Imperial College London

Professor Xiao Yun Xu

Faculty of EngineeringDepartment of Chemical Engineering

Professor, Biofluid Mechanics & Director of Graduate School
 
 
 
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Contact

 

yun.xu Website

 
 
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Location

 

407ACE ExtensionSouth Kensington Campus

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Summary

 

Publications

Publication Type
Year
to

252 results found

Gu B, Adjiman C, Xu X, 2021, Correlations for concentration polarisation and pressure drop in spacer-filled RO membrane modules based on CFD simulations, Membranes, ISSN: 2077-0375

Journal article

Xu X, Manchester E, Pirola S, Salmasi M, O'Regan D, Athanasiou Tet al., 2021, Analysis of Turbulence Effects in a Patient-Specific Aorta with Aortic Valve Stenosis, Cardiovascular Engineering and Technology, ISSN: 1869-408X

Journal article

Huang Y, Gu B, Salles II, Taylor KA, Yu L, Ren J, Liu X, Emerson M, Longstaff C, Hughes AD, Thom SA, Xu XY, Chen Ret al., 2021, Fibrinogen-mimicking, multi-arm nanovesicles for human thrombus-specific delivery of tissue plasminogen activator and targeted thrombolytic therapy, Science Advances, ISSN: 2375-2548

Clinical use of tissue plasminogen activator (tPA) in thrombolytic therapy is limited by its short circulation time and hemorrhagic side effects. Inspired by fibrinogen binding to activated platelets, we report a fibrinogen-mimicking, multi-arm nanovesicle for thrombus-specific tPA delivery and targeted thrombolysis. This novel system is based on the lipid nanovesicle coated with polyethylene glycol (PEG) terminally conjugated with a cyclic RGD (cRGD) peptide. Our experiments with human blood demonstrated its highly selective binding to activated platelets and efficient tPA release at a thrombus site under both static and physiological flow conditions. Its clot dissolution time in a microfluidic system was comparable to that of free tPA. Furthermore, we report a purpose-built computational model capable of simulating targeted thrombolysis of the tPA-loaded nanovesicle and with potential in predicting the dynamics of thrombolysis in physiologically realistic scenarios. This combined experimental and computational work presents a promising platform for development of thrombolytic nanomedicines.

Journal article

Armour C, Guo B, Pirola S, Saitta S, Liu Y, Dong Z, Xu Xet al., 2021, The influence of inlet velocity profile on predicted flow in type B aortic dissection, Biomechanics and Modeling in Mechanobiology, Vol: 20, Pages: 481-490, ISSN: 1617-7940

In order for computational fluid dynamics to provide quantitative parameters to aid in the clinical assessment of type B aortic dissection, the results must accurately mimic the hemodynamic environment within the aorta. The choice of inlet velocity profile (IVP) therefore is crucial; however, idealised profiles are often adopted, and the effect of IVP on hemodynamics in a dissected aorta is unclear. This study examined two scenarios with respect to the influence of IVP—using (a) patient-specific data in the form of a three-directional (3D), through-plane (TP) or flat IVP; and (b) non-patient-specific flow waveform. The results obtained from nine simulations using patient-specific data showed that all forms of IVP were able to reproduce global flow patterns as observed with 4D flow magnetic resonance imaging. Differences in maximum velocity and time-averaged wall shear stress near the primary entry tear were up to 3% and 6%, respectively, while pressure differences across the true and false lumen differed by up to 6%. More notable variations were found in regions of low wall shear stress when the primary entry tear was close to the left subclavian artery. The results obtained with non-patient-specific waveforms were markedly different. Throughout the aorta, a 25% reduction in stroke volume resulted in up to 28% and 35% reduction in velocity and wall shear stress, respectively, while the shape of flow waveform had a profound influence on the predicted pressure. The results of this study suggest that 3D, TP and flat IVPs all yield reasonably similar velocity and time-averaged wall shear stress results, but TP IVPs should be used where possible for better prediction of pressure. In the absence of patient-specific velocity data, effort should be made to acquire patient’s stroke volume and adjust the applied IVP accordingly.

Journal article

Tan WT, Liew YM, Mohamed Mokhtarudin MJ, Pirola S, Wan Ab Naim WN, Amry Hashim S, Xu XY, Lim Eet al., 2021, Effect of Vessel Tortuosity on Stress Concentration at The Distal Stent-Vessel Interface: Possible Link With New Entry Formation Through Biomechanical Simulation., J Biomech Eng

A computational approach is used to investigate potential risk factors for distal stent graft-induced new entry (dSINE) in aortic dissection (AD) patients. Patient-specific simulations were performed based on computed tomography images acquired from six AD patients (three dSINE and three non-dSINE) to analyze the correlation between anatomical characteristics and stress/strain distributions. Sensitivity analysis was carried out using idealized models to independently assess the effect of stent graft length, stent tortuosity and wedge apposition angle at the landing zone on key biomechanical variables. Mismatch of biomechanical properties between the stented and nonstented regions led to high stress at the distal stent graft-vessel interface in all patients, as well as shear strain in the neighbouring region, which coincides with the location of tear formation. Stress was observed to increase with the increase of stent tortuosity (from 263kPa at a tortuosity angle of 50o to 313 kPa at 30o). It was further amplified by stent graft landing at the inflection point of a curve. Malapposition of the stent graft led to an asymmetrical segment within the aorta, therefore changing the location and magnitude of the maximum von Mises stress substantially (up to +25.9% with a +25o change in the distal wedge apposition angle). In conclusion, stent tortuosity and wedge apposition angle serve as important risk predictors for dSINE formation in AD patients.

