Search

SUMMARY Structural heterogeneity is a hallmark of living cells that drives local mechanical properties and dynamic cellular responses. However, the robust quantification of intracellular mechanics is lacking from conventional methods. Here, we describe the development of deformation microscopy, which leverages conventional imaging and an automated hyperelastic warping algorithm to investigate strain history, deformation dynamics, and changes in structural heterogeneity within the interior of cells and cell nuclei. Using deformation microscopy, we found that partial or complete disruption of LINC complexes in cardiomyocytes in vitro and lamin A/C deficiency in myocytes in vivo abrogate dominant tensile loading in the nuclear interior. We also found that cells cultured on stiff substrates or in hyperosmotic conditions displayed abnormal strain burden and asymmetries at interchromatin regions, which are associated with active transcription. Deformation microscopy represents a foundational approach toward intracellular elastography, with the potential utility to provide mechanistic and quantitative insights in diverse mechanobiological applications., Graphical Abstract, In Brief Ghosh et al. show that deformation microscopy, a technique based on image analysis and mechanics, reveals deformation dynamics and structural heterogeneity changes for several applications and at multiple scales, including tissues, cells, and nuclei. They reveal how the disruption of nuclear proteins and pathological conditions abrogate mechanical strain in the nuclear interior.

In several nuclear cardiac imaging applications (SPECT and PET), images are formed by reconstructing tomographic data using an iterative reconstruction algorithm with corrections for physical factors involved in the imaging detection process and with corrections for cardiac and respiratory motion. The physical factors are modeled as coefficients in the matrix of a system of linear equations and include attenuation, scatter, and spatially varying geometric response. The solution to the tomographic problem involves solving the inverse of this system matrix. This requires the design of an iterative reconstruction algorithm with a statistical model that best fits the data acquisition. The most appropriate model is based on a Poisson distribution. Using Bayes Theorem, an iterative reconstruction algorithm is designed to determine the maximum a posteriori estimate of the reconstructed image with constraints that maximizes the Bayesian likelihood function for the Poisson statistical model. The a priori distribution is formulated as the joint entropy (JE) to measure the similarity between the gated cardiac PET image and the cardiac MRI cine image modeled as a FE mechanical model. The developed algorithm shows the potential of using a FE mechanical model of the heart derived from a cardiac MRI cine scan to constrain solutions of gated cardiac PET images.

The Living Heart Model (LHM) was developed as part of the Living Heart Project by Dassault Systemes to provide a numerical finite element (FE) model of the human heart that accurately reproduces the normal cardiac physiology. We previously incorporated the LHM into the 4D extended cardiac-torso (XCAT) phantom for imaging research, rigidly transforming the model to fit it within different anatomies. This captured the variation in the overall size, position, and orientation of the heart but did not capture more subtle geometrical changes. Anatomic measurements of normal heart structures can show standard deviation variations of upwards of 25-30%. In this work, we investigate the use of Hyperelastic Warping to non-rigidly fit the LHM to new anatomies based on 4D CT data from anatomically diverse, normal patients. For each patient target, the mid-diastolic frame from the CT (heart is most relaxed) was segmented to define the cardiac chambers. The geometry of the LHM was then altered to match the targets using Hyperelastic Warping to register the LHM mesh, in its relaxed state, to each segmented dataset. The altered meshes were imported back into the FE software to simulate cardiac motion from the new geometries to incorporate into the XCAT phantom. By preserving the underlying LHM architecture, our work shows that Hyperelastic Warping allows for efficient revision of the LHM geometry. This method can produce a diverse collection of heart models, with added interior variability, to incorporate into the XCAT phantom to investigate 4D imaging methods used to diagnose and treat cardiac disease.

The 4-D extended cardiac-torso (XCAT) phantom has provided a valuable tool to study the effects of anatomy and motion on medical images, especially cardiac motion. One limitation of the XCAT was that it did not have a physiological basis which to realistically simulate variations in cardiac function. In this paper, we incorporate into the XCAT anatomy the four-chamber finite element (FE) living heart model (LHM) developed by the living heart project. The LHM represents the state of the art in cardiac FE simulation because of its ability to accurately replicate the biomechanical motion of the entire heart and its variations. We create a new series of 4-D phantoms capable of simulating patients with varying body sizes and shapes; cardiac positions, orientations, and dynamics. While extendable to other imaging modalities and technologies, our goal is to use the FE-enhanced XCAT models to investigate the optimal use of computed tomography for the evaluation of coronary artery disease. With the ability to simulate realistic, predictive, patient quality 4-D imaging data, the enhanced XCAT models will enable optimization studies to identify the most promising systems or system parameters for further clinical validation.

Structural heterogeneity is a hallmark of living cells and nuclei that drives local mechanical properties and dynamic cellular responses, including adhesion, gene expression, and differentiation. However, robust quantification of intracellular or intranuclear mechanics are lacking from conventional methods. Here, we describe new development of deformation microscopy that leverages conventional imaging and an automated hyperelastic warping algorithm to investigate strain history, deformation dynamics, and changes in structural heterogeneity within the interior of cells and nuclei. Using deformation microscopy, we found that tensile loading modes dominated intranuclear architectural dynamics in cardiomyocytes in vitro or myocytes in vivo, which was compromised by disruption of LINC complex molecule nesprin-3 or Lamin A/C, respectively. We also found that cells cultured on stiff substrates or in hyperosmotic conditions displayed abnormal strain burden and asymmetries compared to controls at interchromatin regions where active translation was expected. Deformation microscopy represents a foundational approach toward intracellular elastography, with potential utility to provide new mechanistic and quantitative insights in diverse mechanobiological applications.

