Non-invasive Evaluation of Aortic Stiffness Dependence with Aortic Blood Pressure and Internal Radius by Shear Wave Elastography and Ultrafast Imaging

Elastic properties of arteries have long been recognized as playing a major role in the cardiovascular system. However, non-invasive in vivo assessment of local arterial stiffness remains challenging and imprecise as current techniques rely on indirect estimates such as wall deformation or pulse wave velocity. Recently, Shear Wave Elastography (SWE) has been proposed to non-invasively assess the intrinsic arterial stiffness. In this study, we applied SWE in the abdominal aortas of rats while increasing blood pressure (BP) to investigate the dependence of shear wave speed with invasive arterial pressure and non-invasive arterial diameter measurements. A 15MHz linear array connected to an ultrafast ultrasonic scanner, set non-invasively, on the abdominal aorta of anesthetized rats (N=5) was used. The SWE acquisition followed by an ultrafast (UF) acquisition was repeated at different moment of the cardiac cycle to assess shear wave speed and arterial diameter variations respectively. Invasive arterial BP catheter placed in the carotid, allowed the accurate measurement of pressure responses to increasing does of phenylephrine infused via a venous catheter. The SWE acquisition coupled to the UF acquisition was repeated for different range of pressure. For normal range of BP, the shear wave speed was found to follow the aortic BP variation during a cardiac cycle. A minimum of (5.06$\pm$0.82) m/s during diastole and a maximum of (5.97$\pm$0.90) m/s during systole was measured. After injection of phenylephrine, a strong increase of shear wave speed (13.85$\pm$5.51) m/s was observed for a peak systolic arterial pressure of (190$\pm$10) mmHg. A non-linear relationship between shear wave speed and arterial BP was found. A complete non-invasive method was proposed to characterize the artery with shear wave speed combined with arterial diameter variations. Finally, the results were validated against two parameters the incremental elastic modulus and the pressure elastic modulus derived from BP and arterial diameter variations

Viscoelasticidad renal durante la disminución gradual de flujo sanguíneo en un modelo porcino in vivo: estudio piloto

Elasticity imaging methods have been used to study kidney mechanical properties and have demonstrated that the kidney elastic modulus increases with disease state. However, studies in swine suggest that kidney elastic modulus is also affected by hemodynamic variables. A newly emerging method called Shearwave Dispersion Ultrasound Vibrometry (SDUV) offers a tool to determine renal elasticity and viscosity in vivo. The purpose of this study was directed toward evaluating the feasibility of SDUV for in vivo measurements of healthy swine kidney during acute gradual decease of renal blood flow. In this study in vivo SDUV measurements were made on a group of 5 normal swine kidneys at baseline renal blood flow (RBF) and 25, 50, 75 and 100% decrease in RBF. The shear elastic modulus at full baseline was 7.04 ± 0.92 kPa and 3.48 ± 0.20 kPa at 100% decrease in RBF. The viscosity did not change between baseline (2.23 ± 0.33 Pa•s) and 100% decrease in RBF (2.03 ± 0.32 Pa•s). The data from this study indicates that other variables such as local blood flow, pressure and volume as well as method accuracy need to be measured to illustrate the relationship between shear elasticity and viscosity associated with acute kidney processes.Métodos de imágenes de elasticidad se han utilizado para estudiar las propiedades mecánicas renales y han demostrado que el módulo elástico de los riñones del aumenta con el estado de enfermedades renales. Sin embargo, estudios en cerdos sugieren que el riñón módulo elástico también se ve afectada por las variables hemodinámicas. Un método emergente llamado Shearwave Dispersion Ultrasound Vibrometry (SDUV) ofrece una herramienta para determinar la elasticidad y la viscosidad renal. El propósito de este estudio se dirige a la evaluación de la viabilidad de SDUV para mediciones las propiedades viscoelasticas del riñón saludable durante variación aguda del flujo sanguíneo renal. En este estudio el método SDUV se realizó en un grupo de 5 riñones porcinos normales al inicio del flujo sanguíneo renal (RBF) basal y 25, 50, 75 y 100% de disminución en el RBF. El módulo elástico basal fue de 7,04 ± 0,92 kPa y 3,48 ± 0,20 kPa a 100% de disminución del RBF. La viscosidad no cambió entre el momento basal (2,23 ± 0,33 Pa • s) y el 100% de disminución del RBF (2,03 ± 0,32 Pa • s). Los datos de este estudio indican que variables tales como el flujo local de sangre, la presión y el volumen así como el método exactitud deben ser medidos para ilustrar la relación entre la elasticidad y la viscosidad asociada con los procesos renales agudos

