In Vivo Measurement of Brain Tumor Elasticity Using Intraoperative Shear Wave Elastography.

Purpose: Objective Shear wave elastography (SWE) enabled living tissue assessment of stiffness. This is routinely used for breast, thyroid and liver diseases, but there is currently no data for the brain. We aim to characterize elasticity of normal brain parenchyma and brain tumors using SWE. Materials and Methods: Patients with scheduled brain tumor removal were included in this study. In addition to standard ultrasonography, intraoperative SWE using an ultrafast ultrasonic device was used to measure the elasticity of each tumor and its surrounding normal brain. Data were collected by an investigator blinded to the diagnosis. Descriptive statistics, box plot analysis as well as intraoperator and interoperator reproducibility analysis were also performed. Results: 63 patients were included and classified into four main types of tumor: meningiomas, low-grade gliomas, high-grade gliomas and metastasis. Young's Modulus measured by SWE has given new insight to differentiate brain tumors: 33.1 ±â€Š5.9 kPa, 23.7 ±â€Š4.9 kPa, 11.4 ±â€Š3.6 kPa and 16.7 ±â€Š2.5 kPa, respectively, for the four subgroups. Normal brain tissue has been characterized by a reproducible mean stiffness of 7.3 ±â€Š2.1 kPa. Moreover, low-grade glioma stiffness is different from high-grade glioma stiffness (p = 0.01) and normal brain stiffness is very different from low-grade gliomas stiffness (p < 0.01). Conclusion: This study demonstrates that there are significant differences in elasticity among the most common types of brain tumors. With intraoperative SWE, neurosurgeons may have innovative information to predict diagnosis and guide their resection.

Placental elastography in a murine intrauterine growth restriction model.

OBJECTIVE: To compare placental elasticity in normal versus intrauterine growth restriction (IUGR) murine pregnancies using shear wave elastography (SWE). METHODS: Intrauterine growth restriction was created by ligation of the left uterine artery of Sprague-Dawley rats on E17. Ultrasonography (US) and elastography were performed 2 days later on exteriorized horns after laparotomy. Biparietal diameter (BPD) and abdominal diameter (AD) were measured and compared in each horn. Placental elasticity of each placenta was compared in the right and left horns, respectively, using the Young's modulus, which increases with increasing stiffness of the tissue. RESULTS: Two hundred seventeen feto-placental units from 18 rats were included. Fetuses in the left ligated horn had smaller biometric measurements than those in the right horn (6.7 vs 7.2 mm, p < 0.001, and 9.2 vs 11.2 mm, p < 0.001 for BPD and AD, respectively). Mean fetal weight was lower in the pups from the left than the right horn (1.65 vs 2.11 g; p < 0.001). Mean (SD) Young's modulus was higher for placentas from the left than the right horn (11.7 ± 1.5 kPa vs 8.01 ± 3.8 kPa, respectively; p < 0.001), indicating increased stiffness in placentas from the left than the right horn. There was an inverse relationship between fetal weight and placental elasticity (r = 0.42; p < 0.001). CONCLUSION: Shear wave elastography may be used to provide quantitative elasticity measurements of the placenta. In our model, placentas from IUGR fetuses demonstrated greater stiffness, which correlated with the degree of fetal growth restriction.

New semi-analytical method for fast transcranial ultrasonic field simulation.

Objective.To optimize and ensure the safety of ultrasound brain therapy, personalized transcranial ultrasound simulations are very useful. They allow to predict the pressure field, depending on the patient skull and probe position. Most transcranial ultrasound simulations are based on numerical methods which have a long computation time and a high memory usage. The goal of this study is to develop a new semi-analytical field computation method that combines realism and computation speed.Approach.Instead of the classic ray tracing, the ultrasonic paths are computed by time of flight minimization. Then the pressure field is computed using the pencil method. This method requires a smooth and homogeneous skull model. The simulation algorithm, so-called SplineBeam, was numerically validated, by comparison with existing solvers, and experimentally validated by comparison with hydrophone measured pressure fields through anex vivohuman skull.Main results.SplineBeam simulated pressure fields were close to the experimentally measured ones, with a focus position difference of the order of the positioning error and a maximum pressure difference lower than 6.02%. In addition, for those configurations, SplineBeam computation time was lower than another simulation software, k-Wave's, by two orders of magnitude, thanks to its capacity to compute the field only at the focal spot.Significance.These results show the potential of this new method to compute fast and realistic transcranial pressure fields. The combination of this two assets makes it a promising tool for real time transcranial pressure field prediction during ultrasound brain therapy interventions.

