Nenad Filipovic

Computer Modeling in Bioengineering: Theoretical Background, Examples and Software

Contributors. Preface. Part I: Theoretical Background of Computational Methods. 1. Notation - Matrices and Tensors. 2. Fundamentals of Continuum Mechanics. 3. Heat Transfer, Diffusion, Fluid Mechanics, and Fluid Flow through Porous Deformable Media. Part II: Fundamentals of Computational Methods. 4. Isoparametric Formulation of Finite Elements. 5. Dynamic Finite Element Analysis. 6. Introduction to Nonlinear Finite Element Analysis. 7. Finite Element Modeling of Field Problems. 8. Discrete Particle Methods for Modeling of Solids and Fluids. Part III: Computational Methods in Bioengineering. 9. Introduction to Bioengineering. 10. Bone Modeling. 11. Biological Soft Tissue. 12. Skeletal Muscles. 13. Blood Flow and Blood Vessels. 14. Modeling Mass Transport and Thrombosis in Arteries. 15. Cartilage Mechanics. 16. Cell Mechanics. 17. Extracellular Mechanotransduction: Modeling Ligand Concentration Dynamics in the Lateral Intercellular Space of Compressed Airway Epithelial Cells. 18. Spider Silk: Modeling Solvent Removal during Synthetic and Nephila clavipes Fiber Spinning. 19. Modeling in Cancer Nanotechnology. Index.

Modelling thrombosis using dissipative particle dynamics method

Aim. Arterial occlusion is a leading cause of cardiovascular disease. The main mechanism causing vessel occlusion is thrombus formation, which may be initiated by the activation of platelets. The focus of this study is on the mechanical aspects of platelet-mediated thrombosis which includes the motion, collision, adhesion and aggregation of activated platelets in the blood. A review of the existing continuum-based models is given. A mechanical model of platelet accumulation onto the vessel wall is developed using the dissipative particle dynamics (DPD) method in which the blood (i.e. colloidal-composed medium) is treated as a group of mesoscale particles interacting through conservative, dissipative, attractive and random forces. Methods. Colloidal fluid components (plasma and platelets) are discretized by mesoscopic (micrometre-size) particles that move according to Newtons law. The size of each mesoscopic particle is small enough to allow tracking of each constituent of the colloidal fluid, but significantly larger than the size of atoms such that, in contrast to the molecular dynamics approach, detailed atomic level analysis is not required. Results. To test this model, we simulated the deposition of platelets onto the wall of an expanded tube and compared our computed results with the experimental data of Karino et al. (Miscrovasc. Res. 17, 238–269, 1977). By matching our simulations to the experimental results, the platelet aggregation/adhesion binding force (characterized by an effective spring constant) was determined and found to be within a physiologically reasonable range. Conclusion. Our results suggest that the DPD method offers a promising new approach to the modelling of platelet-mediated thrombosis. The DPD model includes interaction forces between platelets both when they are in the resting state (non-activated) and when they are activated, and therefore it can be extended to the analysis of kinetics of binding and other phenomena relevant to thrombosis.

Finite element 3D reconstruction of the pulmonary acinus imaged by synchrotron X-ray tomography

The alveolated structure of the pulmonary acinus plays a vital role in gas exchange function. Three-dimensional (3D) analysis of the parenchymal region is fundamental to understanding this structure-function relationship, but only a limited number of attempts have been conducted in the past because of technical limitations. In this study, we developed a new image processing methodology based on finite element (FE) analysis for accurate 3D structural reconstruction of the gas exchange regions of the lung. Stereologically well characterized rat lung samples (Pediatr Res 53: 72-80, 2003) were imaged using high-resolution synchrotron radiation-based X-ray tomographic microscopy. A stack of 1,024 images (each slice: 1024 x 1024 pixels) with resolution of 1.4 mum(3) per voxel were generated. For the development of FE algorithm, regions of interest (ROI), containing approximately 7.5 million voxels, were further extracted as a working subunit. 3D FEs were created overlaying the voxel map using a grid-based hexahedral algorithm. A proper threshold value for appropriate segmentation was iteratively determined to match the calculated volume density of tissue to the stereologically determined value (Pediatr Res 53: 72-80, 2003). The resulting 3D FEs are ready to be used for 3D structural analysis as well as for subsequent FE computational analyses like fluid dynamics and skeletonization.

Mechanical weakening of devitalized teeth: three-dimensional Finite Element Analysis and prediction of tooth fracture.

