Introduction.

Diagnostic ultrasound imaging has gained wide acceptance for a broad range of clinical uses. In many cases, ultrasonography is the first-line imaging modality selected for its ease of access and absence of ionizing radiation. Over the last decades, ultrasonography has considerably evolved and is currently contributing to important improvements in patient diagnosis and treatment. Modern ultrasound imaging can provide soft tissue anatomical (shape, size…) and functional information (tissue movements, blood flow) in 3D and 4D, characterization and distinction among tissues (echostructure) and quantification of tissue properties (microstructure, tissue stiffness). Soft tissue quantitative ultrasound (QUS) refers to methods specifically developed to assess quantitative variables reflecting tissue physical properties, usually by analyzing the raw radiofrequency signals and/or its spectral characteristics.

Clinical Devices for Bone Assessment.

Although it has been over 30 years since the first recorded use of quantitative ultrasound (QUS) technology to predict bone strength, the field has not yet reached its maturity. Among several QUS technologies available to measure cortical or cancellous bone sites, at least some of them have demonstrated potential to predict fracture risk with an equivalent efficiency compared to X-ray densitometry techniques, and the advantages of being non-ionizing, inexpensive, portable, highly acceptable to patients and repeatable. In this Chapter, we review instrumental developments that have led to in vivo applications of bone QUS, emphasizing the developments occurred in the decade 2010-2020. While several proposals have been made for practical clinical use, there are various critical issues that still need to be addressed, such as quality control and standardization. On the other side, although still at an early stage of development, recent QUS approaches to assess bone quality factors seem promising. These include guided waves to assess mechanical and structural properties of long cortical bones or new QUS technologies adapted to measure the major fracture sites (hip and spine). New data acquisition and signal processing procedures are prone to reveal bone properties beyond bone mineral quantity and to provide a more accurate assessment of bone strength.

Axial Transmission: Techniques, Devices and Clinical Results.

Recent progress in quantitative ultrasound have sparked increasing interest towards the measurement of long cortical bones (e.g., radius or tibia), because their ability to sustain loading and resist fractures is known to be related to their mechanical properties at different length scales. In particular, applying guided waves for the assessment of cortical bone is inspired by widely used techniques developed earlier in the field of nondestructive testing and evaluation of different waveguide structures. This approach is based on the experimental evidence that the cortex of long bones can act as a natural waveguide for ultrasound, despite its irregular geometry, attenuation, and heterogeneous material properties. Because guided waves could yield the characterization of several bone properties (e.g., cortical thickness, anisotropic stiffness or porosity) at the mesoscopic level by fitting the dispersion characteristics of a waveguide model to the measured dispersion curves (i.e., solving an inverse problem), this method has a strong clinical potential as a tool for bone status assessment. This chapter revisits the roadmap that allowed the so-called bidirectional axial transmission technique to progress from a pure laboratory concept to a diagnostic tool of clinical interest over the second decade of the twenty-first century and discusses the current clinical challenges associated with cortical bone characterization by ultrasound guided waves.

Inverse Problem in Resonant Ultrasound Spectroscopy With Sampling and Optimization: A Comparative Study on Human Cortical Bone.

The Bayesian inference with prior knowledge has been proposed recently to solve the inverse problem in resonant ultrasound spectroscopy. It allows inferring the elastic properties of high damping materials, such as cortical bone with less dependence on the initial guessed values. In this method, the estimation of the stiffness coefficients is expressed as a probabilistic solution to the inverse problem, which can be achieved by sampling or optimization methods. However, the detailed performance comparison of these two strategies applied to high damping materials has not been fully studied. In this work, the full stiffness tensor of 52 transversely isotropic cortical bone specimens was obtained using Markov chain Monte Carlo (MCMC) sampling and particle swarm optimization (PSO), respectively. Results showed that the local probability distributions of stiffness coefficients estimated by the two methods are consistent. Compared with MCMC, the average calculation speed of PSO is ten times faster [614 s ± 59 s (MCMC) versus 53 s ± 22 s (PSO)]. The mean standard error between theoretical and experimental resonant frequencies was slightly smaller for PSO compared with MCMC. In conclusion, PSO, a global optimization strategy, is suitable to solve the inverse problem for high damping materials.

