The relationships among vascular geometry, hemodynamics, and plaque development in the coronary arteries are complex and not yet well understood. This paper reports a methodology for the quantitative analysis of in vivo coronary morphology and hemodynamics, with particular emphasis placed on the critical issues of image segmentation and the automated classification of disease severity. We were motivated by the observation that plaque more often developed at the inner curvature of a vessel, presumably due to the relatively lower wall shear stress at these locations. The presented studies are based on our validated methodology for the three-dimensional fusion of intravascular ultrasound (IVUS) and X-ray angiography, introducing a novel approach for IVUS segmentation that incorporates a robust, knowledge-based cost function and a fully optimal, threedimensional segmentation algorithm. Our first study shows that circumferential plaque distribution depends on local vessel curvature in the majority of vessels. The second study analyzes the correlation between plaque distribution and wall shear stress in a set of 48 in vivo vessel segments. The results were conclusive for both studies, with a stronger correlation of circumferential plaque thickness with local curvature than with wall shear stress. The inverse relationship between local wall shear stress and plaque thickness was significantly more pronounced (p < 0.025) in vessel cross sections exhibiting compensatory enlargement (positive remodeling) without luminal narrowing than when the full spectrum of disease severity was considered. The inverse relationship was no longer observed in vessels where less than 35% of vessel cross sections remained without luminal narrowing. The findings of this study confirm, in vivo, the hypothesis that relatively lower wall shear stress is associated with early plaque development.

Tissue engineered heart valves (TEHV) have been observed to respond to mechanical conditioning in vitro by expression of activated myofibroblast phenotypes followed by improvements in tissue maturation. In separate studies, cyclic flexure, stretch, and flow (FSF) have been demonstrated to exhibit both independent and coupled stimulatory effects. Synthesis of these observations into a rational framework for TEHV mechanical conditioning has been limited, however, due to the functional complexity of trileaflet valves and the inherent differences of separate bioreactor systems. Toward quantifying the effects of individual mechanical stimuli similar to those that occur during normal valve function, a novel bioreactor was developed in which FSF mechanical stimuli can be applied to engineered heart valve tissues independently or in combination. The FSF bioreactor consists of two identically equipped chambers, each having the capacity to hold up to 12 rectangular tissue specimens (25 × 7.5 × 1 mm) via a novel "spiralbound" technique. Specimens can be subjected to changes-in-curvature up to 50 mm −1 and uniaxial tensile strains up to 75%. Steady laminar flow can be applied by a magnetically coupled paddlewheel system. Computational fluid dynamic (CFD) simulations were conducted and experimentally validated by particle image velocimetry (PIV). Tissue specimen wall shear stress profiles were predicted as a function of paddlewheel speed, culture medium viscosity, and the quasi-static state of specimen deformation (i.e., either undeformed or completely flexed). Velocity profiles predicted by 2D CFD simulations of the paddlewheel mechanism compared well with PIV measurements, and were used to determine boundary conditions in localized 3D simulations. For undeformed specimens, predicted inter-specimen variations in wall shear stress were on average ±7%, with an average wall shear stress of 1.145 dyne/cm 2 predicted at a paddlewheel speed of 2000 rpm and standard culture conditions. In contrast, while the average wall shear stress predicted for specimens in the quasi-static flexed state was ~59% higher (1.821 dyne/cm 2 ), flexed specimens exhibited a broad intra-specimen wall shear stress distribution between the convex and concave sides that correlated with specimen curvature, with peak wall shear stresses of ~10 dyne/ cm 2 . This result suggests that by utilizing simple flexed geometric configurations, the present system can also be used to study the effects of spatially varying shear stresses. We conclude that the present design provides a robust tool for the study of mechanical stimuli on in vitro engineered heart valve tissue formation.