Nuclear structure and mechanics play a critical role in diverse cellular functions, such as organizing direct access of chromatin to transcriptional regulators. Here, we use a new, to our knowledge, hybrid method, based on microscopy and hyperelastic warping, to determine three-dimensional strain distributions inside the nuclei of single living cells embedded within their native extracellular matrix. During physiologically relevant mechanical loading to tissue samples, strain was transferred to individual nuclei, resulting in submicron distributions of displacements, with compressive and tensile strain patterns approaching a fivefold magnitude increase in some locations compared to tissue-scale stimuli. Moreover, nascent RNA synthesis was observed in the interchromatin regions of the cells studied and spatially corresponded to strain patterns. Our ability to measure large strains in the interchromatin space, which reveals that movement of chromatin in the nucleus may not be due to random or biochemical mechanisms alone, but may result from the transfer of mechanical force applied at a distant tissue surface.

Biological tissues have a complex hierarchical architecture that spans organ to subcellular scales and comprises interconnected biophysical and biochemical machinery. Mechanotransduction, gene regulation, gene protection, and structure-function relationships in tissues depend on how force and strain are modulated from macro to micro scales, and vice versa. Traditionally, computational and experimental techniques have been used in common model systems (e.g., embryos) and simple strain measures were applied. But the hierarchical transfer of mechanical parameters like strain in mammalian systems is largely unexplored in vivo. Here, we experimentally probed complex strain transfer processes in mammalian skeletal muscle tissue over multiple biological scales using complementary in vivo ultrasound and optical imaging approaches. An iterative hyperelastic warping technique quantified the spatially-dependent strain distributions in tissue, matrix, and subcellular (nuclear) structures, and revealed a surprising increase in strain magnitude and heterogeneity in active muscle as the spatial scale also increased. The multiscale strain heterogeneity indicates tight regulation of mechanical signals to the nuclei of individual cells in active muscle, and an emergent behavior appearing at larger (e.g. tissue) scales characterized by dramatically increased strain complexity.

Purpose: The authors previously introduced a methodology to generate a realistic three-dimensional (3D), high-resolution, computer-simulated breast phantom based on empirical data. One of the key components of such a phantom is that it provides a means to produce a realistic simulation of clinical breast compression. In the current study, they have evaluated a finite element (FE) model of compression and have demonstrated the effect of a variety of mechanical properties on the model using a dense mesh generated from empirical breast data. While several groups have demonstrated an effective compression simulation with lower density finite element meshes, the presented study offers a mesh density that is able to model the morphology of the inner breast structures more realistically than lower density meshes. This approach may prove beneficial for multimodality breast imaging research, since it provides a high level of anatomical detail throughout the simulation study. Methods: In this paper, the authors describe methods to improve the high-resolution performance of a FE compression model. In order to create the compressible breast phantom, dedicated breast CT data was segmented and a mesh was generated with 4-noded tetrahedral elements. Using an explicit FE solver to simulate breast compression, several properties were analyzed to evaluate their effect on the compression model including: mesh density, element type, density, and stiffness of various tissue types, friction between the skin and the compression plates, and breast density. Following compression, a simulated projection was generated to demonstrate the ability of the compressible breast phantom to produce realistic simulated mammographic images. Results: Small alterations in the properties of the breast model can change the final distribution of the tissue under compression by more than 1 cm; which ultimately results in different representations of the breast model in the simulated images. The model properties that impact displacement the most are mesh density, friction between the skin and the plates, and the relative stiffness of the different tissue types. Conclusions: The authors have developed a 3D, FE breast model that can yield high spatial resolution breast deformations under uniaxial compression for imaging research purposes and demonstrated that small changes in the mechanical properties can affect images generated using the phantom.

The objective of this research was to assess applicability of a technique known as hyperelastic warping for the measurement of local strains in the left ventricle (LV) directly from microPET image data sets. The technique uses differences in image intensities between template (reference) and target (loaded) image data sets to generate a body force that deforms a finite element (FE) representation of the template so that it registers with the target images. For validation, the template image was defined as the end-systolic microPET image data set from a Wistar Kyoto (WKY) rat. The target image was created by mapping the template image using the deformation results obtained from a FE model of diastolic filling. Regression analysis revealed highly significant correlations between the simulated forward FE solution and image derived warping predictions for fiber stretch (R 2 = 0.96), circumferential strain (R 2 = 0.96), radial strain (R 2 = 0.93), and longitudinal strain (R 2 = 0.76) (p

