Quantitative Viscoelastic Response (QVisR): Direct Estimation of Viscoelasticity with Neural Networks.

We present a machine learning method to directly estimate viscoelastic moduli from displacement time-series profiles generated by Viscoelastic Response (VisR) ultrasound excitations. VisR uses two colocalized acoustic radiation force pushes to approximate tissue viscoelastic creep response and tracks displacements on-axis to measure the material relaxation. A fully-connected neural network is trained to learn a nonlinear mapping from VisR displacements, the push focal depth, and the measurement axial depth to the material elastic and viscous moduli. In this work, we assess the validity of Quantitative Viscoelastic Response (QVisR) in simulated materials, propose a method of domain adaption to phantom VisR displacements, and show in vivo estimates from a clinically acquired dataset.

Comparing Focused-Tracked and Plane Wave-Tracked ARFI Log(VoA) In Silico and in Application to Human Carotid Atherosclerotic Plaque, Ex Vivo.

A significant risk factor for ischemic stroke is carotid atherosclerotic plaque that is susceptible to rupture, with rupture potential conveyed by plaque morphology. Human carotid plaque composition and structure have been delineated noninvasively and in vivo by evaluating log(VoA), a parameter derived as the decadic log of the second time derivative of displacement induced by an acoustic radiation force impulse (ARFI). In prior work, ARFI-induced displacement was measured using conventional focused tracking; however, this requires a long data acquisition period, thereby reducing framerate. We herein evaluate if ARFI log(VoA) framerate can be increased without a reduction in plaque imaging performance using plane wave tracking instead. In silico, both focused- and plane wave-tracked log(VoA) decreased with increasing echobrightness, quantified as signal-to-noise ratio (SNR), but did not vary with material elasticity for SNRs below 40 dB. For SNRs of 40-60 dB, both focused- and plane wave-tracked log(VoA) varied with SNR and material elasticity. Above 60 dB SNR, both focused- and plane wave-tracked log(VoA) varied with material elasticity alone. This suggests that log(VoA) discriminates features according to a combination of their echobrightness and mechanical property. Further, while both focused- and plane-wave tracked log(VoA) values were artifactually inflated by mechanical reflections at inclusion boundaries, plane wave-tracked log(VoA) was more strongly impacted by off-axis scattering. Applied to three excised human cadaveric carotid plaques with spatially aligned histological validation, both log(VoA) methods detected regions of lipid, collagen, and calcium (CAL) deposits. These findings support that plane wave tracking performs comparably to focused tracking for log(VoA) imaging and that plane wave-tracked log(VoA) is a viable approach to discriminating clinically relevant atherosclerotic plaque features at a 30-fold higher framerate than by focused tracking.

Development of a Robotic Shear Wave Elastography System for Noninvasive Staging of Liver Disease in Murine Models.

Shear wave elastography (SWE) is an ultrasound-based stiffness quantification technology that is used for noninvasive liver fibrosis assessment. However, despite widescale clinical adoption, SWE is largely unused by preclinical researchers and drug developers for studies of liver disease progression in small animal models due to significant experimental, technical, and reproducibility challenges. Therefore, the aim of this work was to develop a tool designed specifically for assessing liver stiffness and echogenicity in small animals to better enable longitudinal preclinical studies. A high-frequency linear array transducer (12-24 MHz) was integrated into a robotic small animal ultrasound system (Vega; SonoVol, Inc., Durham, NC) to perform liver stiffness and echogenicity measurements in three dimensions. The instrument was validated with tissue-mimicking phantoms and a mouse model of nonalcoholic steatohepatitis. Female C57BL/6J mice (n = 40) were placed on choline-deficient, L-amino acid-defined, high-fat diet and imaged longitudinally for 15 weeks. A subset was sacrificed after each imaging timepoint (n = 5) for histological validation, and analyses of receiver operating characteristic (ROC) curves were performed. Results demonstrated that robotic measurements of echogenicity and stiffness were most strongly correlated with macrovesicular steatosis (R2  = 0.891) and fibrosis (R2  = 0.839), respectively. For diagnostic classification of fibrosis (Ishak score), areas under ROC (AUROCs) curves were 0.969 for ≥Ishak1, 0.984 for ≥Ishak2, 0.980 for ≥Ishak3, and 0.969 for ≥Ishak4. For classification of macrovesicular steatosis (S-score), AUROCs were 1.00 for ≥S2 and 0.997 for ≥S3. Average scanning and analysis time was <5 minutes/liver. Conclusion: Robotic SWE in small animals is feasible and sensitive to small changes in liver disease state, facilitating in vivo staging of rodent liver disease with minimal sonographic expertise.

