Low Shear Stress at Baseline Predicts Expansion and Aneurysm-Related Events in Patients With Abdominal Aortic Aneurysm.

BACKGROUND: Low shear stress has been implicated in abdominal aortic aneurysm (AAA) expansion and clinical events. We tested the hypothesis that low shear stress in AAA at baseline is a marker of expansion rate and future aneurysm-related events. METHODS: Patients were imaged with computed tomography angiography at baseline and followed up every 6 months >24 months with ultrasound measurements of maximum diameter. From baseline computed tomography angiography, we reconstructed 3-dimensional models for automated computational fluid dynamics simulations and computed luminal shear stress. The primary composite end point was aneurysm repair and/or rupture, and the secondary end point was aneurysm expansion rate. RESULTS: We included 295 patients with median AAA diameter of 49 mm (interquartile range, 43-54 mm) and median follow-up of 914 (interquartile range, 670-1112) days. There were 114 (39%) aneurysm-related events, with 13 AAA ruptures and 98 repairs (one rupture was repaired). Patients with low shear stress (<0.4 Pa) experienced a higher number of aneurysm-related events (44%) compared with medium (0.4-0.6 Pa; 27%) and high (>0.6 Pa; 29%) shear stress groups (P=0.010). This association was independent of known risk factors (adjusted hazard ratio, 1.72 [95% CI, 1.08-2.73]; P=0.023). Low shear stress was also independently associated with AAA expansion rate (ß=+0.28 mm/y [95% CI, 0.02-0.53]; P=0.037). CONCLUSIONS: We show for the first time that low shear stress (<0.4 Pa) at baseline is associated with both AAA expansion and future aneurysm-related events. Aneurysms within the lowest tertile of shear stress, versus those with higher shear stress, were more likely to rupture or reach thresholds for elective repair. Larger prospective validation trials are needed to confirm these findings and translate them into clinical management.

Association between erythrocyte dynamics and vessel remodelling in developmental vascular networks.

Sprouting angiogenesis is an essential vascularization mechanism consisting of sprouting and remodelling. The remodelling phase is driven by rearrangements of endothelial cells (ECs) within the post-sprouting vascular plexus. Prior work has uncovered how ECs polarize and migrate in response to flow-induced wall shear stress (WSS). However, the question of how the presence of erythrocytes (widely known as red blood cells (RBCs)) and their impact on haemodynamics affect vascular remodelling remains unanswered. Here, we devise a computational framework to model cellular blood flow in developmental mouse retina. We demonstrate a previously unreported highly heterogeneous distribution of RBCs in primitive vasculature. Furthermore, we report a strong association between vessel regression and RBC hypoperfusion, and identify plasma skimming as the driving mechanism. Live imaging in a developmental zebrafish model confirms this association. Taken together, our results indicate that RBC dynamics are fundamental to establishing the regional WSS differences driving vascular remodelling via their ability to modulate effective viscosity.

Spatiotemporal Dynamics of Dilute Red Blood Cell Suspensions in Low-Inertia Microchannel Flow.

Microfluidic technologies are commonly used for the manipulation of red blood cell (RBC) suspensions and analyses of flow-mediated biomechanics. To enhance the performance of microfluidic devices, understanding the dynamics of the suspensions processed within is crucial. We report novel, to our knowledge, aspects of the spatiotemporal dynamics of RBC suspensions flowing through a typical microchannel at low Reynolds number. Through experiments with dilute RBC suspensions, we find an off-center two-peak (OCTP) profile of cells contrary to the centralized distribution commonly reported for low-inertia flows. This is reminiscent of the well-known "tubular pinch effect," which arises from inertial effects. However, given the conditions of negligible inertia in our experiments, an alternative explanation is needed for this OCTP profile. Our massively parallel simulations of RBC flow in real-size microfluidic dimensions using the immersed-boundary-lattice-Boltzmann method confirm the experimental findings and elucidate the underlying mechanism for the counterintuitive RBC pattern. By analyzing the RBC migration and cell-free layer development within a high-aspect-ratio channel, we show that such a distribution is co-determined by the spatial decay of hydrodynamic lift and the global deficiency of cell dispersion in dilute suspensions. We find a cell-free layer development length greater than 46 and 28 hydraulic diameters in the experiment and simulation, respectively, exceeding typical lengths of microfluidic designs. Our work highlights the key role of transient cell distribution in dilute suspensions, which may negatively affect the reliability of experimental results if not taken into account.

