Haemodynamics of stent-mounted neural interfaces in tapered and deformed blood vessels.

The endovascular neural interface provides an appealing minimally invasive alternative to invasive brain electrodes for recording and stimulation. However, stents placed in blood vessels have long been known to affect blood flow (haemodynamics) and lead to neointimal growth within the blood vessel. Both the stent elements (struts and electrodes) and blood vessel wall geometries can affect the mechanical environment on the blood vessel wall, which could lead to unfavourable vascular remodelling after stent placement. With increasing applications of stents and stent-like neural interfaces in venous blood vessels in the brain, it is necessary to understand how stents affect blood flow and tissue growth in veins. We explored the haemodynamics of a stent-mounted neural interface in a blood vessel model. Results indicated that blood vessel deformation and tapering caused a substantial change to the lumen geometry and the haemodynamics. The neointimal proliferation was evaluated in sheep implanted with an endovascular neural interface. Analysis showed a negative correlation with the mean Wall Shear Stress pattern. The results presented here indicate that the optimal stent oversizing ratio must be considered to minimise the haemodynamic impact of stenting.

Computational Fluid Dynamics of Stent-Mounted Neural Interfaces in an Idealized Cerebral Venous Sinus.

Hemodynamic changes in stented blood vessels play a critical role in stent-associated complications. The majority of work on the hemodynamics of stented blood vessels has focused on coronary arteries but not cerebral venous sinuses. With the emergence of endovascular electrophysiology, there is a growing interest in stenting cerebral blood vessels. We investigated the hemodynamic impact of a stent-mounted neural interface inside the cerebral venous sinus. The stent was virtually implanted into an idealized superior sagittal sinus (SSS) model. Local venous blood flow was simulated. Results showed that blood flow was altered by the stent, generating recirculation and low wall shear stress (WSS) around the device. However, the effect of the electrodes on blood flow was not prominent due to their small size. This is an early exploration of the hemodynamics of a stent-mounted neural interface. Future work will shed light on the key factors that influence blood flow and stenting outcomes.Clinical Relevance-The study investigates blood flow through a stent-based electrode array inside the cerebral venous sinus. The hemodynamic impact of the stent can provide insight into neointimal growth and thrombus formation.

Numerical simulation of the cavopulmonary connection flow with conduit stenoses of varying configurations.

The circulation in the total cavopulmonary connection (TCPC) is a low-energy system which operation and efficiency are subjected to multiple factors. Some retrospective studies report that the abnormal narrowing of vessels in the system, i.e. stenosis, is one of the most dangerous geometric factors which can result in heart failure. In the present study, the effect of varying extracardiac conduit (ECC) stenosis on the hemodynamics in a surrogate TCPC model is investigated using high-fidelity numerical simulations. The efficiency of the surrogate TCPC model was quantified according to the power loss, relative perfusion in lungs and the percentage of conduit surface area with abnormally low and high wall shear stress for venous flow. Additionally, the impact of respiration and asymmetry in the stenosis geometry to the system was examined. The results show that the flow in the TCPC model exhibits pronounced unsteadiness even under the steady initial boundary conditions, while the uneven pulmonary flow distribution and the presence of the ECC stenosis amplify the chaotic nature of the flow. Energy efficiency of the system is shown to strongly correlate with amount of vortical structures in the model and their range of scales. Finally, the study demonstrates that the presence of respiration in the model adds to perturbations in the flow which causes increase in the power loss. Results obtained in the study provide valuable insights on how the ECC stenosis effect the flow in the surrogate TCPC model under different flow conditions.

A microfluidic method to investigate platelet mechanotransduction under extensional strain.