Journal article

Alamer M, Xu X, 2021, The influence of tumour vasculature on fluid flow in solid tumours: a mathematical modelling study, Biophysics Reports, Vol: 7, Pages: 35-54, ISSN: 2364-3439

Tumour vasculature is known to be aberrant, tortuous and erratic which can have significant implications for fluid flow. Fluid dynamics in tumour tissue plays an important part in tumour growth, metastasis and the delivery of therapeutics. Mathematical models are increasingly employed to elucidate the complex interplay between various aspects of the tumour vasculature and fluid flow. Previous models usually assume a uniformly distributed vasculature without explicitly describing its architecture or incorporate the distribution of vasculature without accounting for real geometric features of the network. In this study, an integrated computational model is developed by resolving fluid flow at the single capillary level across the whole tumour vascular network. It consists of an angiogenesis model and a fluid flow model which resolves flow as a function of the explicit vasculature by coupling intravascular flow and interstitial flow in tumour tissue. The integrated model has been used to examine the influence of microvascular distribution, necrosis and vessel pruning on fluid flow, as well as the effect of heterogeneous vessel permeability. Our results reveal the level of nonuniformity in tumour interstitial fluid pressure (IFP), with large variations in IFP profile between necrotic and non-necrotic tumours. Changes in microscopic features of the vascular network can significantly influence fluid flow in the tumour where removal of vessel blind ends has been found to reduce IFP and promote interstitial fluid flow. Our results demonstrate the importance of incorporating microscopic properties of the tumour vasculature and intravascular flow when predicting fluid flow in tumour tissue.

Journal article

Amrahli M, Centelles M, Cressey P, Prusevicius M, Gedroyc W, Xu XY, So P-W, Wright M, Thanou Met al., 2021, MR-labelled liposomes and focused ultrasound for spatiotemporally controlled drug release in triple negative breast cancers in mice., Nanotheranostics, Vol: 5, Pages: 125-142, ISSN: 2206-7418

Rationale: Image-guided, triggerable, drug delivery systems allow for precisely placed and highly localised anti-cancer treatment. They contain labels for spatial mapping and tissue uptake tracking, providing key location and timing information for the application of an external stimulus to trigger drug release. High Intensity Focused Ultrasound (HIFU or FUS) is a non-invasive approach for treating small tissue volumes and is particularly effective at inducing drug release from thermosensitive nanocarriers. Here, we present a novel MR-imageable thermosensitive liposome (iTSL) for drug delivery to triple-negative breast cancers (TNBC). Methods: A macrocyclic gadolinium-based Magnetic Resonance Imaging (MRI) contrast agent was covalently linked to a lipid. This was incorporated at 30 mol% into the lipid bilayer of a thermosensitive liposome that was also encapsulating doxorubicin. The resulting iTSL-DOX formulation was assessed for physical and chemical properties, storage stability, leakage of gadolinium or doxorubicin, and thermal- or FUS-induced drug release. Its effect on MRI relaxation time was tested in phantoms. Mice with tumours were used for studies to assess both tumour distribution and contrast enhancement over time. A lipid-conjugated near-infrared fluorescence (NIRF) probe was also included in the liposome to facilitate the real time monitoring of iTSL distribution and drug release in tumours by NIRF bioimaging. TNBC (MDA-MB-231) tumour-bearing mice were then used to demonstrate the efficacy at retarding tumour growth and increasing survival. Results: iTSL-DOX provided rapid FUS-induced drug release that was dependent on the acoustic power applied. It was otherwise found to be stable, with minimum leakage of drug and gadolinium into buffers or under challenging conditions. In contrast to the usually suggested longer FUS treatment we identified that brief (~3 min) FUS significantly enhanced iTSL-DOX uptake to a targeted tumour and triggered near-total rele

Journal article

Yuan X, Kan X, Xu XY, Nienaber CAet al., 2020, Finite element modeling to predict procedural success of thoracic endovascular aortic repair in type A aortic dissection, JTCVS Techniques, Vol: 4, Pages: 40-47, ISSN: 2666-2507

ObjectiveThoracic endovascular aortic repair (TEVAR) is recommended for type B aortic dissection and recently has even been used in selected cases of proximal (Stanford type A) aortic dissections in scenarios of prohibitive surgical risk. However, mechanical interactions between the native aorta and stent-graft are poorly understood, as some cases ended in failure. The aim of this study is to explore and better understand biomechanical changes after TEVAR and predict the result via virtual stenting.MethodsA case of type A aortic dissection was considered inoperable and selected for TEVAR. The procedure failed due to stent-graft migration even with precise deployment. A novel patient-specific virtual stent-graft deployment model based on finite element method was employed to analyze TEVAR-induced changes under such conditions. Two landing positions were simulated to investigate the reason for stent-graft migration immediately after TEVAR and explore options for optimization.ResultsSimulation of the actual procedure revealed that the proximal bare metal stent pushed the lamella into the false lumen and led to further stent-graft migration during the launch phase. An alternative landing position has reduced the local deformation of the dissection lamella and avoided stent-graft migration. Higher maximum principal stress (>20 KPa) was found on the lamella with deployment at the actual position, while the alternative strategy would have reduced the stress to <5 KPa.ConclusionsVirtual stent-graft deployment simulation based on finite element model could be helpful to both predict outcomes of TEVAR and better plan future endovascular procedures.