Biomechanical Assessment Predicts Aneurysm Related Events in Patients with Abdominal Aortic Aneurysm.

OBJECTIVE: To test whether aneurysm biomechanical ratio (ABR; a dimensionless ratio of wall stress and wall strength) can predict aneurysm related events. METHODS: In a prospective multicentre clinical study of 295 patients with an abdominal aortic aneurysm (AAA; diameter ≥ 40 mm), three dimensional reconstruction and computational biomechanical analyses were used to compute ABR at baseline. Participants were followed for at least two years and the primary end point was the composite of aneurysm rupture or repair. RESULTS: The majority were male (87%), current or former smokers (86%), most (72%) had hypertension (mean ± standard deviation [SD] systolic blood pressure 140 ± 22 mmHg), and mean ± SD baseline diameter was 49.0 ± 6.9 mm. Mean ± SD ABR was 0.49 ± 0.27. Participants were followed up for a mean ± SD of 848 ± 379 days and rupture (n = 13) or repair (n = 102) occurred in 115 (39%) cases. The number of repairs increased across tertiles of ABR: low (n = 24), medium (n = 34), and high ABR (n = 44) (p = .010). Rupture or repair occurred more frequently in those with higher ABR (log rank p = .009) and ABR was independently predictive of this outcome after adjusting for diameter and other clinical risk factors, including sex and smoking (hazard ratio 1.41; 95% confidence interval 1.09-1.83 [p = .010]). CONCLUSION: It has been shown that biomechanical ABR is a strong independent predictor of AAA rupture or repair in a model incorporating known risk factors, including diameter. Determining ABR at baseline could help guide the management of patients with AAA.

On the optimization of low-cost FDM 3D printers for accurate replication of patient-specific abdominal aortic aneurysm geometry.

BACKGROUND: There is a potential for direct model manufacturing of abdominal aortic aneurysm (AAA) using 3D printing technique for generating flexible semi-transparent prototypes. A patient-specific AAA model was manufactured using fused deposition modelling (FDM) 3D printing technology. A flexible, semi-transparent thermoplastic polyurethane (TPU), called Cheetah Water (produced by Ninjatek, USA), was used as the flexible, transparent material for model manufacture with a hydrophilic support structure 3D printed with polyvinyl alcohol (PVA). Printing parameters were investigated to evaluate their effect on 3D-printing precision and transparency of the final model. ISO standard tear resistance tests were carried out on Ninjatek Cheetah specimens for a comparison of tear strength with silicone rubbers. RESULTS: It was found that an increase in printing speed decreased printing accuracy, whilst using an infill percentage of 100% and printing nozzle temperature of 255 °C produced the most transparent results. The model had fair transparency, allowing external inspection of model inserts such as stent grafts, and good flexibility with an overall discrepancy between CAD and physical model average wall thicknesses of 0.05 mm (2.5% thicker than the CAD model). The tear resistance test found Ninjatek Cheetah TPU to have an average tear resistance of 83 kN/m, higher than any of the silicone rubbers used in previous AAA model manufacture. The model had lower cost (4.50 GBP per model), shorter manufacturing time (25 h 3 min) and an acceptable level of accuracy (2.61% error) compared to other methods. CONCLUSIONS: It was concluded that the model would be of use in endovascular aneurysm repair planning and education, particularly for practicing placement of hooked or barbed stents, due to the model's balance of flexibility, transparency, robustness and cost-effectiveness.

Wall Stress and Geometry of the Thoracic Aorta in Patients With Aortic Valve Disease.

