Effects of local geometry and fluid dynamics on regional platelet deposition on artificial surfaces.

Schoephoerster, Richard T.; Oynes, Finn; Nunez, G.; Kapadvanjwala, Monsoor; Dewanjee, Mrinal K.

doi:10.1161/01.atv.13.12.1806

Cited by 89 publications

(170 citation statements)

References 24 publications

(15 reference statements)

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“…Already in the 1970s, it was suggested that alterations in blood flow dynamics around atherosclerotic plaques link to occlusive thrombus formation (12), and that mild vascular damage in the presence of lumen reduction has thrombotic consequences, such as in the classical Foltz model of thromboembolism (18). Fluid dynamic studies from the 1990s reported that stenotic regions influenced platelet aggregation by way of flow perturbations and recirculation zones (19,20). In particular, collagen ligands in combination with extremely high shear rates were used to detect poststenotic aggregate formation (21,22).…”

Section: Discussionmentioning

confidence: 99%

Atherosclerotic geometries exacerbate pathological thrombus formation poststenosis in a von Willebrand factor-dependent manner

Westein

Meer

Kuijpers

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

242

257

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Rupture of a vulnerable atherosclerotic plaque causes thrombus formation and precipitates cardiovascular diseases. In addition to the thrombogenic content of a plaque, also the hemodynamic microenvironment plays a major role in thrombus formation. How the altered hemodynamics around a plaque promote pathological thrombus formation is not well understood. In this study, we provide evidence that plaque geometries result in fluid mechanical conditions that promote platelet aggregation and thrombus formation by increased accumulation and activity of von Willebrand factor (vWF) at poststenotic sites. Resonant-scanning multiphoton microscopy revealed that in vivo arterial stenosis of a damaged carotid artery markedly increased platelet aggregate formation in the stenotic outlet region. Complementary in vitro studies using microfluidic stenotic chambers, designed to mimic the flow conditions in a stenotic artery, showed enhanced platelet aggregation in the stenotic outlet region at 60-80% channel occlusion over a range of input wall shear rates. The poststenotic thrombus formation was critically dependent on bloodborne vWF and autocrine platelet stimulation. In stenotic chambers containing endothelial cells, flow provoked increased endothelial vWF secretion in the stenotic outlet region, contributing to exacerbated platelet aggregation. Taken together, this study identifies a role for the shear-sensitive protein vWF in transducing hemodynamic forces that are present around a stenosis to a prothrombogenic microenvironment resulting in spatially confined and exacerbated platelet aggregation in the stenosis outlet region. The developed stenotic microfluidic chamber offers a realistic platform for in vitro evaluation of shear-dependent thrombus formation in the setting of atherosclerosis.

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Section: Discussionmentioning

confidence: 99%

Atherosclerotic geometries exacerbate pathological thrombus formation poststenosis in a von Willebrand factor-dependent manner

Westein

Meer

Kuijpers

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

242

257

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show abstract

“…These areas of disrupted flow elevate the risk of thrombosis and should be minimized (e.g., [25][26][27][28]). One way to reduce the volume of stagnant/recirculating flow is to streamline the shape of all thrombi trapped along the wall, which reduces the vorticity downstream of the thrombus.…”

Section: Discussionmentioning

confidence: 99%

“…Consequently, the formulation of an objective function that incorporates medically relevant design criteria is essential for constructing medical devices that are clinically viable. Wall shear stress is a measure of the velocity gradient along the wall of a vessel, and regions of abnormal WSS are correlated with an elevated risk of thrombosis [5,6,[25][26][27][28]. As a result, medical devices that induce minimal disruption to otherwise normal WSS profiles may reduce the risk of thrombosis caused by the device.…”

Section: Design Optimization Criteriamentioning

confidence: 99%

Design Optimization of Vena Cava Filters: An Application to Dual Filtration Devices