Journal article

Chong MY, Gu B, Chan BT, Ong ZC, Xu XY, Lim Eet al., 2020, Effect of intimal flap motion on flow in acute type B aortic dissection by using fluid-structure interaction., International Journal for Numerical Methods in Biomedical Engineering, Vol: 36, Pages: 1-22, ISSN: 1069-8299

A monolithic, fully coupled fluid-structure interaction (FSI) computational framework was developed to account for dissection flap motion in acute type B aortic dissection (TBAD). Analysis of results included wall deformation, pressure, flow, wall shear stress (WSS), von. Mises stress and comparison of hemodynamics between rigid wall and FSI models. Our FSI model mimicked realistic wall deformation that resulted in maximum compression of the distal true lumen (TL) by 21.4%. The substantial movement of intimal flap mostly affected flow conditions in the false lumen (FL). Flap motion facilitated more flow entering the FL at peak systole, with the TL to FL flow split changing from 88:12 in the rigid model to 83:17 in the FSI model. There was more disturbed flow in the FL during systole (5.8% FSI vs. 5.2% rigid) and diastole (13.5% FSI vs. 9.8% rigid), via a λ2  -criterion. The flap-induced disturbed flow near the tears in the FSI model caused an increase of local WSS by up to 70.0% during diastole. This resulted in a significant reduction in the size of low time-averaged WSS (TAWSS) regions in the FL (113.11 cm2 FSI vs. 177.44 cm2 rigid). Moreover, the FSI model predicted lower systolic pressure, higher diastolic pressure, and hence lower pulse pressure. Our results provided new insights into the possible impact of flap motion on flow in aortic dissections, which are particularly important when evaluating hemodynamics of acute TBAD. This article is protected by copyright. All rights reserved.

Journal article

Salmasi M, Jarral OA, Pirola S, Sasidharan S, Pepper J, Oo A, Moore J, Xu XY, Athanasiou Tet al., 2020, In-vivo blood flow parameters can predict at-risk aortic aneurysms and dissection: a comprehensive biomechanics model, EUROPEAN HEART JOURNAL, Vol: 41, Pages: 2339-2339, ISSN: 0195-668X

Journal article

Xu X, Manchester E, 2020, The effect of turbulence on transitional flow in the FDA’s benchmark nozzle model using large-eddy simulation, International Journal for Numerical Methods in Biomedical Engineering, Vol: 36, Pages: 1-15, ISSN: 1069-8299

The Food and Drug Administration's (FDA) benchmark nozzle model has been studied extensively both experimentally and computationally. Although considerable efforts have been made on validations of a variety of numerical models against available experimental data, the transitional flow cases are still not fully resolved, especially with regards to detailed comparison of predicted turbulence quantities with experimental measurements. This study aims to fill this gap by conducting large‐eddy simulations (LES) of flow through the FDA's benchmark model, at a transitional Reynolds number of 2000. Numerical results are compared to previous interlaboratory experimental results, with an emphasis on turbulence characteristics. Our results show that the LES methodology can accurately capture laminar quantities throughout the model. In the pre‐jet breakdown region, predicted turbulence quantities are generally larger than high resolution experimental data acquired with laser Doppler velocimetry. In the jet breakdown regions, where maximum Reynolds stresses occur, Reynolds shear stresses show excellent agreement. Differences of up to 4% and 20% are observed near the jet core in the axial and radial normal Reynolds stresses, respectively. Comparisons between viscous and Reynolds shear stresses show that peak viscous shear stresses occur in the nozzle throat reaching a value of 18 Pa in the boundary layer, whilst peak Reynolds shear stresses occur in the jet breakdown region reaching a maximum value of 87 Pa. Our results highlight the importance in considering both laminar and turbulent contributions towards shear stresses and that neglecting the turbulence effect can significantly underestimate the total shear force exerted on the fluid.

Journal article

Johari NH, Hamady M, Xu XY, 2020, A computational study of the effect of stent design on local hemodynamic factors at the carotid artery bifurcation, Artery Research, Vol: 26, Pages: 161-169, ISSN: 1872-9312

Background: Previous clinical studies have shown that the incidence of restenosis after carotid and coronary stenting varies with stent design and deployment configuration. This study aims to determine how stent design may affect in-stent hemodynamics in stented carotid arteries by means of Computational Fluid Dynamics (CFD).Methods: A robust computational method was developed to integrate detailed stent strut geometry in a patient-specific carotid artery reconstructed from medical images. Three stent designs, including two closed-cell stents and one open-cell stent, were reproduced and incorporated into the reconstructed post-stent carotid bifurcation. CFD simulations were performed under patient-specific flow conditions. Local hemodynamic parameters were evaluated and compared in terms of Wall Shear Stress (WSS), Oscillatory Shear Index (OSI) and Relative Residence Time (RRT).Results: All simulated stent designs induced some degree of flow disruption as manifested through flow separation and recirculation zones downstream of stent struts and quantified by WSS-related indices. Compared to the simulated open-cell stent, closed-cell stents created slightly larger areas of low WSS, elevated OSI and high RRT, due to a greater number of stent struts protruding into the lumen.Conclusion: Detailed stent design and patient-specific geometric features of the stented vessel have a strong influence on the evaluated hemodynamic parameters. Our limited computational results suggest that closed-cell stents may pose a higher risk for in-stent restenosis (ISR) than open-cell stent design. Further large-scale prospective studies are warranted to elucidate the role of stent design in the development of ISR after CAS.