BACKGROUND: Aortic valve disease increases velocity and changes the way blood enters the aorta. Over time, the biomechanical environment can cause aortic remodelling. We hypothesized that aortic geometry and wall stress would be different in patients with aortic valve disease compared with controls. METHODS: We examined 40 patients with aortic sclerosis (n = 10) or mild (n = 10), moderate (n = 10), and severe (n = 10) aortic stenosis, and also 10 control individuals. The thoracic aorta of each individual was reconstructed into a three-dimensional model from computed tomography. We measured geometric variables and used finite element analysis to compute aortic wall stress. Statistical analyses were performed to test our hypothesis. RESULTS: Aortic wall stress was significantly associated with tortuosity of the descending aorta (r = 0.35, p = 0.01), arch radius (r = 0.49, p < 0.01), ascending aortic diameter (r = 0.59, p < 0.01), and aortic centerline length (r = 0.39, p < 0.01). Wall stress was highest in patients with severe stenosis (p = 0.02), although elevations in wall stress were also noted in those with mild stenosis (p = 0.02), and aortic sclerosis (p = 0.02) compared with controls. Similar trends were observed when we corrected for difference in blood pressure. Total centerline tortuosity was higher in patients with severe aortic stenosis than in controls (p = 0.04), as was descending aorta tortuosity (p = 0.04). CONCLUSIONS: Aortic geometry is associated with aortic wall stress. Patients with aortic valve disease have higher aortic wall stress than controls, and those with severe aortic stenosis have more tortuous aortas. However, increases in geometric measures and wall stress are not stepwise with increasing disease severity.

Testing a new surfactant in a widely-used blood mimic for ultrasound flow imaging.

BACKGROUND: A blood-mimicking fluid developed by Ramnarine et al. has been widely used in flow phantoms for ultrasound flow imaging research, and it has also been cited by IEC 61685 as a reference for making blood-mimicking fluid.However, the surfactant material Synperonic N in this blood-mimicking fluid recipe is phased out from the European market due to environmental issues. The aim of this study is to test whether Synperonic N can be substituted by biodegradable Synperonic A7 in making blood-mimicking fluid for ultrasound flow imaging research. METHODS AND MATERIALS: A flow phantom was fabricated to test the blood-mimicking fluid with Synperonic N and Synperonic A7 as surfactants separately. Doppler images and velocity data were collected using a clinical ultrasound scanner under constant and pulsatile flows; and images and measured velocities were compared. RESULTS: It was found that both blood mimics can provide exactly the same images under spectral Doppler ultrasound and colour Doppler ultrasound in terms of their image qualities. The maximum velocities under constant flow were measured by the spectral Doppler ultrasound as 0.4714 ± 0.001 m.s-1 and 0.4644 ± 0.001 m.s-1 for blood-mimicking fluid with Synperonic N and blood-mimicking fluid with Synperonic A7, respectively. Measured velocities using the two different blood-mimicking fluids were statistically different (p < 0.001), but this difference was less than 2%. The Synperonic A7 can be used as a substitute for Synperonic N as a surfactant material in making the blood-mimicking fluid for ultrasound flow imaging research.

Exploring the Biological and Mechanical Properties of Abdominal Aortic Aneurysms Using USPIO MRI and Peak Tissue Stress: A Combined Clinical and Finite Element Study.

Inflammation detected through the uptake of ultrasmall superparamagnetic particles of iron oxide (USPIO) on magnetic resonance imaging (MRI) and finite element (FE) modelling of tissue stress both hold potential in the assessment of abdominal aortic aneurysm (AAA) rupture risk. This study aimed to examine the spatial relationship between these two biomarkers. Patients (n = 50) > 40 years with AAA maximum diameters > = 40 mm underwent USPIO-enhanced MRI and computed tomography angiogram (CTA). USPIO uptake was compared with wall stress predictions from CTA-based patient-specific FE models of each aneurysm. Elevated stress was commonly observed in areas vulnerable to rupture (e.g. posterior wall and shoulder). Only 16% of aneurysms exhibited co-localisation of elevated stress and mural USPIO enhancement. Globally, no correlation was observed between stress and other measures of USPIO uptake (i.e. mean or peak). It is suggested that cellular inflammation and stress may represent different but complimentary aspects of AAA disease progression.