Shear wave elastography of tumour growth in a human breast cancer model with pathological correlation.

OBJECTIVE: To assess stiffness in a human breast cancer implanted in mice using shear wave elastography (SWE) during tumour growth and to correlate the results with pathology. METHODS: Local ethics committee for animal research approval was obtained. A human invasive ductal carcinoma was implanted subcutaneously in 24 athymic nude female mice. Ultrasound was longitudinally performed in 22 tumours, every 1-2 weeks. Maximum diameter and mean stiffness were collected. Seven tumours were measured both in vivo and ex vivo. Tumours of different sizes were removed for pathological analysis on which the percentages of viable cellular tissue, fibrosis and necrosis were measured. RESULTS: A total of 63 SWE measurements were performed. Stiffness increased during tumour growth with an excellent correlation with size (r = 0.94, P < 0.0001). No differences were found between the values of stiffness in vivo and ex vivo (P = 0.81). There was a significant correlation between elasticity and fibrosis (r = 0.83, P < 0.0001), a negative correlation with necrosis (r = -0.76, p = 0.0004) but no significant correlation with cellular tissue (r = 0.40, p = 0.1). CONCLUSION: Fibrosis plays an important role in stiffness as measured by SWE, whereas necrosis is correlated with softness. KEY POINTS: • In a breast cancer model, ultrasound tumour stiffness is correlated with size. • Stiffness changes with tumour growth are correlated with pathological changes. • Stiffness is very well correlated with proportion of tumour fibrosis. • Stiffness is inversely correlated with proportion of tumour necrosis. • Tumour stiffness measurements are similar in vivo and ex vivo.

Characterization of muscle belly elastic properties during passive stretching using transient elastography.

Passive muscle stretching can be used in vivo to assess the viscoelastic properties of the entire musculo-articular complex, but does not allow the specific determination of the muscle or tendon viscoelasticity. In this respect, the local muscle hardness (LMH) of the gastrocnemius medialis (GM) belly was measured during a passive ankle stretching of 10 subjects using transient elastography. A Biodex isokinetic dynamometer was used to stretch ankle plantar flexors, to measure ankle angle, and the passive torque developed by the ankle joint in resistance to the stretch. Results show that the LMH increased during the stretching protocol, with an averaged ratio between maximal LMH and minimal LMH of 2.62+/-0.46. Furthermore, LMH-passive torque relationships were nicely fitted using a linear model with mean correlation coefficients (R(2)) of 0.828+/-0.099. A good reproducibility was found for the maximal passive torque (ICC=0.976, SEM=2.9Nm, CV=5.5%) and the y-intercept of the LMH-passive torque relationship (ICC=0.893, SEM=105Pa, CV=7.8%). However, the reproducibility was low for the slope of this relationship (ICC=0.631, SEM=10.35m(-2), CV=60.4%). The y-intercept of the LMH-passive torque relationship was not significantly changed after 10min of static stretching. This result confirms the finding of a previous study indicating that changes in passive torque following static stretching could be explained by an acute increase in muscle length without any changes in musculo-articular intrinsic mechanical properties.

Acoustoelasticity in soft solids: assessment of the nonlinear shear modulus with the acoustic radiation force.