Ultrasound shear wave imaging for diagnosis of nonalcoholic fatty liver disease

Pour le diagnostic et la stratification de la fibrose hépatique, la rigidité du foie est un biomarqueur quantitatif estimé par des méthodes d'élastographie. L'élastographie par ondes de cisaillement (« shear wave », SW) utilise des ultrasons médicaux non invasifs pour évaluer les propriétés mécaniques du foie sur la base des propriétés de propagation des ondes de cisaillement. La vitesse des ondes de cisaillement (« shear wave speed », SWS) et l'atténuation des ondes de cisaillement (« shear wave attenuation », SWA) peuvent fournir une estimation de la viscoélasticité des tissus. Les tissus biologiques sont intrinsèquement viscoélastiques et un modèle mathématique complexe est généralement nécessaire pour calculer la viscoélasticité en imagerie SW. Le calcul précis de l'atténuation est essentiel, en particulier pour une estimation précise du module de perte et de la viscosité. Des études récentes ont tenté d'augmenter la précision de l'estimation du SWA, mais elles présentent encore certaines limites. Comme premier objectif de cette thèse, une méthode de décalage de fréquence revisitée a été développée pour améliorer les estimations fournies par la méthode originale de décalage en fréquence [Bernard et al 2017]. Dans la nouvelle méthode, l'hypothèse d'un paramètre de forme décrivant les caractéristiques spectrales des ondes de cisaillement, et assumé initialement constant pour tous les emplacements latéraux, a été abandonnée permettant un meilleur ajustement de la fonction gamma du spectre d'amplitude. En second lieu, un algorithme de consensus d'échantillons aléatoires adaptatifs (« adaptive random sample consensus », A-RANSAC) a été mis en œuvre pour estimer la pente du paramètre de taux variable de la distribution gamma afin d’améliorer la précision de la méthode. Pour valider ces changements algorithmiques, la méthode proposée a été comparée à trois méthodes récentes permettant d’estimer également l’atténuation des ondes de cisaillements (méthodes de décalage en fréquence, de décalage en fréquence en deux points et une méthode ayant comme acronyme anglophone AMUSE) à l'aide de données de simulations ou fantômes numériques. Également, des fantômes de gels homogènes in vitro et des données in vivo acquises sur le foie de canards ont été traités. Comme deuxième objectif, cette thèse porte également sur le diagnostic précoce de la stéatose hépatique non alcoolique (NAFLD) qui est nécessaire pour prévenir sa progression et réduire la mortalité globale. À cet effet, la méthode de décalage en fréquence revisitée a été testée sur des foies humains in vivo. La performance diagnostique de la nouvelle méthode a été étudiée sur des foies humains sains et atteints de la maladie du foie gras non alcoolique. Pour minimiser les sources de variabilité, une méthode d'analyse automatisée faisant la moyenne des mesures prises sous plusieurs angles a été mise au point. Les résultats de cette méthode ont été comparés à la fraction de graisse à densité de protons obtenue de l'imagerie par résonance magnétique (« magnetic resonance imaging proton density fat fraction », MRI-PDFF) et à la biopsie du foie. En outre, l’imagerie SWA a été utilisée pour classer la stéatose et des seuils de décision ont été établis pour la dichotomisation des différents grades de stéatose. Finalement, le dernier objectif de la thèse consiste en une étude de reproductibilité de six paramètres basés sur la technologie SW (vitesse, atténuation, dispersion, module de Young, viscosité et module de cisaillement). Cette étude a été réalisée chez des volontaires sains et des patients atteints de NAFLD à partir de données acquises lors de deux visites distinctes. En conclusion, une méthode robuste de calcul du SWA du foie a été développée et validée pour fournir une méthode de diagnostic de la NAFLD.For diagnosis and staging of liver fibrosis, liver stiffness is a quantitative biomarker estimated by elastography methods. Ultrasound shear wave (SW) elastography utilizes noninvasive medical ultrasound to assess the mechanical properties of the liver based on the monitoring of the SW propagation. SW speed (SWS) and SW attenuation (SWA) can provide an estimation of tissue viscoelasticity. Biological tissues are inherently viscoelastic in nature and a complex mathematical model is usually required to compute viscoelasticity in SW imaging. Accurate computation of attenuation is critical, especially for accurate loss modulus and viscosity estimation. Recent studies have made attempts to increase the precision of SWA estimation, but they still face some limitations. As a first objective of this thesis, a revisited frequency-shift method was developed to improve the estimates provided by the original implementation of the frequency-shift method [Bernard et al 2017]. In the new method, the assumption of a constant shape parameter of the gamma function describing the SW magnitude spectrum has been dropped for all lateral locations, allowing a better gamma fitting. Secondly, an adaptive random sample consensus algorithm (A-RANSAC) was implemented to estimate the slope of the varying rate parameter of the gamma distribution to improve the accuracy of the method. For the validation of these algorithmic changes, the proposed method was compared with three recent methods proposed to estimate SWA (frequency-shift, two-point frequency-shift and AMUSE methods) using simulation data or numerical phantoms. In addition, in vitro homogenous gel phantoms and in vivo animal (duck) liver data were processed. As a second objective, this thesis also aimed at improving the early diagnosis of nonalcoholic fatty liver disease (NAFLD), which is necessary to prevent its progression and decrease the overall mortality. For this purpose, the revisited frequency-shift method was tested on in vivo human livers. The new method's diagnosis performance was investigated with healthy and NAFLD human livers. To minimize sources of variability, an automated analysis method averaging measurements from several angles has been developed. The results of this method were compared to the magnetic resonance imaging proton density fat fraction (MRI-PDFF) and to liver biopsy. SWA imaging was used for grading steatosis and cut-off decision thresholds were established for dichotomization of different steatosis grades. As a third objective, this thesis is proposing a reproducibility study of six SW-based parameters (speed, attenuation, dispersion, Young’s modulus, viscosity and shear modulus). The assessment was performed in healthy volunteers and NAFLD patients using data acquired at two separate visits. In conclusion, a robust method for computing the liver’s SWA was developed and validated to provide a diagnostic method for NAFLD