Investigation of Ultrasound-Measured Flow Velocity, Flow Rate and Wall Shear Rate in Radial and Ulnar Arteries Using Simulation.

Parameters of blood flow measured by ultrasound in radial and ulnar arteries, such as flow velocity, flow rate and wall shear rate, are widely used in clinical practice and clinical research. Investigation of these measurements is useful for evaluating accuracy and providing knowledge of error sources. A method for simulating the spectral Doppler ultrasound measurement process was developed with computational fluid dynamics providing flow-field data. Specific scanning factors were adjusted to investigate their influence on estimation of the maximum velocity waveform, and flow rate and wall shear rate were derived using the Womersley equation. The overestimation in maximum velocity increases greatly (peak systolic from about 10% to 30%, time-averaged from about 30% to 50%) when the beam-vessel angle is changed from 30° to 70°. The Womersley equation was able to estimate flow rate in both arteries with less than 3% error, but performed better in the radial artery (2.3% overestimation) than the ulnar artery (15.4% underestimation) in estimating wall shear rate. It is concluded that measurements of flow parameters in the radial and ulnar arteries with clinical ultrasound scanners are prone to clinically significant errors.

Nonlinear multiscale regularisation in MR elastography: Towards fine feature mapping.

Fine-featured elastograms may provide additional information of radiological interest in the context of in vivo elastography. Here a new image processing pipeline called ESP (Elastography Software Pipeline) is developed to create Magnetic Resonance Elastography (MRE) maps of viscoelastic parameters (complex modulus magnitude |G*| and loss angle ϕ) that preserve fine-scale information through nonlinear, multi-scale extensions of typical MRE post-processing techniques. METHODS: A new MRE image processing pipeline was developed that incorporates wavelet-domain denoising, image-driven noise estimation, and feature detection. ESP was first validated using simulated data, including viscoelastic Finite Element Method (FEM) simulations, at multiple noise levels. ESP images were compared with MDEV pipeline images, both in the FEM models and in three ten-subject cohorts of brain, thigh, and liver acquisitions. ESP and MDEV mean values were compared to 2D local frequency estimation (LFE) mean values for the same cohorts as a benchmark. Finally, the proportion of spectral energy at fine frequencies was quantified using the Reduced Energy Ratio (RER) for both ESP and MDEV. RESULTS: Blind estimates of added noise (σ) were within 5.3% ± 2.6% of prescribed, and the same technique estimated σ in the in vivo cohorts at 1.7 ± 0.8%. A 5 × 5 × 5 truncated Gabor filter bank effectively detects local spatial frequencies at wavelengths λ ≤ 10px. For FEM inversions, mean |G*| of hard target, soft target, and background remained within 8% of prescribed up to σ=20%, and mean ϕ results were within 10%, excepting hard target ϕ, which required redrawing around a ring artefact to achieve similar accuracy. Inspection of FEM |G*| images showed some spatial distortion around hard target boundaries and inspection of ϕ images showed ring artefacts around the same target. For the in vivo cohorts, ESP results showed mean correlation of R=0.83 with MDEV and liver stiffness estimates within 7% of 2D-LFE results. Finally, ESP showed statistically significant increase in fine feature spectral energy as measured with RER for both |G*| (p<1×10-9) and ϕ (p<1×10-3). CONCLUSION: Information at finer frequencies can be recovered in ESP elastograms in typical experimental conditions, however scatter- and boundary-related artefacts may cause the fine features to have inaccurate values. In in vivo cohorts, ESP delivers an increase in fine feature spectral energy, and better performance with longer wavelengths, than MDEV while showing similar stability and robustness.

Fabrication of Two Flow Phantoms for Doppler Ultrasound Imaging.

Flow phantoms are widely used in studies associated with Doppler ultrasound measurements, acting as an effective experimental validation system in cardiovascular-related research and in new algorithm/instrumentation development. The development of materials that match the acoustic and mechanical properties of the vascular system is of great interest while designing flow phantoms. Although recipes that meet the flow phantom standard defined by the International Electrotechnical Commission 61685 are already available in the literature, the standard procedure for material preparations and phantom fabrications has not been well established. In this paper, two types of flow phantoms, with and without blood vessel mimic, are described in detail in terms of the material preparation and phantom fabrication. The phantom materials chosen for the two phantoms are from published phantom studies, and their physical properties have been investigated previously. Both the flow phantoms have been scanned by ultrasound scanners and images from different modes are presented. These phantoms may be used in the validation and characterization of Doppler ultrasound measurements in blood vessels with a diameter above 1 mm.

