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  • 1.
    Biasetti, Jacopo
    KTH, School of Engineering Sciences (SCI), Solid Mechanics (Dept.).
    On the interplay between hemodynamics and biochemsitry of the normal and aneurysmatic abdominal aorta2011Licentiate thesis, comprehensive summary (Other academic)
  • 2.
    Biasetti, Jacopo
    KTH, School of Engineering Sciences (SCI), Solid Mechanics (Dept.), Biomechanics.
    Physics of blood flow in arteries and its relation to intra-luminal thrombus and atherosclerosis2013Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Vascular pathologies such as Abdominal Aortic Aneurysm (AAA) and atherosclerosis are complex vascular diseases involving biological, mechanical, and fluid-dynamical factors. This thesis follows a multidisciplinary approach and presents an integrated fluid-chemical theory of ILT growth and analyzes the shear-induced migration of red blood cells (RBCs) in large arteries with respect to hypoxia and its possible role in atherosclerosis. The concept of Vortical Structures (VSs) is employed, with which a theory of uid-chemically-driven ILT growth is formulated. The theory proposes that VSs play an important role in convecting and activating platelets in the aneurysmatic bulge. In particular, platelets are convected toward the distal aneurysm region inside vortex cores and are activated via a combination of high residence times and relatively high shear stress at the vortex boundary. After vortex breakup, platelets are free to adhere to the thrombogenic wall surface. VSs also convect thrombin, a potent procoagulant enzyme, captured in their core, through the aneurysmatic lumen and force its accumulation in the distal portion of the AAA. This framework is in line with the clinical observation that the thickest ILT is usually seen in the distal AAA region. The investigation of the fluid-dynamics in arteries led to the study of the shear-induced migration of RBCs in large vessels such as the abdominal aorta and the carotid artery. Marked RBCs migration is observed in the region of the carotid sinus and in the iliac arteries, regions prone to atherogenesis. This leads to the hypothesis that oxyhemoglobin availability can decrease in the near-wall region thus contributing to wall hypoxia, a factor implicated in atherosclerosis. The thesis proposes a new potential mechanism of ILT growth, driven by fluid and chemical stimuli, which can be used to study ILT progression over physiologically relevant timeframes and be used as a framework to test new hypotheses; the thesis also provides new insights on the oxyhemoglobin availability in the near-wall region with direct inuence on atherosclerosis.

  • 3.
    Biasetti, Jacopo
    et al.
    KTH, School of Engineering Sciences (SCI), Solid Mechanics (Dept.), Biomechanics.
    Gasser, T. Christian
    KTH, School of Engineering Sciences (SCI), Solid Mechanics (Dept.), Biomechanics.
    Auer, Martin
    VASCOPS GmbH, Graz, Austria.
    Hedin, Ulf
    Department of Molecular Medicine and Surgery, Karolinska Universty Hospital, Stockholm, Sweden.
    Labruto, Fausto
    Department of Radoilogy, Karolinska University Hospital, Stockholm, Sweden.
    Hemodynamics of the Normal Aorta Compared to Fusiform and Saccular Abdominal Aortic Aneurysms with Emphasis on a Potential Thrombus Formation Mechanism2010In: Annals of Biomedical Engineering, ISSN 0090-6964, E-ISSN 1573-9686, Vol. 38, no 2, p. 380-390Article in journal (Refereed)
    Abstract [en]

    Abdominal Aortic Aneurysms (AAAs), i.e., focal enlargements of the aorta in the abdomen are frequently observed in the elderly population and their rupture is highly mortal. An intra-luminal thrombus is found in nearly all aneurysms of clinically relevant size and multiply affects the underlying wall. However, from a biomechanical perspective thrombus development and its relation to aneurysm rupture is still not clearly understood. In order to explore the impact of blood flow on thrombus development, normal aortas (n = 4), fusiform AAAs (n = 3), and saccular AAAs (n = 2) were compared on the basis of unsteady Computational Fluid Dynamics simulations. To this end patient-specific luminal geometries were segmented from Computerized Tomography Angiography data and five full heart cycles using physiologically realistic boundary conditions were analyzed. Simulations were carried out with computational grids of about half a million finite volume elements and the Carreau-Yasuda model captured the non-Newtonian behavior of blood. In contrast to the normal aorta the flow in aneurysm was highly disturbed and, particularly right after the neck, flow separation involving regions of high streaming velocities and high shear stresses were observed. Naturally, at the expanded sites of the aneurysm average flow velocity and wall shear stress were much lower compared to normal aortas. These findings suggest platelets activation right after the neck, i.e., within zones of pronounced recirculation, and platelet adhesion, i.e., thrombus formation, downstream. This mechanism is supported by recirculation zones promoting the advection of activated platelets to the wall.