Why Are Viscosity and Nonlinearity Bound to Make an Impact in Clinical Elastographic Diagnosis?

The contributions by Antonio Gomez, Monica Contreras and Francisca S. Molina are gratefully acknowledged.The adoption of multiscale approaches by the biomechanical community has caused a major improvement in quality in the mechanical characterization of soft tissues. The recent developments in elastography techniques are enabling in vivo and non-invasive quantification of tissues’ mechanical properties. Elastic changes in a tissue are associated with a broad spectrum of pathologies, which stems from the tissue microstructure, histology and biochemistry. This knowledge is combined with research evidence to provide a powerful diagnostic range of highly prevalent pathologies, from birth and labor disorders (prematurity, induction failures, etc.), to solid tumors (e.g., prostate, cervix, breast, melanoma) and liver fibrosis, just to name a few. This review aims to elucidate the potential of viscous and nonlinear elastic parameters as conceivable diagnostic mechanical biomarkers. First, by providing an insight into the classic role of soft tissue microstructure in linear elasticity; secondly, by understanding how viscosity and nonlinearity could enhance the current diagnosis in elastography; and finally, by compounding preliminary investigations of those elastography parameters within different technologies. In conclusion, evidence of the diagnostic capability of elastic parameters beyond linear stiffness is gaining momentum as a result of the technological and imaging developments in the field of biomechanics.This research was funded by Ministerio de Educación, Cultura y Deporte grant numbers DPI2017-83859-R, DPI2014-51870-R, UNGR15-CE-3664 and EQC2018-004508-P; Ministerio de Sanidad, Servicios Sociales e Igualdad grant numbers DTS15/00093 and PI16/00339; Instituto de Salud Carlos III y Fondos Feder; Junta de Andalucía grant numbers PI-0107-2017, PIN-0030-2017 and IE2017-5537; Juan de la Cierva Incorporación IJC2018-037167-I, Ministerio de Ciencia, Innovación y Universidades grant number PRE2018-086085

