Shear Stress Exposure Time Research Articles

Enhancement of endothelial cell adhesion through treatment with CEACAM6 or TNF-? [Medical College of Wisconsin

610,000 Americans die of heart disease every year and over 1 million Americans undergo coronary interventions each year. Risks of these coronary interventions include thrombosis, embolization, infection, and re-narrowing of the artery. However, it is currently believed that improving the adhesion capabilities of endothelial cells may significantly reduce the associated risks of coronary interventions, especially with regards to cardiovascular stent and graft placement procedures. In the present study, we investigated a method to biochemically facilitate endothelial cell adhesion. Using the Reactome database, we identified biochemical methods/targets which could be modified to promote endothelial cell adhesion. Here we describe a potential method of enhancing endothelial cell adhesion through controlled application of two treatment conditions: Carcinoembryonic Antigen-related Cell Adhesion Molecule 6 (CEACAM6) with Fibronectin-1 (CEACAM6+, FN1+) and Tumor Necrosis Factor-? (TNF-?) with Fibronectin-1 (TNF-?+, FN1+). DAPI stained porcine blood outgrowth endothelial cells (BOECs) were exposed to these treatments or a control treatment (FN1+) for one hour. Each treatment/control condition was then placed into a validated parallel plate flow chamber (PPFC) apparatus (flow rate accuracy and laminar flow were both validated) and exposed to a shear stress of 15 dyn/cm2 (to replicate in vivo shear stress conditions) for 30 minutes using saline solution. Fluorescent images were taken of all replicates before and after shear stress testing in order to determine the effects of treatments on cell adhesion. Statistical analysis of preliminary trials indicated that the treatment groups demonstrated a trend towards higher percentage cell retention (or lower percentage cell loss) with 82.3%, 70.2%, and 50.2% average cell retention for TNF-?, CEACAM6, and the control, respectively; however, statistical significance could not be reached using n=2 and p<0.05. Preliminary results of the TNF-? treatment are promising. In the future, an experiment with a larger sample size and a longer shear stress exposure time (e.g. 1 hour) is needed.

Wall shear stress exposure time: a Lagrangian measure of near-wall stagnation and concentration in cardiovascular flows.

Near-wall transport is of utmost importance in connecting blood flow mechanics with cardiovascular disease progression. The near-wall region is the interface for biologic and pathophysiologic processes such as thrombosis and atherosclerosis. Most computational and experimental investigations of blood flow implicitly or explicitly seek to quantify hemodynamics at the vessel wall (or lumen surface), with wall shear stress (WSS) quantities being the most common descriptors. Most WSS measures are meant to quantify the frictional force of blood flow on the vessel lumen. However, WSS also provides an approximation to the near-wall blood flow velocity. We herein leverage this fact to compute a wall shear stress exposure time (WSSET) measure that is derived from Lagrangian processing of the WSS vector field. We compare WSSET against the more common relative residence time (RRT) measure, as well as a WSS divergence measure, in several applications where hemodynamics are known to be important to disease progression. Because these measures seek to quantify near-wall transport and because near-wall transport is important in several cardiovascular pathologies, surface concentration computed from a continuum transport model is used as a reference. The results show that compared to RRT, WSSET is able to better approximate the locations of near-wall stagnation and concentration build-up of chemical species, particularly in complex flows. For example, the correlation to surface concentration increased on average from 0.51 (RRT) to 0.79 (WSSET) in abdominal aortic aneurysm flow. Because WSSET considers integrated transport behavior, it can be more suitable in regions of complex hemodynamics that are traditionally difficult to quantify, yet encountered in many disease scenarios.

Estudio hemodinámico mediante simulación numérica para completar el diagnóstico en estenosis carotídeas tributarias de endarterectomía

IntroductionIn patients with moderate symptomatic or severe asymptomatic carotid stenosis, prior to an endarterectomy it is recommended to do a detailed study, in which the complet set of morphological and hemodynamic parameters are included.In this work the effect that the location and shape of the stenosis has on the distribution of wall shear stresses and their impact on clinical diagnosis in these cases is analyzed. Materials and methodsFirst the model of the area to study is generated and the numerical simulation is done. Then the wall shear stress, the oscilation index and the wall shear stress exposure time are established, and the impact of the results for embolization risk or the growth of arterial plaque because of intimal hiperpasia are analysed. The methodology is applied to three idealized carotids with different localization and geometrical slope of the stenosis. ResultsFor the idealized carotids it is obtained that stenosis close to bifurcation present a higher embolization risk that the most distant one and has more risk as more stenosis slope it has. For the clinical case, the results show a high risk of embolization by break located near the atheromatous plaque. As well, it is obtained that the risk the arterial plaque to continue growing is low. ConclusionsThe results show that the location of a moderate stenosis related to carotid bifurcation and their geometry they are factors that aid to complete the diagnosis of lesion.