Quantitative Estimation of Mechanical Anisotropy Using Acoustic Radiation Force (ARF)-Induced Peak Displacements (PD): In Silico and Experimental Demonstration.

Elastic degree of anisotropy (DoA) is a diagnostically relevant biomarker in muscle, kidney, breast, and other organs. Previously, elastic DoA was qualitatively assessed as the ratio of peak displacements (PD) achieved with the long-axis of a spatially asymmetric Acoustic Radiation Force Impulse (ARFI) excitation point spread function (PSF) aligned along versus across the axis of symmetry (AoS) in transversely isotropic materials. However, to better enable longitudinal and cross-sectional analyses, a quantitative measure of elastic DoA is desirable. In this study, qualitative ARFI PD ratios are converted to quantitative DoA, measured as the ratio of longitudinal over transverse shear elastic moduli, using a model empirically derived from Field II and finite element method (FEM) simulations. In silico, the median absolute percent error (MAPE) in ARFI-derived shear moduli ratio (SMR) was 1.75%, and predicted SMRs were robust to variations in transverse shear modulus, Young's moduli ratio, speed of sound, attenuation, density, and ARFI excitation PSF dimension. Further, ARFI-derived SMRs distinguished two materials when the true SMRs of the compared materials differed by as little as 10%. Experimentally, ARFI-derived SMRs linearly correlated with the corresponding ratios measured by Shear Wave Elasticity Imaging (SWEI) in excised pig skeletal muscle ( [Formula: see text], MAPE = 13%) and in pig kidney, in vivo ( [Formula: see text], MAPE = 5.3%). These results demonstrate the feasibility of using the ARFI PD to quantify elastic DoA in biological tissues.

Electronic Point Spread Function Rotation Using a Three-Row Transducer for ARFI-Based Elastic Anisotropy Assessment: In Silico and Experimental Demonstration.

Degree of anisotropy (DoA) of mechanical properties has been assessed as the ratio of acoustic radiation force impulse (ARFI)-induced peak displacements (PDs) achieved using spatially asymmetric point spread functions (PSFs) that are rotated 90° to each other. Such PSF rotation has been achieved by manually rotating a linear array transducer, but manual rotation is cumbersome and prone to misalignment errors and higher variability in measurements. The purpose of this work is to evaluate the feasibility of electronic PSF rotation using a three-row transducer, which will reduce variability in DoA assessment. A Siemens 9L4, with 3×192 elements, was simulated in Field II to generate spatially asymmetric ARFI PSFs that were electronically rotated 63° from each other. Then, using the finite element method (FEM), PD due to the ARFI excitation PSFs in 42 elastic, incompressible, transversely isotropic (TI) materials with shear moduli ratios of 1.0-6.0 were modeled. Finally, the ratio of PDs achieved using the two rotated PSFs was evaluated to assess elastic DoA. DoA increased with increasing shear moduli ratios and distinguished materials with 17% or greater difference in shear moduli ratios (Wilcoxon, ). Experimentally, the ratio of PDs achieved using ARFI PSF rotated 63° from each other distinguished the biceps femoris muscle from two pigs, which had median shear moduli ratios of 4.25 and 3.15 as assessed by shear wave elasticity imaging (SWEI). These results suggest that ARFI-based DoA assessment can be achieved without manual transducer rotation using a three-row transducer capable of electronically rotating PSFs by 63°. It is expected that electronic PSF rotation will facilitate data acquisitions and improve the reproducibility of elastic anisotropy assessments.

A 1.5-D Array for Acoustic Radiation Force (ARF)-Induced Peak Displacement-Based Tissue Anisotropy Assessment With a Row-Column Excitation Method.

