We present tissue phantoms with a 3D-printed tumor perfusion model for the validation of integrated diffuse correlation tomography and ultrasound shear wave elastography imaging. These techniques in combination can be used for efficacy prediction of neoadjuvant breast cancer therapy.

Terahertz time-domain imaging has been performed on hepatic fibrosis in rodent models of liver injury. Two-dimensional maps are generated using refractive index and absorption coefficient as imaging markers using a maximum a-posteriori probability estimation algorithm.

Objective: Viscoelasticity is mapped by dispersion in shearwave elastography. Incomplete spectral information of shearwaves is therefore used to estimate mechanical stiffness. We propose capturing the "full-waveform-information" of the shear wave spectra to better resolve complex shear modulus mu* (omega). Approach is validated on phantom models, animal tissues, and feasibility demonstrated on human post-delivery placenta. Methods: We captured robust estimates of mu* in ex-vivo livers subjected to water bath ablation, glutaraldehyde exposure and in the placenta. Results: Complex modulus at 200 Hz is more reflective of tissue stiffness than cross-correlation estimate. Bias increased in phantoms with higher gelatin (G) (0.65: 6% G) and oil (O) (0.58: 6% G and 40% O) concentration, compared to elastic phantoms with low stiffness (0.33: 3% G). Actual tissues also reported higher bias in cross-correlation estimate (rabbit liver: 0.61, porcine liver: 2.20, and human placenta: 0.63). Stiffness is sensitive to ablation temperature, where the overall modulus changed from 3.02 KPa at 16 degrees C to 2.75 KPa at 56 degrees C in water bath. With exposure to Glutaraldehyde, the overall modulus increased from 2.37 to 9.03 KPa. Reconstruction errors in the loss modulus decreased by 68% with the power law compared to a Maxwell model in porcine livers with Cole-Cole inverse fitting. Conclusion: Omitting Shear wave attenuation leads to bias. Reconstruction of rheological response with a model is sensitive to its architecture and also the framework.

We demonstrate a novel method employing the principle of mechanical reciprocity to image the relative ultrasound attenuation. In this approach, which we call shearwave reciprocity imaging (SRI), acoustic radiation force is used to push on the medium at one location while displacement is tracked at a second location. The push and track locations are then transposed. Differences in the measured displacements reveal differences in acoustic radiation force due to differences in attenuation. In contrast to shear wave elastography, the use of mechanical reciprocity ensures that this approach provides attenuation images independent of tissue elasticity. Imaging was performed with a Verasonics Vantage 64 LE system and ATL L7-4 linear array on tissue-mimicking phantoms of gelatin and Zerdine containing lesions of enhanced attenuation. We demonstrate imaging of the increased attenuation of the inclusions relative to background, independent of their elastic modulus. These attenuation measurements are complimentary to elastogram and B-mode data and provide an additional source of image contrast for lesion characterization.

Nonlinear shear modulus (NLSM) can potentially differentiate benign and malignant pathologies. Previous studies demonstrated the discriminatory value of mapping quantitative estimates of material non-linearity, yet estimates remain biased due to unaccounted shear-wave dispersion within the tissue. We demonstrate a finite element simulation of an inversion technique that combines traditional quasi-static and dynamic elasticity imaging to generate a multi-frequency estimate of the third-order shear modulus A(x,z,ω) over a broad bandwidth (200-600 Hz). We show that our reconstruction results are superior to those obtained by traditional group speed by a factor of two in terms of contrast enhancement measures. Experimental ultrasound elastography on a custom oil-in-gelatin emulsion confirms the presence of dispersion in the NLSM parameter. Constitutive hyper-viscoelastic model responses of spectral NLSM are simulated based on matched linear shear modulus data of experimental phantoms. Hyper-elastic Ogden with a Voigt loss is shown to describe NLSM behavior at frequencies greater than 400 Hz. Reconstruction accuracy in the presence of simulated tracking and correlation noise demonstrates the robustness of our estimates.