Singer

Wang

Diachin³

2010

Journal of Biomechanical Engineering

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Background: Pulmonary embolism (PE) is a significant medical problem that results in over 300,000 fatalities per year. A common preventative treatment for PE is the insertion of a metallic filter into the inferior vena cava that traps thrombi before they reach the lungs. The goal of this work is to use methods of mathematical modeling and design optimization to determine the configuration of trapped thrombi that minimizes the hemodynamic disruption. The resulting configuration has implications for constructing an optimally designed vena cava filter.Approach: Computational fluid dynamics is coupled with a nonlinear optimization algorithm to determine the optimal configuration of trapped model thrombus in the inferior vena cava. The location and shape of the thrombus are parameterized, and an objective function, based on wall shear stresses, determines the worthiness of a given configuration. The methods are fully automated and demonstrate the capabilities of a design optimization framework that is broadly applicable.Results: Changes to thrombus location and shape alter the velocity contours and wall shear stress profiles significantly. For vena cava filters that trap two thrombi simultaneously, the undesirable flow dynamics past one thrombus can be mitigated by leveraging the flow past the other thrombus. Streamlining the shape of thrombus trapped along the cava wall reduces the disruption to the flow, but increases the area exposed to abnormal wall shear stress. Conclusions:Computer-based design optimization is a useful tool for developing vena cava filters. Characterizing and parameterizing the design requirements and constraints is essential for constructing devices that address clinical complications. In addition, formulating a well-defined objective function that quantifies clinical risks and benefits is needed for designing devices that are clinically viable.

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“…The ability of particles to avoid immune clearance and accumulate at the target depends on several parameters, including size, shape, surface chemistry, and flexibility (17)(18)(19)(20)(21)(22). The role of shape in vascular dynamics has long been known in terms of its influence on the behavior of circulatory cells such as erythrocytes and platelets (23,24). The shape of nanoparticles in the circulation is of particular interest because it has a significant impact on hydrodynamics, and interactions with vascular targets (25,26).…”

mentioning

confidence: 99%

Using shape effects to target antibody-coated nanoparticles to lung and brain endothelium

Kolhar

Anselmo²,

Gupta³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

576

507

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Vascular endothelium offers a variety of therapeutic targets for the treatment of cancer, cardiovascular diseases, inflammation, and oxidative stress. Significant research has been focused on developing agents to target the endothelium in diseased tissues. This includes identification of antibodies against adhesion molecules and neovascular expression markers or peptides discovered using phage display. Such targeting molecules also have been used to deliver nanoparticles to the endothelium of the diseased tissue. Here we report, based on in vitro and in vivo studies, that the specificity of endothelial targeting can be enhanced further by engineering the shape of ligand-displaying nanoparticles. In vitro studies performed using microfluidic systems that mimic the vasculature (synthetic microvascular networks) showed that rodshaped nanoparticles exhibit higher specific and lower nonspecific accumulation under flow at the target compared with their spherical counterparts. Mathematical modeling of particle-surface interactions suggests that the higher avidity and specificity of nanorods originate from the balance of polyvalent interactions that favor adhesion and entropic losses as well as shear-induced detachment that reduce binding. In vivo experiments in mice confirmed that shape-induced enhancement of vascular targeting is also observed under physiological conditions in lungs and brain for nanoparticles displaying anti-intracellular adhesion molecule 1 and anti-transferrin receptor antibodies.biodistribution | morphology | SMN | cylinder | drug delivery

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Effects of local geometry and fluid dynamics on regional platelet deposition on artificial surfaces.

Cited by 89 publications

References 24 publications

Atherosclerotic geometries exacerbate pathological thrombus formation poststenosis in a von Willebrand factor-dependent manner

Atherosclerotic geometries exacerbate pathological thrombus formation poststenosis in a von Willebrand factor-dependent manner

Design Optimization of Vena Cava Filters: An Application to Dual Filtration Devices

Using shape effects to target antibody-coated nanoparticles to lung and brain endothelium

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