Patient-specific modelling of abdominal aortic aneurysms: The influence of wall thickness on predicted clinical outcomes.

Rupture of abdominal aortic aneurysms (AAAs) is linked to aneurysm morphology. This study investigates the influence of patient-specific (PS) AAA wall thickness on predicted clinical outcomes. Eight patients under surveillance for AAAs were selected from the MA(3)RS clinical trial based on the complete absence of intraluminal thrombus. Two finite element (FE) models per patient were constructed; the first incorporated variable wall thickness from CT (PS_wall), and the second employed a 1.9mm uniform wall (Uni_wall). Mean PS wall thickness across all patients was 1.77±0.42mm. Peak wall stress (PWS) for PS_wall and Uni_wall models was 0.6761±0.3406N/mm(2) and 0.4905±0.0850N/mm(2), respectively. In 4 out of 8 patients the Uni_wall underestimated stress by as much as 55%; in the remaining cases it overestimated stress by up to 40%. Rupture risk more than doubled in 3 out of 8 patients when PS_wall was considered. Wall thickness influenced the location and magnitude of PWS as well as its correlation with curvature. Furthermore, the volume of the AAA under elevated stress increased significantly in AAAs with higher rupture risk indices. This highlights the sensitivity of standard rupture risk markers to the specific wall thickness strategy employed.

Investigation of Ultrasound-Measured Flow Rate and Wall Shear Rate in Wrist Arteries Using Flow Phantoms.

The aim of this study was to evaluate the errors in measurement of volumetric flow rate and wall shear rate measured in radial and ulnar arteries using a commercial ultrasound scanning system. The Womersley equations were used to estimate the flow rate and wall shear rate waveforms, based on the measured vessel diameter and centerline velocity waveform. In the experiments, each variable (vessel depth, diameter, flow rate, beam-vessel angle and different waveform) in the phantom was investigated in turn, and its value was varied within a normal range while others were fixed at their typical values. The outcomes revealed that flow rate and wall shear rate were overestimated in all cases, from around 13% to nearly 50%. It is concluded that measurements of flow rate and wall shear rate in radial and ulnar arteries with a clinical ultrasound scanner are vulnerable to overestimation.

Assessment of Spectral Doppler for an Array-Based Preclinical Ultrasound Scanner Using a Rotating Phantom.

Velocity measurement errors were investigated for an array-based preclinical ultrasound scanner (Vevo 2100, FUJIFILM VisualSonics, Toronto, ON, Canada). Using a small-size rotating phantom made from a tissue-mimicking material, errors in pulse-wave Doppler maximum velocity measurements were observed. The extent of these errors was dependent on the Doppler angle, gate length, gate depth, gate horizontal placement and phantom velocity. Errors were observed to be up to 172% at high beam-target angles. It was found that small gate lengths resulted in larger velocity errors than large gate lengths, a phenomenon that has not previously been reported (e.g., for a beam-target angle of 0°, the error was 27.8% with a 0.2-mm gate length and 5.4% with a 0.98-mm gate length). The error in the velocity measurement with sample volume depth changed depending on the operating frequency of the probe. Some edge effects were observed in the horizontal placement of the sample volume, indicating a change in the array aperture size. The error in the velocity measurements increased with increased phantom velocity, from 22% at 2.4 cm/s to 30% at 26.6 cm/s. To minimise the impact of these errors, an angle-dependent correction factor was derived based on a simple ray model of geometric spectral broadening. Use of this angle-dependent correction factor reduces the maximum velocity measurement errors to <25% in all instances, significantly improving the current estimation of maximum velocity from pulse-wave Doppler ultrasound.