Elastic characteristics of the pig, sheep and cow vocal folds were investigated through a series of in vitro experiments. Sample strips of the vocal fold tissue were dissected from pig, sheep and cow vocal folds and mounted inside a saline-filled ergometer chamber that was maintained at 37°C ± 1°C. Sinusoidal elongation was applied on the samples to obtain the passive force measurements. Force and elongation data from the samples were recorded electronically with a dual-servo system (ergometer). Stress-Strain data were compared to characterize the interspecies differences in the elastic properties of vocal folds. Pig vocal folds exhibited the most nonlinear stress-strain relationship, indicating the presence of a high level of collagen fibers. Cow vocal folds had the highest Young's modulus, but the tissue displayed a nearly linear stress-strain profile. Previous studies of phonation in these three species have indicated that pig larynges have the highest range of phonation frequencies, making them a good candidate for animal studies. The current study provides quantitative data for the elastic properties of the oscillating laryngeal tissue in these species and indicates that nonlinear behavior of these tissues may lead to wider oscillation ranges.

A computational fluid dynamic (CFD) analysis is pre sented to describe local flow dynamics in both 3-D spatial and 4-D spatial and temporal domains from reconstructions of intravascular ultrasound (IVUS) and bi-plane angiographic fusion images. A left anterior descending (LAD) coronary artery segment geometry was accurately reconstructed and subsequently its motion was incorporated into the CFD model. The results indicate that the incorporation of motion had appreciable effects on blood flow patterns. The velocity profiles in the region of a stenosis and the circumferential distribution of the axial wall shear stress (WSS) patterns in the vessel are altered with the wall motion introduced in the simulation. The time-averaged axial WSS between simulations of steady flow and unsteady flow without arterial motion were comparable (-0.3 to 13.7 Pa in unsteady flow versus -0.2 to 10.1 Pa in steady flow) while the magnitudes decreased when motion was introduced (0.3-4.5 Pa). The arterial wall motion affects the time-mean WSS and the oscillatory shear index in the coronary vessel fluid dynamics and may provide more realistic predictions on the progression of atherosclerotic disease.

SUMMARYThere are numerous examples of fluid-structure interactions (FSIs) within the human body. In all cases, a computer model capable of simulating the phenomenon can aid in the understanding of organ function, failure, and implant design or improvement. In the current paper, two approaches are examined for use in simulating the FSI problem of the dynamics of tissue heart valves. Valve leaflets have nonlinear anisotropic material properties, and undergo complex deformation. Their motion affects-and is affected by-the surrounding blood. This two-way coupling necessitates a robust algorithm in order to overcome numerical stiffness, convergence challenges, and stability issues. A locally refined Cartesian mesh, sharp interface method has been developed for the fluid flow solution. In the structural domain, the valve leaflet is represented in a Lagrangian fashion and moves based on its experimentally determined material properties. In computing leaflet motion, the anisotropic, nonlinear material properties of the valve leaflet are incorporated using a finite element solver, which calculates the leaflet deformation and stresses based on the stress imparted by the surrounding fluid. Two FSI algorithms have been studied in the context of a sharp-interface Cartesian grid setting, and each has been validated with benchmark results. The two approaches are compared, and ultimately one is selected as most appropriate for simulating tissue heart valves. In the selected approach, a strongly coupled, partitioned method is used in which subiterations of the fluid and structure solutions are performed at each time step. During the subiterations, the leaflet motion is used as a boundary condition on the fluid, and the fluid stresses act as a boundary condition on the leaflet. In this way, continuity is ensured and two-way coupling is achieved. The selected approach has overcome the challenges faced by previous simulations reported in the literature, and a robust FSI solution is achieved using physiologic Reynolds numbers, realistic material properties, highly resolved grids, and a dynamic simulation. This approach has the advantage of handling both thin and volumetric embedded objects in a unified fashion, and of treating rigid and deformable structures in the same way, thus allowing a spectrum of potential applications.