A Numerical Investigation of Blood Damage in the Hinge Area of Aortic Bileaflet Mechanical Heart Valves During the Leakage Phase

Previous experimental and numerical blood studies have shown that high shear stress levels, long exposure times to these shear stresses, and flow recirculation promote thromboembolism. Artificial heart valves, in particular bileaflet mechanical heart valves (BMHVs), are prone to developing thromboembolic complications. These complications often form at the hinge regions of BMHVs and the associated geometry has been shown to affect the local flow dynamics and the associated thrombus formation. However, to date no study has focused on simulating the motion of realistically modeled blood elements within the hinge region to numerically estimate the hinge-related blood damage. Consequently, this study aims at (a) simulating the motion of realistically modeled platelets during the leakage (mid-diastole) phase in different BMHV hinge designs placed in the aortic position and (b) quantitatively comparing the blood damage associated with different designs. Three designs are investigated to assess the effects of hinge geometry and dimensions: a 23 mm St. Jude Medical Regent™ valve hinge with two different gap distances between the leaflet ear and hinge recess; and a 23 mm CarboMedics (CM) aortic valve hinge. The recently developed lattice-Boltzmann method with external boundary force method is used to simulate the hinge flow and capture the dynamics and surface shear stresses of individual platelets. A blood damage index (BDI) value is then estimated based on a linear shear stress-exposure time BDI model. The velocity boundary conditions are obtained from previous 3D large-scale simulations of the hinge flow fields. The trajectories of the blood elements in the hinge region are found to be qualitatively similar for all three hinges, but the shear stresses experienced by individual platelets are higher for the CM hinge design, leading to a higher BDI. The results of this study are also shown to be in good agreement with previous studies, thus validating the numerical method for future research in BMHV flows. This study provides a general numerical tool to optimize the hinge design based on both hemodynamic and thromboembolic performance.

Effects of physiologically relevant dynamic shear stress on platelet complement activation

Disturbed shear stress, commonly found in cardiovascular diseases, plays important roles in platelet activation and functions. It has been reported that when activated by elevated shear stress, platelets were able to support complement activation to completion. In this study, through a dynamic cone and plate shearing device, three physiologically relevant shear stresses were applied to platelets, mimicking the shear conditions when platelets pass through a normal left coronary artery (0.05–1 Pa), a 60% stenosis (elevated shear stress at 6.5 Pa for less than 0.1 s), and when platelets are trapped in a recirculation zone past a stenosis (<0.5 Pa). After shear exposure, platelet-surface complement activation (C1q, C4d, iC3b, and SC5b-9 depositions) was measured using a solid-phase ELISA approach and flow cytometry. Production of complement regulatory proteins – C1-inhibitor (C1-INH) and complement receptor 1 (CR1), was also measured. Results demonstrated that low-pulsatile shear stress (recirculation) was able to initiate platelet complement activation, by increasing C1q deposition significantly. Both pathological shear stresses triggered significant increases in C1 inhibitor generation and noticeable changes in CR1 production, effectively preventing complement activation from completion. These results suggested that for platelets, low-pulsatile shear stress may be more pro-atherogenic, compared to elevated shear stress, especially when the shear stress exposure time is short.

Quantifying the effects of shear stress and shear exposure duration regulation on flow induced platelet activation and aggregation

A heightened flow shear stress magnitude or increased exposure duration at any shear stress magnitude enhances platelet activation. It has been suggested that increased circulating activated platelets are an indication of enhanced cardiovascular risk and that activated platelets can perpetuate cardiovascular diseases. However, the combined effects that shear stress and shear exposure duration have on platelet activation and aggregation are not clear. Our objective was to identify a new parameter ("shear stress-exposure time") to predict platelet functional changes better than the absolute magnitude of shear stress. Platelets were exposed to shear stress waveforms, with different combinations of shear stress magnitude and exposure duration, in a circulation flow loop. Timed samples were removed from the flow loop to quantify thrombogenicity (modified prothrombinase assay), aggregation potential (optical platelet aggregometry), and cell surface marker expression (flow cytometry). Flow induced platelet activation and aggregation was enhanced with increased shear stress-exposure time. Platelets that were exposed to waveforms with the same shear stress-exposure time had the same thrombogenicity and aggregation potential. This was true even for waveforms that exposed platelets to shear stress magnitudes varying from 4 to 40 dynes/cm(2). These results indicate that shear stress-exposure time is a good predictor of platelet activation and aggregation levels and it may be able to predict the likelihood of cardiovascular disease onset.