Background: Blood platelets have evolved a complex mechanotransduction machinery to rapidly respond to hemodynamic conditions. A variety of microfluidic flow-based approaches have been developed to explore platelet mechanotransduction; however, these experimental models primarily focus on the effects of increased wall shear stress on platelet adhesion events and do not consider the critical effects of extensional strain on platelet activation in free flow. Objectives: We report the development and application of a hyperbolic microfluidic assay that allows for investigation of platelet mechanotransduction under quasi-homogenous extensional strain rates in the absence of surface adhesions. Methods: Using a combined computational fluid dynamic and experimental microfluidic approach, we explore 5 extensional strain regimes (geometries) and their effect on platelet calcium signal transduction. Results: We demonstrate that in the absence of canonical adhesion, receptor engagement platelets are highly sensitive to both initial increase and subsequent decrease in extensional strain rates within the range of 747 to 3319/s. Furthermore, we demonstrate that platelets rapidly respond to the rate of change in extensional strain and define a threshold of ≥7.33 × 106/s/m, with an optimal range of 9.21 × 107 to 1.32 × 108/s/m. In addition, we demonstrate a key role of both the actin-based cytoskeleton and annular microtubules in the modulation of extensional strain-mediated platelet mechanotransduction. Conclusion: This method opens a window onto a novel platelet signal transduction mechanism and may have potential diagnostic utility in the identification of patients who are prone to thromboembolic complications associated with high-grade arterial stenosis or are on mechanical circulatory support systems, for which the extensional strain rate is a predominant hemodynamic driver.

Vascular remodeling in sheep implanted with endovascular neural interface.

Objective.The aim of this work was to assess vascular remodeling after the placement of an endovascular neural interface (ENI) in the superior sagittal sinus (SSS) of sheep. We also assessed the efficacy of neural recording using an ENI.Approach.The study used histological analysis to assess the composition of the foreign body response. Micro-CT images were analyzed to assess the profiles of the foreign body response and create a model of a blood vessel. Computational fluid dynamic modeling was performed on a reconstructed blood vessel to evaluate the blood flow within the vessel. Recording of brain activity in sheep was used to evaluate efficacy of neural recordings.Main results.Histological analysis showed accumulated extracellular matrix material in and around the implanted ENI. The extracellular matrix contained numerous macrophages, foreign body giant cells, and new vascular channels lined by endothelium. Image analysis of CT slices demonstrated an uneven narrowing of the SSS lumen proportional to the stent material within the blood vessel. However, the foreign body response did not occlude blood flow. The ENI was able to record epileptiform spiking activity with distinct spike morphologies.Significance. This is the first study to show high-resolution tissue profiles, the histological response to an implanted ENI and blood flow dynamic modeling based on blood vessels implanted with an ENI. The results from this study can be used to guide surgical planning and future ENI designs; stent oversizing parameters to blood vessel diameter should be considered to minimize detrimental vascular remodeling.

MRI in CFD for chronic type B aortic dissection: Ready for prime time?

OBJECTIVES: Better tools are needed for risk assessment of Type B aortic dissection (TBAD) to determine optimal treatment for patients with uncomplicated disease. Magnetic resonance imaging (MRI) has the potential to inform computational fluid dynamics (CFD) simulations for TBAD by providing individualised quantification of haemodynamic parameters, for assessment of complication risks. This systematic review aims to present an overview of MRI applications for CFD studies of TBAD. METHODS: Following PRISMA guidelines, a search in Medline, Embase, and the Scopus Library identified 136 potentially relevant articles. Studies were included if they used MRI to inform CFD simulation in TBAD. RESULTS: There were 20 articles meeting the inclusion criteria. 19 studies used phase contrast MRI (PC-MRI) to provide data for CFD flow boundary conditions. In 12 studies, CFD haemodynamic parameter results were validated against PC-MRI. In eight studies, geometric models were developed from MR angiography. In three studies, aortic wall or intimal flap motion data were derived from PC/cine MRI. CONCLUSIONS: MRI provides complementary patient-specific information in CFD haemodynamic studies for TBAD that can be used for personalised care. MRI provides structural, dynamic and flow data to inform CFD for pre-treatment planning, potentially advancing its integration into clinical decision-making. The use of MRI to inform CFD in TBAD surgical planning is promising, however further validation and larger cohort studies are required.

Analysis of sound pressure levels generated by nozzle-emitted large bubbles.

The sound radiated by newly formed bubbles can be used to determine their properties. However, details of the fluid dynamics driving the acoustic emission remain unclear. A neck-collapsing model has been proposed to explain the sound generation at bubble pinch-off. The model uses a forcing function which drives the Rayleigh-Plesset equation and is linked to the bubble acoustic pressure. Here, the model is tested on bubbles of diameter up to 7 mm generated in distilled water, tap water, and alcohol-water solution. The model works well for bubbles less than 2.2 mm radius but the error increases up to 71% for larger diameters.