AIM To determine to which extent cavity preparation and each step of dentine removal in the process of root canal treatment (access cavity preparation and root canal enlargement) both individually and jointly contribute to the weakening of the tooth. METHODS Numerical analysis using finite element method (FEM) of separate and combined influence of two-surface Class II preparation and root canal treatment was undertaken to evaluate the decrease in tooth strength. The influence of the two stages in root canal treatment, access cavity preparation and root canal enlargement, was also analysed separately and jointly. After each of these phases, the crown was restored with composite resin, and the FEA was performed only on restored teeth. To estimate the influence of all these procedures on tooth fracture resistance numerically, a Failure Index based on the maximum principal stress criterion (MPCS) was applied. Compressive and tensile stresses were analysed separately and corresponding Failure Indices were calculated. RESULTS A two-surface resin composite restoration weakened the tooth by 23.25%. Nevertheless, the Failure Indices showed that this tooth was not likely to fracture even under high occlusal stress (710N). However, after access cavity preparation, the Failure Indices reached the point where, under high occlusal force that may occur in the posterior area, a tooth fracture occurred. The enlargement of root canals had an additional, but relatively small impact on tooth weakening, making the tooth even more susceptible to fracture. The combined influence of both cavity preparation and root canal enlargement led to weakening of 62.6% under a load of 710N, ultimately causing tooth fracture. CONCLUSION The combined finite element method and the maximum principal stress analysis gave insight into the fracture mechanisms of teeth with two-surface composite restorations followed by root canal preparation. Removal of tooth tissue, despite its subsequent restoration with dental materials, weakened the tooth by changing the stress intensity and distribution through tooth structures. Access cavity preparation had the greatest influence on tooth strength whilst canal enlargement did not contribute to this process substantially.

ARTreat project: Three-dimensional numerical simulation of plaque formation and development in the arteries

Atherosclerosis is a progressive disease characterized by the accumulation of lipids and fibrous elements in arteries. It is characterized by dysfunction of endothelium and vasculitis, and accumulation of lipid, cholesterol, and cell elements inside blood vessel wall. In this study, a continuum-based approach for plaque formation and development in 3-D is presented. The blood flow is simulated by the 3-D Navier-Stokes equations, together with the continuity equation while low-density lipoprotein (LDL) transport in lumen of the vessel is coupled with Kedem-Katchalsky equations. The inflammatory process was solved using three additional reaction-diffusion partial differential equations. Transport of labeled LDL was fitted with our experiment on the rabbit animal model. Matching with histological data for LDL localization was achieved. Also, 3-D model of the straight artery with initial mild constriction of 30% plaque for formation and development is presented.

Mechanistic study of the structure–activity relationship for the free radical scavenging activity of baicalein

AbstractDensity functional theory calculations were performed to evaluate the antioxidant activity of baicalein. The conformational behaviors of both the isolated and the aqueous-solvated species (simulated with the conductor-like polarizable continuum solvation model) were analyzed at the M052X/6-311 + G(d,p) level. The most stable tautomers of various forms of baicalein displayed three IHBs between O4 and OH5, O5 and OH6, and O6 and OH7. The most stable tautomer of the baicalein radical was obtained by dehydrogenating the hydroxyl at C6, while the most stable anion tautomer was obtained by deprotonating the C7 hydroxyl in gaseous and aqueous phases. The expected antioxidant activity of baicalein was explained by its ionization potentials (IPs) and homolytic O–H bond dissociation enthalpies (BDEs), which were obtained via the UM052X optimization level of the corresponding radical species. Heterolytic O–H bond cleavages (proton dissociation enthalpies, PDEs) were also computed. The calculated IP, BDE, and PDE values suggested that one-step H-atom transfer, rather than sequential proton loss–electron transfer or electron transfer–proton transfer, would be the most favorable mechanism for explaining the antioxidant activity of baicalein in the gas phase and in nonpolar solvents. In aqueous solution, the SPLET mechanism was more important. FigureSpin density map of the most stable baicalein radical form

Computer simulation of three-dimensional plaque formation and progression in the carotid artery