Journal article

Zadrazil I, Corzo C, Voulgaropoulos V, Markides C, Xu XYet al., 2020, A combined experimental and computational study of the flow characteristics in a Type B aortic dissection: effect of primary and secondary tear size, Chemical Engineering Research and Design, Vol: 160, Pages: 240-253, ISSN: 0263-8762

Aortic dissection is related to the separation of the tunica intima from the aortic wall, which can cause blood to flow through the newly formed lumen, thereby further damaging the torn vessel. This type of pathology is the most common catastrophic event that affects the aorta and is associated with complications such as malperfusion. In this work, an idealised, simplified geometric model of Type B aortic dissection is investigated experimentally using particle image velocimetry (PIV) and numerically using computational fluid dynamic (CFD) simulations. The flow characteristics through the true and false lumina are investigated parametrically over a range of tear sizes. Specifically, four different tear sizes and size ratios are considered, each representing a different dissection case or stage, and the experimental and numerical results of the flow-rate profiles through the two lumina in each case, along with the phase-averaged velocity vector maps at mid-acceleration, mid-deceleration, relaminarisation and peak systole, and their corresponding velocity profiles are compared. The experimental and numerical results are in good qualitative as well as quantitative agreement. The flow characteristics found here provide insight into the importance of the re-entry tear. We observe that an increase in the re-entry tear size increases considerably the flow rate in the false lumen, decreases significantly the wall shear stress (WSS) and decreases the pressure difference between the false and the true lumen. On the contrary, an increase in the entry tear, increases the flow rate through the false lumen, increases slightly the WSS and increases the pressure difference between the false and the true lumen. These are crucial findings that can help interpret medical diagnosis and accelerate prevention and treatment, especially in high-risk patients.

Journal article

Chen R, Huang Y, Xu XY, Thom Set al., 2020, Red Blood Cell-Derived Vesicle

Patent

Armour C, Menichini C, Milinis K, Gibbs R, Xu Xet al., 2020, The location of re-entry tears affects false lumen thrombosis in aortic dissection following TEVAR, Journal of Endovascular Therapy, Vol: 27, Pages: 396-404, ISSN: 1074-6218

Purpose. Thoracic endovascular aortic repair (TEVAR) has been shown to be an effective treatment method for acute type B aortic dissection. However, it remains unclear which factors determine false lumen thrombosis (FLT) after TEVAR. In this study we assess the influence of the distance between the distal end of the stent graft and first re-entry tear (SG-FET)on the progression of FLT.Methods.Three post-operative patient-specific models were reconstructed from computed tomography scans. Two additional models were created byartificially changing the SG-FET distance in patient 1 and 2. In all five models, computational fluid dynamics simulations coupled with thrombus formation modelling were performed at physiological flow conditions.Predicted FLT was compared with follow-up scans.Results.Ourresults showed reduced false lumen flow and low time-averaged wall shear stress (TAWSS) inpatients withlarge SG-FET distances. Predicted thrombus formation and growth were consistent with follow-up scansfor all patients. Reducingthe SG-FET distanceby 30 mm in patient 1 increased flowandTAWSS in the upper abdominal false lumen, reducing the thrombus volume by 9.6%. Increasingthe SG-FET distance inpatient 2 resulted in fasterthoracic thrombosis and increased total thrombus volume.Conclusion.The location of re-entry tears can influencethe progression of FLT following TEVAR. The more distal the re-entry tear in the aorta the more likely FLTis. Hence, the distal landing zone of the stent graft should be chosen carefully to ensure a sufficient SG-FET distance.

Journal article

Jarral OA, Tan MKH, Salmasi MY, Pirola S, Pepper JR, O'Regan DP, Xu XY, Athanasiou Tet al., 2020, Phase-contrast magnetic resonance imaging and computational fluid dynamics assessment of thoracic aorta blood flow: a literature review, European Journal of Cardio-Thoracic Surgery, Vol: 57, Pages: 438-446, ISSN: 1010-7940

The death rate from thoracic aortic disease is on the rise and represents a growing global health concern as patients are often asymptomatic before acute events, which have devastating effects on health-related quality of life. Biomechanical factors have been found to play a major role in the development of both acquired and congenital aortic diseases. However, much is still unknown and translational benefits of this knowledge are yet to be seen. Phase-contrast cardiovascular magnetic resonance imaging of thoracic aortic blood flow has emerged as an exceptionally powerful non-invasive tool enabling visualization of complex flow patterns, and calculation of variables such as wall shear stress. This has led to multiple new findings in the areas of phenotype-dependent bicuspid valve flow patterns, thoracic aortic aneurysm formation and aortic prosthesis performance assessment. Phase-contrast cardiovascular magnetic resonance imaging has also been used in conjunction with computational fluid modelling techniques to produce even more sophisticated analyses, by allowing the calculation of haemodynamic variables with exceptional temporal and spatial resolution. Translationally, these technologies may potentially play a major role in the emergence of precision medicine and patient-specific treatments in patients with aortic disease. This clinically focused review will provide a systematic overview of key insights from published studies to date.