The assessment of viscoelastic properties of soft tissues is enjoying a growing interest in the field of medical imaging as pathologies are often correlated with a local change of stiffness. To date, advanced techniques in that field have been concentrating on the estimation of the second order elastic modulus (mu). In this paper, the nonlinear behavior of quasi-incompressible soft solids is investigated using the supersonic shear imaging technique based on the remote generation of polarized plane shear waves in tissues induced by the acoustic radiation force. Applying a theoretical approach of the strain energy in soft solid [Hamilton et al., J. Acoust. Soc. Am. 116, 41-44 (2004)], it is shown that the well-known acoustoelasticity experiment allowing the recovery of higher order elastic moduli can be greatly simplified. Experimentally, it requires measurements of the local speed of polarized plane shear waves in a statically and uniaxially stressed isotropic medium. These shear wave speed estimates are obtained by imaging the shear wave propagation in soft media with an ultrafast echographic scanner. In this situation, the uniaxial static stress induces anisotropy due to the nonlinear effects and results in a change of shear wave speed. Then the third order elastic modulus (A) is measured in agar-gelatin-based phantoms and polyvinyl alcohol based phantoms.

Muscle parameters estimation based on biplanar radiography.

The evaluation of muscle and joint forces in vivo is still a challenge. Musculo-Skeletal (musculo-skeletal) models are used to compute forces based on movement analysis. Most of them are built from a scaled-generic model based on cadaver measurements, which provides a low level of personalization, or from Magnetic Resonance Images, which provide a personalized model in lying position. This study proposed an original two steps method to access a subject-specific musculo-skeletal model in 30 min, which is based solely on biplanar X-Rays. First, the subject-specific 3D geometry of bones and skin envelopes were reconstructed from biplanar X-Rays radiography. Then, 2200 corresponding control points were identified between a reference model and the subject-specific X-Rays model. Finally, the shape of 21 lower limb muscles was estimated using a non-linear transformation between the control points in order to fit the muscle shape of the reference model to the X-Rays model. Twelfth musculo-skeletal models were reconstructed and compared to their reference. The muscle volume was not accurately estimated with a standard deviation (SD) ranging from 10 to 68%. However, this method provided an accurate estimation the muscle line of action with a SD of the length difference lower than 2% and a positioning error lower than 20 mm. The moment arm was also well estimated with SD lower than 15% for most muscle, which was significantly better than scaled-generic model for most muscle. This method open the way to a quick modeling method for gait analysis based on biplanar radiography.

In vivo quantification of the shear modulus of the human Achilles tendon during passive loading using shear wave dispersion analysis.

The shear wave velocity dispersion was analyzed in the Achilles tendon (AT) during passive dorsiflexion using a phase velocity method in order to obtain the tendon shear modulus (C 55). Based on this analysis, the aims of the present study were (i) to assess the reproducibility of the shear modulus for different ankle angles, (ii) to assess the effect of the probe locations, and (iii) to compare results with elasticity values obtained with the supersonic shear imaging (SSI) technique. The AT shear modulus (C 55) consistently increased with the ankle dorsiflexion (N = 10, p < 0.05). Furthermore, the technique showed a very good reproducibility (all standard error of the mean values <10.7 kPa and all coefficient of variation (CV) values ⩽ 0.05%). In addition, independently from the ankle dorsiflexion, the shear modulus was significantly higher in the proximal location compared to the more distal one. The shear modulus provided by SSI was always lower than C55 and the difference increased with the ankle dorsiflexion. However, shear modulus values provided by both methods were highly correlated (R = 0.84), indicating that the conventional shear wave elastography technique (SSI technique) can be used to compare tendon mechanical properties across populations. Future studies should determine the clinical relevance of the shear wave dispersion analysis, for instance in the case of tendinopathy or tendon tear.

Effects of pressure on the shear modulus, mass and thickness of the perfused porcine kidney.