  • 4.
    Biasetti, Jacopo
    et al.
    KTH, School of Engineering Sciences (SCI), Solid Mechanics (Dept.), Biomechanics.
    Gasser, Thomas Christian
    KTH, School of Engineering Sciences (SCI), Solid Mechanics (Dept.), Biomechanics.
    A Blood Flow based model for Platelet Activation in Abdominal Aortic Aneurisms2010Conference paper (Refereed)
    Abstract [en]

    Introduction

    Thrombus formation is the physiological response to vascular injury, it prevents loss of blood and permits wound healing, however, it is also associated with pathological conditions like hypoxia, anoxia and infarction [1]. Consequently, thrombus development must be carefully modulated to avoid uncontrolled growth, which in turn could lead to organ malfunctions. Specifically, an Intra-Luminal Thrombus (ILT) is found in almost all larger (clinically relevant) Abdominal Aortic Aneurysms (AAAs) and multiple biochemical [2] and biomechanical [3] implications on the underlying wall tissue have been reported. Despite the dominant role played by the ILT in AAA disease little is known regarding its development, and hence, the present study investigates ILT formation with particular emphasis on platelet activation triggered by biomechanical and biochemical field variables.

    Method

    The proposed model assumes that platelet activation is defined by a single field variable

    representing the accumulation of mechanical [4] and chemical [5] factors as the platelet moves along its path line. Platelet activation is given as soon asovercomes a certain threshold thought to be a constitutive property of blood. Specifically, the rate of the activation variable is determined by the maximum shear stress and the local concentrations of agonists and antagonists. To implement the model the fluid mechanical problem was solved in (COMSOL, COMSOL AB) and a particle tracking analysis (MATLAB, The MathWorks) was applied as a post processing step. The flow in a circular tube and the Backward Facing Step (BFS) problem under varying initial conditions were used for a basic investigation of the model and to relate its predictions to available data in the literature. Finally, platelet activation in patient specific AAAs was predicted and related to ILT development, which was estimated from Computer Tomography-Angiography (CT-A) data recorded from patient follow-up studies.

    Results and Conclusions

    The platelet activation variable

     is complex distributed (highly heterogeneous) in the flow field, where, specifically, at the boundary of vortexes [6] and in the boundary layer of the non- endothelialized wall highest values were predicted. Continuous release of antagonists from the endothelialized wall lowers  in its vicinity, and hence, despite the high shear stress platelet activation

    is prevented. The proposed model links biomechanical and biochemical mechanisms of platelet activation and is able to predict the onset of thrombus formation of the BFS problem. The model is also able to predict some features of ILT development in the AAA, however, the change in luminal geometry is a cumulative effect of ILT growth, wall growth and their mechanical interactions, and hence, data recorded form patient follow-up studies needs to be analyzed carefully when validating the present model.

    References

    [1] J. D. Humphrey,

    Springer-Verlag, New York, 2002.

    [2] M. Kazi, et. al.

    J. Vasc. Surg., 38:1283-1292, 2003.

    [3] W. R. Mower et. al.,

    J. Vasc. Surg., 33:602-608, 1997.

    [4] J. D. Hellums,

    Ann. Biomed. Eng., 22: 445-455, 1994.

    [5] B. Alberts et. al.

    Molecular Biology of the cell, 2002.

    [6] J. Biasetti et. al.

    Ann. Biomed. Eng., 38: 380–390 2010.