Application of differential evolution on elasticity measurement of low quality factor materials using FEM-based resonant ultrasound spectroscopy.

Finite element method based resonant ultrasound spectroscopy (FEM-based RUS) allows elasticity measurement for a material with high quality factor (Q) and arbitrary geometry by minimizing the differences between its theoretically calculated resonant frequencies and the corresponding experimentally measured ones. As Q decreases, some experimental frequencies remain undetermined, which makes it difficult to pair the calculated and experimental frequencies and to correctly identify the elastic constants. Additional difficulty need be tackled for irregularly-shaped low-Q materials due to the adoption of time-consuming FEM, thus efficiency of the identification method needs to be focused on. To apply FEM-based RUS to low-Q materials, a new elastic constant identification method is proposed based on a differential evolution algorithm in this paper. This method can perform a global search combining with local optimizations in the elastic constant space, and improve the overall efficiency by limiting the number of the frequency calculations. By using numerical experiments, the effectiveness of the proposed method under different frequency missing situations was verified and its efficiency was measured from the required frequency calculation numbers, showing an approximate two third reduction compared with an existing method. Finally, the elastic constants of an actual irregular cortical bone-mimicking material (Q ≈ 25) were measured using the two methods, yielding consistent Young's moduli (calculated from the identified constants) with the data provided by the manufacturer and a similar improvement in computational efficiency of the proposed method.

Cortical bone viscoelastic damping assessed with resonant ultrasound spectroscopy reflects porosity and mineral content.

Viscoelasticity is an essential property of bone related to fragility, which is altered in aging and bone disease. Bone viscoelastic behavior is attributed to several mechanisms involving collagen and mineral properties, porosities, and bone hierarchical tissue organization. We aimed to assess the relationships between cortical bone viscoelastic damping measured with Resonant Ultrasound Spectroscopy (RUS), microstructural and compositional characteristics. We measured 52 bone specimens from the femur of 26 elderly human donors. RUS provided a shear damping coefficient at a frequency of the order of 150 kHz. The characteristics of the structure of the vascular pore network and tissue mineral density were measured using synchrotron radiation high-resolution computed tomography (SR-µCT). Fourier transformed infrared microspectroscopy (FTIRM) was used to quantify mineral-to-organic phase ratio, mineral maturity, crystallinity, and collagen maturity. Cross-links were quantified from biochemistry. Viscoelastic damping was found to increase with vascular porosity (r=0.68), to decrease with the degree of mineralization of the extravascular matrix (r=-0.68), and was marginally affected by collagen. We built a multilinear model suggesting that when porosity is controlled, the variation of mineral content explains a small additional part of the variability of damping. The work supports the consideration of viscoelasticity measurement as a potential biomarker of fragility and provides a documentation of bone viscoelastic behavior and its determinants in a frequency range rarely investigated.

Bulk Wave Velocities in Cortical Bone Reflect Porosity and Compression Strength.

The goal of this study was to evaluate whether ultrasonic velocities in cortical bone can be considered as a proxy for mechanical quality of cortical bone tissue reflected by porosity and compression strength. Micro-computed tomography, compression mechanical testing and resonant ultrasound spectroscopy were used to assess, respectively, porosity, strength and velocity of bulk waves of both shear and longitudinal polarisations propagating along and perpendicular to osteons, in 92 cortical bone specimens from tibia and femur of elderly human donors. All velocities were significantly associated with strength (r = 0.65-0.83) and porosity (r = -0.64 to -0.77). Roughly, according to linear regression models, a decrease in velocity of 100 m/s corresponded to a loss of 20 MPa in strength (which is approximately 10% of the largest strength value) and to an increase in porosity of 5%. These results provide a rationale for the in vivo measurement of one or several velocities for the diagnosis of bone fragility.

Particle Swarm Optimization-Based Identification of the Elastic Properties in Resonant Ultrasound Spectroscopy.