Eleven fresh ex vivo porcine kidneys were perfused in the artery, vein and ureter with degassed Dulbecco׳s Modified Eagle Medium (DMEM). The effect of perfusion pressure was evaluated using ten different pressures combinations. The shear modulus of the tissues was estimated during perfusion using shear wave elastography. The organ weight change was measured by a digital scale and cameras were used to follow the changes of the dimensions after each pressure combination. The effect of perfusion on the weight and the thickness was non-reversible, whereas the effect on the shear modulus was reversible. Pressure was found to increase the average shear modulus in the cortex by as much as 73%. A pressure of 80 mmHg was needed to observe tissues shear modulus in the same range as in vivo tests (Gcortex=9.1 kPa, Gmedulla=8.5 kPa ex vivo versus Gcortex=9.1 kPa, Gmedulla=8.7 kPa in vivo in Gennisson et al., 2012).

Observation of the internal response of the kidney during compressive loading using ultrafast ultrasonography.

A protocol based on ultrafast ultrasonography was developed to study the internal response of isolated perfused human (n=3) and porcine (n=11) kidneys subjected to loading at 0.003 m/s and 0.3m/s respectively. Regional uniaxial strains were calculated based on natural target tracking. The effect of loading speed and regional differences could be statistically detected on the porcine specimens. However, despite the inhomogeneity of their anatomical structures, strains' responses appeared relatively homogeneous at 0.3m/s in both porcine and human kidneys. Failure, identified as a sudden change on the ultrasonography movie, also appeared at similar compression levels for both species (38.3% of applied strain in average for human and 35.8% of applied strain in average for porcine).

In vivo breast tumor detection using transient elastography.

This paper presents first in vivo experiments for breast tumor detection using transient elastography. This technique has been developed for detection and quantitative mapping of hard lesions in soft tissues. It consists in following the propagation inside soft tissues of very low-frequency shear waves (approximately 60 Hz) generated by a vibrating system located at the body surface. Because transient shear waves propagate through the medium in less than 0.1 s, the shear propagation imaging is performed with an ultrafast echographic scanner able to reach frame rates up to 6000 Hz. The local shear wave speed is directly linked to the local shear Young's modulus of the medium. The shear elasticity map of the medium can then be computed using an inversion algorithm. In vivo experiments were conducted on 15 women who had palpable breast lesions. For clinical adaptability reasons, shear waves were generated by the surface of the ultrasound (US) imaging transducer itself, which was linked to a mechanical vibrator. Our preliminary in vivo results demonstrate the clinical applicability of the transient elastography technique for breast lesion detection.

In vivo evaluation of the elastic anisotropy of the human Achilles tendon using shear wave dispersion analysis.

Non-invasive evaluation of the Achilles tendon elastic properties may enhance diagnosis of tendon injury and the assessment of recovery treatments. Shear wave elastography has shown to be a powerful tool to estimate tissue mechanical properties. However, its applicability to quantitatively evaluate tendon stiffness is limited by the understanding of the physics on the shear wave propagation in such a complex medium. First, tendon tissue is transverse isotropic. Second, tendons are characterized by a marked stiffness in the 400 to 1300 kPa range (i.e. fast shear waves). Hence, the shear wavelengths are greater than the tendon thickness leading to guided wave propagation. Thus, to better understand shear wave propagation in tendons and consequently to properly estimate its mechanical properties, a dispersion analysis is required. In this study, shear wave velocity dispersion was measured in vivo in ten Achilles tendons parallel and perpendicular to the tendon fibre orientation. By modelling the tendon as a transverse isotropic viscoelastic plate immersed in fluid it was possible to fully describe the experimental data (deviation<1.4%). We show that parallel to fibres the shear wave velocity dispersion is not influenced by viscosity, while it is perpendicularly to fibres. Elasticity (found to be in the range from 473 to 1537 kPa) and viscosity (found to be in the range from 1.7 to 4 Pa.s) values were retrieved from the model in good agreement with reported results.

Effects of storage temperature on the mechanical properties of porcine kidney estimated using shear wave elastography.

