Combined anti-angiogenic and cytotoxic treatment of a solid tumour: in silico investigation of a xenograft animal model's digital twin.

Anti-angiogenic (AA) treatments have received significant research interest due to the key role of angiogenesis in cancer progression. AA agents can have a strong effect on cancer regression, by blocking new vessels and reducing the density of the existing vasculature. Moreover, in a process termed vascular normalisation, AA drugs can improve the abnormal structure and function of the tumour vasculature, enhancing the delivery of chemotherapeutics to the tumour site. Despite their promising potential, an improved understanding of AA treatments is necessary to optimise their administration as a monotherapy or in combination with other cancer treatments. In this work we present an in silico multiscale cancer model which is used to systematically interrogate the role of individual mechanisms of action of AA drugs in tumour regression. Focus is placed on the reduction of vascular density and on vascular normalisation through a parametric study, which are considered either as monotherapies or in combination with conventional/ metronomic chemotherapy. The model is specified to data from a mammary carcinoma xenograft in immunodeficient mice, to enhance the physiological relevance of model predictions. Our results suggest that conventional chemotherapy might be more beneficial when combined with AA treatments, hindering tumour growth without causing excessive damage on healthy tissue. Notably, metronomic chemotherapy has shown significant potential in stopping tumour growth with minimal toxicity, even as a monotherapy. Our findings underpin the potential of our in silico framework for non-invasive and cost-effective evaluation of treatment strategies, which can enhance our understanding of combined therapeutic strategies and contribute towards improving cancer treatment management.

Computational Fluid Dynamics Support for Fontan Planning in Minutes, Not Hours: The Next Step in Clinical Pre-Interventional Simulations.

Computational fluid dynamics (CFD) modeling may aid in planning of invasive interventions in Fontan patients. Clinical application of current CFD techniques is however limited by complexity and long computation times. Therefore, we validated a "lean" CFD method to magnetic resonance imaging (MRI) and an "established" CFD method, ultimately aiming to reduce complexity to enable predictive CFD during ongoing interventions. Fifteen Fontan patients underwent MRI for CFD modeling. The differences between lean and established approach, in hepatic and total flow percentage to the left pulmonary artery (%LPA), power loss and relative wall shear stress area were 1.5 ± 4.0%, -0.17 ± 1.1%, -0.055 ± 0.092 mW and 1.1 ± 1.4%. Compared with MRI, the lean and established method showed a bias in %LPA of -1.9 ± 3.4% and -1.8 ± 3.1%. Computation time was for the lean and established approach 3.0 ± 2.0 min and 7.0 ± 3.4 h, respectively. We conclude that the proposed lean method provides fast and reliable results for future CFD support during interventions.

Blood flow imaging by optimal matching of computational fluid dynamics to 4D-flow data.

PURPOSE: Three-dimensional, time-resolved blood flow measurement (4D-flow) is a powerful research and clinical tool, but improved resolution and scan times are needed. Therefore, this study aims to (1) present a postprocessing framework for optimization-driven simulation-based flow imaging, called 4D-flow High-resolution Imaging with a priori Knowledge Incorporating the Navier-Stokes equations and the discontinuous Galerkin method (4D-flow HIKING), (2) investigate the framework in synthetic tests, (3) perform phantom validation using laser particle imaging velocimetry, and (4) demonstrate the use of the framework in vivo. METHODS: An optimizing computational fluid dynamics solver including adjoint-based optimization was developed to fit computational fluid dynamics solutions to 4D-flow data. Synthetic tests were performed in 2D, and phantom validation was performed with pulsatile flow. Reference velocity data were acquired using particle imaging velocimetry, and 4D-flow data were acquired at 1.5 T. In vivo testing was performed on intracranial arteries in a healthy volunteer at 7 T, with 2D flow as the reference. RESULTS: Synthetic tests showed low error (0.4%-0.7%). Phantom validation showed improved agreement with laser particle imaging velocimetry compared with input 4D-flow in the horizontal (mean -0.05 vs -1.11 cm/s, P < .001; SD 1.86 vs 4.26 cm/s, P < .001) and vertical directions (mean 0.05 vs -0.04 cm/s, P = .29; SD 1.36 vs 3.95 cm/s, P < .001). In vivo data show a reduction in flow rate error from 14% to 3.5%. CONCLUSIONS: Phantom and in vivo results from 4D-flow HIKING show promise for future applications with higher resolution, shorter scan times, and accurate quantification of physiological parameters.