Ligament function and propensity for injury are directly related to regional stresses and strains. However, noninvasive techniques for measurement of strain are currently limited. This study validated the use of Hyperelastic Warping, a deformable image registration technique, for noninvasive strain measurement in the human medial collateral ligament using direct comparisons with optical measurements. Hyperelastic Warping determines the deformation map that aligns consecutive images of a deforming material, allowing calculation of strain. Diffeomorphic deformations are ensured by representing the deformable image as a hyperelastic material. Ten cadaveric knees were subjected to six loading scenarios each. Tissue deformation was documented with magnetic resonance imaging (MRI) and video-based experimental measurements. MRI datasets were analyzed using Hyperelastic Warping, representing the medial collateral ligament (MCL) with a hexahedral finite element (FE) model projected to a manually segmented ligament surface. The material behavior was transversely isotropic hyperelastic. Warping predictions of fiber stretch were strongly correlated with experimentally measured strains (R (2) = 0.81). Both sets of measurements were in agreement with previous ex vivo studies. Warping predictions of fiber stretch were insensitive to bulk:shear modulus ratio, fiber stiffness, and shear modulus in the range of +2.5SD to -1.0SD. Correlations degraded when the shear modulus was decreased to 2.5SD below the mean (R (2) = 0.56), and when an isotropic constitutive model was substituted for the transversely isotropic model (R (2) = 0.65). MCL strains in the transitional region near the joint line, where the material behavior and material symmetry are more complex, showed the most sensitivity to changes in shear modulus. These results demonstrate that Hyperelastic Warping requires the use of a constitutive model that reflects the material symmetry, but not subject-specific material properties for accurate strain predictions for this application. Hyperelastic Warping represents a powerful technique for noninvasive strain measurement of musculoskeletal tissues and has many advantages over other image-based strain measurement techniques.

This paper describes the process in which complex lesion geometries (specified by computer generated perfusion defects) are incorporated in the description of nonlinear finite element (FE) mechanical models used for specifying the motion of the left ventricle (LV) in the 4D extended cardiac torso (XCAT) phantom to simulate gated cardiac image data. An image interrogation process was developed to define the elements in the LV mesh as ischemic or infarcted based upon the values of sampled intensity levels of the perfusion maps. The intensity values were determined for each of the interior integration points of every element of the FE mesh. The average element intensity levels were then determined. The elements with average intensity values below a user-controlled threshold were defined as ischemic or infarcted depending upon the model being defined. For the infarction model cases, the thresholding and interrogation process were repeated in order to define a border zone (BZ) surrounding the infarction. This methodology was evaluated using perfusion maps created by the perfusion cardiac-torso (PCAT) phantom an extension of the 4D XCAT phantom. The PCAT was used to create 3D perfusion maps representing 90% occlusions at four locations (left anterior descending (LAD) segments 6 and 9, left circumflex (LCX) segment 11, right coronary artery (RCA) segment 1) in the coronary tree. The volumes and shapes of the defects defined in the FE mechanical models were compared with perfusion maps produced by the PCAT. The models were incorporated into the XCAT phantom. The ischemia models had reduced stroke volume (SV) by 18–59 ml. and ejection fraction (EF) values by 14–50% points compared to the normal models. The infarction models, had less reductions in SV and EF, 17–54 ml. and 14–45% points, respectively. The volumes of the ischemic/infarcted regions of the models were nearly identical to those volumes obtained from the perfusion images and were highly correlated (R2 = 0.99).

The assessment of regional heart wall motion (local strain) can localize ischemic myocardial disease, evaluate myocardial viability, and identify impaired cardiac function due to hypertrophic or dilated cardiomyopathies. The objectives of this research were to develop and validate a technique known as hyperelastic warping for the measurement of local strains in the left ventricle from clinical cine-magnetic resonance imaging (MRI) image datasets. The technique uses differences in image intensities between template (reference) and target (loaded) image datasets to generate a body force that deforms a finite element (FE) representation of the template so that it registers with the target image. To validate the technique, MRI image datasets representing two deformation states of a left ventricle were created such that the deformation map between the states represented in the images was known. A beginning diastolic cine-MRI image dataset from a normal human subject was defined as the template. A second image dataset (target) was created by mapping the template image using the deformation results obtained from a forward FE model of diastolic filling. Fiber stretch and strain predictions from hyperelastic warping showed good agreement with those of the forward solution (R2=0.67 stretch, R2=0.76 circumferential strain, R2=0.75 radial strain, and R2=0.70 in-plane shear). The technique had low sensitivity to changes in material parameters (ΔR2=−0.023 fiber stretch, ΔR2=−0.020 circumferential strain, ΔR2=−0.005 radial strain, and ΔR2=0.0125 shear strain with little or no change in rms error), with the exception of changes in bulk modulus of the material. The use of an isotropic hyperelastic constitutive model in the warping analyses degraded the predictions of fiber stretch. Results were unaffected by simulated noise down to a signal-to-noise ratio (SNR) of 4.0 (ΔR2=−0.032 fiber stretch, ΔR2=−0.023 circumferential strain, ΔR2=−0.04 radial strain, and ΔR2=0.0211 shear strain with little or no increase in rms error). This study demonstrates that warping in conjunction with cine-MRI imaging can be used to determine local ventricular strains during diastole.

Atherosclerotic plaque rupture is responsible for the majority of myocardial infarctions and acute coronary syndromes. Rupture is initiated by mechanical failure of the plaque cap, and thus study of the deformation of the plaque in the artery can elucidate the events that lead to myocardial infarction. Intravascular ultrasound (IVUS) provides high resolution in vitro and in vivo cross-sectional images of blood vessels. To extract the deformation field from sequences of IVUS images, a registration process must be performed to correlate material points between image pairs. The objective of this study was to determine the efficacy of an image registration technique termed Warping to determine strains in plaques and coronary arteries from paired IVUS images representing two different states of deformation. The Warping technique uses pointwise differences in pixel intensities between image pairs to generate a distributed body force that acts to deform a finite element model. The strain distribution estimated by image-based Warping showed excellent agreement with a known forward finite element solution, representing the gold standard, from which the displaced image was created. The Warping technique had a low sensitivity to changes in material parameters or material model and had a low dependency on the noise present in the images. The Warping analysis was also able to produce accurate strain distributions when the constitutive model used for the Warping analysis and the forward analysis was different. The results of this study demonstrate that Warping in conjunction with in vivo IVUS imaging will determine the change in the strain distribution resulting from physiological loading and may be useful as a diagnostic tool for predicting the likelihood of plaque rupture through the determination of the relative stiffness of the plaque constituents.

