Biomechanical Investigation of Disturbed Hemodynamics-Induced Tissue Degeneration in Abdominal Aortic Aneurysms Using Computational and Experimental Techniques.

Abdominal aortic aneurysm (AAA) is the dilatation of the aorta beyond 50% of the normal vessel diameter. It is reported that 4-8% of men and 0.5-1% of women above 50 years of age bear an AAA and it accounts for ~15,000 deaths per year in the United States alone. If left untreated, AAA might gradually expand until rupture; the most catastrophic complication of the aneurysmal disease that is accompanied by a striking overall mortality of 80%. The precise mechanisms leading to AAA rupture remains unclear. Therefore, characterization of disturbed hemodynamics within AAAs will help to understand the mechanobiological development of the condition which will contribute to novel therapies for the condition. Due to geometrical complexities, it is challenging to directly quantify disturbed flows for AAAs clinically. Two other approaches for this investigation are computational modeling and experimental flow measurement. In computational modeling, the problem is first defined mathematically, and the solution is approximated with numerical techniques to get characteristics of flow. In experimental flow measurement, once the setup providing physiological flow pattern in a phantom geometry is constructed, velocity measurement system such as particle image velocimetry (PIV) enables characterization of the flow. We witness increasing number of applications of these complimentary approaches for AAA investigations in recent years. In this paper, we outline the details of computational modeling procedures and experimental settings and summarize important findings from recent studies, which will help researchers for AAA investigations and rupture mechanics

Computational modeling of motile cilia generated cerebral flow dynamics in zebrafish embryo

Background: Motile cilia are hair-like microscopic structures which move the fluids along the epithelial surfaces. Cilia cover a wide range of regions in the nervous system, such as the nasal cavity, spinal cord central canal, and brain ventricles. Motile cilia-driven cerebrospinal fluid (CSF) flow in the brain ventricles has an important role in the brain development. Embryos lacking motile cilia develop neurological defects due to altered CSF flow. Aim: To investigate the effect of motile-cilia motion on the altered CSF flow, and to understand the role of CSF flow in the brain development and physiology. Methods: The dynamics of motile-cilia driven flow is analyzed employing computational fluid dynamics (CFD) modeling. A 2D model is generated using the time-lapse microscopic movies showing movements of a fluorescently labeled motile-cilia in a zebrafish embryo (48-hour post-fertilization). The effects on the generated flow are elucidated by investigating the cilia beating angle, multiple cilia formations, and the phase difference between different ciliary beats. Results: Ciliary beating generated a directional flow in the form of a circulating vortex. The angle of ciliary beating significantly affected the flow velocity. As the angle between the wall and cilia decreases, the flow becomes more efficient by achieving higher velocities. Multiple cilia formations increased the flow velocity but the significance of multiple cilia is not as critical as the beating angle. Interestingly, phase difference between the multiple cilia beats increased the directional flow velocity. Conclusion: Motile-cilia generated flow dynamics are investigated, and it is concluded that out-of-phase multiple ciliary beating is the optimum form of beating in order to generate a directional flo

Numerical Investigation of the Fetal Left Heart Hemodynamics During Gestational Stages

Flow-driven hemodynamic forces on the cardiac tissues have critical importance, and have a significant role in the proper development of the heart. These mechanobiological mechanisms govern the cellular responses for the growth and remodeling of the heart, where the altered hemodynamic environment is believed to be a major factor that is leading to congenital heart defects (CHDs). In order to investigate the mechanobiological development of the normal and diseased hearts, identification of the blood flow patterns and wall shear stresses (WSS) on these tissues are required for an accurate hemodynamic assessment. In this study, we focus on the left heart hemodynamics of the human fetuses throughout the gestational stages. Computational fetal left heart models are created for the healthy fetuses using the ultrasound images at various gestational weeks. Realistic inflow boundary conditions are implemented in the models using the Doppler ultrasound measurements for resolving the specific blood flow waveforms in the mitral valve. Obtained results indicate that WSS and vorticity levels in the fetal left heart decrease with the development of the fetus. The maximum WSS around the mitral valve is determined around 36 Pa at the gestational week of 16. This maximum WSS decreases to 11 Pa at the gestational week of 27, indicating nearly three-times reduction in the peak shear stress. These findings reveal the highly dynamic nature of the left heart hemodynamics throughout the development of the human fetus and shed light into the relevance of hemodynamic environment and development of CHDs.Qatar National Research Fun

Computational Modeling of Motile Cilia-Driven Cerebrospinal Flow in the Brain Ventricles of Zebrafish Embryo.

