Endothelial Responses to Curvature-Induced Flow Patterns in Engineered Cerebral Aneurysms.

Hemodynamic factors have long been associated with clinical outcomes in the treatment of cerebral aneurysms. Computational studies of cerebral aneurysm hemodynamics have provided valuable estimates of the mechanical environment experienced by the endothelium in both the parent vessel and aneurysmal dome walls and have correlated them with disease state. These computational-clinical studies have recently been correlated with the response of endothelial cells (EC) using either idealized or patient-specific models. Here, we present a robust workflow for generating anatomic-scale aneurysm models, establishing luminal cultures of ECs at physiological relevant flow profiles, and comparing EC responses to curvature mediated flow. We show that flow patterns induced by parent vessel curvature produce changes in wall shear stress (WSS) and wall shear stress gradients (WSSG) that are correlated with differences in cell morphology and cellular protein localization. Cells in higher WSS regions align better with the flow and display strong Notch1-extracellular domain (ECD) polarization, while, under low WSS, differences in WSSG due to curvature change were associated with less alignment and attenuation of Notch1-ECD polarization in ECs of the corresponding regions. These proof-of-concept results highlight the use of engineered cellularized aneurysm models for connecting computational fluid dynamics to the underlying endothelial biology that mediates disease.

The effect of Dean, Reynolds, and Womersley number on the flow in a spherical cavity on a curved round pipe. Part 1. Fluid mechanics in the cavity as a canonical flow representing intracranial aneurysms.

Flow in side-wall cerebral aneurysms can be ideally modelled as the combination of flow over a spherical cavity and flow in a curved circular pipe, two canonical flows. Flow in a curved pipe is known to depend on the Dean number De, combining the effects of Reynolds number, Re, and of the curvature along the pipe centreline, κ. Pulsatility in the flow introduces a dependency on the Womersley number Wo. Using stereo PIV measurements, this study investigated the effect of these three key non-dimensional parameters, by modifying pipe curvature (De), flow-rate (Re), and pulsatility frequency (Wo), on the flow patterns in a spherical cavity. A single counter-rotating vortex was observed in the cavity for all values of pipe curvature κ and Re, for both steady and pulsatile inflow conditions. Increasing the pipe curvature impacted both the flow patterns in the pipe and the cavity, by shifting the velocity profile towards the cavity opening and increasing the flow rate into the cavity. The circulation in the cavity was found to collapse well with only the Dean number, for both steady and pulsatile inflows. For pulsatile inflow, the counter-rotating vortex was unstable and the location of its centre over time was impacted by the curvature of the pipe, as well as the Re and the Wo in the freestream. The circulation in the cavity was higher for steady inflow than for the equivalent average Reynolds and Dean number pulsatile inflow, with very limited impact of the Womersley in the range studied.

The effect of Dean, Reynolds and Womersley numbers on the flow in a spherical cavity on a curved round pipe. Part 2. The haemodynamics of intracranial aneurysms treated with flow-diverting stents.

The flow in a spherical cavity on a curved round pipe is a canonical flow that describes well the flow inside a sidewall aneurysm on an intracranial artery. Intracranial aneurysms are often treated with a flow-diverting stent (FDS), a low-porosity metal mesh that covers the entrance to the cavity, to reduce blood flow into the aneurysm sac and exclude it from mechanical stresses imposed by the blood flow. Successful treatment is highly dependent on the degree of reduction of flow inside the cavity, and the resulting altered fluid mechanics inside the aneurysm following treatment. Using stereoscopic particle image velocimetry, we characterize the fluid mechanics in a canonical configuration representative of an intracranial aneurysm treated with a FDS: a spherical cavity on the side of a curved round pipe covered with a metal mesh formed by an actual medical FDS. This porous mesh coverage is the focus of Part 2 of the paper, characterizing the effects of parent vessel Re, De and pulsatility, Wo, on the fluid dynamics, compared with the canonical configuration with no impediments to flow into the cavity that is described in Part 1 (Chassagne et al., J. Fluid Mech., vol. 915, 2021, A123). Coverage with a FDS markedly reduces the flow Re in the aneurysmal cavity, creating a viscous-dominated flow environment despite the parent vessel Re > 100. Under steady flow conditions, the topology that forms inside the cavity is shown to be a function of the parent vessel De. At low values of De, flow enters the cavity at the leading edge and remains attached to the wall before exiting at the trailing edge, a novel behaviour that was not found under any conditions of the high-Re, unimpeded cavity flow described in Part 1. Under these conditions, flow in the cavity co-rotates with the direction of the free-stream flow, similar to Stokes flow in a cavity. As De increases, the flow along the leading edge begins to separate, and the recirculation zone grows with increasing De, until, above De ≈ 180, the flow inside the cavity is fully recirculating, counter-rotating with respect to the free-stream flow. Under pulsatile flow conditions, the vortex inside the cavity progresses through the same cycle - switching from attached and co-rotating with the free-stream flow at the beginning of the cycle (low velocity and positive acceleration) to separated and counter-rotating as De reaches a critical value. The location of separation within the harmonic cycle is shown to be a function of both De and Wo. The values of aneurysmal cavity Re based on both the average velocity and the circulation inside the cavity are shown to increase with increasing values of De, while Wo is shown to have little influence on the time-averaged metrics. As De increases, the strength of the secondary flow in the parent vessel grows, due to the inertial instability in the curved pipe, and the flow rate entering the cavity increases. Thus, the effectiveness of FDS treatment to exclude the aneurysmal cavity from the haemodynamic stresses is compromised for aneurysms located on high-curvature arteries, i.e. vessels with high De, and this can be a fluid mechanics criterion to guide treatment selection.

