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Right ventricular assist device (RVAD) associated thrombosis is a serious complication that may arise due to unfavorable blood flow dynamics (blood stasis) caused by RVAD cannula protrusion within the chambers. This study aims to investigate the thrombosis risk of cannulation viathe right atrium (RA) and right ventricle (RV) (diaphragmatic) under full RVAD support using computational fluid dynamics. A HeartWare HVAD inflow cannula was virtually implanted in either the RA or RV of a rigid-walled right heart geometry (including RA, RV, superior, and inferior vena cava) extracted from computed tomography data of a biventricular support patient. Transient simulations, validated with particle image velocimetry, were performed with constant inflow. Thrombosis risk was predicted by analyzing the time-averaged blood velocity, blood stagnation volume, washout rate, and blood residence time (BRT). Results showed that RA cannulation disturbed the physiological swirling flow structure which can be found in an uncannulated RA. This led to a large low-velocity recirculation flow in the RV, increasing the thrombosis risk. Contrarily, RV diaphragmatic cannulation showed better preservation of swirling flow in the RA and flow ejection into the RV. Consequently, RV diaphragmatic cannulation exhibited a better washout rate (99% vs.57% of old blood was replaced in 12 s), lower blood stagnation volume (0.13 ml vs. 32.85 ml), and BRT (4.2 s vs. 7.1 s) than the RA cannulation in this simulated non-pulsatile case. Our findings suggest that RV diaphragmatic cannulation had a lower thrombosis risk and might be more favorable in a full RVAD-supported setting.

Thrombosis is a potentially life-threatening complication in veno-arterial extracorporeal membrane oxygenation (ECMO) circuits, which may originate from the drainage cannula due to unfavorable blood flow dynamics. This study aims to numerically investigate the effect of cannula design parameters on local fluid dynamics, and thus thrombosis potential, within ECMO drainage cannulas. A control cannula based on the geometry of a 17 Fr Medtronic drainage cannula concentrically placed in an idealized, rigid-walled geometry of the right atrium and superior and inferior vena cava was numerically modeled. Simulated flow dynamics in the control cannula were systematically compared with 10 unique cannula designs which incorporated changes to side hole diameter, the spacing between side holes, and side hole angles. Local blood velocities, maximum wall shear stress (WSS), and blood residence time were used to predict the risk of thrombosis. Numerical results were experimentally validated using particle image velocimetry. The control cannula exhibited low blood velocities (59 mm/s) at the cannula tip, which may promote thrombosis. Through a reduction in the side hole diameter (2 mm), the spacing between the side holes (3 mm) and alteration in the side hole angle (30° relative to the flow direction), WSS was reduced by 52%, and cannula tip blood velocity was increased by 560% compared to the control cannula. This study suggests that simple geometrical changes can significantly alter the risk of thrombosis in ECMO drainage cannulas.

ABSTRACTThis study presents the benefits of changing the delivery of a second-year engineering course from the traditional lecture-based format to the flipped approach that is becoming increasingly embraced by universities. The new format involved replacing theoretical lectures with online recordings and devoting the class time to working through problems (workshops). These workshops were complemented by pre- and post-class activities. The success of this change is measured by comparing the outcomes of the flipped and traditional offerings of the same course. This comparison reveals the following benefits from flipping the course: higher marks; improved engagement; and widespread student satisfaction with the flipped format based on student feedback. These outcomes are compared with those reported in the literature for similar teaching approaches. This paper differs from most previous studies by considering all of these outcomes together for one course. The detailed explanation of how the course was flipped provides a model that can be applied to successfully flip other courses. This paper concludes by provocatively raising several key issues that are surprisingly absent or glossed over in the literature. Further studies of these issues are proposed to make a firm case for flipped learning.