Resonant ultrasound spectroscopy (RUS) is an experimental measurement method for obtaining elastic constants of an anisotropic material from the free resonant frequencies of a sample. One key step of the method is to adjust elastic constants to minimize the difference between calculated and experimental frequencies. The method has been widely used in the determination of elastic constants of solid materials with high Q value, such that the resonant frequencies can be easily extracted from the measured spectrum. However, for materials with high damping, the identification of the resonant modes becomes difficult due to the overlap of resonant peaks and the absence of some modes. Thus, the success of RUS depends largely on initial guessing of elastic constants. In this article, these limitations are addressed with a new RUS approach. First, the identification of resonant modes is transformed into a linear assignment problem solved by the Hungarian algorithm. Second, the inversion of the elastic tensor is achieved using the particle swarm optimization (PSO) algorithm. This method, having the ability of global optimization in the search space, is less sensitive to the initial guess of the elastic constants. The PSO algorithm was successfully applied for the first time to RUS data, providing estimates of elastic constants that were in good agreement with reference values. First, simulated data for a transversely isotropic sample of enamel of rectangular parallelepiped shape were used to validate the proposed RUS method. Second, the proposed RUS approach was validated using experimental data collected on a sample of transversally isotropic bone-mimicking material.

A resonant frequency retrieving method for low Q-factor materials based on resonant ultrasound spectroscopy.

Resonant ultrasound spectroscopy (RUS) allows identification of the elastic properties of solid materials vibrating under an ultrasonic excitation from the measurement of their inherent frequencies. Retrieving the resonant frequencies is therefore a key signal processing step in RUS, which is generally addressed using a linear prediction filter. In this study, the Empirical Mode Decomposition (EMD) was proposed to retrieve the inherent resonant frequencies of materials with low Q-factor (quality factor). EMD was used to decompose the frequency response of the tested sample into intrinsic mode functions (IMF). The relevant IMF was selected from which the resonant frequencies could be computed. A bovine cortical bone sample was measured and its resonant frequencies were identified with EMD and with linear prediction for comparison. The elastic constants were also derived using both approaches. The number of resonant frequencies (45) extracted with EMD was larger than the number of frequencies (26) identified using the classical linear prediction approach. In particular, EMD proved to be more effective in detecting resonance in the higher frequency range (i.e., between 235 kHz and 400 kHz), i.e., on the weak excitation side where the spectral amplitude is low. The number of measured frequencies matching with the calculated ones was also larger for EMD (39) compared to linear prediction (17). If these results are confirmed in further studies on more samples, EMD combined with RUS, by improving the extraction of resonant frequencies for low Q-factor materials, may be considered to be useful not only to improve the reliability of the estimation of elastic parameters, but also to extend the application range of RUS.

Computed tomography porosity and spherical indentation for determining cortical bone millimetre-scale mechanical properties.

The cortex of the femoral neck is a key structural element of the human body, yet there is not a reliable metric for predicting the mechanical properties of the bone in this critical region. This study explored the use of a range of non-destructive metrics to measure femoral neck cortical bone stiffness at the millimetre length scale. A range of testing methods and imaging techniques were assessed for their ability to measure or predict the mechanical properties of cortical bone samples obtained from the femoral neck of hip replacement patients. Techniques that can potentially be applied in vivo to measure bone stiffness, including computed tomography (CT), bulk wave ultrasound (BWUS) and indentation, were compared against in vitro techniques, including compression testing, density measurements and resonant ultrasound spectroscopy. Porosity, as measured by micro-CT, correlated with femoral neck cortical bone's elastic modulus and ultimate compressive strength at the millimetre length scale. Large-tip spherical indentation also correlated with bone mechanical properties at this length scale but to a lesser extent. As the elastic mechanical properties of cortical bone correlated with porosity, we would recommend further development of technologies that can safely measure cortical porosity in vivo.

Homogenization of cortical bone reveals that the organization and shape of pores marginally affect elasticity.