Motile cilia are hair-like microscopic structures which generate directional flow to provide fluid transport in various biological processes. Ciliary beating is one of the sources of cerebrospinal flow (CSF) in brain ventricles. In this study, we investigated how the tilt angle, quantity, and phase relationship of cilia affect CSF flow patterns in the brain ventricles of zebrafish embryos. For this purpose, two-dimensional computational fluid dynamics (CFD) simulations are performed to determine the flow fields generated by the motile cilia. The cilia are modeled as thin membranes with prescribed motions. The cilia motions were obtained from a two-day post-fertilization zebrafish embryo previously imaged via light sheet fluorescence microscopy. We observed that the cilium angle significantly alters the generated flow velocity and mass flow rates. As the cilium angle gets closer to the wall, higher flow velocities are observed. Phase difference between two adjacent beating cilia also affects the flow field as the cilia with no phase difference produce significantly lower mass flow rates. In conclusion, our simulations revealed that the most efficient method for cilia-driven fluid transport relies on the alignment of multiple cilia beating with a phase difference, which is also observed in vivo in the developing zebrafish brain.Part of this work was supported by a FRIPRO grant from the Research Council of Norway (N.J.-Y. grant number 314189). The publication of this article was funded by the Qatar National Library

Hemodynamic and Structural Comparison of Human Fetal Heart Development Between Normally Growing and Hypoplastic Left Heart Syndrome-Diagnosed Hearts

Congenital heart defects (CHDs) affect a wide range of societies with an incidence rate of 1.0–1.2%. These defects initiate at the early developmental stage and result in critical health disorders. Although genetic factors play a role in the formation of CHDs, the occurrence of cases in families with no history of CHDs suggests that mechanobiological forces may also play a role in the initiation and progression of CHDs. Hypoplastic left heart syndrome (HLHS) is a critical CHD, which is responsible for 25–40% of all prenatal cardiac deaths. The comparison of healthy and HLHS hearts helps in understanding the main hemodynamic differences related to HLHS. Echocardiography is the most common imaging modality utilized for fetal cardiac assessment. In this study, we utilized echocardiographic images to compare healthy and HLHS human fetal hearts for determining the differences in terms of heart chamber dimensions, valvular flow rates, and hemodynamics. The cross-sectional areas of chamber dimensions are determined from 2D b-mode ultrasound images. Valvular flow rates are measured via Doppler echocardiography, and hemodynamic quantifications are performed with the use of computational fluid dynamics (CFD) simulations. The obtained results indicate that cross-sectional areas of the left and right sides of the heart are similar for healthy fetuses during gestational development. The left side of HLHS heart is underdeveloped, and as a result, the hemodynamic parameters such as flow velocity, pressure, and wall shear stress (WSS) are significantly altered compared to those of healthy hearts.This study was funded by the Qatar National Research Fund (QNRF), National Priority Research Program (NPRP 10-0123-170222). Open access funding was provided by the Qatar National Library

Blood Flow Disturbance and Morphological Alterations Following the Right Atrial Ligation in the Chick Embryo.

Collectively known as congenital heart defects (CHDs), cardiac abnormalities at birth are the most common forms of neonatal defects. Being principally responsible for the heart's pumping power, ventricles are particularly affected by developmental abnormalities, such as flow disturbances or genomic defects. Hypoplastic Right Heart Syndrome (HRHS) is a rare disease where the right ventricle is underdeveloped. In this study, we introduce a surgical procedure performed on chick embryo, termed right atrial ligation (RAL) for disturbing hemodynamics within the right heart aiming in order to generate an animal model of HRHS. RAL is a new surgical manipulation, similar to the well-studied left atrial ligation (LAL) surgery but it induces the hemodynamic change into the right side of the heart. After inducing RAL, We utilized techniques such as Doppler ultrasound, x-ray micro-CT, histology, and computational fluid dynamics (CFD) analysis, for a comprehensive functional and structural analysis of a developing heart. Our results displayed that RAL does not induce severe flow disturbance and ventricular abnormalities consistent with clinical findings. This study allows us to better understand the hemodynamics-driven CHD development and sensitivities of ventricles under disturbed flows

Computational Modeling of Motile Cilia-Driven Cerebrospinal Flow in the Brain Ventricles of Zebrafish Embryo

Motile cilia are hair-like microscopic structures which generate directional flow to provide fluid transport in various biological processes. Ciliary beating is one of the sources of cerebrospinal flow (CSF) in brain ventricles. In this study, we investigated how the tilt angle, quantity, and phase relationship of cilia affect CSF flow patterns in the brain ventricles of zebrafish embryos. For this purpose, two-dimensional computational fluid dynamics (CFD) simulations are performed to determine the flow fields generated by the motile cilia. The cilia are modeled as thin membranes with prescribed motions. The cilia motions were obtained from a two-day post-fertilization zebrafish embryo previously imaged via light sheet fluorescence microscopy. We observed that the cilium angle significantly alters the generated flow velocity and mass flow rates. As the cilium angle gets closer to the wall, higher flow velocities are observed. Phase difference between two adjacent beating cilia also affects the flow field as the cilia with no phase difference produce significantly lower mass flow rates. In conclusion, our simulations revealed that the most efficient method for cilia-driven fluid transport relies on the alignment of multiple cilia beating with a phase difference, which is also observed in vivo in the developing zebrafish brain