Numerical simulation of the blood flow through the coronary artery stenosis: Effects of varying eccentricity.

Blockages within arteries, called stenoses, are a common cause of coronary artery disease (CAD). Stenosis is a result of atherosclerotic plaque build-up limits blood flow and hence oxygen and nutrient supplies. Past studies on stenosed arterial flows often assumed stenosis to be axisymmetric in shape. However, medical imaging modalities have shown that stenoses in the coronary arteries are often asymmetric. To address it, an asymmetric stenosis is considered in the model which is based on common dimensions of the left anterior descending artery (LAD). The hemodynamic impacts are studied over a range of degrees of eccentricity (DoE) and degree of stenosis (DoS). Blood flow within the artery is analyzed by solving the incompressible Navier-Stokes equations with both resting and hyperemic flow rates. The wall shear stress (WSS), oscillatory shear index (OSI) and fractional flow reserve (FFR) are calculated. The eccentricity makes the flow deflect away from the model's centerline. Behavior of the deflected flow is significantly altered downstream of the stenosis. Transverse dimension of the recirculation zone grows with increasing DoE, while its longitudinal dimension mainly depends on DoS. Eccentricity also contributes to the development of secondary flow distal to the stenosis. Such complex flow behavior contributes to a further pressure loss and hence a significant change in FFR (<0.8). Calculated WSS and OSI indicate that in actual eccentric stenotic LAD the asymmetric remodeling is anticipated. Thus, consideration of the DoE, along with the DoS, could lead to better patient stratification.

Non-Newtonian Endothelial Shear Stress Simulation: Does It Matter?

Patient-specific coronary endothelial shear stress (ESS) calculations using Newtonian and non-Newtonian rheological models were performed to assess whether the common assumption of Newtonian blood behavior offers similar results to a more realistic but computationally expensive non-Newtonian model. 16 coronary arteries (from 16 patients) were reconstructed from optical coherence tomographic (OCT) imaging. Pulsatile CFD simulations using Newtonian and the Quemada non-Newtonian model were performed. Endothelial shear stress (ESS) and other indices were compared. Exploratory indices including local blood viscosity (LBV) were calculated from non-Newtonian simulation data. Compared to the Newtonian results, the non-Newtonian model estimates significantly higher time-averaged ESS (1.69 (IQR 1.36)Pa versus 1.28 (1.16)Pa, p < 0.001) and ESS gradient (0.90 (1.20)Pa/mm versus 0.74 (1.03)Pa/mm, p < 0.001) throughout the cardiac cycle, under-estimating the low ESS (<1Pa) area (37.20 ± 13.57% versus 50.43 ± 14.16%, 95% CI 11.28-15.18, p < 0.001). Similar results were also found in the idealized artery simulations with non-Newtonian median ESS being higher than the Newtonian median ESS (healthy segments: 0.8238Pa versus 0.6618Pa, p < 0.001 proximal; 0.8179Pa versus 0.6610Pa, p < 0.001 distal; stenotic segments: 0.8196Pa versus 0.6611Pa, p < 0.001 proximal; 0.2546Pa versus 0.2245Pa, p < 0.001 distal) On average, the non-Newtonian model has a LBV of 1.45 times above the Newtonian model with an average peak LBV of 40-fold. Non-Newtonian blood model estimates higher quantitative ESS values than the Newtonian model. Incorporation of non-Newtonian blood behavior may improve the accuracy of ESS measurements. The non-Newtonian model also allows calculation of exploratory viscosity-based hemodynamic indices, such as local blood viscosity, which may offer additional information to detect underlying atherosclerosis.

High endothelial shear stress and stress gradient at plaque erosion persist up to 12 months.