Journal article

Zhu Y, Zhan W, Hamady M, Xu XYet al., 2020, A pilot study of aortic hemodynamics before and after thoracic endovascular repair with a double-branched endograft, Medicine in Novel Technology and Devices, Vol: 4, Pages: 1-17, ISSN: 2590-0935

Branched endografts have been developed to treat complex pathology in the aortic arch and ascending aorta. This study aims to evaluate the haemodynamic performance of a double-branched thoracic endograft by detailed comparison of flow patterns and wall shear stress in the aorta and supra-aortic branches before and after stent-graft implantation. Pre- and post-intervention CT images were acquired from two patients who underwent thoracic endovascular aortic repair (TEVAR) with a double-branched endograft for thoracic aortic aneurysms. These images were used to reconstruct patient-specific models, which were analysed using computational fluid dynamics employing physiologically realistic boundary conditions. Our results showed that there was sufficient blood perfusion through the arch branches. The presence of inner tunnels caused flow derangement and asymmetric wall shear stress in the ascending aorta, where shear range index was up to 6 times higher than in the pre-intervention model. Wall shear stress in the aortic arch increased considerably after intervention as a result of accelerated flow. The maximum flow-induced displacement forces on the branched endografts were around 22 ​N for both patients, which was below the threshold for device migration. Results from this pilot study demonstrated that aortic flow patterns were significantly altered by the branched endograft which caused increased spatial variation of wall shear stress in the ascending aorta and the arch. Although no obvious adverse hemodynamic features were found immediately after intervention for the cases we analysed, follow-up studies will be needed to assess durability of the device.

Journal article

Pirola S, Guo B, Menichini C, Saitta S, Fu W, Dong Z, Xu XYet al., 2019, 4D flow MRI-based computational analysis of blood flow in patient-specific aortic dissection, IEEE Transactions on Biomedical Engineering, Vol: 66, Pages: 3411-3419, ISSN: 0018-9294

OBJECTIVE: Computational hemodynamics studies of aortic dissections usually combine patient-specific geometries with idealized or generic boundary conditions. In this study we present a comprehensive methodology for simulations of hemodynamics in type B aortic dissection (TBAD) based on fully patient-specific BCs. METHODS: Pre-operative 4D flow magnetic resonance imaging (MRI) and Doppler-wire pressure measurements (pre- and post-operative) were acquired from a TBAD patient. These data were used to derive boundary conditions for computational modelling of flow before and after thoracic endovascular repair (TEVAR). Validations of the computational results were performed by comparing predicted flow patterns with pre-TEVAR 4D flow MRI, as well as pressures with in vivo measurements. RESULTS AND CONCLUSION: Comparison of instantaneous velocity streamlines showed a good qualitative agreement with 4D flow MRI. Quantitative comparison of predicted pressures with pressure measurements revealed a maximum difference of 11 mmHg (-9.7%). Furthermore, our model correctly predicted the reduction of true lumen pressure from 74/115 mmHg pre-TEVAR to 64/107 mmHg post-TEVAR (diastolic/systolic pressures at entry tear level), compared to the corresponding measurements of 72/118 mmHg and 64/114 mmHg. This demonstrates that pre-TEVAR 4D flow MRI can be used to tune boundary conditions for post-TEVAR hemodynamic analyses.

Journal article

Huang Y, Gu B, Liu C, Stebbing J, Gedroyc W, Thanou M, Xu Xet al., 2019, Thermosensitive liposome-mediated drug delivery in chemotherapy: mathematical modelling for spatio-temporal drug distribution and model-based optimisation, Pharmaceutics, Vol: 11, ISSN: 1999-4923

Thermosensitive liposome-mediated drug delivery has shown promising results in terms of improved therapeutic efficacy and reduced side effects compared to conventional chemotherapeutics. In order to facilitate our understanding of the transport mechanisms and their complex interplays in the drug delivery process, computational models have been developed to simulate the multiple steps involved in liposomal drug delivery to solid tumours. In this study we employ a multicompartmental model for drug-loaded thermosensitive liposomes, with an aim to identify the key transport parameters in determining therapeutic dosing and outcomes. The computational model allows us to not only examine the temporal and spatial variations of drug concentrations in the different compartments by utilising the tumour cord concept, but also assess the therapeutic efficacy and toxicity. In addition, the influences of key factors on systemic plasma concentration and intracellular concentration of the active drug are investigated; these include different chemotherapy drugs, release rate constants and heating duration. Our results show complex relationships between these factors and the predicted therapeutic outcome, making it difficult to identify the “best” parameter set. To overcome this challenge, a model-based optimisation method is proposed in an attempt to find a set of release rate constants and heating duration that can maximise intracellular drug concentration while minimising systemic drug concentration. Optimisation results reveal that under the operating conditions and ranges examined, the best outcome would be achieved with a low drug release rate at physiological temperature, combined with a moderate to high release rate at mild hyperthermia and 1 h heating after injection.

Journal article

Gu B, Piebalgs A, Huang Y, Roi D, Lobotesis K, Longstaff C, Hughes AD, Chen R, Thom SA, Xu XYet al., 2019, Computational simulations of thrombolysis in acute stroke: Effect of clot size and location on recanalisation, Medical Engineering & Physics, Vol: 73, Pages: 9-17, ISSN: 1350-4533

Acute ischaemic stroke can be treated by intravenous thrombolysis whereby tissue plasminogen activator (tPA) is infused to dissolve clots that block blood supply to the brain. In this study, we aim to examine the influence of clot location and size on lysis pattern and recanalisation by using a recently developed computational modelling framework for thrombolysis under physiological flow conditions. An image-based patient-specific model is reconstructed which consists of the internal carotid bifurcation with the A1 segment of anterior cerebral arteries and M1 segment of middle cerebral arteries, and the M1 bifurcation containing the M2 segments. By varying the clot size and location, 7 scenarios are simulated mimicking thrombolysis of M1 and M2 occlusions. Our results show that initial breakthrough always occurs along the inner curvature of the occluded cerebral artery, due to prolonged tPA residence time in the recirculation zone. For a given occlusion site, lysis completion time appears to increase almost quadratically with the initial clot volume; whereas for a given clot volume, the simulated M2 occlusions take up to 30% longer for complete lysis compared to the corresponding M1 occlusions.