Many biological tissues, including muscle or kidney, are mechanically anisotropic, and the degree of anisotropy (DoA) in mechanical properties is diagnostically relevant. DoA can be assessed either using the ratio of shear wave velocities (SWVs) or acoustic radio forced impulse (ARFI)-induced peak displacements (PD) measured longitudinal over transverse orientations. Whether using SWV or PD as a basis, DoA expressed as the ratio of values requires 90° transducer rotation when a linear array is employed. This large rotation angle is prone to misalignment errors. One solution is the use of a fully sampled matrix array for electronic rotation of point spread function (PSF). However, the challenges of matrix array are its high fabrication cost and complicated fabrication procedures. The cheaper and simpler alternative of matrix array is the use of a row-column array. A 3×64 elements 1.5-D array with a row-column excitation mode is proposed to assess DoA in mechanical properties using the PD ratio. Different numbers of elements in elevational and lateral directions were selected to have orthogonal ARFI excitation beams without rotating the transducer. A custom-designed flex circuit was used to fabricate the array with a simpler electrode connection than a fully sampled matrix array. The performance of the array was evaluated in Field II simulation and experiment. The output pressure was 0.57-MPa output under a 40- [Formula: see text] excitation with a -6-dB point spread dimension of 14×4 mm2 in orthogonal directions. The PD was measured to be [Formula: see text] in an isotropic elastic phantom with Young's modulus of 5.4 kPa. These results suggest that the array is capable of assessing DoA using PD ratio without physical rotation of the transducer. The array has the potential to reduce the misalignment errors for DoA assessment.

Carotid Plaque Fibrous Cap Thickness Measurement by ARFI Variance of Acceleration: In Vivo Human Results.

This study evaluates the performance of an acoustic radiation force impulse (ARFI)-based outcome parameter, the decadic logarithm of the variance of acceleration, or log(VoA), for measuring carotid fibrous cap thickness. Carotid plaque fibrous cap thickness measurement by log(VoA) was compared to that by ARFI peak displacement (PD) in patients undergoing clinically indicated carotid endarterectomy using a spatially-matched histological validation standard. Fibrous caps in parametric log(VoA) and PD images were automatically segmented using a custom clustering algorithm, and a pathologist with expertise in atherosclerosis hand-delineated fibrous caps in histology. Over 10 fibrous caps, log(VoA)-derived thickness was more strongly correlated to histological thickness than PD-derived thickness, with Pearson correlation values of 0.98 for log(VoA) compared to 0.89 for PD. The log(VoA)-derived cap thickness also had better agreement with histology-measured thickness, as assessed by the concordance correlation coefficient (0.95 versus 0.62), and, by Bland-Altman analysis, was more consistent than PD-derived fibrous cap thickness. These results suggest that ARFI log(VoA) enables improved discrimination of fibrous cap thickness relative to ARFI PD and further contributes to the growing body of evidence demonstrating ARFI's overall relevance to delineating the structure and composition of carotid atherosclerotic plaque for stroke risk prediction.

Viscoelastic Response Ultrasound Derived Relative Elasticity and Relative Viscosity Reflect True Elasticity and Viscosity: In Silico and Experimental Demonstration.

Viscoelastic response (VisR) ultrasound characterizes the viscoelastic properties of tissue by fitting acoustic radiation force (ARF)-induced displacements in the region of ARF excitation to a 1-D mass-spring-damper (MSD) model. Elasticity and viscosity are calculated separately but relative to the applied ARF amplitude. We refer to these parameters as "relative elasticity (RE)" and "relative viscosity (RV)." We herein test the hypothesis that RE and RV linearly correlate to true elasticity and viscosity in tissue. VisR imaging was simulated in 144 homogeneous viscoelastic materials with varying elasticities and viscosities. Derived RE linearly correlated with material elasticity and varied by an average of 2.52% when the material viscosity changed from 0.1 to 1.3 Pa · s. Derived RV linearly correlated with material viscosity but varied by an average of 102.5% when material elasticity changed from 3.33 to 20 kPa. The effect of elasticity on RV measurement was compensated using the slope of the linear relationship between RV and natural frequency ( ωtextn ). After compensation, RV [Formula: see text] (elasticity compensated RV) linearly correlated with material viscosity and varied by less than 1.00% on average when the modeled shear elastic modulus changed from 3.3 to 20 kPa. In addition to elasticity compensation, variation in ARF amplitude over depth was compensated, yielding REDC and [Formula: see text]. REDC and [Formula: see text] successfully contrasted elastic and viscous inclusions, respectively, in three simulated phantoms. Experimentally, in the homogeneous oil-in-gelatin phantoms and excised livers, REDC linearly correlated with shear wave dispersion ultrasound vibrometry (SDUV) derived shear elastic modulus, and [Formula: see text] linearly correlated with SDUV-derived shear viscosity. In excised livers containing viscoelastic oil-in-gelatin inclusions, the inclusions were successfully contrasted from the liver background by both REDC and [Formula: see text]. These results suggest that RE and RV are relevant for qualitatively assessing the elastic and viscous properties of tissue.