Platelet activation is reversible and dependent on the shear stress‐exposure time integral

Our goal was to determine whether platelets have a memory for shear induced activation and if this is reversible. During cardiovascular diseases, such as atherosclerosis, platelets are subjected to complex pathological shear stress waveforms at particular vascular locations. Platelets may pass this location every circuit inducing a predisposition towards activation. We hypothesized that platelet activation was governed by the shear stress‐exposure time and not the absolute shear stress level. To test this, platelets were exposed to tailored shear stress waveforms to examine if platelets remember past shear stress histories. Activation was quantified with a prothrombinase assay, flow cytometry and aggregometry (agonized with TRAP6). Our prothrombinase assay depends on FVa and PS expression. To verify this assay and aggregation, CD62P, Annexin V and CD41/61 expression was measured. Platelet activation was waveform independent, if the shear stress‐exposure time was the same. This was true even for platelets subjected to supra‐critical shear stress levels (Hellum's curve). With increasing shear stress‐exposure time, activation was enhanced. Platelets that were subjected to a supra‐critical shear stress early were not more susceptible to subsequent shear exposures. Therefore, platelet activation is reversible and dependent on the shear stress‐exposure time and not the absolute value of shear stress.

Deformability of Red Blood Cells and Its Relation to Blood Trauma in Rotary Blood Pumps

In this study, mechanical trauma to red blood cells was evaluated by conventional hemolysis test and a newly developed cyclically reversing shear flow generator. The fresh porcine blood obtained from a local slaughterhouse was subjected to the conventional hemolysis test using a commercial centrifugal blood pump for the duration of 8 h. The measurements consisted of (i) plasma-free hemoglobin based on the standard optical measurement and (ii) the deformability of red blood cells (RBCs) using a cyclically reversing shear flow generator and microscope image acquisition system. The deformability of RBCs was expressed by the L/W value where L and W were the longer and shorter axes of the elongated RBCs' images. Although the plasma-free hemoglobin level increased with the pumping duration, the L/W remained unchanged for the duration of 8 h of pumping to indicate no alteration in the deformability. It was speculated that (i) although RBCs might have been circulated for so many times through the test pump, after each exposure to mechanical stress, RBCs might have recovered, and net effect due to shear stress-exposure time might have been small; and (ii) RBCs' deformability might be maintained near normal until sudden burst or membrane rupture, or the hemoglobin might have continuously leaked through the pores of the thinned membrane created by the mechanical stress. The deformability testing under a fluctuating shear flow could be a new method to quantify subhemolytic mechanical damage that has been accumulated in the RBCs' membrane and that may not be assessed by the conventional hemolysis test.

ESTIMATION OF FLOW-INDUCED BLOOD DAMAGE IN BIOMEDICAL DEVICES

Biomedical devices are widely used in modern medicine to repair or replace various elements of the cardiovascular system. Unfortunately, in many cases, these devices cause dangerous pathological complications triggered by non-physiological conditions, such as undesired shear stress. The ability to predict blood damage induced by the destructive shear stresses within these devices is critical towards device design optimization process. Hemolysis and platelet activation are two major factors that cause device-related complications or device failure. Currently, no general, accurate predictive mathematical model of blood damage has resulted from over 40 years collective efforts due to physiologic complexities associated with multiscale blood flow dynamics; there still remains a general overestimation of current modeling capabilities for blood damage predication. The objective of this study is to provide an effective means using computational fluid dynamics (CFD) method to quantitatively estimate blood damage level, and provide a first-order assessment of hemolysis or platelet activation caused by shear stress without resorting to complex mathematical models. Shear stress and exposure time are two parameters that are employed to characterize blood trauma by simply plotting them into a shear stress-exposure time blood damage plane. This method was verified by in-vitro experimental results of various oxygenators and blood pumps, and can be used to evaluate the hemolysis or platelet activation level caused by shear stress in a device, therefore easily to determine its applicability for long term clinical application.