Breast imaging is an important area of research with many new techniques being investigated to further reduce the morbidity and mortality of breast cancer through early detection. Computerized phantoms can provide an essential tool to quantitatively compare new imaging systems and techniques. Current phantoms, however, lack sufficient realism in depicting the complex 3D anatomy of the breast. In this work, we created one-hundred realistic and detailed 3D computational breast phantoms based on high-resolution CT datasets from normal patients. We also developed a finiteelement application to simulate different compression states of the breast, making the phantoms applicable to multimodality imaging research. The breast phantoms and tools developed in this work were packaged into user-friendly software applications to distribute for breast imaging research.

A significant challenge in diagnosing cardiac disease is determining the viability of myocardial tissue when evaluating the prognosis of vascular bypass surgery. A finite element mechanical model of the left ventricular myocardium was developed to evaluate myocardial deformation, which is an important indicator of viable myocardial tissue. The model of the heart muscle mechanics was derived from the passive and active behavior of skeletal muscle, which is considered to be a quasi-incompressible transversely isotropic hyperelastic material of a specified helical fiber structure configuration. Contraction of the myocardium was replicated by simulating active contractions along the helical fibers, then solving (quasi-statically) for the associated boundary valued problem at a sequence of time steps between end-diastole and end-systole of the cardiac cycle. At each time step the finite element software package ABAQUS was used to determine the deformation of the left ventricle, which was loaded by intra-ventricular pressure. A cylindrical model of the left ventricle was developed under both passive loading and active contraction. Some parameters that describe the material properties of the myocardium were estimated by fitting the motion of the cylindrical model to gated SPECT and cine MRI data. Results from the finite element analysis were compared to those from a mathematical cylindrical model. In the future, more realistic meshes derived from imaging data will be used to perform the finite element analysis. The deformation of the mechanical model will be fitted to a complete strain map from tagged MRI or image warping. Finally, it is proposed to introduce electrical propagation into the finite element model.

BACKGROUND In order to identify those age-related factors in the development of coronary atherosclerosis that would affect the stability of the plaque system, we have developed idealized, finite-element, cross-sectional models of the arterial wall and associated lesions, derived from population-based data. METHODS The physical development and morphology of coronary plaques was documented in the Pathobiological Determinants of Atherosclerosis in Youth histological study. Using this database, finite-element analysis models were created for five age groups (15-19, 20-24, 25-29 and 30-34 years) and for the 25 largest lesions. Cosmos (Structural Research, Inc., Los Angeles, California, USA) was used to create and analyze the models. RESULTS The area of greatest stress shifted from the intima opposite the lesion in the 15-19 years age group to the edge of the cap and adjacent healthy tissue in the later age groups. Increasing age had a strong positive correlation with the shoulder stress level (r = 0.95) and the per cent stenosis correlated well with shoulder stress (r = 0.99, P < 0.002). Increasing the cap stiffness from a soft cap to a fibrous cap in the 30-34 year age group model resulted in a localized increase in shoulder surface stress by 10%. A calcified cap increased this shoulder surface stress by 30%. CONCLUSIONS This finite-element analysis of the population-based data shows that the increase in stress appears to be closely related to the impaired load-bearing capability of the lipid pool that develops with age. The shoulder area of the lesion has been shown to be the location of most of the plaque fractures.

The cell nucleus directs the regulation of normal cellular functions as well as the expression of proteins required for adaption to environmental changes. Mechanical forces are an important determinant of gene expression, and yet the measurement of intranuclear mechanics (e.g. strain) in cells embedded within their native tissue in situ remains a challenge.Copyright © 2013 by ASME

Myocardial disarray is a fiber distribution that deviates away from the tightly organized, parallel alignment of myocardial fibers that characterizes the normal myocardium. This coherently-organized distribution of the myofibers results in the twisting contraction of the normal left ventricle (LV). With myofiber disarray, the fibers have random directionality, either locally or globally, within the LV.

The nucleus is a regulation center for cellular gene expression 1. Mechanical forces transfer to the nucleus directly and indirectly through cellular cytoskeletal structures and pathways 2, 3. The transmitted strains often cause nuclear deformation which is thought to trigger mechanosensitive gene expression within the nucleus 4. Protein dynamics inside the nucleus are additionally important for maintaining the nuclear structure and in facilitating gene expression at the transcription level 5. Probing spatiotemporal relationships between mechanical forces and localized gene expression (i.e. biophysical and biochemical factors) in the nuclei of cells is important in order to clarify variability observed in large and heterogeneous cell populations within complex tissues. This requires the development of innovative methods for intranuclear strain measurements of cells in situ, and the further capability to quantify associated biochemical responses. This abstract describes a method combining the simultaneous measurement of newly synthesized RNA with spatiotemporal intranuclear strain mapping in single cells embedded in native tissue.Copyright © 2013 by ASME

Hypertension currently affects approximately one third the population in the United States, and represents a major economic burden on the health care system with an estimated annual direct and indirect cost of $50.6 billion [1]. In the case of systemic hypertension, the left ventricle (LV) must work against increased pressure load to pump blood to the body. Over time, this excessive work causes hypertrophy of the myocardium (thickening of the myofibers). While initially a compensatory mechanism, hypertrophy can eventually lead to heart failure (HF) [2]. Predictive modeling of the hypertrophic growth will lead to a better understanding of the disease mechanisms, which in turn has the potential to lead to better treatment strategies.