With ageing and various diseases, the vascular pore volume fraction (porosity) in cortical bone increases, and the morphology of the pore network is altered. Cortical bone elasticity is known to decrease with increasing porosity, but the effect of the microstructure is largely unknown, while it has been thoroughly studied for trabecular bone. Also, popular micromechanical models have disregarded several micro-architectural features, idealizing pores as cylinders aligned with the axis of the diaphysis. The aim of this paper is to quantify the relative effects on cortical bone anisotropic elasticity of porosity and other descriptors of the pore network micro-architecture associated with pore number, size and shape. The five stiffness constants of bone assumed to be a transversely isotropic material were measured with resonant ultrasound spectroscopy in 55 specimens from the femoral diaphysis of 29 donors. The pore network, imaged with synchrotron radiation X-ray micro-computed tomography, was used to derive the pore descriptors and to build a homogenization model using the fast Fourier transform (FFT) method. The model was calibrated using experimental elasticity. A detailed analysis of the computed effective elasticity revealed in particular that porosity explains most of the variations of the five stiffness constants and that the effects of other micro-architectural features are small compared to usual experimental errors. We also have evidence that modelling the pore network as an ensemble of cylinders yields biased elasticity values compared to predictions based on the real micro-architecture. The FFT homogenization method is shown to be particularly efficient to model cortical bone.

Elastic constants identification of irregular hard biological tissue materials using FEM-based resonant ultrasound spectroscopy.

This paper aims to apply the resonant ultrasound spectroscopy technique (RUS) combined with micro computed tomography (µ-CT) and finite element method (FEM) to quantify the elastic constants of the irregular hard biological tissue material such as enamel. In this method, the resonant frequencies of an irregular shaped sample tested under stress-free boundary conditions are measured first. Then, micro-computed tomography (µ-CT) is used to acquire three-dimensional (3-D) geometry information of the sample, and the resonant frequencies are calculated with FEM. Thereby, an optimization procedure using the Levenberg-Marquardt algorithm updates the elastic constants in the FEM model until the output natural frequencies from the model fit the results from the RUS experiments. The proposed method has been tested first on a calibration material. To this purpose, titanium has been selected. The elastic constants of a rectangular parallelepiped shaped titanium sample obtained by the conventional RUS method and those of five irregular samples obtained by FEM-based RUS were in good agreement, displaying differences less than 2%. Once the method has been validated on titanium, it was applied to an enamel sample. The results show that the FEM-based RUS method can effectively identify the elastic constants of irregular titanium and enamel samples. This study expands the application range of RUS technology and provides a new method for the measurement of elastic properties of irregular hard biological tissue materials.

Anisotropic elastic properties of human femoral cortical bone and relationships with composition and microstructure in elderly.

The strong dependence between cortical bone elasticity at the millimetre-scale (mesoscale) and cortical porosity has been evidenced by previous studies. However, bone is an anisotropic composite material made by mineral, proteins and water assembled in a hierarchical structure. Whether the variations of structural and compositional properties of bone affect the different elastic coefficients at the mesoscale is not clear. Aiming to understand the relationships between bone elastic properties and compositions and microstructure, we applied state-of-the-art experimental modalities to assess these aspects of bone characteristics. All elastic coefficients (stiffness tensor of the transverse isotropic bone material), structure of the vascular pore network, collagen and mineral properties were measured in 52 specimens from the femoral diaphysis of 26 elderly donors. Statistical analyses and micromechanical modeling showed that vascular pore volume fraction and the degree of mineralization of bone are the most important determinants of cortical bone anisotropic mesoscopic elasticity. Though significant correlations were observed between collagen properties and elasticity, their effects in bone mesoscopic elasticity were minor in our data. This work also provides a unique set of data exhibiting a range of variations of compositional and microstructural cortical bone properties in the elderly and gives strong experimental evidence and basis for further development of biomechanical models for human cortical bone. STATEMENT OF SIGNIFICANCE: This study reports the relationships between microstructure, composition and the mesoscale anisotropic elastic properties of human femoral cortical bone in elderly. For the first time, we provide data covering the complete anisotropic elastic tensor, the microstructure of cortical vascular porosity, mineral and collagen characteristics obtained from the same or adjacent samples in each donor. The results revealed that cortical vascular porosity and degree of mineralization of bone are the most important determinants of bone anisotropic stiffness at the mesoscale. The presented data gives strong experimental evidence and basis for further development of biomechanical models for human cortical bone.

Ex vivo cortical porosity and thickness predictions at the tibia using full-spectrum ultrasonic guided-wave analysis.

