to conventional cardiac array transducers with similar SNR, bandwidth, and penetration depth for US imaging, according to phantom and in vivo cardiac imaging. A CT-compatible US transducer might be used to identify cardiac quiescence and prospectively gate CTCA acquisition, reducing challenges associated with current gating approaches, specifically relatively high rates of non-diagnostic scans for prospective ECG gating and high radiation dose for retrospective gating.

A Robotically Steerable Guidewire With Forward-Viewing Ultrasound: Development of Technology for Minimally-Invasive Imaging.

OBJECTIVE: The current standard of care for peripheral chronic total occlusions involves the manual routing of a guidewire under fluoroscopy. Despite significant improvements in recent decades, navigation remains clinically challenging with high rates of procedural failure and iatrogenic injury. To address this challenge, we present a proof-of-concept robotic guidewire system with forward-viewing ultrasound imaging to allow visualization and maneuverability through complex vasculature. METHODS: A 0.035" guidewire-specific ultrasound transducer with matching layer and acoustic backing was designed, fabricated, and characterized. The effect of guidewire motion on signal decorrelation was assessed with simulations and experimentally, driving the development of a synthetic aperture beamforming approach to form images as the transducer is steered on the robotic guidewire. System performance was evaluated by imaging wire targets in water. Finally, proof-of-concept was demonstrated by imaging an ex vivo artery. RESULTS: The designed custom transducer was fabricated with a center frequency of 15.7 MHz, 45.4% fractional bandwidth, and 31 dB SNR. In imaging 20 µm wire targets at a depth of 6 mm, the lateral -6 dB target width was 0.25 ± 0.03 mm. The 3D artery reconstruction allowed visualization of vessel wall structure and lumen. CONCLUSION: Initial proof-of-concept for an ultrasound transducer-tipped steerable guidewire including 3D image formation without an additional sensor to determine guidewire position was demonstrated for a sub-mm system with an integrated ultrasound transducer and a robotically-steered guidewire. SIGNIFICANCE: The developed forward-viewing, robotically-steered guidewire may enable navigation through occluded vascular regions that cannot be crossed with current methods.

Patient-Specific 3D Bioprinted Models of Developing Human Heart.

The heart is the first organ to develop in the human embryo through a series of complex chronological processes, many of which critically rely on the interplay between cells and the dynamic microenvironment. Tight spatiotemporal regulation of these interactions is key in heart development and diseases. Due to suboptimal experimental models, however, little is known about the role of microenvironmental cues in the heart development. This study investigates the use of 3D bioprinting and perfusion bioreactor technologies to create bioartificial constructs that can serve as high-fidelity models of the developing human heart. Bioprinted hydrogel-based, anatomically accurate models of the human embryonic heart tube (e-HT, day 22) and fetal left ventricle (f-LV, week 33) are perfused and analyzed both computationally and experimentally using ultrasound and magnetic resonance imaging. Results demonstrate comparable flow hemodynamic patterns within the 3D space. We demonstrate endothelial cell growth and function within the bioprinted e-HT and f-LV constructs, which varied significantly in varying cardiac geometries and flow. This study introduces the first generation of anatomically accurate, 3D functional models of developing human heart. This platform enables precise tuning of microenvironmental factors, such as flow and geometry, thus allowing the study of normal developmental processes and underlying diseases.

A 3D Bioprinted In Vitro Model of Pulmonary Artery Atresia to Evaluate Endothelial Cell Response to Microenvironment.

Vascular atresia are often treated via transcatheter recanalization or surgical vascular anastomosis due to congenital malformations or coronary occlusions. The cellular response to vascular anastomosis or recanalization is, however, largely unknown and current techniques rely on restoration rather than optimization of flow into the atretic arteries. An improved understanding of cellular response post anastomosis may result in reduced restenosis. Here, an in vitro platform is used to model anastomosis in pulmonary arteries (PAs) and for procedural planning to reduce vascular restenosis. Bifurcated PAs are bioprinted within 3D hydrogel constructs to simulate a reestablished intervascular connection. The PA models are seeded with human endothelial cells and perfused at physiological flow rate to form endothelium. Particle image velocimetry and computational fluid dynamics modeling show close agreement in quantifying flow velocity and wall shear stress within the bioprinted arteries. These data are used to identify regions with greatest levels of shear stress alterations, prone to stenosis. Vascular geometry and flow hemodynamics significantly affect endothelial cell viability, proliferation, alignment, microcapillary formation, and metabolic bioprofiles. These integrated in vitro-in silico methods establish a unique platform to study complex cardiovascular diseases and can lead to direct clinical improvements in surgical planning for diseases of disturbed flow.

Phase Modulation Beamforming for Ultrafast Plane-Wave Imaging.