A series of models were developed in which a circulatory system model was coupled to an existing series of finite element (FE) models of the left ventricle (LV). The circulatory models were used to provide realistic boundary conditions for the LV models. This was developed for the JSim analysis package and was composed of a systemic arterial, capillary, and venous system in a closed loop with a varying elastance LV and left atria to provide the driving pressures and flows matching those of the FE model. Three coupled models were developed, a normal LV under normotensive aortic loading (116/80mm Hg), a mild hypertension (137/89mm Hg) model, and a moderate hypertension model (165/100mm Hg). The initial step in the modeling analysis was that the circulation was optimized to the enddiastolic pressure and volume values of the LV model. The cardiac FE models were then optimized to the systolic pressure/volume characteristics of the steady-state JSim circulatory model solution. Comparison of the stress predictions for the three models indicated that the mild hypertensive case produced a 21% increase in the average fiber stress levels, and the moderate hypertension case had a 36% increase in average stress. The circulatory work increased by 18% and 43% over that of the control for the mild and moderate hypertensive cases, respectively. [DOI: 10.1115/1.4023697]

The objectives of the following research were to evaluate the utility of a deformable image registration technique known as hyperelastic warping for the measurement of local strains in the left ventricle through the analysis of clinical, gated PET image datasets. Two normal human male subjects were sequentially imaged with PET and tagged MRI imaging. Strain predictions were made for systolic contraction using warping analyses of the PET images and HARP based strain analyses of the MRI images. Coefficient of determinationR2values were computed for the comparison of circumferential and radial strain predictions produced by each methodology. There was good correspondence between the methodologies, withR2values of 0.78 for the radial strains of both hearts and from anR2=0.81andR2=0.83for the circumferential strains. The strain predictions were not statistically different(P≤0.01). A series of sensitivity results indicated that the methodology was relatively insensitive to alterations in image intensity, random image noise, and alterations in fiber structure. This study demonstrated that warping was able to provide strain predictions of systolic contraction of the LV consistent with those provided by tagged MRI Warping.

International audience; Left ventricular hypertrophy induced by systemic hypertension is generally regarded a morphological precursor of unfortunate cardiovascular events. Myocardial fiber disarray has been long recognized as a prevalent hallmark of this pathology. In this chapter, ex vivo diffusion tensor magnetic resonance imaging is employed to delineate the regional loss of myocardial organization that is present in the excised heart of a spontaneously hypertensive rat, as opposed to a control. Fiber tracking results are provided that illustrate in great detail the alterations in the integrity of cardiac muscle microstructure due to the disease. A quantitative analysis is also performed. Another contribution of this chapter is the model-based assessment of the role of the myofiber disarray in modulating the mechanical properties of the myocardium. The results of this study improve our understanding of the structural remodeling mechanisms that are associated with hypetensive left ventricular hypertrophy and their role.

The authors previously introduced a methodology to generate a realistic three-dimensional (3D), high-resolution, computer-simulated breast phantom based on empirical data. One of the key components of such a phantom is that it provides a means to produce a realistic simulation of clinical breast compression. In the current study, they have evaluated a finite element (FE) model of compression and have demonstrated the effect of a variety of mechanical properties on the model using a dense mesh generated from empirical breast data. While several groups have demonstrated an effective compression simulation with lower density finite element meshes, the presented study offers a mesh density that is able to model the morphology of the inner breast structures more realistically than lower density meshes. This approach may prove beneficial for multimodality breast imaging research, since it provides a high level of anatomical detail throughout the simulation study.In this paper, the authors describe methods to improve the high-resolution performance of a FE compression model. In order to create the compressible breast phantom, dedicated breast CT data was segmented and a mesh was generated with 4-noded tetrahedral elements. Using an explicit FE solver to simulate breast compression, several properties were analyzed to evaluate their effect on the compression model including: mesh density, element type, density, and stiffness of various tissue types, friction between the skin and the compression plates, and breast density. Following compression, a simulated projection was generated to demonstrate the ability of the compressible breast phantom to produce realistic simulated mammographic images.Small alterations in the properties of the breast model can change the final distribution of the tissue under compression by more than 1 cm; which ultimately results in different representations of the breast model in the simulated images. The model properties that impact displacement the most are mesh density, friction between the skin and the plates, and the relative stiffness of the different tissue types.The authors have developed a 3D, FE breast model that can yield high spatial resolution breast deformations under uniaxial compression for imaging research purposes and demonstrated that small changes in the mechanical properties can affect images generated using the phantom.