The estimation of cortical thickness (Ct.Th) and porosity (Ct.Po) at the tibia using axial transmission ultrasound was successfully validated ex vivo against site-matched micro-computed tomography. The assessment of cortical parameters based on full-spectrum guided-wave analysis might improve the prediction of bone fractures in a cost-effective and radiation-free manner. PURPOSE: Cortical thickness (Ct.Th) and porosity (Ct.Po) are key parameters for the identification of patients with fragile bones. The main objective of this ex vivo study was to validate the measurement of Ct.Po and Ct.Th at the tibia using a non-ionizing, low-cost, and portable 500-kHz ultrasound axial transmission system. Additional ultrasonic velocities and site-matched reference parameters were included in the study to broaden the analysis. METHODS: Guided waves were successfully measured ex vivo in 17 human tibiae using a novel 500-kHz bi-directional axial transmission probe. Theoretical dispersion curves of a transverse isotropic free plate model with invariant matrix stiffness were fitted to the experimental dispersion curves in order to estimate Ct.Th and Ct.Po. In addition, the velocities of the first arriving signal (υFAS) and A0 mode (υA0) were measured. Reference Ct.Po, Ct.Th, and vBMD were obtained from site-matched micro-computed tomography. Scanning acoustic microscopy (SAM) provided the acoustic impedance of the axial cortical bone matrix. RESULTS: The best predictions of Ct.Po (R2 = 0.83, RMSE = 2.2%) and Ct.Th (R2 = 0.92, RMSE = 0.2 mm, one outlier excluded) were obtained from the plate model. The second best predictors of Ct.Po and Ct.Th were vBMD (R2 = 0.77, RMSE = 2.6%) and υA0 (R2 = 0.28, RMSE = 0.67 mm), respectively. CONCLUSIONS: Ct.Th and Ct.Po were accurately predicted at the human tibia ex vivo using a transverse isotropic free plate model with invariant matrix stiffness. The model-based predictions were not further enhanced when we accounted for variations in axial tissue stiffness as reflected by the acoustic impedance from SAM.

Elastic properties measurement of human enamel based on resonant ultrasound spectroscopy.

OBJECTIVES: To investigate the elastic properties of human enamel using resonant ultrasound spectroscopy (RUS). METHODS: Six rectangular parallelepiped specimens were prepared from six human third molars. For all specimens, the theoretical resonant frequencies were calculated using the Rayleigh-Ritz method, knowing the specimen mass density and dimensions, and using a priori stiffness constants. The experimental resonant frequencies were measured and extracted by RUS. Then, the optimal stiffness constants were retrieved by adjustment of the theoretical resonant frequencies to the measured ones based on the Levenberg-Marquardt method. The engineering elastic moduli, including Young's moduli, shear moduli, and Poisson's ratios, were also calculated based on the optimal stiffness constants. RESULTS: The five independent stiffness constants C11, C12, C13, C33, and C44 were 90.2 ±â€¯6.65 GPa, 34.7 ±â€¯6.90 GPa, 29.5 ±â€¯4.82 GPa, 83.5 ±â€¯8.93 GPa, and 37.0 ±â€¯10.9 GPa, respectively. Young's moduli E11 and E33, shear moduli G13 and G12, and Poisson's ratios υ12 and υ13 were 71.7 ±â€¯7.34 GPa, 69.2 ±â€¯7.32 GPa, 37.0 ±â€¯10.9 GPa, 28.1 ±â€¯4.35 GPa, 0.303 ±â€¯0.098, and 0.248 ±â€¯0.060, respectively. SIGNIFICANCE: Elastic properties are critical for developing dental materials and designing dental prostheses. The RUS method may provide more precise measurement of elastic properties of dental materials.

Dispersive Radon transform.