Real-World Variability in the Prediction of Intracranial Aneurysm Wall Shear Stress: The 2015 International Aneurysm CFD Challenge.

PURPOSE: Image-based computational fluid dynamics (CFD) is widely used to predict intracranial aneurysm wall shear stress (WSS), particularly with the goal of improving rupture risk assessment. Nevertheless, concern has been expressed over the variability of predicted WSS and inconsistent associations with rupture. Previous challenges, and studies from individual groups, have focused on individual aspects of the image-based CFD pipeline. The aim of this Challenge was to quantify the total variability of the whole pipeline. METHODS: 3D rotational angiography image volumes of five middle cerebral artery aneurysms were provided to participants, who were free to choose their segmentation methods, boundary conditions, and CFD solver and settings. Participants were asked to fill out a questionnaire about their solution strategies and experience with aneurysm CFD, and provide surface distributions of WSS magnitude, from which we objectively derived a variety of hemodynamic parameters. RESULTS: A total of 28 datasets were submitted, from 26 teams with varying levels of self-assessed experience. Wide variability of segmentations, CFD model extents, and inflow rates resulted in interquartile ranges of sac average WSS up to 56%, which reduced to < 30% after normalizing by parent artery WSS. Sac-maximum WSS and low shear area were more variable, while rank-ordering of cases by low or high shear showed only modest consensus among teams. Experience was not a significant predictor of variability. CONCLUSIONS: Wide variability exists in the prediction of intracranial aneurysm WSS. While segmentation and CFD solver techniques may be difficult to standardize across groups, our findings suggest that some of the variability in image-based CFD could be reduced by establishing guidelines for model extents, inflow rates, and blood properties, and by encouraging the reporting of normalized hemodynamic parameters.

Morphological and hemodynamical alterations in brachial artery and cephalic vein. An image-based study for preoperative assessment for vascular access creation.

The current study aims to computationally evaluate the effect of right upper arm position on the geometric and hemodynamic characteristics of the brachial artery (BA) and cephalic vein (CV) and, furthermore, to present in detail the methodology to characterise morphological and hemodynamical healthy vessels. Ten healthy volunteers were analysed in two configurations, the supine (S) and the prone (P) position. Lumen 3D surface models were constructed from images acquired from a non-contrast MRI sequence. Then, the models were used to numerically compute the physiological range of geometric (n = 10) and hemodynamic (n = 3) parameters in the BA and CV. Geometric parameters such as curvature and tortuosity, and hemodynamic parameters based on wall shear stress (WSS) metrics were calculated with the use of computational fluid dynamics. Our results highlight that changes in arm position had a greater impact on WSS metrics of the BA by altering the mean and maximum blood flow rate of the vessel. Whereas, curvature and tortuosity were found not to be significantly different between positions. Inter-variability was associated with antegrade and retrograde flow in BA, and antegrade flow in CV. Shear stress was low and oscillatory shear forces were negligible. This data suggests that deviations from this state may contribute to the risk of accelerated intimal hyperplasia of the vein in arteriovenous fistulas. Therefore, preoperative conditions coupled with post-operative longitudinal data will aid the identification of such relationships.

Imaging in Vascular Access.