  • 5.
    Biasetti, Jacopo
    et al.
    KTH, School of Engineering Sciences (SCI), Solid Mechanics (Dept.), Biomechanics.
    Gasser, Thomas Christian
    KTH, School of Engineering Sciences (SCI), Solid Mechanics (Dept.), Biomechanics.
    A Fluid-chemical model of thrombus formation2011In: CMBE2011: 2nd International Conference on Mathematical and Computational Biomedical Engineering / [ed] P. Nithiarasu, R. Löhner, 2011Conference paper (Refereed)
    Abstract [en]

    Our understanding of the genesis and evolution of Abdominal Aortic Aneurysms (AAAs), withparticular emphasis on Intra-Luminal Thrombus’ evolution, may be improved by studying thecomplex interplay between fluid-dynamics and biochemistry. To investigate the evolution of prothromboticchemicals inside the blood flow, in particular thrombin (factor IIa), a fluido-chemicalmodel has been developed. To this end a series of convection-diffusion-reaction (CDR) equationsdescribing the tissue factor pathway to thrombin have been solved on top of the biofluiddynamics problem. The proposed model integrates biochemistry and fluids dynamics, and hence,supports a comprehensive understanding of how ILT in AAAs may develop.

  • 6.
    Biasetti, Jacopo
    et al.
    KTH, School of Engineering Sciences (SCI), Solid Mechanics (Dept.), Biomechanics.
    Hussain, Fazle
    Department of Mechanical Engineering, University of Houston, Houstohn, TX, USA.
    Gasser, T. Christian
    KTH, School of Engineering Sciences (SCI), Solid Mechanics (Dept.), Biomechanics.
    Blood flow and coherent vortices in the normal and aneurysmatic aortas: a fluid dynamical approach to intraluminal thrombus formation2011In: Journal of the Royal Society Interface, ISSN 1742-5689, E-ISSN 1742-5662, Vol. 8, no 63, p. 1449-1461Article in journal (Refereed)
    Abstract [en]

    Abdominal aortic aneurysms (AAAs) are frequently characterized by the development of an intra-luminal thrombus (ILT), which is known to have multiple biochemical and biomechanical implications. Development of the ILT is not well understood, and shear-stress-triggered activation of platelets could be the first step in its evolution. Vortical structures (VSs) in the flow affect platelet dynamics, which motivated the present study of a possible correlation between VS and ILT formation in AAAs. VSs educed by the lambda(2)-method using computational fluid dynamics simulations of the backward-facing step problem, normal aorta, fusiform AAA and saccular AAA were investigated. Patient-specific luminal geometries were reconstructed from computed tomography scans, and Newtonian and Carreau-Yasuda models were used to capture salient rheological features of blood flow. Particularly in complex flow domains, results depended on the constitutive model. VSs developed all along the normal aorta, showing that a clear correlation between VSs and high wall shear stress (WSS) existed, and that VSs started to break up during late systole. In contrast, in the fusiform AAA, large VSs developed at sites of tortuous geometry and high WSS, occupying the entire lumen, and lasting over the entire cardiac cycle. Downward motion of VSs in the AAA was in the range of a few centimetres per cardiac cycle, and with a VS burst at that location, the release (from VSs) of shear-stress-activated platelets and their deposition to the wall was within the lower part of the diseased artery, i.e. where the thickest ILT layer is typically observed. In the saccular AAA, only one VS was found near the healthy portion of the aorta, while in the aneurysmatic bulge, no VSs occurred. We present a fluid-dynamics-motivated mechanism for platelet activation, convection and deposition in AAAs that has the potential of improving our current understanding of the pathophysiology of fluid-driven ILT growth.

  • 7.
    Biasetti, Jacopo
    et al.
    KTH, School of Engineering Sciences (SCI), Solid Mechanics (Dept.).
    Spazzini, Pier Giorgio
    Mechanics Division, National Institute of Metrological Research (INRiM), Turin, Italy.
    Gasser, Christian
    KTH, School of Engineering Sciences (SCI), Solid Mechanics (Dept.).
    An integrated fluido-chemical model towards modeling the formation of intra-luminal thrombus in abdominal aortic aneurysms2011Article in journal (Other academic)
    Abstract [en]

    Abdominal Aortic Aneurysms (AAAs) are frequently characterized by the presence of an Intra-Luminal Thrombus (ILT) known to influence biochemically and biomechanically their evolution. ILT progression mechanism is still unclear and little is known regarding the impact of chemicals transported by blood flow. It is expected that chemical agonists and antagonists of platelets activation, aggregation, and adhesion play an important role in ILT development. Starting fromthis assumption, the evolution of chemical species related to the coagulation cascade (CC), their relation to coherent vortical structures (VSs) and their effect on ILT evolution have been studied. To this end a fluido-chemical model that simulates the CC through a series of convection-diffusion-reaction (CDR) equations and considers blood as a non-Newtonian incompressible fluid has been developed. In addition to the relation between VSs and thrombin distribution, high thrombin concentrations at the distal portion of the AAA were observed, i.e. the region where the thickest ILT is usually seen. The proposed model, due to its ability to couple the fluid and chemical domains, provides an integrated mechanochemical picture that potentially could unveil mechanisms of ILT formation and development.