Shear Wave Propagation in Soft Tissue with Ultrasound Vibrometry

Studies have found that shear moduli, having the dynamic range of several orders of magnitude for various biological tissues, are highly correlated with the pathological statues of human tissue such as livers. Shear moduli can be investigated by measuring the attenuation and velocity of the shear wave propagation in a tissue region. Many efforts have been made to measure shear wave propagations induced by different types of force, which include the motion force of human organs, external applied force, and ultrasound radiation force. In the past 15 years, ultrasound radiation force has been successfully used to induce tissue motion for imaging tissue elasticity. Vibroacoustography (VA) uses bifocal beams to remotely induce vibration in a tissue region and detect the vibration using a hydrophone. The vibration center is sequentially moved in the tissue region to form a two-dimensional image. Acoustic Radiation Force Imaging (ARFI) uses focused ultrasound to apply localized radiation force to small volumes of tissue for short durations and the resulting tissue displacements are mapped using ultrasonic correlation based methods. Supersonic shear image remotely vibrates tissue and sequentially moves vibration center along the beam axis to create intense shear plan wave that is imaged at a high frame rate (5000 frames per second). These image methods provide measurements of tissue elasticity, but not the viscosity. Because of the dispersive property of biological tissue, the induced tissue displacement and the shear wave propagation are frequency dependent. Tissue shear property can be modeled by several models including Kelvin-Voigt (Voigt) model, Maxwell model, and Zener model. The Voigt model effectively describes the creep behavior of tissue, The Maxwell model effectively describes the relaxation process, and the Zener model effectively describes both creep and relaxation but it requires one extra parameter. The Voigt model is often used by many researchers because of its simplicity and the effectiveness of modeling soft tissue. The Voigt model consists of a purely viscous damper and a purely elastic spring connected in parallel. For Voigt tissue, the tissue motion at a very low frequency largely depends on the elasticity, while the motion at a very high frequency largely depends on the viscosity. In general, the tissue motion depends on both elasticity and viscosity, and estimates of elasticity by ignoring viscosity are biased or erroneous. In 1951, Dr. Oestreicher published his work to solve the wave equation for the Voigt soft tissue with harmonic motions. With assumptions of isotropic tissue and plane wave, he derived equations that relate the shear wave attenuation and speed to the elasticity and viscosity of soft tissue. However, Oestreicher’s method was not realized for applications until the half century later. In the past ten years, Oestreicher’s method was utilized to quantitatively measure both tissue elasticity and viscosity. Ultrasound vibrometry has been developed to noninvasively and quantitatively measure tissue shear moduli. It induces shear waves using ultrasound radiation force and estimates the shear moduli using shear wave phase velocities at several frequencies by measuring the phase shifts of the propagating shear wave over a short distance using pulse echo ultrasound. Applications of the ultrasound vibrometry were conducted for viscoelasticities of liver, bovine and porcine striated muscles, blood vessels, and hearts. A recent in vivo liver study shows that the ultrasound vibrometry can be implemented on a clinical ultrasound scanner of using an array transducer. One potential application of ultrasound vibrometry is to characterize shear moduli of livers. The shear moduli of liver are highly correlated with liver pathology status. Recently, the shear viscoelasticity of liver tissue has been investigated by several research groups. Most of these studies applied ultrasound radiation force in liver tissue regions, measured the phase velocities of shear wave in a limited frequency range, and inversely solved the Voigt model with an assumption that liver local tissue is isotropic without considering boundary conditions. Because of the boundary conditions, shear wave propagations are impacted by the limited physical dimensions of tissue. Studies shows that considerations of boundary conditions should be taken for characterizing tissue that have limited physical dimensions such as heart, blood vessels, and liver, when ultrasound vibrometry is used

Viscoelasticity Imaging of Biological Tissues and Single Cells Using Shear Wave Propagation

Changes in biomechanical properties of biological soft tissues are often associated with physiological dysfunctions. Since biological soft tissues are hydrated, viscoelasticity is likely suitable to represent its solid-like behavior using elasticity and fluid-like behavior using viscosity. Shear wave elastography is a non-invasive imaging technology invented for clinical applications that has shown promise to characterize various tissue viscoelasticity. It is based on measuring and analyzing velocities and attenuations of propagated shear waves. In this review, principles and technical developments of shear wave elastography for viscoelasticity characterization from organ to cellular levels are presented, and different imaging modalities used to track shear wave propagation are described. At a macroscopic scale, techniques for inducing shear waves using an external mechanical vibration, an acoustic radiation pressure or a Lorentz force are reviewed along with imaging approaches proposed to track shear wave propagation, namely ultrasound, magnetic resonance, optical, and photoacoustic means. Then, approaches for theoretical modeling and tracking of shear waves are detailed. Following it, some examples of applications to characterize the viscoelasticity of various organs are given. At a microscopic scale, a novel cellular shear wave elastography method using an external vibration and optical microscopy is illustrated. Finally, current limitations and future directions in shear wave elastography are presented

Non-invasive markers of liver fibrosis: adjuncts or alternatives to liver biopsy?