The objective of this study was to evaluate the effects of different conservation techniques on the mechanical properties of the ex vivo porcine kidney in order to select an appropriate conservation protocol to use prior to mechanical testing. Five groups of eight kidneys each were subjected to different methods of conservation: storage at 4°C, -18°C, -34°C and -71°C, for 7 days, or storage at 20°C for 2 days only (as the tissues degraded quickly). Their shear modulus as a function of depth in the organ was evaluated before (fresh) and after conservation using shear wave elastography. Results obtained on fresh kidneys were collected within 6h of death. Freezing lead to a significant decrease (p<0.05) of the shear modulus in the most superficial zone (renal cortex), irrespectively of the freezing temperature (-18°C, -34°C, -71°C). There were no significant change (p>0.05) in the properties of the renal cortex when stored at 4°C or 20°C. The average moduli in the central region of the kidney (medulla) were much higher than in the cortex and exhibited also exhibited larger specimen to specimen variations. The effects of the conservation method on the central region were not significant. Overall, the results suggest that kidney tissues should not be frozen prior to biomechanical characterization and that inhomogeneity may be important to consider for in biomechanical models.

Ultrasound elastography: principles and techniques.

Ultrasonography has been widely used for diagnosis since it was first introduced in clinical practice in the 1970's. Since then, new ultrasound modalities have been developed, such as Doppler imaging, which provides new information for diagnosis. Elastography was developed in the 1990's to map tissue stiffness, and reproduces/replaces the palpation performed by clinicians. In this paper, we introduce the principles of elastography and give a technical summary for the main elastography techniques: from quasi-static methods that require a static compression of the tissue to dynamic methods that uses the propagation of mechanical waves in the body. Several dynamic methods are discussed: vibro-acoustography, Acoustic Radiation Force Impulsion (ARFI), transient elastography, shear wave imaging, etc. This paper aims to help the reader at understanding the differences between the different methods of this promising imaging modality that may become a significant tool in medical imaging.

Renal ultrasound elastography.

Chronic kidney disease (CKD) incidence and prevalence are increasing in Western countries, due particularly to diabetes mellitus and hypertension-related nephropathies. CKD may lead to end-stage renal failure, with extensive morbidity, mortality and increasing health costs. Primary and secondary prevention requires a better knowledge of mechanisms underlying renal scarring, the development of specific therapies to slow down the progression of the disease and the development of non-invasive diagnostic tools to characterize the process. Ultrasound elastography is a new imaging technique under development that provides information about renal stiffness. Kidney elasticity measurements with ultrasound should be performed with a quantitative technique, such as Shearwave techniques. However kidney stiffness is not only related to fibrosis, as it also sensitive to mechanical and functional parameters such as anisotropy, vascularization, hydronephrosis and external pressure. This paper reviews the existing ultrasound elastography techniques. Elastography is a new tool under development for renal tissue characterization and needs further validation in clinical practice.

Temperature dependence of the shear modulus of soft tissues assessed by ultrasound.

Soft tissue stiffness was shown to significantly change after thermal ablation. To better understand this phenomenon, the study aims (1) to quantify and explain the temperature dependence of soft tissue stiffness for different organs, (2) to investigate the potential relationship between stiffness changes and thermal dose and (3) to study the reversibility or irreversibility of stiffness changes. Ex vivo bovine liver and muscle samples (N = 3 and N = 20, respectively) were slowly heated and cooled down into a thermally controlled saline bath. Temperatures were assessed by thermocouples. Sample stiffness (shear modulus) was provided by the quantitative supersonic shear imaging technique. Changes in liver stiffness are observed only after 45 degrees C. In contrast, between 25 degrees C and 65 degrees C, muscle stiffness varies in four successive steps that are consistent with the thermally induced proteins denaturation reported in the literature. After a 6 h long heating and cooling process, the final muscle stiffness can be either smaller or bigger than the initial one, depending on the stiffness at the end of the heating. Another important result is that stiffness changes are linked to thermal dose. Given the high sensitivity of ultrasound to protein denaturation, this study gives promising prospects for the development of ultrasound-guided HIFU systems.