This review examines four imaging modalities; ultrasound (US), digital subtraction angiography (DSA), magnetic resonance imaging (MRI) and computed tomography (CT), that have common or potential applications in vascular access (VA). The four modalities are reviewed under their primary uses, techniques, advantages and disadvantages, and future directions that are specific to VA. Currently, US is the most commonly used modality in VA because it is cheaper (relative to other modalities), accessible, non-ionising, and does not require the use of contrast agents. DSA is predominantly only performed when an intervention is indicated. MRI is limited by its cost and the time required for image acquisition that mainly confines it to the realm of research where high resolution is required. CT's short acquisition times and high resolution make it useful as a problem-solving tool in complex cases, although accessibility can be an issue. All four imaging modalities have advantages and disadvantages that limit their use in this particular patient cohort. Current imaging in VA comprises an integrated approach with each modality providing particular uses dependent on their capabilities. MRI and CT, which currently have limited use, may have increasingly important future roles in complex cases where detailed analysis is required.

Haemodynamics and Flow Modification Stents for Peripheral Arterial Disease: A Review.

Endovascular stents are widely used for the treatment of peripheral arterial disease (PAD). However, the development of in-stent restenosis and downstream PAD progression remain a challenge. Stent revascularisation of PAD causes arterial trauma and introduces abnormal haemodynamics, which initiate complicated biological processes detrimental to the arterial wall. The interaction between stent struts and arterial cells in contact, and the blood flow field created in a stented region, are highly affected by stent design. Spiral flow is known as a normal physiologic characteristic of arterial circulation and is believed to prevent the development of flow disturbances. This secondary flow motion is lost in atheromatous disease and its re-introduction after endovascular treatment of PAD has been suggested as a method to induce stabilised and coherent haemodynamics. Stent designs able to generate spiral flow may support endothelial function and therefore increase patency rates. This review is focused on secondary flow phenomena in arteries and the development of flow modification stent technologies for the treatment of PAD.

Hemodynamic impact of abdominal aortic aneurysm stent-graft implantation-induced stenosis.

The current study aims to computationally evaluate the hemodynamic impact of a novel sealing mechanism employed by a recently developed endograft (Ovation TriVascular Stent-Graft System) for endovascular aneurysm repair. The exploitation of two inflatable O-rings to achieve sealing may be advantageous in terms of accommodating challenging anatomies, but comes at a price of a marked inflow stenosis. Here, four representative patient cases of inflow stenosis ranging from 30 to 80 % were analyzed. Lumen surface models were constructed from 1 month post-operative computed tomography images and then used to numerically compute the complex endograft flow field. Our results highlight coexistence of stenotic wall regions exposed to high shear rate and post-stenotic recirculation zones. These conditions may implicate platelet activation and predispose thrombus formation and thromboembolic complications. A clinically insignificant cycle-averaged pressure drop along the inflow stenosis and further in the endograft main body legs was predicted (range 0.01-1.72 mmHg) which was, however, notable at peak systole (range 3.52-19.73 mmHg). Although the functional impact of the endograft stenosis at rest flow conditions may appear insignificant, increased flow rate during exercise is expected to strongly accentuate the observed effects. Pressure drop in the endograft legs was attributed to suboptimal, based on Murray's scaling law, cross-sectional area ratio between trunk and legs of the device.

The Computational Fluid Dynamics Rupture Challenge 2013--Phase II: Variability of Hemodynamic Simulations in Two Intracranial Aneurysms.