In order to improve the spatial resolution for high-frame-rate imaging, a new image formation approach is proposed based on introducing very weak aberration into received data, then combining the multiple results by taking the pixel-wise standard deviation of multiple aberrated images and subtracting the result from the delay-and-sum image. This approach is demonstrated in simulations, tissue-mimicking phantom experiments, and in vivo imaging. Simulations indicate the lateral full-width half-maximum (FWHM) of targets decreases by 38.24% ± 6.38%. In imaging wire targets in a tissue-mimicking phantom at 7.8 MHz, wire target FWHM decreases by 35.91% ± 5.39%. However, contrast was observed to decrease by 1.23 dB and contrast-to-noise ratio (CNR) by 18.5% in phantom studies due to the subtraction of similar images, which increases the number of dark pixels in the image. Finally, the proposed technique is tested in vivo, with images showing improvements similar to those in tissue-mimicking phantoms, including increased separation between closely spaced targets.

Transcranial activation and imaging of low boiling point phase-change contrast agents through the temporal bone using an ultrafast interframe activation ultrasound sequence.

PURPOSE: As a cavitation enhancer, low boiling point phase-change contrast agents (PCCA) offer potential for ultrasound-mediated drug delivery in applications including intracerebral hemorrhage or brain tumors. In addition to introducing cavitation, ultrasound imaging also has the ability to provide guidance and monitoring of the therapeutic process by localizing delivery events. However, the highly attenuating skull poses a challenge for achieving an image with useful contrast. In this study, the feasibility of transcranial activation and imaging of low boiling point PCCAs through the human temporal bone was investigated by using a low frequency ultrafast interframe activation ultrasound (UIAU) imaging sequence with singular value decomposition-based denoising. METHODS: Lipid-shelled PCCAs filled with decafluorobutane were activated and imaged at 37°C in tissue-mimicking phantoms both without and with an ex vivo human skull using the new UIAU sequence and a low frequency diagnostic transducer array at frequencies from 1.5 to 3.5 MHz. A singular value decomposition-based denoising filter was developed and used to further enhance transcranial image contrast. The contrast-to-tissue ratio (CTR) and contrast enhancement (CE) of UIAU was quantitatively evaluated and compared with the amplitude modulation pulse inversion (AMPI) and vaporization detection imaging (VDI) approaches. RESULTS: Image results demonstrate enhanced contrast in the phantom channel with suppressed background when the low boiling point PCCA was activated both without and with an ex vivo human skull using the UIAU sequence. Quantitative results show that without the skull, low frequency UIAU imaging provided significantly higher image contrast (CTR ≥ 18.56 dB and CE ≥ 18.66 dB) than that of AMPI and VDI (P < 0.05). Transcranial imaging results indicated that the CE of UIAU (≥18.80 dB) was significantly higher than AMPI for free-field activation pressures of 5 and 6 MPa. The CE of UIAU is also significantly higher than that of VDI when PCCAs were activated at 2.5 MHz and 3 MHz (P < 0.05). The CTR (23.30 [20.07-25.56] dB) of denoised UIAU increased by 12.58 dB relative to the non-denoised case and was significantly higher than that of AMPI at an activation pressure of 4 MPa (P < 0.05). CONCLUSIONS: Results indicate that low boiling point PCCAs can be activated and imaged at low frequencies including imaging through the temporal bone using the UIAU sequence. The UIAU imaging approach provides higher contrast than AMPI and VDI, especially at lower activation pressures with additional removal of electronic noise.

High contrast power Doppler imaging in side-viewing intravascular ultrasound imaging via angular compounding.

The ability to assess likelihood of plaque rupture can determine the course of treatment in coronary artery disease. One indicator of plaque vulnerability is the development of blood vessels within the plaque, or intraplaque neovascularization. In order to visualize these vessels with increased sensitivity in the cardiac catheterization lab, a new approach for imaging blood flow in small vessels using side-viewing intravascular ultrasound (IVUS) is proposed. This approach based on compounding adjacent angular acquisitions was evaluated in tissue mimicking phantoms and ex vivo vessels. In phantom studies, the Doppler CNR increased from 3.3 ± 1.0 to 13 ± 2.6 (conventional clutter filtering) and from 1.9 ± 0.15 to 7.5 ± 1.1 (SVD filtering) as a result of applying angular compounding. When imaging flow at a rate of 5.6 mm/s in 200 µm tubes adjacent to the lumen of ex vivo porcine arteries, the Doppler CNR increased from 5.3 ± 0.95 to 7.2 ± 1.3 (conventional filtering) and from 23 ± 3.3 to 32 ± 6.7 (SVD filtering). Applying these strategies could allow increased sensitivity to slow flow in side-viewing intravascular ultrasound imaging.