Delineation of Human Carotid Plaque Features In Vivo by Exploiting Displacement Variance.

While in vivo acoustic radiation force impulse (ARFI)-induced peak displacement (PD) has been demonstrated to have high sensitivity and specificity for differentiating soft from stiff plaque components in patients with carotid plaque, the parameter exhibits poorer performance for distinguishing between plaque features with similar stiffness. To improve discrimination of carotid plaque features relative to PD, we hypothesize that signal correlation and signal-to-noise ratio (SNR) can be combined, outright or via displacement variance. Plaque feature detection by displacement variance, evaluated as the decadic logarithm of the variance of acceleration and termed "log(VoA)," was compared to that achieved by exploiting SNR, cross correlation coefficient, and ARFI-induced PD outcome metrics. Parametric images were rendered for 25 patients undergoing carotid endarterectomy, with spatially matched histology confirming plaque composition and structure. On average, across all plaques, log(VoA) was the only outcome metric with values that statistically differed between regions of lipid-rich necrotic core (LRNC), intraplaque hemorrhage (IPH), collagen (COL), and calcium (CAL). Further, log(VoA) achieved the highest contrast-to-noise ratio (CNR) for discriminating between LRNC and IPH, COL and CAL, and grouped soft (LRNC and IPH) and stiff (COL and CAL) plaque components. More specifically, relative to the previously demonstrated ARFI PD parameter, log(VoA) achieved 73% higher CNR between LRNC and IPH and 59% higher CNR between COL and CAL. These results suggest that log(VoA) enhances the differentiation of LRNC, IPH, COL, and CAL in human carotid plaques, in vivo, which is clinically relevant to improving stroke risk prediction and medical management.

Mechanical Anisotropy Assessment in Kidney Cortex Using ARFI Peak Displacement: Preclinical Validation and Pilot In Vivo Clinical Results in Kidney Allografts.

The kidney is an anisotropic organ, with higher elasticity along versus across nephrons. The degree of mechanical anisotropy in the kidney may be diagnostically relevant if properly exploited; however, if improperly controlled, anisotropy may confound stiffness measurements. The purpose of this study is to demonstrate the clinical feasibility of acoustic radiation force (ARF)-induced peak displacement (PD) measures for both exploiting and obviating mechanical anisotropy in the cortex of human kidney allografts, in vivo. Validation of the imaging methods is provided by preclinical studies in pig kidneys, in which ARF-induced PD values were significantly higher ( , Wilcoxon) when the transducer executing asymmetric ARF was oriented across versus along the nephrons. The ratio of these PD values obtained with the transducer oriented across versus along the nephrons strongly linearly correlated ( R2 = 0.95 ) to the ratio of shear moduli measured by shear wave elasticity imaging. On the contrary, when a symmetric ARF was implemented, no significant difference in PD was observed ( p > 0.01 ). Similar results were demonstrated in vivo in the kidney allografts of 14 patients. The symmetric ARF produced PD measures with no significant difference ( p > 0.01 ) between along versus across alignments, but the asymmetric ARF yielded PD ratios that remained constant over a six-month observation period post-transplantation, consistent with stable serum creatinine level and urine protein-to-creatinine ratio in the same patient population ( p > 0.01 ). The results of this pilot in vivo clinical study suggest the feasibility of 1) implementing symmetrical ARF to obviate mechanical anisotropy in the kidney cortex when anisotropy is a confounding factor and 2) implementing asymmetric ARF to exploit mechanical anisotropy when mechanical anisotropy is a potentially relevant biomarker.

Corrections to "On the Quantitative Potential of Viscoelastic Response (VisR) Ultrasound Using the One-Dimensional Mass-Spring-Damper Model".

In the original publication of this paper [1], equation (3) contained sign errors for the amplitude of the third and fourth Heaviside functions. The corrected equation is shown in the following: [Formula: see text].