With the increased availability of computational resources, the past decade has seen a rise in the use of computational fluid dynamics (CFD) for medical applications. There has been an increase in the application of CFD to attempt to predict the rupture of intracranial aneurysms, however, while many hemodynamic parameters can be obtained from these computations, to date, no consistent methodology for the prediction of the rupture has been identified. One particular challenge to CFD is that many factors contribute to its accuracy; the mesh resolution and spatial/temporal discretization can alone contribute to a variation in accuracy. This failure to identify the importance of these factors and identify a methodology for the prediction of ruptures has limited the acceptance of CFD among physicians for rupture prediction. The International CFD Rupture Challenge 2013 seeks to comment on the sensitivity of these various CFD assumptions to predict the rupture by undertaking a comparison of the rupture and blood-flow predictions from a wide range of independent participants utilizing a range of CFD approaches. Twenty-six groups from 15 countries took part in the challenge. Participants were provided with surface models of two intracranial aneurysms and asked to carry out the corresponding hemodynamics simulations, free to choose their own mesh, solver, and temporal discretization. They were requested to submit velocity and pressure predictions along the centerline and on specified planes. The first phase of the challenge, described in a separate paper, was aimed at predicting which of the two aneurysms had previously ruptured and where the rupture site was located. The second phase, described in this paper, aims to assess the variability of the solutions and the sensitivity to the modeling assumptions. Participants were free to choose boundary conditions in the first phase, whereas they were prescribed in the second phase but all other CFD modeling parameters were not prescribed. In order to compare the computational results of one representative group with experimental results, steady-flow measurements using particle image velocimetry (PIV) were carried out in a silicone model of one of the provided aneurysms. Approximately 80% of the participating groups generated similar results. Both velocity and pressure computations were in good agreement with each other for cycle-averaged and peak-systolic predictions. Most apparent "outliers" (results that stand out of the collective) were observed to have underestimated velocity levels compared to the majority of solutions, but nevertheless identified comparable flow structures. In only two cases, the results deviate by over 35% from the mean solution of all the participants. Results of steady CFD simulations of the representative group and PIV experiments were in good agreement. The study demonstrated that while a range of numerical schemes, mesh resolution, and solvers was used, similar flow predictions were observed in the majority of cases. To further validate the computational results, it is suggested that time-dependent measurements should be conducted in the future. However, it is recognized that this study does not include the biological aspects of the aneurysm, which needs to be considered to be able to more precisely identify the specific rupture risk of an intracranial aneurysm.

The effect of head rotation on the geometry and hemodynamics of healthy vertebral arteries.

The geometric and hemodynamic characteristics of the left and right vertebral arteries (LVA, RVA) of six healthy volunteers were investigated for the supine (S) and the prone position (P) a common sleeping posture with head rotation. MRI images were used to reconstruct the subject specific three-dimensional solid models of the LVA and RVA from the level of the carotid bifurcation to the vertebrobasilar junction (VJ). Geometric parameters such as cross sectional area ratio, curvature, tortuosity and branch angle were estimated. MR-PCA was used to obtain the blood flow waveforms for the two positions and computational fluid dynamics (CFD) were used to assess the flow field in terms of wall shear stress (WSS) relative residence times (RRT) and localized normalized helicity (LNH). Significant geometric changes but moderate flow changes were observed for both vertebral arteries with head rotation. The CFD results at the VJ show that head rotation causes changes in the WSS distribution, RRT and LNH. Further studies are warranted to assess the clinical significance of the results in terms of atherosclerosis development at the VJ and how the observed geometric changes may affect blood flow to the brain in healthy subjects and vertebral artery stenosis patients, and in terms of increased rapture susceptibility in vertebrobasilar aneurysm patients.

Impact of head rotation on the individualized common carotid flow and carotid bifurcation hemodynamics.

This paper aims at evaluating the changes that head rotation poses on morphological and flow characteristics of the carotid bifurcation (CB) and on the distribution of parameters that are regarded as important in atherosclerosis development, such as relative particle residence time (RRT), normalized oscillatory shear index (nOSI), and helicity (HL). Using a subject-specific approach, six healthy volunteers were MR-scanned in two head postures: supine neutral and prone with rightward head rotation. Cross-sectional flow velocity distribution was obtained using phase-contrast MRI at the common carotid artery (CCA). Our results indicate that peak systolic flow rate is reduced at the prone position in most cases for both CCAs. Morphological MR images are used to segment and construct the CB models. Numerical simulations are performed and areas exposed to high helicity or unfavorable hemodynamics are calculated. Head rotation affects the instantaneous spatial extent of high helicity regions. Posture-related observed differences in the distribution of nOSI and RRT suggest that inlet flow waveform tends to moderate geometry-induced changes in the qualitative and quantitative distribution of atherosclerosis-susceptible wall regions. Overall, presented results indicate that an individualized approach is required to fully assess the postural role in atherosclerosis development and in complications arising in stenotic and stented vessels.