Assessments of regional heart wall deformation (wall motion, thickening, strain) are commonly used to evaluate left ventricular wall function in the clinical setting. Nuclear based imaging modalities such as PET and SPECT are commonly used to localize ischemic myocardial disease, and can identify impairment of cardiac function due to hypertrophic or dilated cardiomyopathies. Regional wall motion analysis in conjunction with global left ventricular (LV) ejection fraction is commonly used to assess systolic and diastolic function. The quantification of ventricular strains throughout the entire cardiac cycle provides valuable information that could be used to more effectively differentiate between diastolic and systolic dysfunction, as well as a more complete picture of overall cardiac performance.Copyright © 2011 by ASME

Cardiac mechanical performance depends upon myocardial tissue elongation and contraction. Deformation, stress and strain within the myofibers provide valuable information about potential tissue adaptation [1]. Specifically, the stress state of the tissue is believed to drive remodeling of the myocardium. Because it is not possible to measure in-vivo stress in the human heart, considerable research has gone into developing patient specific, mathematical models of the heart based on finite element (FE) analysis and cardiac imaging [2, 3]. Stress estimates from these models could yield valuable information about of the material behavior of the myocardium that would provide valuable information for research into cardiac pathologies.Copyright © 2011 by ASME

The 4D NCAT and XCAT phantoms have been found useful in the simulation of medical image data especially SPECT, PET, CT and more recently MRI. The phantoms provide realistic models of the anatomical structures and respiratory and cardiac motions of humans. When combined with accurate models of the physics and instrumentation involved in the imaging process, accurate and realistic simulation data that closely mimic those acquired from patients can be obtained. However, a limitation to the 4D NCAT/XCAT series of phantoms is that the cardiac motion incorporated in the NCAT/XCAT was based on a single set of gated tagged MRI data of a particular normal male subject so that the definitions of pathologies such as ischemia and infarction in the phantoms had no physiological basis. Our previous work sought to overcome this limitation by incorporating into the phantoms, a physiologically based finite-element (FE) mechanical model for the left ventricle (LV). These model was found to accurately simulate both the normal motion of the LV as well as abnormal motions due to ischemia [1] and infarction [2]. One of the primary limitations of these models is that they have overly simplistic geometries (Figure 1) representing the ischemic or infarcted regions. In order to produce more realistic geometries of the ischemic/infarcted regions, the 4D Perfusion CArdiac-Torso (PCAT) phantom was utilized to define a low perfusion region in the LV [3]. The objective of this study was to demonstrate the ability to incorporate this perfusion information directly into an FE model of the left ventricle.

The current 3D XCAT phantom allows users to manually define the regional myocardial perfusion defect (MPD) as a simple pie-shaped wedge region with reduced activity level in the myocardium of left ventricle. To more accurately and realistically model the MPD, we have developed a new regional MPD model for the 3D XCAT phantom for myocardial perfusion SPECT (MP-SPECT) studies based on the location and the severity of the stenosis in a computer generated coronary arterial tree. First, we generated a detailed coronary arterial tree by extending the large proximal branches segmented from patient CT images to cover the whole heart using an iterative rule-based algorithm. Second, we determined the affected downstream vascular segments of a given stenosis. Third, we computed the activity of each myocardial region as a function of the inverse-distance-weighted average of the flow of the neighboring vascular segments. Fourth, we generated a series of bull’s-eye maps of MP-SPECT images of different coronary artery stenosis scenarios. Fifth, we had expert physician readers to qualitatively assess the bull’s-eye maps based on their similarity to typical clinical cases in terms of the shape, the extent, and the severity of the MPDs. Their input was used to iteratively revise the coronary artery tree model so that the MPDs were closely matched to those found in bull’s-eye maps from patient studies. Finally, from our simulated MP-SPECT images, we observed that (1) the locations of the MPDs caused by stenoses at different main arteries were different largely according to their vascular territories, (2) a stenosis at a proximal branch produced a larger MPD than the one at a distal branch, and (3) a more severe stenosis produced a larger MPD than the less severe one. These observations were consistent to those found in clinical cases. Therefore, this new regional MPD model has enhanced the generation of realistic pathological MP-SPECT images using the XCAT phantom. When combining with the mechanical model of the myocardium, the new model can be extended for the simulation of 4D gated MP-SPECT simulation of a pathological heart with both perfusion and motion defects.

A realistic 3D coronary arterial tree (CAT) has been developed for the heart model of the computer generated 3D XCAT phantom. The CAT allows generation of a realistic model of the location, size and shape of the associated regional ischemia or infarction for a given coronary arterial stenosis or occlusion. This in turn can be used in medical imaging applications. An iterative rule-based generation method that systematically utilized anatomic, morphometric and physiologic knowledge was used to construct a detailed realistic 3D model of the CAT in the XCAT phantom. The anatomic details of the myocardial surfaces and large coronary arterial vessel segments were first extracted from cardiac CT images of a normal patient with right coronary dominance. Morphometric information derived from porcine data from the literature, after being adjusted by scaling laws, provided statistically nominal diameters, lengths, and connectivity probabilities of the generated coronary arterial segments in modeling the CAT of an average human. The largest six orders of the CAT were generated based on the physiologic constraints defined in the coronary generation algorithms. When combined with the heart model of the XCAT phantom, the realistic CAT provides a unique simulation tool for the generation of realistic regional myocardial ischemia and infraction. Together with the existing heart model, the new CAT provides an important improvement over the current 3D XCAT phantom in providing a more realistic model of the normal heart and the potential to simulate myocardial diseases in evaluation of medical imaging instrumentation, image reconstruction, and data processing methods.

We previously proposed a three-dimensional computerized breast phantom that combines empirical data with the flexibility of mathematical models1. The goal of this project is to enhance the breast phantom to include a more detailed anatomy than currently visible and create additional phantoms from different breast CT data. To improve the level of detail in our existing segmentations, the breast CT data is reconstructed at a higher resolution and additional image processing techniques are used to correct for noise and scatter in the image data. A refined segmentation algorithm is used that incorporates more detail than previously defined. To further enhance high-resolution detail, mathematical models, implementing branching algorithms to extend the glandular tissue throughout the breast and to define Cooper's ligaments, are under investigation. We perform the simulation of mammography and tomosynthesis using an analytical projection algorithm that can be applied directly to the mathematical model of the breast without voxelization2. This method speeds up image acquisition, reduces voxelization artifacts, and produces higher resolution images than the previously used method. The realistic 3D computerized breast phantom will ultimately be incorporated into the 4DXCAT phantom3-5 to be used for breast imaging research.