Genetic correlates of wall shear stress in a patient-specific 3D-printed cerebral aneurysm model.

OBJECTIVES: To study the correlation between wall shear stress and endothelial cell expression in a patient-specific, three-dimensional (3D)-printed model of a cerebral aneurysm. MATERIALS AND METHODS: A 3D-printed model of a cerebral aneurysm was created from a patient's angiogram. After populating the model with human endothelial cells, it was exposed to media under flow for 24 hours. Endothelial cell morphology was characterized in five regions of the 3D-printed model using confocal microscopy. Endothelial cells were then harvested from distinct regions of the 3D-printed model for mRNA collection and gene analysis via quantitative polymerase chain reaction (qPCR.) Cell morphology and mRNA measurement were correlated with computational fluid dynamics simulations. RESULTS: The model was successfully populated with endothelial cells, which survived under flow for 24 hours. Endothelial morphology showed alignment with flow in the proximal and distal parent vessel and aneurysm neck, but disorganization in the aneurysm dome. Genetic analysis of endothelial mRNA expression in the aneurysm dome and distal parent vessel was compared with the proximal parent vessels. ADAMTS-1 and NOS3 were downregulated in the aneurysm dome, while GJA4 was upregulated in the distal parent vessel. Disorganized morphology and decreased ADAMTS-1 and NOS3 expression correlated with areas of substantially lower wall shear stress and wall shear stress gradient in computational fluid dynamics simulations. CONCLUSIONS: Creating 3D-printed models of patient-specific cerebral aneurysms populated with human endothelial cells is feasible. Analysis of these cells after exposure to flow demonstrates differences in both cell morphology and genetic expression, which correlate with areas of differential hemodynamic stress.

Computational fluid dynamics of cerebral aneurysm coiling using high-resolution and high-energy synchrotron X-ray microtomography: comparison with the homogeneous porous medium approach.

BACKGROUND: Computational modeling of intracranial aneurysms provides insights into the influence of hemodynamics on aneurysm growth, rupture, and treatment outcome. Standard modeling of coiled aneurysms simplifies the complex geometry of the coil mass into a homogeneous porous medium that fills the aneurysmal sac. We compare hemodynamics of coiled aneurysms modeled from high-resolution imaging with those from the same aneurysms modeled following the standard technique, in an effort to characterize sources of error from the simplified model. MATERIALS: Physical models of two unruptured aneurysms were created using three-dimensional printing. The models were treated with coil embolization using the same coils as those used in actual patient treatment and then scanned by synchrotron X-ray microtomography to obtain high-resolution imaging of the coil mass. Computational modeling of each aneurysm was performed using patient-specific boundary conditions. The coils were modeled using the simplified porous medium or by incorporating the X-ray imaged coil surface, and the differences in hemodynamic variables were assessed. RESULTS: X-ray microtomographic imaging of coils and incorporation into computational models were successful for both aneurysms. Porous medium calculations of coiled aneurysm hemodynamics overestimated intra-aneurysmal flow, underestimated oscillatory shear index and viscous dissipation, and over- or underpredicted wall shear stress (WSS) and WSS gradient compared with X-ray-based coiled computational fluid dynamics models. CONCLUSIONS: Computational modeling of coiled intracranial aneurysms using the porous medium approach may inaccurately estimate key hemodynamic variables compared with models incorporating high-resolution synchrotron X-ray microtomographic imaging of complex aneurysm coil geometry.