Comparison of vortical structures induced by arteriovenous grafts using vector Doppler ultrasound.

Arteriovenous prosthetic grafts are used in hemodialysis. Stenosis in the venous anastomosis is the main cause of occlusion and the role of local hemodynamics in this is considered significant. A new spiral graft design has been proposed to stabilize the flow phenomena in the host vein. Cross-flow vortical structures in the outflow of this graft were compared with those from a control device. Both grafts were integrated in identical in-house ultrasound-compatible flow phantoms with realistic surgical configurations. Constant flow rates were applied. In-plane 2-D velocity and vorticity mapping was developed using a vector Doppler technique. One or two vortices were detected for the spiral graft and two to four for the control, along with reduced stagnation points for the former. The in-plane peak velocity and circulation were calculated and found to be greater for the spiral device, implying increased in-plane mixing, which is believed to inhibit thrombosis and neo-intimal hyperplasia.

Manufacturing of microcirculation phantoms using rapid prototyping technologies.

In this paper, we describe a method for the manufacturing of a microcirculation phantom that may be used to investigate hemodynamics using optics based methods. We made an Acrylonitrile Butadiene Styrene (ABS) negative mold, manufactured in a Fused Deposition Modelling (FDM) printer, embedded it in Polydimethysilioxane (PDMS) and dissolved it from within using acetone. We successfully made an enlarged three-dimensional (3D) network of microcirculation, and tested it using red blood cell (RBC) analogues. This phantom may be used for testing medical imaging technology.

Wall-less flow phantom for high-frequency ultrasound applications.

There are currently very few test objects suitable for high-frequency ultrasound scanners that can be rapidly manufactured, have appropriate acoustic characteristics and are suitably robust. Here we describe techniques for the creation of a wall-less flow phantom using a physically robust konjac and carrageenan-based tissue-mimicking material. Vessel dimensions equivalent to those of mouse and rat arteries were achieved with steady flow, with the vessel at a depth of 1.0 mm. We then employed the phantom to briefly investigate velocity errors using pulsed wave Doppler with a commercial preclinical ultrasound system. This phantom will provide a useful tool for testing preclinical ultrasound imaging systems.

acoustic assessment of a konjac­carrageenan tissue-mimicking material aT 5­60 MHZ.

The acoustic properties of a robust tissue-mimicking material based on konjac­carrageenan at ultrasound frequencies in the range 5­60 MHz are described. Acoustic properties were characterized using two methods: a broadband reflection substitution technique using a commercially available preclinical ultrasound scanner (Vevo 770, FUJIFILM VisualSonics, Toronto, ON, Canada), and a dedicated high-frequency ultrasound facility developed at the National Physical Laboratory (NPL, Teddington, UK), which employed a broadband through-transmission substitution technique. The mean speed of sound across the measured frequencies was found to be 1551.7 ± 12.7 and 1547.7 ± 3.3 m s21, respectively. The attenuation exhibited a non-linear dependence on frequency, f (MHz), in the form of a polynomial function: 0.009787f2 1 0.2671f and 0.01024f2 1 0.3639f, respectively. The characterization of this tissue-mimicking material will provide reference data for designing phantoms for preclinical systems, which may, in certain applications such as flow phantoms, require a physically more robust tissuemimicking material than is currently available.

Secondary flow in peripheral vascular prosthetic grafts using vector Doppler imaging.

Prosthetic grafts are used for the treatment of peripheral arterial disease. Re-stenosis in the distal anastomosis of these grafts is a common reason for graft occlusion. The role of local hemodynamics in development of neo-intimal hyperplasia is well known. A new graft design has been proposed for the induction of optimized spiral flow in the host vessel. The secondary flow motions induced by this graft were compared with those of a control device. Both types of grafts were connected with vessel mimic and positioned in ultrasound flow phantoms with identical geometry. Constant flow rates were applied. Data collected in the cross-sectional view distal from the graft outflow and dual-beam vector Doppler was applied to create 2-D velocity maps. A single-spiral flow pattern was found for the flow-modified graft, and double or triple spirals for the control graft. In-plane maximum velocity was greater for the flow-modified graft than for the control device.