Journal article

Saitta S, Pirola S, Piatti F, Votta E, Lucherini F, Pluchinotta F, Carminati M, Lombardi M, Geppert C, Cuomo F, Figueroa C, Xu X, Redaelli Aet al., 2019, Evaluation of 4D Flow MRI-based non-invasive pressure assessment in aortic coarctations, Journal of Biomechanics, Vol: 94, Pages: 13-21, ISSN: 0021-9290

Severity of aortic coarctation (CoA) is currently assessed by estimating trans-coarctation pressure drops through cardiac catheterization or echocardiography. In principle, more detailed information could be obtained non-invasively based on space- and time-resolved magnetic resonance imaging (4D flow) data. Yet the limitations of this imaging technique require testing the accuracy of 4D flow-derived hemodynamic quantities against other methodologies.With the objective of assessing the feasibility and accuracy of this non-invasive method to support the clinical diagnosis of CoA, we developed an algorithm (4DF-FEPPE) to obtain relative pressure distributions from 4D flow data by solving the Poisson pressure equation. 4DF-FEPPE was tested against results from a patient-specific fluid-structure interaction (FSI) simulation, whose patient-specific boundary conditions were prescribed based on 4D flow data. Since numerical simulations provide noise-free pressure fields on fine spatial and temporal scales, our analysis allowed to assess the uncertainties related to 4D flow noise and limited resolution.4DF-FEPPE and FSI results were compared on a series of cross-sections along the aorta. Bland-Altman analysis revealed very good agreement between the two methodologies in terms of instantaneous data at peak systole, end-diastole and time-averaged values: biases (means of differences) were +0.4 mmHg, −1.1 mmHg and +0.6 mmHg, respectively. Limits of agreement (2 SD) were ±0.978 mmHg, ±1.06 mmHg and ±1.97 mmHg, respectively. Peak-to-peak and maximum trans-coarctation pressure drops obtained with 4DF-FEPPE differed from FSI results by 0.75 mmHg and −1.34 mmHg respectively. The present study considers important validation aspects of non-invasive pressure difference estimation based on 4D flow MRI, showing the potential of this technology to be more broadly applied to the clinical practice.

Journal article

Guo B, Dong Z, Pirola S, Liu Y, Menichini C, Xu XY, Guo D, Fu Wet al., 2019, Dissection level within aortic wall layers is associated with propagation of type B aortic dissection: a swine model study, European Journal of Vascular and Endovascular Surgery, Vol: 58, Pages: 415-425, ISSN: 1078-5884

OBJECTIVE: Haemodynamic and geometric factors play pivotal roles in the propagation of acute type B aortic dissection (TBAD). The aim of this study was to evaluate the association between dissection level within all aortic layers and the propagation of acute TBAD in porcine aorta. METHODS: Twelve pig acute TBAD models were created. In model A, the aortic wall tear was superficial and close to the intima (thin intimal flap), whereas in model B it was deep and close to the adventitia (thick intimal flap). Dissection propagation was evaluated using angiography or computed tomography scans, and the haemodynamic measurements were acquired using Doppler wires. Most pigs were followed up at 1, 3, 6, 12, 18, and up to 24 months; four animals were euthanised at three and six months, respectively (two from each group). RESULTS: Both models were successfully created. No statistical difference was observed for the median antegrade propagation distance intra-operatively between the two models (p = .092). At 24 months, the longitudinal propagation distance was significantly greater in model B than in model A (p = .016). No statistical difference in retrograde propagation was noted (p = .691). Over time, aortic wall dissection progressed most notably over the first three months in model A, whereas it continued over the first 12 months in model B. Flow velocity was significantly greater in the true lumen than in false lumen at the level of the primary tear (p = .001) and in the middle of the dissection (p = .004). The histopathological images at three and six months demonstrated the fibres were stretched linearly at the outside wall of false lumen in both models, while the depth of intimal tears developed to be superficial and similar at the distal dissection. CONCLUSION: In this swine model of TBAD, a deeper intimal tear resulted in greater dissection propagation.

Journal article

Su J, Chai G, Wang L, Cao W, Gu Z, Chen C, Xu Xet al., 2019, Pore-scale direct numerical simulation of particle transport in porous media, Chemical Engineering Science, Vol: 199, Pages: 613-627, ISSN: 1873-4405

A computational platform for direct numerical simulation of fluid-particle two-phase flow in porous media is presented in this study. In the proposed platform, the Navier-Stokes equations are used to describe the motion of the continuous phase, while the discrete element method (DEM) is employed to evaluate particle-particle and particle-wall interactions, with a fictitious domain method being adopted to evaluate particle-fluid interactions. Particle-wall contact states are detected by the ERIGID scheme. Moreover, a new scheme, namely, base point-increment method is developed to improve the accuracy of particle tracking in porous media. In order to improve computationally efficiency, a time splitting strategy is applied to couple the fluid and DEM solvers, allowing different time steps to be used which are adaptively determined according to the stability conditions of each solver. The proposed platform is applied to particle transport in a porous medium with its pore structure being reconstructed from micro-CT scans from a real rock. By incorporating the effect of pore structure which has a comparable size to the particles, numerical results reveal a number of distinct microscopic flow mechanisms and the corresponding macroscopic characteristics. The time evolution of the inlet to outlet pressure-difference consists of large-scale spikes and small-scale fluctuations. Apart from the influence through direct contacts between particles, the motion of a particle can also be affected by particles without contact through blocking a nearby passage for fluid flow. Particle size has a profound influence on the macroscopic motion behavior of particles. Small particles are easier to move along the main stream and less dispersive in the direction perpendicular to the flow than large particles.