To characterize vasodynamic response in placentae associated with healthy pregnancies and those complicated by placental-mediated disease with elastography. Sonographic elastography is an emerging technology being applied to clinical placental assessment. Administration of vasoactive agents to perfused placentae is a novel strategy to define the role of vascular dynamics in generation of sonographic parameters. Prospective, descriptive cohort study of patients enrolled for post-delivery placental collection with uncomplicated pregnancies and those with ischemic placental disease (IPD; preeclampsia, fetal growth restriction), gestational hypertension (gHTN) or chronic hypertension (cHTN). Following single lobule placental perfusion, shear wave speeds (SWS) obtained via ultrasound elasticity under physiologic conditions and with sequential introduction of vasodilator and vasoconstrictor, then analyzed descriptively and normalized to individual subject level reference conditions. 13 term patients enrolled with 12 placental regions analyzed per perfusion state in triplicate totaling 689 SWS measurements. Mean SWS computed in each perfusion condition across tissue surfaces (Figure 1). Subject level data normalized to physiologic perfusion conditions and the SWS difference between administration of vasoconstrictor and vasodilator assessed (Figure 2). In healthy placentae, there was a small but consistent increase in SWS from vasodilation to vasoconstriction as the tissue became stiffer. In contrast, only the maternal surface in IPD demonstrated greater stiffness and cHTN, gHTN placentae demonstrated a paradoxical response throughout with increased tissue compliance. Direct vasoactive manipulation of the perfused placenta demonstrates subtle stiffening with vasoconstriction in healthy placentae and a variable response across disease states. This may represent a downstream consequence of disease-related vascular injury or a potentially pathogenic upstream atypical vascular response; the later would represent an opportunity for studies predicting placental-mediated disease.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Shear wave elasticity imaging (SWEI) is a non-invasive technique to assess mechanical properties of tissue, including elasticity and viscoelasticity by introducing acoustic energy by introduction of a radiation force. Traditional Acoustic Radiation Force Impulse (ARFI) are produced by focused and unfocused beams. Due to diminished acoustic intensity outside the focal zone, focused ARFI posseses limited depth-of-field, beyond which elasticity estimates are unreliable. Imaging quality in unfocused beams on the other hand are limited to the Fraunhofer zone due to near-field oscillations of the pressure profile. We report a SWEI approach with Bessel apodized ARFI that can reduce diffraction in the Fresnel zone and at the same time retain a large high intensity focal illumination. We evaluate elastogram image quality produced by Gaussian focused and Bessel apodized ARF with time domain simulations using k-wave which is an open-source acoustic wave field toolbox. Our results show image quality evaluated by CNRdB improves from 6.04 in focused ARF SWEI images to 16.06 in Bessel ARF SWEI.

Viscoelasticity assessments in placenta is an emerging marker of fetal health. Non invasive bio-rheological measurements with shear waves have so far relied on ideal elastic assumptions for mapping material properties. However, shear waves in soft tissues undergo losses due to dispersion and attenuation while propagation. We present a framework of viscoelasticty reconstruction in frequency domain that incorporates both dispersion and attenuation of the propagating wave from its spatio-temporal profile. Such a framework, in contrast to conventional dispersion curve fitting, is able to exploit the full shear wave data set for rheological parameter mapping. Our shear wave excitation-detection scheme, known as Single Track Location Acoustic radiation Force Impulse (STL-ARFI), minimizes bias due to differential speckle at tracking zones, which enable creating a robust cross-spectral density estimate of the wave and aid in including absorption in dynamic elastography. We demonstrate feasibility of the technique on ex-vivo human placenta by creating quasi-local estimates of viscoleasticity over a broad bandwidth (10–350 Hz) mapped by a two time constant Generalized Maxwell Model (GMM). Furthermore, we demonstrate that our measurements are invariant when probed under different imaging configurations, reinforcing their robustness.

A novel modality of ultrasound imaging known as elastography has been shown to improve cancer detection for women with dense breast tissue. However, the scanning procedure for this technique is often difficult for a human to perform in a consistent manner and could conceivably benefit from robot assistance. In this work, we present a novel robot-assisted probabilistic elasticity mapping algorithm which uses Gaussian filter techniques to produce elastograms and uncertainty maps. We demonstrate the proposed approach using a 7-DOF robot manipulator on a gelatin phantom designed to imitate the elasticity of human tissue. The results indicate the algorithm is capable of imaging a 6.5 mm lesion and reducing map uncertainty in the observable region.