Atherosclerosis is becoming the number one cause of death worldwide. In this study, three-dimensional computer model of plaque formation and development for human carotid artery is developed. The three-dimensional blood flow is described by the Navier–Stokes equation, together with the continuity equation. Mass transfer within the blood lumen and through the arterial wall is coupled with the blood flow and is modeled by a convection–diffusion equation. The low-density lipoproteins transports in lumen of the vessel and through the vessel tissue are coupled by Kedem–Katchalsky equations. The inflammatory process is modeled using three additional reaction–diffusion partial differential equations. Fluid–structure interaction is used to estimate effective wall stress analysis. Plaque growth functions for volume progression are correlated with shear stress and effective wall stress distribution. We choose two specific patients from MRI study with significant plaque progression. Plaque volume progression using three time points for baseline, 3- and 12-month follow up is fitted. Our results for plaque localization correspond to low shear stress zone and we fitted parameters from our model using nonlinear least-square method. Determination of plaque location and composition, and computer simulation of progression in time for a specific patient shows a potential benefit for the prediction of disease progression. The proof of validity of three-dimensional computer modeling in the evaluation of atherosclerotic plaque burden may shift the clinical information of MRI from morphological assessment toward a functional tool. Understanding and prediction of the evolution of atherosclerotic plaques either into vulnerable or stable plaques are major tasks for the medical community.

Patient-Specific Prediction of Coronary Plaque Growth From CTA Angiography: A Multiscale Model for Plaque Formation and Progression

Computational fluid dynamics methods based on in vivo 3-D vessel reconstructions have recently been identified the influence of wall shear stress on endothelial cells as well as on vascular smooth muscle cells, resulting in different events such as flow mediated vasodilatation, atherosclerosis, and vascular remodeling. Development of image-based modeling technologies for simulating patient-specific local blood flows is introducing a novel approach to risk prediction for coronary plaque growth and progression. In this study, we developed 3-D model of plaque formation and progression that was tested in a set of patients who underwent coronary computed tomography angiography (CTA) for anginal symptoms. The 3-D blood flow is described by the Navier-Stokes equations, together with the continuity equation. Mass transfer within the blood lumen and through the arterial wall is coupled with the blood flow and is modeled by a convection-diffusion equation. The low density lipoprotein (LDL) transports in lumen of the vessel and through the vessel tissue (which has a mass consumption term) are coupled by Kedem-Katchalsky equations. The inflammatory process is modeled using three additional reaction-diffusion partial differential equations. A full 3-D model was created. It includes blood flow and LDL concentration, as well as plaque formation and progression. Furthermore, features potentially affecting plaque growth, such as patient risk score, circulating biomarkers, localization and composition of the initial plaque, and coronary vasodilating capability were also investigated. The proof of concept of the model effectiveness was assessed by repetition of CTA, six months after the baseline evaluation. Besides the low values of local shear stress, plaque characteristics, risk profile, pattern of circulating adhesion molecules, and reduced coronary flow reserve at baseline appeared to affect plaque progression toward flow-limiting lesions at follow-up evaluation. Although preliminary, our multidisciplinary approach to a “personalized” prediction of coronary plaque progression suggests that incorporation in atherosclerotic models of systemic and local hemodynamic features may better predict evolution of plaques in coronary artery disease stable patients.

Blood flow shapes intravascular pillar geometry in the chick chorioallantoic membrane

The relative contribution of blood flow to vessel structure remains a fundamental question in biology. To define the influence of intravascular flow fields, we studied tissue islands--here defined as intravascular pillars--in the chick chorioallantoic membrane. Pillars comprised 0.02 to 0.5% of the vascular system in 2-dimensional projection and were predominantly observed at vessel bifurcations. The bifurcation angle was generally inversely related to the length of the pillar (R = -0.47, P < .001). The pillar orientation closely mirrored the axis of the dominant vessel with an average variance of 5.62 ± 6.96 degrees (p = .02). In contrast, the variance of pillar orientation relative to nondominant vessels was 36.78 ± 21.33 degrees (p > .05). 3-dimensional computational flow simulations indicated that the intravascular pillars were located in regions of low shear stress. Both wide-angle and acute-angle models mapped the pillars to regions with shear less than 1 dyn/cm2. Further, flow modeling indicated that the pillars were spatially constrained by regions of higher wall shear stress. Finally, the shear maps indicated that the development of new pillars was limited to regions of low shear stress. We conclude that mechanical forces produced by blood flow have both a limiting and permissive influence on pillar development in the chick chorioallantoic membrane.

Multiscale - Patient-Specific Artery and Atherogenesis Models

In this work, we present a platform for the development of multiscale patient-specific artery and atherogenesis models. The platform, called ARTool, integrates technologies of 3-D image reconstruction from various image modalities, blood flow and biological models of mass transfer, plaque characterization, and plaque growth. Patient images are acquired for the development of the 3-D model of the patient specific arteries. Then, blood flow is modeled within the arterial models for the calculation of the wall shear stress distribution (WSS). WSS is combined with other patient-specific parameters for the development of the plaque progression models. Real-time simulation can be performed for same cases in grid environment. The platform is evaluated using both animal and human data.