A Row-Column (RC) Addressed 2D Capacitive Micromachined Ultrasonic Transducer (CMUT) Array on a Glass Substrate: Preliminary Results.

In this work, we present preliminary characterization results from a 32 x 32 row-column (RC) addressed 2D capacitive micromachined ultrasonic transducer (CMUT) array. The device was fabricated using anodic bonding on a borosilicate glass substrate, which eliminates the substrate - bottom electrode coupling previously observed in traditional CMUT RC arrays fabricated on silicon substrates. The characterization results were compared for the top and bottom electrodes and include impedance measurements, pulseecho impulse responses, and 2D scans of the pressure field using a calibrated hydrophone. The results showed that the array elements behave similarly when ground and hot electrodes were switched between the top and bottom electrodes for all of the measured parameters including device capacitance, center frequency, and pulse-echo response amplitude. The pressure scans verified the highly customizable nature of RC arrays by showing multiple active element configurations. A sample cross-sectional image of a metal target was also demonstrated.

In Vivo Viscoelastic Response (VisR) Ultrasound for Characterizing Mechanical Anisotropy in Lower-Limb Skeletal Muscles of Boys with and without Duchenne Muscular Dystrophy.

Our group has previously found that in silico, mechanical anisotropy may be interrogated by exciting transversely isotropic materials with geometrically asymmetric acoustic radiation force excitations and then monitoring the associated induced displacements in the region of excitation. We now translate acoustic radiation force-based anisotropy assessment to human muscle in vivo and investigate its clinical relevance to monitoring muscle degeneration in Duchenne muscular dystrophy (DMD). Clinical anisotropy assessments were performed using Viscoelastic Response ultrasound, with a degree of anisotropy reflected by the ratios of Viscoelastic Response relative elasticity (RE) or relative viscosity (RV) measured with the asymmetric radiation force oriented parallel versus perpendicular to muscle fiber alignment. In vivo results from rectus femoris and gastrocnemius muscles of boys aged ∼7.9-10.4 y indicate that RE and RV anisotropy ratios in rectus femoris muscles of boys with DMD were significantly higher than those of healthy control boys (RE: DMD = 1.51 ± 0.87, control = 0.99 ± 0.69, p = 0.04, Wilcoxon rank sum test; RV: DMD = 1.04 ± 0.71, control = 0.74 ± 0.22, p = 0.02). In the gastrocnemius muscle, only the RV anisotropy ratio was significantly higher in dystrophic than control patients (DMD = 1.23 ± 0.35, control = 0.88 ± 0.31, p = 0.04). In the dystrophic rectus femoris muscle, the RE anisotropy ratio was inversely correlated (slope = -0.03/lbf, r = -0.43, p = 0.07, Pearson correlation) with quantitative muscle testing functional output measures but was not correlated with quantitative muscle testing in the dystrophic gastrocnemius. These results suggest that Viscoelastic Response RE and RV measures reflect differences in mechanical anisotropy associated with functional impairment with dystrophic degeneration that are relevant to monitoring DMD clinically.

Effect of Model Thrombus Volume and Elastic Modulus on Magnetomotive Ultrasound Signal Under Pulsatile Flow.

Direct ultrasonic imaging of arterial and venous thrombi could aid in diagnosis and treatment planning by providing rapid and cost-effective measurements of thrombus volume and elastic modulus. Toward this end, it was demonstrated that open-air magnetomotive ultrasound (MMUS) provides specific contrast to superparamagnetic iron oxide-labeled model thrombi embedded in gelatin-based blood vessel-mimicking flow phantoms. MMUS was performed on model thrombi in the presence of pulsatile flow that mimics cardiac-induced motion found in real vasculature. The MMUS signal and contrast-to-noise ratio (CNR) were measured across a range of physiologically relevant thrombus volumes and elastic moduli. Model thrombus volumes as small as 0.5 ml were shown to be detectable (CNR > 1) over the entire range of elastic moduli tested (3.5-40 kPa). It was also found that MMUS signal and CNR are increased with increasing thrombus volume ( ) and decreasing elastic modulus ( ), while variations in pulsatile flow rate had little effect. These findings demonstrate that MMUS has promise as a direct in vivo thrombosis imaging modality for quantifying thrombus volume and stiffness.

Blind Source Separation-Based Motion Detector for Imaging Super-Paramagnetic Iron Oxide (SPIO) Particles in Magnetomotive Ultrasound Imaging.