Liver fibrosis reflects sustained liver injury often from multiple, simultaneous factors. Whilst the presence of mild fibrosis on biopsy can be a reassuring finding, the identification of advanced fibrosis is critical to the management of patients with chronic liver disease. This necessity has lead to a reliance on liver biopsy which itself is an imperfect test and poorly accepted by patients. The development of robust tools to non-invasively assess liver fibrosis has dramatically enhanced clinical decision making in patients with chronic liver disease, allowing a rapid and informed judgment of disease stage and prognosis. Should a liver biopsy be required, the appropriateness is clearer and the diagnostic yield is greater with the use of these adjuncts. While a number of non-invasive liver fibrosis markers are now used in routine practice, a steady stream of innovative approaches exists. With improvement in the reliability, reproducibility and feasibility of these markers, their potential role in disease management is increasing. Moreover, their adoption into clinical trials as outcome measures reflects their validity and dynamic nature. This review will summarize and appraise the current and novel non-invasive markers of liver fibrosis, both blood and imaging based, and look at their prospective application in everyday clinical care

Viscoelastic Biomarkers of Ex Vivo Liver Samples via TorsionalWave Elastography

We thank the Department of Electronics and Computer Technology of the University of Granada for assistance with the electronic system of the torsional wave sensor.The clinical ultrasound community demands mechanisms to obtain the viscoelastic biomarkers of soft tissue in order to quantify the tissue condition and to be able to track its consistency. Torsional Wave Elastography (TWE) is an emerging technique proposed for interrogating soft tissue mechanical viscoelastic constants. Torsional waves are a particular configuration of shear waves, which propagate asymmetrically in-depth and are radially transmitted by a disc and received by a ring. This configuration is shown to be particularly efficient in minimizing spurious p-waves components and is sensitive to mechanical constants, especially in cylinder-shaped organs. The objective of this work was to validate (TWE) technique against Shear Wave Elasticity Imaging (SWEI) technique through the determination of shear wave velocity, shear moduli, and viscosity of ex vivo chicken liver samples and tissue mimicking hydrogel phantoms. The results of shear moduli for ex vivo liver tissue vary 1.69–4.0kPa using TWE technique and 1.32–4.48kPa using SWEI technique for a range of frequencies from 200 to 800Hz. Kelvin–Voigt viscoelastic parameters reported values of μ = 1.51kPa and η = 0.54Pa·s using TWE and μ = 1.02kPa and η = 0.63Pa·s using SWEI. Preliminary results show that the proposed technique successfully allows reconstructing shear wave velocity, shear moduli, and viscosity mechanical biomarkers from the propagated torsional wave, establishing a proof of principle and warranting further studies.This research was funded by the Ministry of Education grant numbers DPI2017-83859-R, DPI2014-51870-R, and UNGR15-CE-3664; Ministry of Health grant numbers DTS15/00093 and PI16/00339 Carlos III Instituto de Salud y Fondos Feder; and Junta de Andalucía grant numbers, PI-0107-2017 and PIN-0030-2017. Juan de la Cierva Incorporación IJC2018-037167-I

COMPUTATIONAL ULTRASOUND ELASTOGRAPHY: A FEASIBILITY STUDY

Ultrasound Elastography (UE) is an emerging set of imaging modalities used to assess the biomechanical properties of soft tissues. UE has been applied to numerous clinical applications. Particularly, results from clinical trials of UE in breast lesion differentiation and staging liver fibrosis indicated that there was a lack of confidence in UE measurements or image interpretation. Confidence on UE measurements interpretation is critically important for improving the clinical utility of UE. The primary objective of my thesis is to develop a computational simulation platform based on open-source software packages including Field II, VTK, FEBio and Tetgen. The proposed virtual simulation platform can be used to simulate SE and acoustic radiation force based SWE simulations, including pSWE, SSI and ARFI. To demonstrate its usefulness, in this thesis, examples for breast cancer detections were provided. The simulated results can reproduce what has been reported in the literature. To statistically analyze the intrinsic variations of shear wave speed (SWS) in the fibrotic liver tissues, a probability density function (PDF) of the SWS distribution in conjunction with a lossless stochastic tissue model was derived using the principle of Maximum Entropy (ME). The performance of the proposed PDF was evaluated using Monte-Carlo (MC) simulated shear wave data and against three other commonly used PDFs. We theoretically demonstrated that SWS measurements follow a non-Gaussian distribution for the first time. One advantage of the proposed PDF is its physically meaningful parameters. Also, we conducted a case study of the relationship between shear wave measurements and the microstructure of fibrotic liver tissues. Three different virtual tissue models were used to represent underlying microstructures of fibrotic liver tissues. Furthermore, another innovation of this thesis is the inclusion of “biologically-relevant” fibrotic liver tissue models for simulation of shear wave elastography. To link tissue structure, composition and architecture to the ultrasound measurements directly, a “biologically relevant” tissue model was established using Systems Biology. Our initial results demonstrated that the simulated virtual liver tissues qualitatively could reproduce histological results and wave speed measurements. In conclusions, these computational tools and theoretical analysis can improve the confidence on UE image/measurements interpretation