  • 8.
    Biasetti, Jacopo
    et al.
    KTH, School of Engineering Sciences (SCI), Solid Mechanics (Dept.), Biomechanics.
    Spazzini, Pier Giorgio
    Mechanics Division, National Institute of Metrological Research (INRiM), Turin, Italy.
    Gasser, T. Christian
    KTH, School of Engineering Sciences (SCI), Solid Mechanics (Dept.), Biomechanics.
    Shear-induced migration of red blood cells in the abdominal aorta and thecarotid bifurcation: considerations on oxygen transport2013Report (Other academic)
    Abstract [en]

    Shear-induced migration of red blood cells (RBCs) is a well known phenomenon characterizing blood flow in the small vessels (micron to mm size) of the cardiovascular system. In large vessels, like the abdominal aorta and the carotid artery (mm to cm size), the extent of this migration has not been fully elucidated. RBCs migration exerts its influence primarily on platelet concentration, oxygen transport and oxygen availability at the luminal surface; this being of primary importance in, for example, intra-luminal thrombus (ILT) growth, atherosclerosis and intima hyperplasia. Phillips’ shear-induced particle migration model coupled to the Quemada viscosity model was employed to simulate the macroscopic behavior of RBCs in four patient-specific geometries: a normal abdominal aorta, an abdominal aortic aneurysm (AAA), a normal carotid bifurcation and a stenotic carotid bifurcation. Simulations show a migration of RBCs from the near wall region with a lowering of wall hematocrit (volume fraction of RBCs) on the posterior side of the normal aorta and in the iliac arteries. A marked migration is observed on the outer wall of the carotid sinus, the inner curvature wall of the common carotid artery and in the carotid stenosis. No significant migration is observed in the AAA. The spatial and temporal patterns of wall hematocrit are correlated with the near-wall shear layer and with the secondary flow induced by the vessel curvature. The results reinforce data in literature showing a decrease in oxygen partial pressure on the inner curvature wall of the carotid sinus and, more in general, on the inner curvature wall. The lowering of wall hematocrit is postulated to induce a decrease in oxygen availability at the luminal surface through a diminished concentration of oxyhemoglobin, hence contributing, with the lowered oxygen partial pressure, to local hypoxia.

  • 9.
    Biasetti, Jacopo
    et al.
    KTH, School of Engineering Sciences (SCI), Solid Mechanics (Dept.).
    Spazzini, Pier Giorgio
    Hedin, Ulf
    Gasser, T. Christian
    Synergy between shear-induced migration and secondary flows on red blood cells transport in arteries: considerations on oxygen transport2014In: Journal of the Royal Society Interface, ISSN 1742-5689, E-ISSN 1742-5662, Vol. 11, no 97, p. 20140403-Article in journal (Refereed)
    Abstract [en]

    Shear-induced migration of red blood cells (RBCs) is a well-known phenomenon characterizing blood flow in the small vessels (micrometre to millimetre size) of the cardiovascular system. In large vessels, like the abdominal aorta and the carotid artery (millimetre to centimetre size), the extent of this migration and its interaction with secondary flows has not been fully elucidated. RBC migration exerts its influence primarily on platelet concentration, oxygen transport and oxygen availability at the luminal surface, which could influence vessel wall disease processes in and adjacent to the intima. Phillips' shear-induced particle migration model, coupled to the Quemada viscosity model, was employed to simulate the macroscopic behaviour of RBCs in four patient-specific geometries: a normal abdominal aorta, an abdominal aortic aneurysm (AAA), a normal carotid bifurcation and a stenotic carotid bifurcation. Simulations show a migration of RBCs from the near-wall region with a lowering of wall haematocrit (volume fraction of RBCs) on the posterior side of the normal aorta and on the lateral-external side of the iliac arteries. A marked migration is observed on the outer wall of the carotid sinus, along the common carotid artery and in the carotid stenosis. No significant migration is observed in the AAA. The spatial and temporal patterns of wall haematocrit are correlated with the near-wall shear layer and with the secondary flows induced by the vessel curvature. In particular, secondary flows accentuate the initial lowering in RBC near-wall concentration by convecting RBCs from the inner curvature side to the outer curvature side. The results reinforce data in literature showing a decrease in oxygen partial pressure on the inner curvature wall of the carotid sinus induced by the presence of secondary flows. The lowering of wall haematocrit is postulated to induce a decrease in oxygen availability at the luminal surface through a diminished concentration of oxyhaemoglobin, hence contributing, with the reported lowered oxygen partial pressure, to local hypoxia.