BACKGROUND: Local hemodynamics are known to play an important role in the development of plaque erosion. Recent studies showed that erosion patients might be treated conservatively without stent implantation. We investigated evolution of hemodynamic parameters on the plaque erosion site in conservatively treated patients. METHODS: Computational fluid dynamics (CFD) simulations were performed using the coronary angiogram and optical coherence tomography (OCT) images of non-stent treated erosion patients who had serial OCT studies. Calculated CFD parameters included endothelial shear stress (ESS), ESS gradient (ESSG), and oscillatory shear index (OSI). RESULTS: The CFD parameters at the erosion and non-erosion sites were compared among baseline (n = 23), and 1-month (n = 20) and 12-month (n = 16) follow-ups. The erosion site had higher ESS and ESSG values than the non-erosion sites at baseline (mean ESS: 3.00 vs 1.36 Pa, p < 0.01; mean ESSG: 1.71 vs. 0.65 Pa/mm, p = 0.01), 1-month (mean ESS: 2.89 vs 1.19 Pa, p < 0.01; mean ESSG: 1.71 vs. 0.60 Pa/mm, p < 0.01), and 12-month (mean ESS: 3.26 vs 1.59 Pa, p < 0.01; mean ESSG: 1.87 vs. 0.78 Pa/mm, p < 0.01). OSI was not different between erosion and and non-erosion sites. CONCLUSIONS: ESS and ESSG values were higher at the plaque erosion sites compared to non-erosion sites. Elevated ESS and ESSG at the erosion site persisted up to 12 months. These data indicate that a local thrombogenic milieu related to hemodynamic perturbation persists up to 12 months at the plaque erosion sites following conservative treatment. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov: NCT02041650.

An extensional strain sensing mechanosome drives adhesion-independent platelet activation at supraphysiological hemodynamic gradients.

BACKGROUND: Supraphysiological hemodynamics are a recognized driver of platelet activation and thrombosis at high-grade stenosis and in blood contacting circulatory support devices. However, whether platelets mechano-sense hemodynamic parameters directly in free flow (in the absence of adhesion receptor engagement), the specific hemodynamic parameters at play, the precise timing of activation, and the signaling mechanism(s) involved remain poorly elucidated. RESULTS: Using a generalized Newtonian computational model in combination with microfluidic models of flow acceleration and quasi-homogenous extensional strain, we demonstrate that platelets directly mechano-sense acute changes in free-flow extensional strain independent of shear strain, platelet amplification loops, von Willebrand factor, and canonical adhesion receptor engagement. We define an extensional strain sensing "mechanosome" in platelets involving cooperative Ca2+ signaling driven by the mechanosensitive channel Piezo1 (as the primary strain sensor) and the fast ATP gated channel P2X1 (as the secondary signal amplifier). We demonstrate that type II PI3 kinase C2α activity (acting as a "clutch") couples extensional strain to the mechanosome. CONCLUSIONS: Our findings suggest that platelets are adapted to rapidly respond to supraphysiological extensional strain dynamics, rather than the peak magnitude of imposed wall shear stress. In the context of overall platelet activation and thrombosis, we posit that "extensional strain sensing" acts as a priming mechanism in response to threshold levels of extensional strain allowing platelets to form downstream adhesive interactions more rapidly under the limiting effects of supraphysiological hemodynamics.

High spatial endothelial shear stress gradient independently predicts site of acute coronary plaque rupture and erosion.

AIMS: To investigate local haemodynamics in the setting of acute coronary plaque rupture and erosion. METHODS AND RESULTS: Intracoronary optical coherence tomography performed in 37 patients with acute coronary syndromes caused by plaque rupture (n = 19) or plaque erosion (n = 18) was used for three-dimensional reconstruction and computational fluid dynamics simulation. Endothelial shear stress (ESS), spatial ESS gradient (ESSG), and oscillatory shear index (OSI) were compared between plaque rupture and erosion through mixed-effects logistic regression. Lipid, calcium, macrophages, layered plaque, and cholesterol crystals were also analysed. By multivariable analysis, only high ESSG [odds ratio (OR) 5.29, 95% confidence interval (CI) 2.57-10.89, P < 0.001], lipid (OR 12.98, 95% CI 6.57-25.67, P < 0.001), and layered plaque (OR 3.17, 95% CI 1.82-5.50, P < 0.001) were independently associated with plaque rupture. High ESSG (OR 13.28, 95% CI 6.88-25.64, P < 0.001), ESS (OR 2.70, 95% CI 1.34-5.42, P = 0.005), and OSI (OR 2.18, 95% CI 1.33-3.54, P = 0.002) independently associated with plaque erosion. ESSG was higher at rupture sites than erosion sites [median (interquartile range): 5.78 (2.47-21.15) vs. 2.62 (1.44-6.18) Pa/mm, P = 0.009], OSI was higher at erosion sites than rupture sites [1.04 × 10-2 (2.3 × 10-3-4.74 × 10-2) vs. 1.29 × 10-3 (9.39 × 10-5-3.0 × 10-2), P < 0.001], but ESS was similar (P = 0.29). CONCLUSIONS: High ESSG is independently associated with plaque rupture while high ESSG, ESS, and OSI associate with plaque erosion. While ESSG is higher at rupture sites than erosion sites, OSI is higher at erosion sites and ESS was similar. These results suggest that ESSG and OSI may play critical roles in acute plaque rupture and erosion, respectively.