The goal of this work is to create a detailed three-dimensional (3D) digital breast phantom based on empirical data and to incorporate it into the four-dimensional (4D) NCAT phantom, a computerized model of the human anatomy widely used in imaging research. Twenty sets of high-resolution breast CT data were used to create anatomically diverse models. The datasets were segmented using techniques developed in our laboratory and the breast structures will be defined using a combination of non-uniform rational b-splines (NURBS) and subdivision surfaces (SD). Imaging data from various modalities (x-ray and nuclear medicine) were simulated to demonstrate the utility of the new breast phantoms. As a proof of concept, a simple compression technique was used to deform the breast models while maintaining a constant volume to simulate modalities (mammography and tomosynthesis) that involve compression. Initial studies using one CT dataset indicate that the simulated breast phantom is capable of providing a realistic and flexible representation of breast tissue and can be used with different acquisition methods to test varying imaging parameters such as dose, resolution, and patient motion. The final model will have a more accurate depiction of the internal breast structures and will be scaleable in terms of size and density. Also, more realistic finite-element techniques will be used to simulate compression. With the ability to simulate realistic, predictive patient imaging data, we believe the phantom will provide a vital tool to investigate current and emerging breast imaging methods and techniques.

The objective of this study was to validate a deformable image registration technique, termed Hyperelastic Warping, for left ventricular strain measurement during systole using cine-gated, non-tagged MR images with strains measured from tagged MRI. The technique combines deformation from high resolution, non-tagged MR image data with a detailed computational model, including estimated myocardial material properties, fiber direction, and active fiber contraction, to provide a comprehensive description of myocardial contractile function. A normal volunteer (male, age 30) with no history of cardiac pathology was imaged with a 1.5 T Siemens Avanto clinical scanner using a TrueFISP imaging sequence and a 32-channel cardiac coil. Both tagged and non-tagged cine MR images were obtained. The Hyperelastic Warping solution was evolved using a series of non-tagged images in ten intermediate phases from end-diastole to end-systole. The solution may be considered as ten separate warping problems with multiple templates and targets. At each stage, an active contraction was initially applied to a finite element model, and then image-based warping penalty forces were utilized to generate the final registration. Warping results for circumferential strain (R(2)=0.75) and radial strain (R(2)=0.78) were strongly correlated with results obtained from tagged MR images analyzed with a Harmonic Phase (HARP) algorithm. Results for fiber stretch, LV twist, and transmural strain distributions were in good agreement with experimental values in the literature. In conclusion, Hyperelastic Warping provides a unique alternative for quantifying regional LV deformation during systole without the need for tags.

A search for baryonia with negative and positive strangeness decaying respectively into\(\Lambda + \bar p + pions\) and\(\bar \Lambda + p + pions\) has been carried out in a neutron beam with a mean momentum of ≅40 GeV/c in an experiment performed at the Serpukhov accelerator. There is a strong indication of the existence of these baryonia. The following four charge states are observed for negative and positive strangeness: neutral, negative, positive and doubly charged. Their mean mass is 3055±25 MeV/c2 and the width Γ≦36±15 MeV/c2. The data show that the isotopic spin of the baryonia is ≧3/2. The baryonia production cross sections in the acceptable kinematic regionXF≧0.2 andPT≦1 GeV/c times the branching ratios of the observed decays are of the order of 1 μb per nucleon.

The extraction of quantitative information regarding growth and deformation from series of image data is of significant importance in many fields of science and medicine. Imaging techniques such as MRI, CT and ultrasound provide a means to examine the morphology and in some cases metabolism of tissues. The registration of this image data between different time points after external loading, treatment, disease or other pathologies is performed using methods known as deformable image registration. The goal of deformable image registration is to find a transformation that best aligns the features of a “template” and “target” image (Fig. 12.1). In the ideal case, the quantity and quality of the image texture present in the template and target images, as well as the similarity in underlying anatomical structure, would yield a unique “best” transformation. In real problems, however, this is not the case. Deformable image registration is most often ill-posed in the sense of Hadamard [2–3]. No perfect transformation exists, and the solution depends on the choice of the cost function and associated solution methods. Deformable image registration grew primarily out of the pattern recognition field where significant effort has been devoted to the representation of image ensembles (e.g., [4–13]). The approaches that are used are usually classified as either model-based or pixel-based. Model-based approaches typically require

The accurate determination of strain in deforming biological tissues is a necessary and important part of experimental investigations in biomechanics. We have developed a method, referred to as Hyperelastic Warping, to combine medical image data with a solid mechanics analysis approach to allow estimation of tissue strains in the absence of detailed information about boundary conditions and in some cases constitutive information. The method makes use of medical image data to provide information about the deforming tissue and thus the strain and stress fields. The mathematical problem is to search through all admissible configurations for the one that minimizes the difference between a transformed template image and a target image collected experimentally. The resulting deformation map is used to determine the strain field. This technique has been applied successfully to determine strain in several biological soft tissues. This paper describes the theory, implementation and validation of the technique for measurement of transmural strains in the left ventricle.

