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

Simulation-Based Joint Estimation of Body Deformation and Elasticity Parameters for Medical Image Analysis

Estimation of tissue stiffness is an important means of noninvasive cancer detection. Existing elasticity reconstruction methods usually depend on a dense displacement field (inferred from ultrasound or MR images) and known external forces. Many imaging modalities, however, cannot provide details within an organ and therefore cannot provide such a displacement field. Furthermore, force exertion and measurement can be difficult for some internal organs, making boundary forces another missing parameter. We propose a general method for estimating elasticity and boundary forces automatically using an iterative optimization framework, given the desired (target) output surface. During the optimization, the input model is deformed by the simulator, and an objective function based on the distance between the deformed surface and the target surface is minimized numerically. The optimization framework does not depend on a particular simulation method and is therefore suitable for different physical models. We show a positive correlation between clinical prostate cancer stage (a clinical measure of severity) and the recovered elasticity of the organ. Since the surface correspondence is established, our method also provides a non-rigid image registration, where the quality of the deformation fields is guaranteed, as they are computed using a physics-based simulation

Preoperative Systems for Computer Aided Diagnosis based on Image Registration: Applications to Breast Cancer and Atherosclerosis

Computer Aided Diagnosis (CAD) systems assist clinicians including radiologists and cardiologists to detect abnormalities and highlight conspicuous possible disease. Implementing a pre-operative CAD system contains a framework that accepts related technical as well as clinical parameters as input by analyzing the predefined method and demonstrates the prospective output. In this work we developed the Computer Aided Diagnostic System for biomedical imaging analysis of two applications on Breast Cancer and Atherosclerosis. The aim of the first CAD application is to optimize the registration strategy specifically for Breast Dynamic Infrared Imaging and to make it user-independent. Base on the fact that automated motion reduction in dynamic infrared imaging is on demand in clinical applications, since movement disarranges time-temperature series of each pixel, thus originating thermal artifacts that might bias the clinical decision. All previously proposed registration methods are feature based algorithms requiring manual intervention. We implemented and evaluated 3 different 3D time-series registration methods: 1. Linear affine, 2. Non-linear Bspline, 3. Demons applied to 12 datasets of healthy breast thermal images. The results are evaluated through normalized mutual information with average values of 0.70±0.03, 0.74±0.03 and 0.81±0.09 (out of 1) for Affine, BSpline and Demons registration, respectively, as well as breast boundary overlap and Jacobian determinant of the deformation field. The statistical analysis of the results showed that symmetric diffeomorphic Demons registration method outperforms also with the best breast alignment and non-negative Jacobian values which guarantee image similarity and anatomical consistency of the transformation, due to homologous forces enforcing the pixel geometric disparities to be shortened on all the frames. We propose Demons registration as an effective technique for time-series dynamic infrared registration, to stabilize the local temperature oscillation. The aim of the second implemented CAD application is to assess contribution of calcification in plaque vulnerability and wall rupture and to find its maximum resistance before break in image-based models of carotid artery stenting. The role of calcification inside fibroatheroma during carotid artery stenting operation is controversial in which cardiologists face two major problems during the placement: (i) “plaque protrusion” (i.e. elastic fibrous caps containing early calcifications that penetrate inside the stent); (ii) “plaque vulnerability” (i.e. stiff plaques with advanced calcifications that break the arterial wall or stent). Finite Element Analysis was used to simulate the balloon and stent expansion as a preoperative patient-specific virtual framework. A nonlinear static structural analysis was performed on 20 patients acquired using in vivo MDCT angiography. The Agatston Calcium score was obtained for each patient and subject-specific local Elastic Modulus (EM) was calculated. The in silico results showed that by imposing average ultimate external load of 1.1MPa and 2.3MPa on balloon and stent respectively, average ultimate stress of 55.7±41.2kPa and 171±41.2kPa are obtained on calcifications. The study reveals that a significant positive correlation (R=0.85, p<0.0001) exists on stent expansion between EM of calcification and ultimate stress as well as Plaque Wall Stress (PWS) (R=0.92, p<0.0001), comparing to Ca score that showed insignificant associations with ultimate stress (R=0.44, p=0.057) and PWS (R=0.38, p=0.103), suggesting minor impact of Ca score in plaque rupture. These average data are in good agreement with results obtained by other research groups and we believe this approach enriches the arsenal of tools available for pre-operative prediction of carotid artery stenting procedure in the presence of calcified plaques