Active Micropump-Mixer for Rapid Antiplatelet Drug Screening in Whole Blood.

There is a need for scalable automated lab-on-chip systems incorporating precise hemodynamic control that can be applied to high-content screening of new more efficacious antiplatelet therapies. This paper reports on the development and characterization of a novel active micropump-mixer microfluidic to address this need. Using a novel reciprocating elastomeric micropump design, we take advantage of the flexible structural and actuation properties of this framework to manage the hemodynamics for on-chip platelet thrombosis assay on type 1 fibrillar collagen, using whole blood. By characterizing and harnessing the complex three-dimensional hemodynamics of the micropump operation in conjunction with a microvalve controlled reagent injection system we demonstrate that this prototype can act as a real-time assay of antiplatelet drug pharmacokinetics. In a proof-of-concept preclinical application, we utilize this system to investigate the way in which rapid dosing of human whole blood with isoform selective inhibitors of phosphatidylinositol 3-kinase dose dependently modulate platelet thrombus dynamics. This modular system exhibits utility as an automated multiplexable assay system with applications to high-content chemical library screening of new antiplatelet therapies.

Numerical Study of Incomplete Stent Apposition Caused by Deploying Undersized Stent in Arteries With Elliptical Cross Sections.

Incomplete stent apposition (ISA) is one of the causes leading to poststent complications, which can be found when an undersized or an underexpanded stent is deployed at lesions. The previous research efforts have focused on ISA in idealized coronary arterial geometry with circular cross section. However, arterial cross section eccentricity plays an important role in both location and severity of ISA. Computational fluid dynamics (CFD) simulations are carried out to systematically study the effects of ISA in arteries with elliptical cross section, as such stents are partially embedded on the minor axis sides of the ellipse and malapposed elsewhere. Overall, ISA leads to high time-averaged wall shear stress (TAWSS) at the proximal end of the stent and low TAWSS at the ISA transition region and the distal end. Shear rate depends on both malapposition distance and blood stream locations, which is found to be significantly higher at the inner stent surface than the outer surface. The proximal high shear rate signifies increasing possibility in platelet activation, when coupled with low TAWSS at the transition and distal regions which may indicate a nidus for in-stent thrombosis.

Early strut protrusion and late neointima thickness in the Absorb bioresorbable scaffold: a serial wall shear stress analysis up to five years.

AIMS: The aim of the study was to evaluate the effect of strut protrusion (SP) on wall shear stress (WSS) and neointimal growth (NG) one and five years after implantation of an Absorb bioresorbable vascular scaffold. METHODS AND RESULTS: Eight patients were selected from a first-in-man study. Following three-dimensional (3D) reconstruction of coronaries, WSS was quantified using Newtonian steady-flow simulation in each cross-section at 5° subunits (sectors) of the circumferential luminal surface. At one year, neointimal thickness (NT) was measured by optical coherence tomography (OCT) and correlated to WSS and SP post procedure. Median SP was 112.9 (90.8, 133.1) µm post implantation. Post procedure, a logarithmic inverse relationship between SP and post-implantation WSS (r=-0.425, p<0.001; correlation coefficients in a range from -0.143 to -0.553) was observed, whereas a correlation between baseline logarithm-transformed WSS (log-WSS) and NT (r=-0.451, p<0.001; correlation coefficients ranged from -0.140 to -0.662) was documented at one year. Mixed-effects analysis between baseline log-WSS and NT at follow-up yielded a slope of 30 µm/ln Pascal (Pa) and a y-intercept of 98 µm. As a result of NG, median flow area decreased from 6.91 (6.53, 7.48) mm2 post implantation to 5.65 (5.47, 6.02) mm2 at one-year follow-up (p=0.01) and to 5.75±1.37 mm2 at five-year follow-up (p=0.024). However, the vessel surface exposed to low WSS (<1 Pa) decreased significantly post procedure (42%) to one year (35.9%) and five years (15.2%) (p-overall <0.0001). CONCLUSIONS: SP disturbs laminar flow, creates regions of low WSS (<1.0 Pa) that are associated with NG and lumen area reduction. Low WSS post implantation reduced significantly at long-term follow-up. Thin struts with effective embedment would substantially reduce NG and accelerate homogenisation of WSS towards physiological values.