Polymeric heart valves have the potential to reduce thrombogenic complications associated with current mechanical valves and overcome fatigue-related problems experienced by bioprosthetic valves. In this paper we characterize the in vitrovelocity and Reynolds Shear Stress (RSS) fields inside and downstream of three different prototype trileaflet polymeric heart valves. The fluid dynamic differences are then correlated with variations in valve design parameters. The three valves differ in leaflet thickness, ranging from 80 to 120 μm, and commisural design, either closed, opened, or semi-opened. The valves were subjected to aortic flow conditions and the velocity measured using three-dimensional stereo Particle Image Velocimetry. The peak forward flow phase in the three valves was characterized by a strong central orifice jet of approximately 2 m/s with a flat profile along the trailing edge of the leaflets. Leakage jets, with principle RSS magnitudes exceeding 4,500 dyn/cm2, were observed in all valves with larger leaflet thicknesses and also corresponded to larger leakage volumes. Additional leakage jets were observed at the commissural region of valves with the open and the semi-open commissural designs. The results of the present study indicate that commissural design and leaflet thickness influence valve fluid dynamics and thus the thrombogenic potential of trileaflet polymeric valves.Polymeric heart valves have the potential to reduce thrombogenic complications associated with current mechanical valves and overcome fatigue-related problems experienced by bioprosthetic valves. In this paper we characterize the in vitrovelocity and Reynolds Shear Stress (RSS) fields inside and downstream of three different prototype trileaflet polymeric heart valves. The fluid dynamic differences are then correlated with variations in valve design parameters. The three valves differ in leaflet thickness, ranging from 80 to 120 μm, and commisural design, either closed, opened, or semi-opened. The valves were subjected to aortic flow conditions and the velocity measured using three-dimensional stereo Particle Image Velocimetry. The peak forward flow phase in the three valves was characterized by a strong central orifice jet of approximately 2 m/s with a flat profile along the trailing edge of the leaflets. Leakage jets, with principle RSS magnitudes exceeding 4,500 dyn/cm2, were observed in all valves with larger leaflet thicknesses and also corresponded to larger leakage volumes. Additional leakage jets were observed at the commissural region of valves with the open and the semi-open commissural designs. The results of the present study indicate that commissural design and leaflet thickness influence valve fluid dynamics and thus the thrombogenic potential of trileaflet polymeric valves.

Abstract Polymeric heart valves have the potential to reduce thrombogenic complications associated with current mechanical valves and overcome fatigue-related problems experienced by bioprosthetic valves. In this in vitro study, the velocity fields inside and downstream of two different prototype tri-lealfet polymeric heart valves were studied. Experiments were conducted on two 23 mm prototype polymeric valves, provided by AorTech Europe, having open or closed commissure designs and leaflet thickness of 120 and 80 µm, respectively. A two-dimensional LDV system was used to measure the velocity fields in the vicinity of the two valves under simulated physiological conditions. Both commissural design and leaflet thickness were found to affect the flow characteristics. In particular, very high levels of Reynolds shear stress of 13,000 dynes/cm2 were found in the leakage flow of the open commisure design. Maximum leakage velocities in the open and closed designs were 3.6 m/s and 0.5 m/s respectively; the peak forward flow velocities were 2.0 m/s and 2.6 m/s, respectively. In both valve designs, shear stress levels exceeding 4,000 dyne/cm2 were observed at the trailing edge of the leaflets and in the leakage and central orifice jets during peak systole. Additionally, regions of low velocity flow conducive to thrombus formation were observed in diastole. The flow structures measured in these experiments are consistent with the location of thrombus formation observed in preliminary animal experiments.

Background:Animal and clinical studies have shown that bileaflet mechanical heart valve designs are plagued by thromboembolic complications, with higher rates in the mitral than in the aortic position. This study evaluated the hinge flow dynamic of the 23 mm St. Jude Medical (SJM) Regent and the 23 mm CarboMedics (CM) valves under aortic conditions and compared these results with previous findings under mitral conditions. Method:Velocity and Reynolds shear stress fields were captured using two-component laser Doppler velocimetry. Results:Under aortic conditions, both the SJM and CM hinge flow fields exhibited a strong forward flow pattern during systole (maximum velocities of 2.31 and 1.75 m/s, respectively) and two main leakage jets during diastole (maximum velocities of 3.08 and 2.27 m/s, respectively). Conclusions:Aortic and mitral flow patterns within the two hinges were similar, but with a more dynamic flow during the forward flow phase under aortic conditions. Velocity magnitudes and shear stresses measured under mitral conditions were generally higher than those obtained in the aortic position, which may explain the higher rates of thromboembolism in the mitral implants when compared with the aortic implants.