In magnetomotive ultrasound (MMUS) imaging, an oscillating external magnetic field displaces tissue loaded with super-paramagnetic iron oxide (SPIO) particles. The induced motion is on the nanometer scale, which makes its detection and its isolation from background motion challenging. Previously, a frequency and phase locking (FPL) algorithm was used to suppress background motion by subtracting magnetic field off ( -off) from on ( -on) data. Shortcomings to this approach include long tracking ensembles and the requirement for -off data. In this paper, a novel blind source separation-based FPL (BSS-FPL) algorithm is presented for detecting motion using a shorter ensemble length (EL) than FPL and without -off data. MMUS imaging of two phantoms containing an SPIO-laden cubical inclusion and one control phantom was performed using an open-air MMUS system. When background subtraction was used, contrast and contrast to noise ratio (CNR) were, respectively, 1.20±0.20 and 1.56±0.34 times higher in BSS-FPL as compared to FPL-derived images for EL < 3.5 s. However, contrast and CNR were similar for BSS-FPL and FPL for EL ≥ 3.5 s. When only -on data was used, contrast and CNR were 1.94 ± 0.21 and 1.56 ± 0.28 times higher, respectively, in BSS-FPL as compared to FPL-derived images for all ELs. Percent error in the estimated width and height was 39.30% ± 19.98% and 110.37% ± 6.5% for FPL and was 7.30% ± 7.6% and 16.21% ± 10.29% for BSS-FPL algorithm. This paper is an important step toward translating MMUS imaging to in vivo application, where long tracking ensembles would increase acquisition time and -off data may be misaligned with -on due to physiological motion.

Evaluating Renal Transplant Status Using Viscoelastic Response (VisR) Ultrasound.

Chronic kidney disease is most desirably and cost-effectively treated by renal transplantation, but graft survival is a major challenge. Although irreversible graft damage can be averted by timely treatment, intervention is delayed when early graft dysfunction goes undetected by standard clinical metrics. A more sensitive and specific parameter for delineating graft health could be the viscoelastic properties of the renal parenchyma, which are interrogated non-invasively by Viscoelastic Response (VisR) ultrasound, a new acoustic radiation force (ARF)-based imaging method. Assessing the performance of VisR imaging in delineating histologically confirmed renal transplant pathologies in vivo is the purpose of the study described here. VisR imaging was performed in patients with (n = 19) and without (n = 25) clinical indication for renal allograft biopsy. The median values of VisR outcome metrics (τ, relative elasticity [RE] and relative viscosity [RV]) were calculated in five regions of interest that were manually delineated in the parenchyma (outer, center and inner) and in the pelvis (outer and inner). The ratios of a given VisR metric for all possible region-of-interest combinations were calculated, and the corresponding ratios were statistically compared between biopsied patients subdivided by diagnostic categories versus non-biopsied, control allografts using the two-sample Wilcoxon test (p <0.05). Although τ ratios non-specifically differentiated allografts with vascular disease, tubular/interstitial scarring, chronic allograft nephropathy and glomerulonephritis from non-biopsied control allografts, RE distinguished only allografts with vascular disease and tubular/interstitial scarring, and RV distinguished only vascular disease. These results suggest that allografts with scarring and vascular disease can be identified using non-invasive VisR RE and RV metrics.

ARFI variance of acceleration (VoA) for noninvasive characterization of human carotid plaques in vivo.

Rather than degree of stenosis, assessing plaque structure and composition is relevant to discerning risk for plaque rupture with downstream ischemic event. The structure and composition of carotid plaque has been assessed noninvasively using Acoustic Radiation Force Impulse (ARFI) ultrasound imaging. In particular, ARFI-derived peak displacement (PD) estimations have been demonstrated for discriminating soft (lipid rich necrotic core (LRNC) or intraplaque hemorrhage (IPH)) from stiff (collagen (COL) or calcium (CAL)) plaque features; however, PD did not differentiate LRNC from IPH or COL from CAL. The purpose of this study is to evaluate a new ARFI-based measurement, the variance of acceleration (VoA), for differentiating among soft and stiff plaque components. Both PD and VoA results were obtained in vivo for a human carotid plaque acquired in a previous study and matched to a histological standard analyzed by a pathologist. With VoA, plaque feature contrast was increased by an average of 60% in comparison to PD.