  • 10.
    Biasetti, Jacopo
    et al.
    KTH, School of Engineering Sciences (SCI), Solid Mechanics (Dept.), Biomechanics.
    Spazzini, Pier Giorgio
    Mechanics Division, National Institute of Metrological Research, Turin, Italy.
    Swedenborg, Jesper
    Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
    Gasser, T. Christian
    KTH, School of Engineering Sciences (SCI), Solid Mechanics (Dept.), Biomechanics.
    An Integrated Fluid-Chemical Model Toward Modeling the Formation of Intra-Luminal Thrombus in Abdominal Aortic Aneurysms2012In: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 3, no 266Article in journal (Refereed)
    Abstract [en]

    Abdominal Aortic Aneurysms (AAAs) are frequently characterized by the presence of an Intra-Luminal Thrombus (ILT) known to influence their evolution biochemically and biomechanically. The ILT progression mechanism is still unclear and little is known regarding the impact of the chemical species transported by blood flow on this mechanism. Chemical agonists and antagonists of platelets activation, aggregation, and adhesion and the proteins involved in the coagulation cascade (CC) may play an important role in ILT development. Starting from this assumption, the evolution of chemical species involved in the CC, their relation to coherent vortical structures (VSs) and their possible effect on ILT evolution have been studied. To this end a fluid-chemical model that simulates the CC through a series of convection-diffusion-reaction (CDR) equations has been developed. The model involves plasma-phase and surface-bound enzymes and zymogens, and includes both plasma-phase and membrane-phase reactions. Blood is modeled as a non-Newtonian incompressible fluid. VSs convect thrombin in the domain and lead to the high concentration observed in the distal portion of the AAA. This finding is in line with the clinical observations showing that the thickest ILT is usually seen in the distal AAA region. The proposed model, due to its ability to couple the fluid and chemical domains, provides an integrated mechanochemical picture that potentially could help unveil mechanisms of ILT formation and development.

  • 11.
    Gasser, Thomas Christian
    et al.
    KTH, School of Engineering Sciences (SCI), Solid Mechanics (Dept.), Biomechanics.
    Auer, M.
    Biasetti, Jacopo
    KTH, School of Engineering Sciences (SCI), Solid Mechanics (Dept.), Biomechanics.
    Structural and Hemodynamical analysis of Aortic Aneurysms from Computerized Tomography Angiography data2010In: WORLD CONGRESS ON MEDICAL PHYSICS AND BIOMEDICAL ENGINEERING, VOL 25, PT 4: IMAGE PROCESSING, BIOSIGNAL PROCESSING, MODELLING AND SIMULATION, BIOMECHANICS, 2010, p. 1584-1587Conference paper (Refereed)
    Abstract [en]

    Evaluating rupture risk of Abdominal Aortic Aneurysms is critically important in reducing related mortality without unnecessarily increasing the rate of elective repair. According to the current clinical practice aneurysm rupture risk is (mainly) estimated from its maximum diameter and/or expansion rate; an approach motivated from statistics but known to fail often in individuals. In particular, the role of the Intraluminal Thrombus is unclear and further research is required to investigate and understand its multiple impacts on aneurysm disease. Biomechanical simulations might be helpful to explore this question, however, model development is time consuming and operator-variability limits their reliability. In this study we propose an automatic procedure to develop hemodynamic and structural models of healthy and diseased abdominal aortas, where Deformable Models segment Computerized Tomography Angiography data. In total 29 numerical models of the health and diseased abdominal aorta have been developed to investigate aneurysm's rupture risk and hemodynamic consequences of aneurismal dilations. The derived results underline the suitability of biomechanical simulations to enrich diagnostic information and to uncover mechanisms of aneurysm pathology.

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