Imaging tissue mechanical properties has shown promise in noninvasive assessment of numerous pathologies. Researchers have successfully measured many linear tissue mechanical properties in laboratory and clinical settings. Currently, multiple complex mechanical effects such as frequency-dependence, anisotropy, and nonlinearity are being investigated separately. However, a concurrent assessment of these complex effects may enable more complete characterization of tissue biomechanics and offer improved diagnostic sensitivity. In this work, we report for the first time a method to map the frequency-dependent nonlinear parameters of soft tissues on a local scale. We recently developed a nonlinear elastography model that combines strain measurements from arbitrary tissue compression with radiation-force-based broadband shear wave speed (WS) measurements. Here, we extended this model to incorporate local measurements of frequency-dependent shear modulus. This combined approach provides a local frequency-dependent nonlinear parameter that can be obtained with arbitrary, clinically realizable tissue compression. Initial assessments using simulations and phantoms validate the accuracy of this approach. We also observed improved contrast in nonlinearity parameter at higher frequencies. Results from ex-vivo liver experiments show 32, 25, 34, and 38 dB higher contrast in elastograms than traditional linear elasticity, elastic nonlinearity, viscosity, and strain imaging methods, respectively. A lesion, artificially created by injection of glutaraldehyde into a liver specimen, showed a 59% increase in the frequency-dependent nonlinear parameter and a 17% increase in contrast ratio.

To demonstrate the diagnostic potential of elasticity imaging to discriminate the characteristics of placentae in health and disease. While the clinical burden of placental dysfunction is high, there are no standard clinical methods to directly quantify placental function thus our goal is to identify easily reproducible, non-invasive placental biomarkers to detect and predict placenta-related disease. Prospective, descriptive cohort study of patients at a tertiary medical center with uncomplicated pregnancies, chronic hypertension (cHTN), gestational hypertension (gHTN), or the ischemic placental diseases of preeclampsia or intrauterine growth restriction (IPD). Patients were enrolled antenatally for post-delivery placental collection. Shear wave speeds (SWS) of the ex vivo placenta were measured with placentae in a water bath at physiologic temperature via ultrasound elasticity techniques on a Siemens S3000 research platform. SWS were compiled to describe the range of measurements with the ability to discriminate between disease states quantified with ROC curves. Twenty-five term patients were enrolled with 12 regions per placenta analyzed in triplicate for a total of 900 SWS measurements. Mean SWS varied across disease states: 1.53±0.42 m/s in uncomplicated pregnancies versus pregnancies complicated by cHTN (1.43±0.40 m/s), gHTN (1.50±0.38 m/s), or IPD (1.28±0.33 m/s). While SWS slowed in all pathologic states, there was pronounced regional variation (Figure 1). Consequently, effective discrimination of disease state as demonstrated by area under a ROC curve relies on either knowledge of placental region quantified or utilizing a larger region of interest (Figure 2). Contrary to limited prior reports, SWS decreases in placental-mediated disease states. However, variation across planes is significant, thus random SWS assessments are less effective at discriminating tissue than location-informed assessment. Elasticity imaging has the potential for disease state discrimination if assessment is informed by the region undergoing analysis.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

ObjectivesTo quantify the bias of shear wave speed (SWS) measurements between different commercial ultrasonic shear elasticity systems and a magnetic resonance elastography (MRE) system in elastic and viscoelastic phantoms.MethodsTwo elastic phantoms, representing healthy through fibrotic liver, were measured with 5 different ultrasound platforms, and 3 viscoelastic phantoms, representing healthy through fibrotic liver tissue, were measured with 12 different ultrasound platforms. Measurements were performed with different systems at different sites, at 3 focal depths, and with different appraisers. The SWS bias across the systems was quantified as a function of the system, site, focal depth, and appraiser. A single MRE research system was also used to characterize these phantoms using discrete frequencies from 60 to 500 Hz.ResultsThe SWS from different systems had mean difference 95% confidence intervals of ±0.145 m/s (±9.6%) across both elastic phantoms and ± 0.340 m/s (±15.3%) across the viscoelastic phantoms. The focal depth and appraiser were less significant sources of SWS variability than the system and site. Magnetic resonance elastography best matched the ultrasonic SWS in the viscoelastic phantoms using a 140 Hz source but had a − 0.27 ± 0.027‐m/s (−12.2% ± 1.2%) bias when using the clinically implemented 60‐Hz vibration source.ConclusionsShear wave speed reconstruction across different manufacturer systems is more consistent in elastic than viscoelastic phantoms, with a mean difference bias of < ±10% in all cases. Magnetic resonance elastographic measurements in the elastic and viscoelastic phantoms best match the ultrasound systems with a 140‐Hz excitation but have a significant negative bias operating at 60 Hz. This study establishes a foundation for meaningful comparison of SWS measurements made with different platforms.