Journal article

Johari NH, Wood NB, Cheng Z, Torii R, Oishi M, Oshima M, Xu XYet al., 2019, Disturbed flow in a stenosed carotid artery bifurcation: Comparison of RANS-based transitional model and LES with experimental measurements, International Journal of Applied Mechanics, Vol: 11, ISSN: 1758-8251

Blood flow in the carotid arteries is usually laminar, but can undergo laminar-turbulent transition in the presence of a high-grade stenosis. In this study, pulsatile flow in a patient-based stenosed carotid artery bifurcation was examined using both large eddy simulation (LES) with dynamic Smagorinsky eddy viscosity model, and a Reynolds-averaged Navier-Stokes (RANS) method with a transitional version of the shear stress transport (SST-Tran) model. In addition, an experimental phantom was built for the same bifurcation geometry and velocity measurements were made using particle image velocimetry (PIV). Comparisons with PIV measurements of axial velocity profiles demonstrated that both SST-Tran and LES predicted the experimental results fairly well, with LES being slightly superior. Furthermore, LES predicted cycle-to-cycle variations in the region where transition to turbulence occurred, indicating the unsteady nature of turbulence transition. On the other hand, the SST-Tran model was able to capture important flow features observed in the PIV experiment, demonstrating its potential as a cost-effective alternative to LES for haemodynamic analyses of highly disturbed flow in diseased arteries.

Journal article

Huang Y, Yu L, Ren J, Gu B, Longstaff C, Hughes AD, Thom SA, Xu XY, Chen Ret al., 2019, An activated-platelet-sensitive nanocarrier enables targeted delivery of tissue plasminogen activator for effective thrombolytic therapy, Journal of Controlled Release, Vol: 300, Pages: 1-12, ISSN: 0168-3659

It remains a major challenge to develop a selective and effective fibrinolytic system for thrombolysis with minimal undesirable side effects. Herein, we report a multifunctional liposomal system (164.6 ± 5.3 nm in diameter) which can address this challenge through targeted delivery and controlled release of tissue plasminogen activator (tPA) at the thrombus site. The tPA-loaded liposomes were PEGylated to improve their stability, and surface coated with a conformationally-constrained, cyclic arginine-glycine-aspartic acid (cRGD) to enable highly selective binding to activated platelets. The in vitro drug release profiles at 37 °C showed that over 90% of tPA was released through liposomal membrane destabilization involving membrane fusion upon incubation with activated platelets within 1 h, whereas passive release of the encapsulated tPA in pH 7.4 PBS buffer was 10% after 6 h. The release of tPA could be readily manipulated by changing the concentration of activated platelets. The presence of activated platelets enabled the tPA-loaded, cRGD-coated, PEGylated liposomes to induce efficient fibrin clot lysis in a fibrin-agar plate model and the encapsulated tPA retained 97.4 ± 1.7% of fibrinolytic activity as compared with that of native tPA. Furthermore, almost complete blood clot lysis was achieved in 75 min, showing considerably higher and quicker thrombolytic activity compared to the tPA-loaded liposomes without cRGD labelling. These results suggest that the nano-sized, activated-platelet-sensitive, multifunctional liposomes could facilitate selective delivery and effective release of tPA at the site of thrombus, thus achieving efficient clot dissolution whilst minimising undesirable side effects.

Journal article

Gu B, Piebalgs A, Huang Y, Longstaff C, Hughes A, Chen R, Thom S, Xu Xet al., 2019, Mathematical modelling of intravenous thrombolysis in acute ischaemic stroke: Effects of dose regimens on levels of fibrinolytic proteins and clot lysis time, Pharmaceutics, Vol: 11, ISSN: 1999-4923

Thrombolytic therapy is one of the medical procedures in the treatment of acute ischaemic stroke (AIS), whereby the tissue plasminogen activator (tPA) is intravenously administered to dissolve the obstructive blood clot. The treatment of AIS by thrombolysis can sometimes be ineffective and it can cause serious complications, such as intracranial haemorrhage (ICH). In this study, we propose an efficient mathematical modelling approach that can be used to evaluate the therapeutic efficacy and safety of thrombolysis in various clinically relevant scenarios. Our model combines the pharmacokinetics and pharmacodynamics of tPA with local clot lysis dynamics. By varying the drug dose, bolus-infusion delay time, and bolus-infusion ratio, with the FDA approved dosing protocol serving as a reference, we have used the model to simulate 13 dose regimens. Simulation results are compared for temporal concentrations of fibrinolytic proteins in plasma and the time that is taken to achieve recanalisation. Our results show that high infusion rates can cause the rapid degradation of plasma fibrinogen, indicative of increased risk for ICH, but they do not necessarily lead to fast recanalisation. In addition, a bolus-infusion delay results in an immediate drop in plasma tPA concentration, which prolongs the time to achieve recanalisation. Therefore, an optimal administration regimen should be sought by keeping the tPA level sufficiently high throughout the treatment and maximising the lysis rate while also limiting the degradation of fibrinogen in systemic plasma. This can be achieved through model-based optimisation in the future.