A Three-Dimensional Computational Model of Collagen Network Mechanics

Extracellular matrix (ECM) strongly influences cellular behaviors, including cell proliferation, adhesion, and particularly migration. In cancer, the rigidity of the stromal collagen environment is thought to control tumor aggressiveness, and collagen alignment has been linked to tumor cell invasion. While the mechanical properties of collagen at both the single fiber scale and the bulk gel scale are quite well studied, how the fiber network responds to local stress or deformation, both structurally and mechanically, is poorly understood. This intermediate scale knowledge is important to understanding cell- ECM interactions and is the focus of this study. We have developed a three-dimensional elastic collagen fiber network model (bead-and-spring model) and studied fiber network behaviors for various biophysical conditions: collagen density, crosslinker strength, crosslinker density, and fiber orientation (random vs. prealigned). We found the best-fit crosslinker parameter values using shear simulation tests in a small strain region. Using this calibrated collagen model, we simulated both shear and tensile tests in a large linear strain region for different network geometry conditions. The results suggest that network geometry is a key determinant of the mechanical properties of the fiber network. We further demonstrated how the fiber network structure and mechanics evolves with a local formation, mimicking the effect of pulling by a pseudopod during cell migration. Our computational fiber network model is a step toward a full biomechanical model of cellular behaviors in various ECM conditions

Exploiting Mechanics-Based Priors for Lateral Displacement Estimation in Ultrasound Elastography

Tracking the displacement between the pre- and post-deformed radio-frequency (RF) frames is a pivotal step of ultrasound elastography, which depicts tissue mechanical properties to identify pathologies. Due to ultrasound's poor ability to capture information pertaining to the lateral direction, the existing displacement estimation techniques fail to generate an accurate lateral displacement or strain map. The attempts made in the literature to mitigate this well-known issue suffer from one of the following limitations: 1) Sampling size is substantially increased, rendering the method computationally and memory expensive. 2) The lateral displacement estimation entirely depends on the axial one, ignoring data fidelity and creating large errors. This paper proposes exploiting the effective Poisson's ratio (EPR)-based mechanical correspondence between the axial and lateral strains along with the RF data fidelity and displacement continuity to improve the lateral displacement and strain estimation accuracies. We call our techniques MechSOUL (Mechanically-constrained Second-Order Ultrasound eLastography) and L1-MechSOUL (L1-norm-based MechSOUL), which optimize L2- and L1-norm-based penalty functions, respectively. Extensive validation experiments with simulated, phantom, and in vivo datasets demonstrate that MechSOUL and L1-MechSOUL's lateral strain and EPR estimation abilities are substantially superior to those of the recently-published elastography techniques. We have published the MATLAB codes of MechSOUL and L1-MechSOUL at http://code.sonography.ai.Comment: Link to the Supplemental Video: https://drive.google.com/file/d/1uOmt-T4i9MwR98jUoMsu-eOhQ2mgjrBd/view?usp=sharin

An Enhanced Method for Full-Inversion-Based Ultrasound Elastography of The Liver

Similar to many other types of cancer, liver cancer is associated with biological changes that lead to tissue stiffening. An effective imaging technique that can be used for liver cancer detection through visualizing tissue stiffness is ultrasound elastography. In this thesis, we show the effectiveness of an enhanced method of tissue motion tracking used in quasi-static ultrasound elastography for liver cancer assessment compared to other state of the art methods. The method utilizes initial estimates of axial and lateral displacement fields obtained using conventional time delay estimation (TDE) methods in conjunction with a recently proposed strain refinement algorithm to generate enhanced versions of the axial and lateral strain images. Another primary objective of this work is to investigate the sensitivity of the proposed method to the quality of these initial displacement estimates. The proposed algorithm is founded on the tissue mechanics principles of incompressibility and strain compatibility. Tissue strain images can serve as input for full-inversion-based elasticity image reconstruction algorithm. In this work, we applied strain images generated by the proposed method in conjunction with an iterative elasticity reconstruction algorithm for full-inversion-based liver elastography. Moreover, a set of in-silico experiments were conducted to validate the assumptions used in the reconstruction technique to improve the realism of the method. Ultrasound RF data collected from a tissue-mimicking phantom and from four liver cancer patients who underwent open surgical RF thermal ablation therapy were used to evaluate the proposed method. The results showed that the proposed method produces superior results to other state of the art methods. Moreover, while there is some sensitivity to the displacement field initial estimates, overall, the proposed method is robust to the quality of the initial estimates