Dispersion results in the spreading and overlapping of the wave-packets, which often limits the capability of signal interpretation; on the other hand, such a phenomenon can also be used for structure or media evaluation. In this study, the authors propose an original dispersive Radon transform (DRT), which is formulated as integration transform along a set of dispersion curves. Multichannel dispersive signals of each individual mode can be concentrated to a well localized region in the DRT domain. The proposed DRT establishes the sparse projection of the dispersive components and provides an efficient solution for mode separation, noise filtering, and missing data reconstruction. Particularly the DRT method allows projecting the temporal signals of dispersive waves on the space of parameters of interest, which can be used to solve the inverse problem for waveguide or media property estimation. The least-square procedure and sparse scheme of the DRT are introduced. A high-resolution DRT is designed based on an iterative reweighting inversion scheme, which resembles the infinite-aperture velocity gather. The proposed method is applied by analyzing ultrasonic guided waves in plate-like structures and in a human radius specimen. The results suggest that the DRT method can significantly enhance the interpretation of dispersive signals.

In vivo ultrasound imaging of the bone cortex.

Current clinical ultrasound scanners cannot be used to image the interior morphology of bones because these scanners fail to address the complicated physics involved for exact image reconstruction. Here, we show that if the physics is properly addressed, bone cortex can be imaged using a conventional transducer array and a programmable ultrasound scanner. We provide in vivo proof for this technique by scanning the radius and tibia of two healthy volunteers and comparing the thickness of the radius bone with high-resolution peripheral x-ray computed tomography. Our method assumes a medium that is composed of different homogeneous layers with unique elastic anisotropy and ultrasonic wave-speed values. The applicable values of these layers are found by optimizing image sharpness and intensity over a range of relevant values. In the algorithm of image reconstruction we take wave refraction between the layers into account using a ray-tracing technique. The estimated values of the ultrasonic wave-speed and anisotropy in cortical bone are in agreement with ex vivo studies reported in the literature. These parameters are of interest since they were proposed as biomarkers for cortical bone quality. In this paper we discuss the physics involved with ultrasound imaging of bone and provide an algorithm to successfully image the first segment of cortical bone.

Quantification of stiffness measurement errors in resonant ultrasound spectroscopy of human cortical bone.

Resonant ultrasound spectroscopy (RUS) is the state-of-the-art method used to investigate the elastic properties of anisotropic solids. Recently, RUS was applied to measure human cortical bone, an anisotropic material with low Q-factor (20), which is challenging due to the difficulty in retrieving resonant frequencies. Determining the precision of the estimated stiffness constants is not straightforward because RUS is an indirect method involving minimizing the distance between measured and calculated resonant frequencies using a model. This work was motivated by the need to quantify the errors on stiffness constants due to different error sources in RUS, including uncertainties on the resonant frequencies and specimen dimensions and imperfect rectangular parallelepiped (RP) specimen geometry. The errors were first investigated using Monte Carlo simulations with typical uncertainty values of experimentally measured resonant frequencies and dimensions assuming a perfect RP geometry. Second, the exact specimen geometry of a set of bone specimens were recorded by synchrotron radiation micro-computed tomography. Then, a "virtual" RUS experiment is proposed to quantify the errors induced by imperfect geometry. Results show that for a bone specimen of ∼1° perpendicularity and parallelism errors, an accuracy of a few percent ( <6.2%) for all the stiffness constants and engineering moduli is achievable.

Dispersion characteristics of the flexural wave assessed using low frequency (50-150kHz) point-contact transducers: A feasibility study on bone-mimicking phantoms.

Guided waves-based techniques are currently under development for quantitative cortical bone assessment. However, the signal interpretation is challenging due to multiple mode overlapping. To overcome this limitation, dry point-contact transducers have been used at low frequencies for a selective excitation of the zeroth order anti-symmetric Lamb A0 mode, a mode whose dispersion characteristics can be used to infer the thickness of the waveguide. In this paper, our purpose was to extend the technique by combining a dry point-contact transducers approach to the SVD-enhanced 2-D Fourier transform in order to measure the dispersion characteristics of the flexural mode. The robustness of our approach is assessed on bone-mimicking phantoms covered or not with soft tissue-mimicking layer. Experiments were also performed on a bovine bone. Dispersion characteristics of measured modes were extracted using a SVD-based signal processing technique. The thickness was obtained by fitting a free plate model to experimental data. The results show that, in all studied cases, the estimated thickness values are in good agreement with the actual thickness values. From the results, we speculate that in vivo cortical thickness assessment by measuring the flexural wave using point-contact transducers is feasible. However, this assumption has to be confirmed by further in vivo studies.