Imaging of tissue nonlinear elastic properties has shown potentials in providing additional information for disease diagnosis alongside traditional linear elastic properties. However, accurate local quantification of nonlinear elasticity requires precise imaging and registration of tissue strain at multiple incremental strain levels. Furthermore, it requires imaging of local stress which is measured from cumulative sum of shear wave speed squared times the differential strain. To solve this problem, here, we report measurements of shear wave speed ratio to evaluate elastic nonlinearity of tissues. In this study, we evaluate the ratio of shear wave speed (SWS) image at incremental global local strain levels to the SWS image at undeformed state of the medium. The shear wave speed ratio imaging at global strain does not require local tracking of tissue motion. On the other hand, shear wave speed ratio imaging at local strain requires local strain estimation, however, it does not require estimation of cumulative stress. Thus errors and noise associated with traditional quantitative nonlinear elasticity imaging are more compared to shear wave speed ratio imaging.

Acoustic radiation force (ARF) induced Shear wave elasticity imaging (SWEI) is a noninvasive method to characterize pathological tissues. Conventionally, ARF is generated by focused beam with limited depth of focus. Supersonic shear imaging (SSI) uses multiple push-beam foci to achieve larger depth of field (DoF) elastograms. Here, we propose a SWEI method based on Bessel apodized ARF to generate larger DoF with lower energy. As a result, Bessel elastogram in gel phantom shows 19% higher contrast-to-noise ration (CNR) and 95% lower energy than SSI. Furthermore, Bessel elastogram in porcine liver shows 61% higher signal-to-noise ratio (SNR) and 56% lower energy than SSI.

Biological tissues exhibit frequency-dependent shear wave dispersion ( $c_{ph}(\omega)$ ) and absorption ( $\alpha(\omega)$ ), which carries potential diagnostic value. However, the frequency content in different elastographic excitation and tracking schemes varies, presenting systematic uncertainty and biases in quantitative shear wave imaging. We propose a maximum aposteriori probability (MAP) estimator for a single track location (STL) elastogra-phy scheme to represent shearwave propagation. The estimator accommodates wavefront and rheological modeling to arrive at material property estimates for tissue mimicking phantoms. We show that a combination of cylindrical wave (CW) geometry and fractional Kelvin-Voigt rheology demonstrate consistent estimates across acquisition parameters. We report a reduction $c_{ph}$ reconstruction bias over a range of shear wave frequencies (200–800 Hz). Results are compared with an existing 2D Fourier transform-based inversion approach and group velocity as the state-of-the-art.

The acoustic radiation force impulse (ARFI) has been widely used in transient shear wave elasticity imaging (SWEI). For SWEI based on focused ARFI, the highest image quality exists inside the focal zone due to the limitation of the depth of focus and diffraction. Consequently, the areas outside the focal zone and in the near field present poor image quality. To address the limitations of the focused beam, we introduce Bessel apodized ARFI that enhances image quality and improves the depth of focus. The objective of this study is to evaluate the feasibility of SWEI based on Bessel ARF in simulation and experiment. We report measurements of elastogram image quality and depth of field in tissue-mimicking phantoms and ex vivo liver tissue. Our results demonstrate improved depth of field, image quality, and shear wave speed (SWS) estimation accuracy using Bessel push beams. As a result, Bessel ARF enlarges the field of view of elastograms. The signal-to-noise ratio (SNR) of Bessel SWEI is improved 26% compared with focused SWEI in homogeneous phantom. The estimated SWS by Bessel SWEI is closer to the measured SWS from a clinical scanner with an error of 0.3% compared to 2.4% with a focused beam. In heterogeneous phantoms, the contrast-to-noise ratios (CNRs) of shallow and deep inclusions are improved by 8.79 and 3.33 dB, respectively, under Bessel ARF. We also compare the results between Bessel SWEI and supersonic shear imaging (SSI), and the SNR of Bessel SWEI is improved by 8.1%. Compared with SSI, Bessel SWEI shows more accurate SWS estimates in high stiffness inclusions. Finally, Bessel SWEI can generate higher quality elastograms with less energy than conventional SSI.