Journal article

Zhan W, Gedroyc W, Xu X, 2019, Towards a multiphysics modelling framework for thermosensitive liposomal drug delivery to solid tumour combined with ultrasound hyperthermia, Biophysics Reports, Vol: 5, Pages: 43-59, ISSN: 2364-3439

Systemic toxicity and insufficient drug accumulation at the tumour site are main barriers in chemotherapy. Thermosensitive liposomes (TSL) combined with high intensity focused ultrasound (HIFU) has emerged as a potential solution to overcome these barriers through targeted drug delivery and localised release. Owing to the multiple physical and biochemical processes involved in this combination therapy, mathematical modelling becomes an indispensable tool for detailed analysis of the transport processes and prediction of tumour drug uptake. To this end, a multiphysics model has been developed to simulate the transport of chemotherapy drugs delivered through a combined HIFU-TSL system. All key delivery processes are considered in the model; these include interstitial fluid flow, HIFU acoustics, bioheat transfer, drug release and transport, as well as tumour drug uptake. The capability of the model is demonstrated through its application to a 2-D prostate tumour model reconstructed from magnetic resonance images. Our results not only demonstrate the feasibility of the model to simulate this combination therapy, but also confirm the advantage of HIFU-TSL drug delivery system with enhancement of drug accumulation in tumour regions and reduction of drug availability in normal tissue. This multiphysics modelling framework can serve as a useful tool to assist in the design of HIFU-TSL drug delivery systems and treatment regimen for improved anticancer efficacy.

Journal article

Piebalgs A, Gu B, Roi D, Lobotesis K, Thom S, Xu Xet al., 2018, Computational simulations of thrombolytic therapy in acute ischaemic stroke, Scientific Reports, Vol: 8, Pages: 1-13, ISSN: 2045-2322

Ischaemic stroke can occur when an artery to the brain is blocked by a blood clot. The use of thrombolytic agents, such as tissue plasminogen activator (tPA), to dissolve the occluding clot is limited by the risk of intracerebral haemorrhage (ICH), a known side effect associated with tPA. We developed a computational thrombolysis model for a 3D patient-specific artery coupled with a compartmental model for temporal concentrations of tPA and lysis proteins during intravenous infusion of tPA, in order to evaluate the effects of tPA dose on the efficacy of thrombolytic therapy and the risk of ICH. The model was applied to a 3-mm-long fibrin clot with two different fibrin fibre radii in the middle cerebral artery (MCA) – a setting relevant to ischaemic stroke, and results for different tPA dose levels and fibrin fibre radii were compared. Our simulation results showed that clot lysis was accelerated at higher tPA doses at the expense of a substantial increase in the risk of ICH. It was also found that a fine clot with a smaller fibre radius dissolved much slowly than a coarse clot due to a slower tPA penetration into the clots.

Journal article

Menichini C, Pirola S, Guo B, Fu W, Dong Z, Xu XYet al., 2018, High wall stress may predict the formation of stent-graft-induced new entries after thoracic endovascular aortic repair, Journal of Endovascular Therapy, Vol: 25, Pages: 571-577, ISSN: 1526-6028

PURPOSE: To explore the potential role of morphological factors and wall stress in the formation of stent-graft-induced new entries (SINE) based on computed tomography (CT) images after thoracic endovascular aortic repair (TEVAR). CASE REPORT: Two female patients aged 59 years (patient 1) and 44 years (patient 2) underwent TEVAR for type B dissection in the chronic (patient 1) or subacute (patient 2) phase. CT scans at 3-month follow-up showed varying degrees of false lumen thrombosis in both patients. At 14-month follow-up, a SINE was observed in patient 1 while the dissected aorta in the other patient remained stable. Morphological and finite element analyses were performed based on the first follow-up CT images. The computational results showed that the SINE patient had higher stent-graft tortuosity than the non-SINE patient and much higher wall stress in the region close to the distal SINE. CONCLUSION: This case study suggests that high stent-graft tortuosity can lead to high wall stress, which is potentially linked to the formation of SINE. Further large population-based studies are needed to confirm this preliminary finding.

Journal article

Zhan W, Alamer M, Xu XY, 2018, Computational modelling of drug delivery to solid tumour: Understanding the interplay between chemotherapeutics and biological system for optimised delivery systems, Advanced Drug Delivery Reviews, Vol: 132, Pages: 81-103, ISSN: 0169-409X

Drug delivery to solid tumour involves multiple physiological, biochemical and biophysical processes taking place across a wide range of length and time scales. The therapeutic efficacy of anticancer drugs is influenced by the complex interplays among the intrinsic properties of tumours, biophysical aspects of drug transport and cellular uptake. Mathematical and computational modelling allows for a well-controlled study on the individual and combined effects of a wide range of parameters on drug transport and therapeutic efficacy, which would not be possible or economically viable through experimental means. A wide spectrum of mathematical models has been developed for the simulation of drug transport and delivery in solid tumours, including PK/PD-based compartmental models, microscopic and macroscopic transport models, and molecular dynamics drug loading and release models. These models have been used as a tool to identify the limiting factors and for optimal design of efficient drug delivery systems. This article gives an overview of the currently available computational models for drug transport in solid tumours, together with their applications to novel drug delivery systems, such as nanoparticle-mediated drug delivery and convection-enhanced delivery.

Journal article

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