An Enhanced Method for Full-Inversion-Based Ultrasound Elastography of The Liver

Similar to many other types of cancer, liver cancer is associated with biological changes that lead to tissue stiffening. An effective imaging technique that can be used for liver cancer detection through visualizing tissue stiffness is ultrasound elastography. In this thesis, we show the effectiveness of an enhanced method of tissue motion tracking used in quasi-static ultrasound elastography for liver cancer assessment compared to other state of the art methods. The method utilizes initial estimates of axial and lateral displacement fields obtained using conventional time delay estimation (TDE) methods in conjunction with a recently proposed strain refinement algorithm to generate enhanced versions of the axial and lateral strain images. Another primary objective of this work is to investigate the sensitivity of the proposed method to the quality of these initial displacement estimates. The proposed algorithm is founded on the tissue mechanics principles of incompressibility and strain compatibility. Tissue strain images can serve as input for full-inversion-based elasticity image reconstruction algorithm. In this work, we applied strain images generated by the proposed method in conjunction with an iterative elasticity reconstruction algorithm for full-inversion-based liver elastography. Moreover, a set of in-silico experiments were conducted to validate the assumptions used in the reconstruction technique to improve the realism of the method. Ultrasound RF data collected from a tissue-mimicking phantom and from four liver cancer patients who underwent open surgical RF thermal ablation therapy were used to evaluate the proposed method. The results showed that the proposed method produces superior results to other state of the art methods. Moreover, while there is some sensitivity to the displacement field initial estimates, overall, the proposed method is robust to the quality of the initial estimates

Data-driven patient-specific breast modeling: a simple, automatized, and robust computational pipeline

Background: Breast-conserving surgery is the most acceptable option for breast cancer removal from an invasive and psychological point of view. During the surgical procedure, the imaging acquisition using Magnetic Image Resonance is performed in the prone configuration, while the surgery is achieved in the supine stance. Thus, a considerable movement of the breast between the two poses drives the tumor to move, complicating the surgeon's task. Therefore, to keep track of the lesion, the surgeon employs ultrasound imaging to mark the tumor with a metallic harpoon or radioactive tags. This procedure, in addition to an invasive characteristic, is a supplemental source of uncertainty. Consequently, developing a numerical method to predict the tumor movement between the imaging and intra-operative configuration is of significant interest. Methods: In this work, a simulation pipeline allowing the prediction of patient-specific breast tumor movement was put forward, including personalized preoperative surgical drawings. Through image segmentation, a subject-specific finite element biomechanical model is obtained. By first computing an undeformed state of the breast (equivalent to a nullified gravity), the estimated intra-operative configuration is then evaluated using our developed registration methods. Finally, the model is calibrated using a surface acquisition in the intra-operative stance to minimize the prediction error. Findings: The capabilities of our breast biomechanical model to reproduce real breast deformations were evaluated. To this extent, the estimated geometry of the supine breast configuration was computed using a corotational elastic material model formulation. The subject-specific mechanical properties of the breast and skin were assessed, to get the best estimates of the prone configuration. The final results are a Mean Absolute Error of 4.00 mm for the mechanical parameters E_breast = 0.32 kPa and E_skin = 22.72 kPa. The optimized mechanical parameters are congruent with the recent state-of-the-art. The simulation (including finding the undeformed and prone configuration) takes less than 20 s. The Covariance Matrix Adaptation Evolution Strategy optimizer converges on average between 15 to 100 iterations depending on the initial parameters for a total time comprised between 5 to 30 min. To our knowledge, our model offers one of the best compromises between accuracy and speed. The model could be effortlessly enriched through our recent work to facilitate the use of complex material models by only describing the strain density energy function of the material. In a second study, we developed a second breast model aiming at mapping a generic model embedding breast-conserving surgical drawing to any patient. We demonstrated the clinical applications of such a model in a real-case scenario, offering a relevant education tool for an inexperienced surgeon