Performance of acoustic radiation force impulse ultrasound imaging for carotid plaque characterization with histologic validation.

OBJECTIVE: Stroke is commonly caused by thromboembolic events originating from ruptured carotid plaque with vulnerable composition. This study assessed the performance of acoustic radiation force impulse (ARFI) imaging, a noninvasive ultrasound elasticity imaging method, for delineating the composition of human carotid plaque in vivo with histologic validation. METHODS: Carotid ARFI images were captured before surgery in 25 patients undergoing clinically indicated carotid endarterectomy. The surgical specimens were histologically processed with sectioning matched to the ultrasound imaging plane. Three radiologists, blinded to histology, evaluated parametric images of ARFI-induced peak displacement to identify plaque features such as necrotic core (NC), intraplaque hemorrhage (IPH), collagen (COL), calcium (CAL), and fibrous cap (FC) thickness. Reader performance was measured against the histologic standard using receiver operating characteristic curve analysis, linear regression, Spearman correlation (ρ), and Bland-Altman analysis. RESULTS: ARFI peak displacement was two-to-four-times larger in regions of NC and IPH relative to regions of COL or CAL. Readers detected soft plaque features (NC/IPH) with a median area under the curve of 0.887 (range, 0.867-0.924) and stiff plaque features (COL/CAL) with median area under the curve of 0.859 (range, 0.771-0.929). FC thickness measurements of two of the three readers correlated with histology (reader 1: R2 = 0.64, ρ = 0.81; reader 2: R2 = 0.89, ρ = 0.75). CONCLUSIONS: This study suggests that ARFI is capable of distinguishing soft from stiff atherosclerotic plaque components and delineating FC thickness.

Acoustic Radiation Force Impulse (ARFI)-Induced Peak Displacements Reflect Degree of Anisotropy in Transversely Isotropic Elastic Materials.

In transversely isotropic (TI) materials, mechanical properties (Young's modulus, shear modulus, and Poisson's ratio) are different along versus across the axis of symmetry (AoS). In this work, the feasibility of interrogating such directional mechanical property differences using acoustic radiation force impulse (ARFI) imaging is investigated. We herein test the hypotheses that 1) ARFI-induced peak displacements (PDs) vary with TI material orientations when an asymmetrical ARFI excitation point spread function (PSF) is used, but not when a symmetrical ARFI PSF is employed; and 2) the ratio of PDs induced with the long axis of an asymmetrical ARFI PSF oriented along versus across the material's AoS is related to the degree of anisotropy of the material. These hypotheses were tested in silico using finite element method (FEM) models and Field II. ARFI excitations had F/1.5, 3, 4, or 5 focal configurations, with the F/1.5 and F/5 cases having the most asymmetrical and symmetrical PSFs at the focal depth, respectively. These excitations were implemented for ARFI imaging in 52 different simulated TI materials with varying degrees of anisotropy, and the ratio of ARFI-induced PDs was calculated. The change in the ratio of PDs with respect to the anisotropy of the materials was highest for the F/1.5, indicating that PD was most strongly impacted by the material orientation when the ARFI excitation was the most asymmetrical. On the contrary, the ratio of PDs did not depend on the anisotropy of the material for the F/5 ARFI excitation, suggesting that PD did not depend on material orientation when the ARFI excitation was symmetrical. Finally, the ratio of PDs achieved using asymmetrical ARFI PSF reflected the degree of anisotropy in TI materials. These results support that symmetrical ARFI focal configurations are desirable when the orientation of the ARFI excitation to the AoS is not specifically known and measurement standardization is important, such as for longitudinal or cross-sectional studies of anisotropic organs. However, asymmetrical focal configurations are useful for exploiting anisotropy, which may be diagnostically relevant. Feasibility for future experimental implementation is demonstrated by simulating ultrasonic displacement tracking and by varying the ARF duration.

Thrombin-Responsive Transcutaneous Patch for Auto-Anticoagulant Regulation.

A thrombin-responsive closed-loop patch is developed for prolonged heparin delivery in a feedback-controlled manner. This microneedle-based patch can sense activated thrombin and subsequently releases heparin to prevent coagulation in the blood flow. This "smart" heparin patch can be transcutaneously inserted into skin without drug leakage and can sustainably regulate blood coagulation in response to thrombin.