Accoustic in-homogeneities within biological tissues are known to degrade image quality in elastography. Previous work has demonstrated the potential of Bessel apodized acoustic radiation force (ARF) beams in elasticity reconstructions. Bessel offers advantages, such as enlarged depth-of-field (DOF) and high diffractive immunity over conventionally focused pushes. In this study, we demonstrate Bessel ARF's ability to generate broader bandwidths for phase velocity recovery. Performance was evaluated against matched supersonic shear imaging (SSI) experiments on commercial and custom viscous phantoms. Bessel's ability to “heal”, after being disrupted by an obstacle makes it a potential candidate for developing better phase reconstruction in the presence of heterogeneity.

Compressional or quasi-static elastography has demonstrated the capability to detect occult cancers in a variety of tissue types, however it has a serious limitation in that the resulting elastograms are generally qualitative whereas other forms of elastography, such as shear-wave, can produce absolute measures of elasticity for histopathological classification. We address this limitation by introducing a stochastic method using an extended Kalman filter and robot-assistance to obtain quantitative elastograms which are resilient to measurement noise and system uncertainty. In this paper, the probabilistic framework is described, which utilizes many ultrasound acquisitions obtained from multiple palpations, to fuse data and uncertainty from a robotic manipulator's joint encoders and force/torque sensor directly into the inverse reconstruction of the elastogram. Quantitative results are demonstrated over homogeneous and inclusion gelatin phantoms using a seven degree of freedom manipulator for a range of initial elasticity assumptions. Results imply resilience to poorly assumed initial conditions as all trials were within 5 kPa of the elasticity measured by a mechanical testing system. Moreover, the presence or absence of an inclusion is clear in all reconstructed elastograms even when artifacts are present in displacement fields, indicating further robustness to measurement noise. The proposed stochastic method allows fusion of data from a robot's sensors directly into compressional elastography image reconstruction which may stabilize optimization and improve accuracy. This approach provides a mathematical framework to readily incorporate measurements from additional sensors in future applications which may extend the capabilities of compressional elastography beyond that of producing quantitative elasticity measurements.

To demonstrate the validity of H-scan— a sonographic method of quantifying scattering associated with tissue microstructure and displaying the results as a colormetric overlay to the standard B-mode image —as a novel method of quantifying the scattering sites within the placentae. Our goal is to identify easily reproducible, direct, and non-invasive, placental biomarkers based on H-scan imaging to detect and predict placenta-related disease. Prospective, descriptive cohort study of unselected women presenting for obstetric care at a tertiary medical center. Patients enrolled antenatally for post-delivery placental collection and ex vivo ultrasound on Siemens S3000 research platform with acquisition of raw acoustic echos and post-processing to generate H-scan images. Raw RF data were acquired in triplicate with the placenta in a water bath at physiologic temperature over a variety of acquisition conditions. H-scan results were compiled to describe the range of measurements within and between placentae and to generate a three dimensional map of placental H-scan measurements. 14 term patients enrolled for ex vivo placental ultrasound with 36 regions analyzed in triplicate across 4 assigned quadrants in 3 acquisition conditions representing a total of 1294 RF sequences. Excellent precision was demonstrated in all acquisition conditions however the heterogeneity of the placental tissue is apparent in the high level of intraplacental variability (Figure 1). The percentage of smaller scatterers was also quantified across and between radial circumferences (Figure 2). H-scan quantification of placental tissue demonstrates high precision with serial sampling across a variety of acquisition strategies including with artifact modeling conditions of antenatal assessment. While intra-placental variability was pronounced, radial ratios across zones demonstrate potential for within tissue correction. Both the precision and ability to generate this quantification from the B-mode RF signal support the feasibility of our novel imaging with H-scan as a placental biomarker.View Large Image Figure ViewerDownload Hi-res image Download (PPT)