It is well known that biological tissue adapts to changes in mechanical loading. The stress level in the myocardium is an important factor in evaluating the cardiac tissue. For example, it may be an indicator of the metabolic rate of cardiac cells. But measuring the stress level in living tissue is very difficult. The deformations of the left ventricle (LV) can be obtained from 3D tagged MRI or image warping. To calculate the stress distribution in the LV, the mechanical properties of myocardium still must be determined. In this paper, we studied the feasibility to use a finite element (FE) model of the LV to estimate the material constants for Humphrey's model of passive cardiac tissue from cine MRI data. In our simulations, the target strain-map was generated by running the forward FE model of the LV with known material constants. The target strain-map was compared with current strain-map and objective functions were defined as the discrepancies between them. Newton-Raphson's method was used to minimize the objective functions iteratively.

The cardiac model of the 4D NCAT phantom was enhanced by incorporating a physiological basis from which to realistically model left ventricular (LV) motion defects. A finite element mechanical model of the LV was developed to simulate deficits in contractile function and to study the effect of ischemia on LV function. The model geometry was based on high resolution CT and MRI data sets of a healthy male subject. The myocardial wall was represented as a transversely isotropic material with the fiber angle varying from -90 degrees at the epicardial surface, through 0 degrees at the mid-wall, to 90 degrees at the endocardial surface. An elastance active contraction model was used to provide fiber contraction. Physiological intraventricular systolic pressure-time curves were used to load the ventricle. These features were incorporated into the 4D NCAT cardiac model through the control points, which are set to move according to the principles that govern the mechanical model. A normal model and two pathologic models were created in order to study the effects of ischemia on cardiac function. In the first pathologic model, a sub-endocardial anterior ischemic region was defined and an NCAT image data set was subsequently produced. A second ischemic model was created with a transmural ischemic region defined in the same location as the sub-endocardial ischemia model. These models were able to demonstrate differences in contractile function between subendocardial and transmural infarcts and how these differences in function are documented in the SPECT images that were produced by the NCAT phantom. As demonstrated in this study the 4D NCAT cardiac model provides a valuable tool for the evaluation of imaging methods that assess cardiac function through measurements of myocardial deformation

2-D mathematical models of the coronary walls have been developed based on actual plaque morphology from a multi-center study of coronary disease (Pathological Determinants of Atherosclerosis in Youths, PDAY). The probability of lipid maps were used to define a typical lesion's physical dimensions for four age ranges. Under physiological loading from intra-arterial pressure, the resulting intramural stress distributions were quantified as a function of patient age. The area of highest stress in the 15-19 year group was shifted from the healthy wall opposite the lesion to the area where the normal intima is adjacent to the plaque cap and increased with age. The age related development of atherosclerosis leads to a predictable increase in localized wall stress, which may predispose a plaque to rupture. >

Image-based finite-element analysis of the left ventricle (LV) was used to determine the deformation and strain developed between mid-diastole and end-diastole. The algorithm used volumetric MRI data to create a body force that deforms a finite-element model of the LV in mid-diastole and tracks tissue deformation. A volumetric MRI data set corresponding to mid-diastole was designated as the reference image and an image corresponding to end-diastole was designated as the deformed image. The reference image was manually segmented and a 3D finite-element mesh was created. The warping version of the nonlinear finite-element program NIKE3D (from Lawrence Livermore National Laboratory) was used to analyze the images. Warping results of the left ventricular circumferential stretch measurements at the base and mid-ventricle were compared with direct measurements of the image data set. The warping results showed less than 3% difference between the methods.

Quantification of time-dependent changes in three-dimensional morphology of brain structures and neural pathways is a fundamental requirement in studies of neurodevelopment, remodeling and progression of neurological diseases [1]. However, local measures of this kind are extremely difficult due to a lack of clear fiducials. Our motivation to develop a reliable technique to quantify time-dependent changes in neuroanatomy originated with the problem of tracking progression of Niemann-Pick disease type C (NP-C), a heritable disease that causes alterations in brain development [2].Copyright © 2002 by ASME

This paper describes our research into the vascular mechanics of the coronary artery and plaque. The three sections describe the determination of arterial mechanical properties using intravascular ultrasound (IVUS), a constitutive relation for the arterial wall, and finite element method (FEM) models of the arterial wall and atheroma.Inflation testing of porcine left anterior descending coronary arteries was conducted. The changes in the vessel geometry were monitored using IVUS, and intracoronary pressure was recorded using a pressure transducer. The creep and quasistatic stress/strain responses were determined. A Standard Linear Solid (SLS) was modified to reproduce the non-linear elastic behavior of the arterial wall. This Standard Non-linear Solid (SNS) was implemented into an axisymetric thick-walled cylinder numerical model. Finite element analysis models were created for five age groups and four levels of stenosis using the Pathobiological Determinants of Atherosclerosis Youth (PDAY) database.The arteries exhibited non-linear elastic behavior. The total tissue creep strain was epsilon creep = 0.082 +/- 0.018 mm/mm. The numerical model could reproduce both the non-linearity of the porcine data and time dependent behavior of the arterial wall found in the literature with a correlation coefficient of 0.985. Increasing age had a strong positive correlation with the shoulder stress level, (r = 0.95). The 30% stenosis had the highest shoulder stress due to the combination of a fully formed lipid pool and a thin cap.Studying the solid mechanics of the arterial wall and the atheroma provide important insights into the mechanisms involved in plaque rupture.