No relevant conflicts of interest to declare.

Platelets respond rapidly to injury, infection and changes in blood shear stress where they engage subendothelial collagen and von Willebrand Factor via platelet-specific receptors glycoprotein (GP)VI and the GPIb-IX-V complex, respectively. Metalloproteolytic shedding of GPVI is one important consequence of platelet activation and occurs via activation of the receptor sheddase A Disintegrin and Metalloproteinase (ADAM)10. We demonstrated that exposure of platelets to brief, elevated shear was sufficient to activate ADAM10-mediated shedding of GPVI and that this activation did not require platelet receptor engagement, intracellular signalling or release of soluble mediators (Al Tamimi et al., Blood, 2012). A critical global question, however, is how ADAM10 activity towards vascular substrates can be so rapidly upregulated in a high shear environment? To directly examine shear-induced activation of a vascular metalloproteinase, we developed the first sensor capable of visualising ADAM10 activity on a forming thrombus, consisting of a GPVI sequence-based ADAM10-sensitive fluorescent peptide with an ADAM10-releasable quencher (GPVI-Cy3). Rapid recombinant (r) ADAM10 (Km= 24.3 μM, kcat= 0.27 s-1) but not rADAM17 cleavage of GPVI-Cy3 permitted direct ADAM10 monitoring on platelets. First, suspensions of human washed platelets were exposed to variable rates of uniform shear in a cone-plate viscometer, or were treated with 10 μg/ml collagen-related peptide (CRP; a GPVI ligand), or 5 mM NEM (a potent generic activator of ADAMs) then mixed with 5-10 μM GPVI-Cy3. Real-time fluorescence was monitored in a fluorescence plate reader. Untreated platelets displayed basal (37% of maximal) levels of ADAM10 activity (2.3 pmol/min/106platelets; 100% denoting NEM-induced levels) consistent with active ADAM10, lacking an inhibitory pro-domain by western blot and flow cytometry, being present on the non-activated platelet surface. ADAM10 activity increased to 59% of maximal activity following CRP treatment and 86% of maximal activity after exposure to 10,000 s-1shear stress for 5 min (5.4 pmol/min/106platelets). Cleavage of GPVI-Cy3 was completely blocked by inclusion of 100 μM GM6001 or 2 μM GI254023 (specific ADAM10 inhibitor). Second, ADAM10 activity was visualised using fluorescence multi-channel confocal imaging (Nikon A1R Plus si, Piezo z-stage and perfect focus system) of thrombi formed by perfusion of collagen-coated capillaries with hirudinated whole blood (input wall shear rate = 1,800 s-1). The channel profile was reconstructed digitally, and a Computational Fluid Dynamics package (OPEN-Foam) accurately simulated the shear forces acting on the flow throughout the domain as a function of time. Importantly, this technique permits shear rates to be precisely determined at the thrombi surface, and provides time-varying data on shear rates experienced by platelets traversing the domain in vitro. Highest ADAM10 activity was observed 5-10 minutes post thrombus formation and colocalized with areas of high (>6000 s-1) shear on the surface of the thrombus. When GPVI-Cy3 was included for the duration of thrombus formation, serial z-stack thrombus cross section images revealed areas of high and low ADAM10 activity within the thrombus core, consistent with elevated ADAM10 activity on platelets involved in the initial stages of thrombus formation. Together, our findings (i) define a novel ADAM10-selective substrate GPVI-Cy3 which reports on ADAM10 activity in vitroand under hydrodynamic flow ex vivo, (ii) enable simultaneous quantitation of ADAM10 activity and local shear rates, and (iii) demonstrate correlation between ADAM10 activity and regions of elevated shear stress for the first time. Future studies will investigate how shear stress under pulsatile or continuous flow activates ADAM10 on vascular cell membranes, ultimately enabling the design of therapeutic agents that discretely target shear-mediated up-regulation of ADAMs activity.