Advanced blood flow assessment in Zebrafish via experimental digital particle image velocimetry and computational fluid dynamics modeling

Over the past few decades, Zebrafish has become a widely used vertebrate model for cardiovascular research. Easy genetic manipulation, low cost, high fecundity, embryonic transparency, and ability to survive in the early stages of development without active circulation are among the advantages of Zebrafish. Cardiac malformations can be induced through genetic manipulations for elucidating the influence of mechanobiological stimuli on the development and progress of the cardiovascular diseases. For this purpose, a reliable in vivo assessment of cardiac function and disturbed hemodynamics is required. Therefore, it is necessary to accurately determine the complex blood flow patterns and associated hemodynamic shear stresses within the developing heart and cardiovascular system. In the traditional approach, brightfield microscopy is used to track the motion of cells in two-dimensions (2D). However, with the development of advanced modalities such as light-sheet fluorescent microscopy, it is now possible to perform 4D (three-dimensional space + time) imaging of Zebrafish embryo and larvae. The integration of digital particle image velocimetry (DPIV) and computational fluid dynamics (CFD) provide an opportunity for detailed investigations using in vivo images. In this review, DPIV and CFD methods are explained for blood flow assessment, and recent relevant research findings from Zebrafish studies are summarized

Computational Investigation of Wall Shear Stress Patterns on Calcified Aortic Valve Leaflets

Background: Aortic valve diseases affect about 25% of the population over 65 years of age. Aortic valve separates the left ventricle from the aorta, and consists of three half-moon shaped leaflets. The leaflets are highly dynamic structures which open during the ventricle contraction and close during the ventricle relaxation. Calcification on leaflet surfaces results in poor valve functioning which deteriorates the valve hemodynamics. Wall shear stresses (WSS) on the leaflet surfaces are considered to be strongly related with the initiation and progression of calcification. Aim: To investigate the effect of altered hemodynamics on the valve leaflet calcification, and to understand the role of WSS patterns in the progression of the aortic valve diseases. Methods: We investigate the hemodynamics of aortic valves using computational modeling. Fluid-structure interaction approach is employed to accurately determine the complex dynamic motion of valve leaflets. A 3D patient-specific aortic valve model is generated. Using finite element modeling, blood flow velocities, pressures, and WSS values are determined within the entire model, employing numerical techniques to obtain the characteristics of altered hemodynamics and spatial WSS patterns. Results: In case of calcification, WSS values are increased at both surfaces of the leaflets. On the ventricularis surface, there is a spatially-regular WSS distribution, which gradually increase from the leaflet attachment region to the leaflet tip. However, a spatially-complex WSS distribution is observed on the aortic leaflet surface. Conclusion: Relatively low WSS levels and spatially-complex WSS patterns on the aortic leaflet surface are observed as potential risk factors for the initiation and progression of aortic valve calcificatio

Computational Modeling of Blood Flow Hemodynamics for Biomechanical Investigation of Cardiac Development and Disease.

The heart is the first functional organ in a developing embryo. Cardiac development continues throughout developmental stages while the heart goes through a serious of drastic morphological changes. Previous animal experiments as well as clinical observations showed that disturbed hemodynamics interfere with the development of the heart and leads to the formation of a variety of defects in heart valves, heart chambers, and blood vessels, suggesting that hemodynamics is a governing factor for cardiogenesis, and disturbed hemodynamics is an important source of congenital heart defects. Therefore, there is an interest to image and quantify the flowing blood through a developing heart. Flow measurement in embryonic fetal heart can be performed using advanced techniques such as magnetic resonance imaging (MRI) or echocardiography. Computational fluid dynamics (CFD) modeling is another approach especially useful when the other imaging modalities are not available and in-depth flow assessment is needed. The approach is based on numerically solving relevant physical equations to approximate the flow hemodynamics and tissue behavior. This approach is becoming widely adapted to simulate cardiac flows during the embryonic development. While there are few studies for human fetal cardiac flows, many groups used zebrafish and chicken embryos as useful models for elucidating normal and diseased cardiogenesis. In this paper, we explain the major steps to generate CFD models for simulating cardiac hemodynamics in vivo and summarize the latest findings on chicken and zebrafish embryos as well as human fetal hearts.This study was funded by Qatar National Research Fund (QNRF), National Priority Research Program (NPRP 10-0123-170222)