Variability of computational fluid dynamics solutions for pressure and flow in a giant aneurysm: the ASME 2012 Summer Bioengineering Conference CFD Challenge.

Stimulated by a recent controversy regarding pressure drops predicted in a giant aneurysm with a proximal stenosis, the present study sought to assess variability in the prediction of pressures and flow by a wide variety of research groups. In phase I, lumen geometry, flow rates, and fluid properties were specified, leaving each research group to choose their solver, discretization, and solution strategies. Variability was assessed by having each group interpolate their results onto a standardized mesh and centerline. For phase II, a physical model of the geometry was constructed, from which pressure and flow rates were measured. Groups repeated their simulations using a geometry reconstructed from a micro-computed tomography (CT) scan of the physical model with the measured flow rates and fluid properties. Phase I results from 25 groups demonstrated remarkable consistency in the pressure patterns, with the majority predicting peak systolic pressure drops within 8% of each other. Aneurysm sac flow patterns were more variable with only a few groups reporting peak systolic flow instabilities owing to their use of high temporal resolutions. Variability for phase II was comparable, and the median predicted pressure drops were within a few millimeters of mercury of the measured values but only after accounting for submillimeter errors in the reconstruction of the life-sized flow model from micro-CT. In summary, pressure can be predicted with consistency by CFD across a wide range of solvers and solution strategies, but this may not hold true for specific flow patterns or derived quantities. Future challenges are needed and should focus on hemodynamic quantities thought to be of clinical interest.

Effect of head posture on the healthy human carotid bifurcation hemodynamics.

Head and neck postures may cause morphology changes to the geometry of the carotid bifurcation (CB) that alter the low and oscillating wall shear stress (WSS) regions previously reported as important in the development of atherosclerosis. Here the right and left CB were imaged by MRI in two healthy subjects in the neutral head posture with the subject in the supine position and in two other head postures with the subject in the prone position: (1) rightward rotation up to 80°, and (2) leftward rotation up to 80°. Image-based computational models were constructed to investigate the effect of posture on arterial geometry and local hemodynamics. The area exposure to unfavorable hemodynamics, based on thresholds set for oscillatory shear index (OSI), WSS and relative residence time, was used to quantify the hemodynamic impact on the wall. Torsion of the head was found to: (1) cause notable changes in the bifurcation and internal carotid artery angles and, in most cases, on cross-sectional area ratios for common, internal and external carotid artery, (2) change the spatial distribution of wall regions exposed to unfavorable hemodynamics, and (3) cause a marked change in the hemodynamic burden on the wall when the OSI was considered. These findings suggest that head posture may be associated with the genesis and development of atherosclerotic disease as well as complications in stenotic and stented vessels.

Effect of posture change on the geometric features of the healthy carotid bifurcation.

Segmented cross-sectional MRI images were used to construct 3-D virtual models of the carotid bifurcation in ten healthy volunteers. Geometric features, such as bifurcation angle, internal carotid artery (ICA) angle, planarity angle, asymmetry angle, tortuosity, curvature, bifurcation area ratio, ICA/common carotid artery (CCA), external carotid artery (ECA)/CCA, and ECA/ICA diameter ratios, were calculated for both carotids in two head postures: 1) the supine neutral position; and 2) the prone sleeping position with head rotation to the right ( ∼ 80°). The results obtained have shown that head rotation causes 1) significant variations in bifurcation angle [32% mean increase for the right carotid (RC) and 21% mean decrease for the left carotid (LC)] and internal carotid artery angle (97% mean increase for the RC, 43% mean decrease for the LC); 2) a slight increase in planarity and asymmetry angles for both RC and LC; 3) minor and variable curvature changes for the CCA and for the branches; 4) slight tortuosity changes for the braches but not for the CCA; and 5) unsubstantial alterations in area and diameter ratios (percentage changes %). The significant geometric changes observed in most subjects with head posture may also cause significant changes in bifurcation hemodynamics and warrant future investigation of the hemodynamic parameters related to the development of atherosclerotic disease such as low oscillating wall shear stress and particle residence times.