Highly resolved three-dimensional (3D) fluid structure interaction (FSI) simulation using patient-specific echocardiographic data can be a powerful tool for accurately and thoroughly elucidating the biomechanics of mitral valve (MV) function and left ventricular (LV) fluid dynamics. We developed and validated a strongly coupled FSI algorithm to fully characterize the LV flow field during diastolic MV opening under physiologic conditions. Our model revealed that distinct MV deformation and LV flow patterns developed during different diastolic stages. A vortex ring that strongly depended on MV deformation formed during early diastole. At peak E wave, the MV fully opened, with a local Reynolds number of ~5500, indicating that the flow was in the laminar-turbulent transitional regime. Our results  showed that during diastasis, the vortex structures caused the MV leaflets to converge, thus increasing mitral jet’s velocity. The vortex ring became asymmetrical, with the vortex structures on the anterior side being larger than on the posterior side. During the late diastolic stages, the flow structures advected toward the LV outflow tract, enhancing fluid transport to the aorta. This 3D-FSI study demonstrated the importance of leaflet dynamics, their effect on the vortex ring, and their influence on MV function and fluid transport within the LV during diastole.

Over 90% of cancer deaths result not from primary tumor development, but from metastatic tumors that arise after cancer cells circulate to distal sites via the circulatory system. While it is known that metastasis is an inefficient process, the effect of hemodynamic parameters such as fluid shear stress (FSS) on the viability and efficacy of metastasis is not well understood. Recent work has shown that select cancer cells may be able to survive and possibly even adapt to FSS in vitro. The current research seeks to characterize the effect of FSS on the mechanical properties of suspended cancer cells in vitro. Nontransformed prostate epithelial cells (PrEC LH) and transformed prostate cancer cells (PC-3) were used in this study. The Young’s modulus was determined using micropipette aspiration. We examined cells in suspension but not exposed to FSS (unsheared) and immediately after exposure to high (6,400 dyn/cm2) and low (510 dyn/cm2) FSS. The PrEC LH cells were ~140% stiffer than the PC-3 cells not exposed to FSS. Post-FSS exposure, there was an increase of ~77% in Young’s modulus after exposure to high FSS and a ~47% increase in Young’s modulus after exposure to low FSS for the PC-3 cells. There was no significant change in the Young’s modulus of PrEC LH cells post-FSS exposure. Our findings indicate that cancer cells adapt to FSS, with an increased Young’s modulus being one of the adaptive responses, and that this adaptation is specific only to PC-3 cells and is not seen in PrEC LH cells. Moreover, this adaptation appears to be graded in response to the magnitude of FSS experienced by the cancer cells. This is the first study investigating the effect of FSS on the mechanical properties of cancer cells in suspension, and may provide significant insights into the mechanism by which some select cancer cells may survive in the circulation, ultimately leading to metastasis at distal sites. Our findings suggest that biomechanical analysis of cancer cells could aid in identifying and diagnosing cancer in the future.

Background Aortic diseases, including aortic aneurysms, are the 12th leading cause of death in the United States. The incidence of descending thoracic aortic aneurysms is estimated at 10.4 per 100,000 patient-years. Growing evidence suggests that stress measurements derived from structural analysis of aortic geometries predict clinical outcomes better than diameter alone. Methods Twenty-five patients undergoing clinical and radiologic surveillance for thoracic aortic aneurysms were retrospectively identified. Custom MATLAB algorithms were employed to extract aortic wall and intraluminal thrombus geometry from computed tomography angiography scans. The resulting reconstructions were loaded with 120 mm Hg of pressure using finite element analysis. Relationships among peak wall stress, aneurysm growth, and clinical outcome were examined. Results The average patient age was 71.6 ± 10.0 years, and average follow-up time was 17.5 ± 9 months (range, 6 to 43). The mean initial aneurysm diameter was 47.8 ± 8.0 mm, and the final diameter was 52.1 ± 10.0 mm. Mean aneurysm growth rate was 2.9 ± 2.4 mm per year. A stronger correlation (r = 0.894) was found between peak wall stress and aneurysm growth rate than between maximal aortic diameter and growth rate (r = 0.531). Aneurysms undergoing surgical intervention had higher peak wall stresses than aneurysms undergoing continued surveillance (300 ± 75 kPa versus 229 ± 47 kPa, p = 0.01). Conclusions Computational peak wall stress in thoracic aortic aneurysms was found to be strongly correlated with aneurysm expansion rate. Aneurysms requiring surgical intervention had significantly higher peak wall stresses. Peak wall stress may better predict clinical outcome than maximal aneurysmal diameter, and therefore may guide clinical decision-making.