Elevated Blood Viscosity and Microrecirculation Resulting From Coronary Stent Malapposition.

One particular complexity of coronary artery is the natural tapering of the vessel with proximal segments having larger caliber and distal tapering as the vessel get smaller. The natural tapering of a coronary artery often leads to proximal incomplete stent apposition (ISA). ISA alters coronary hemodynamics and creates pathological path to develop complications such as in-stent restenosis, and more worryingly, stent thrombosis (ST). By employing state-of-the-art computer-aided design software, generic stent hoops were virtually deployed in an idealized tapered coronary artery with decreasing malapposition distance. Pulsatile blood flow simulations were carried out using computational fluid dynamics (CFD) on these computer-aided design models. CFD results reveal unprecedented details in both spatial and temporal development of microrecirculation environments throughout the cardiac cycle (CC). Arterial tapering also introduces secondary microrecirculation. These primary and secondary microrecirculations provoke significant fluctuations in arterial wall shear stress (WSS). There has been a direct correlation with changes in WSS and the development of atherosclerosis. Further, the presence of these microrecirculations influence strongly on the local levels of blood viscosity in the vicinity of the malapposed stent struts. The observation of secondary microrecirculations and changes in blood rheology is believed to complement the wall (-based) shear stress, perhaps providing additional physical explanations for tissue accumulation near ISA detected from high resolution optical coherence tomography (OCT).

Endothelial shear stress 5 years after implantation of a coronary bioresorbable scaffold.

Aims: As a sine qua non for arterial wall physiology, local hemodynamic forces such as endothelial shear stress (ESS) may influence long-term vessel changes as bioabsorbable scaffolds dissolve. The aim of this study was to perform serial computational fluid dynamic (CFD) simulations to examine immediate and long-term haemodynamic and vascular changes following bioresorbable scaffold placement. Methods and results: Coronary arterial models with long-term serial assessment (baseline and 5 years) were reconstructed through fusion of intravascular optical coherence tomography and angiography. Pulsatile non-Newtonian CFD simulations were performed to calculate the ESS and relative blood viscosity. Time-averaged, systolic, and diastolic results were compared between follow-ups. Seven patients (seven lesions) were included in this analysis. A marked heterogeneity in ESS and localised regions of high blood viscosity were observed post-implantation. Percent vessel area exposed to low averaged ESS (<1 Pa) significantly decreased over 5 years (15.92% vs. 4.99%, P < 0.0001) whereas moderate (1-7 Pa) and high ESS (>7 Pa) did not significantly change (moderate ESS: 76.93% vs. 80.7%, P = 0.546; high ESS: 7.15% vs. 14.31%, P = 0.281), leading to higher ESS at follow-up. A positive correlation was observed between baseline ESS and change in lumen area at 5 years (P < 0.0001). Maximum blood viscosity significantly decreased over 5 years (4.30 ± 1.54 vs. 3.21± 0.57, P = 0.028). Conclusion: Immediately after scaffold implantation, coronary arteries demonstrate an alternans of extremely low and high ESS values and localized areas of high blood viscosity. These initial local haemodynamic disturbances may trigger fibrin deposition and thrombosis. Also, low ESS can promote neointimal hyperplasia, but may also contribute to appropriate scaffold healing with normalisation of ESS and reduction in peak blood viscosity by 5 years.