10 results found
Huang Y, Gu B, Salles II, et al., 2021, Fibrinogen-mimicking, multi-arm nanovesicles for human thrombus-specific delivery of tissue plasminogen activator and targeted thrombolytic therapy, Science Advances, Vol: 7, 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.
Chong MY, Gu B, Chan BT, et 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.
Gu B, Piebalgs A, Huang Y, et 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.
Huang Y, Yu L, Ren J, et 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.
Gu B, Piebalgs A, Huang Y, et 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.
Piebalgs A, Gu B, Roi D, et 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.
Gu B, Adjiman CS, Xu XY, 2016, The effect of feed spacer geometry on membrane performance and concentration polarisation based on 3D CFD simulations, Journal of Membrane Science, Vol: 527, Pages: 78-91, ISSN: 1873-3123
Feed spacers are used in spiral wound reverse osmosis (RO) membrane modules to keep the membrane sheets apart as well as to enhance mixing. They are beneficial to membrane performance but at the expense of additional pressure loss. In this study, four types of feed spacer configurations are investigated, with a total of 20 geometric variations based on commercially available spacers and selected filament angles. The impact of feed spacer design on membrane performance is investigated by means of three-dimensional (3D) computational fluid dynamics (CFD) simulations, where the solution-diffusion model is employed for water and solute transport through RO membranes. Numerical simulation results show that, for the operating and geometric conditions examined, fully woven spacers outperform other spacer configurations in mitigating concentration polarisation (CP). When designed with a mesh angle of 60°, fully woven spacers also deliver the highest water flux, although the associated pressure drops are slightly higher than their nonwoven counterparts. Middle layer geometries with a mesh angle of 30° produce the lowest water flux. On the other hand, spacers with a mesh angle of 90° show the lowest pressure drop among all the filament arrangements examined. Furthermore, the computational model presented here can also be used to predict membrane performance for a given feed spacer type and geometry.
Gu B, Xu XY, Adjiman CS, 2016, A predictive model for spiral wound reverse osmosis membrane modules: The effect of winding geometry and accurate geometric details, Computers and Chemical Engineering, Vol: 96, Pages: 248-265, ISSN: 1873-4375
A new one-dimensional predictive model for spiral wound modules (SWMs) applied to reverse osmosis membrane systems is developed by incorporating a detailed description of the geometric features of SWMs and considering flow in two directions. The proposed model is found to capture existing experimental data well, with similar accuracy to the widely-used plate model in which the SWM is assumed to consist of multiple thin rectangular channels. However, physical parameters that should in principle be model-independent, such as membrane permeability, are found to differ significantly depending on which model is used, when the same data sets are used for parameter estimation. Conversely, when using the same physical parameter values in both models, the water recovery predicted by the plate-like model is 12–20% higher than that predicted by the spiral model. This discrepancy is due to differences in the description of geometric features, in particular the active membrane area and the variable channel heights through the module, which impact on predicted performance and energy consumption. A number of design variables – the number of membrane leaves, membrane dimensions, centre pipe radius and the height of feed and permeate channels – are varied and their effects on performance, energy consumption and calculated module size are analysed. The proposed spiral model provides valuable insights into the effects of complex geometry on the performance of the SWM as well as of the overall system, at a low computational cost.
Mazlan NM, Marchetti P, Maples HA, et al., 2016, Organic fouling behaviour of structurally and chemically different forward osmosis membranes – A study of cellulose triacetate and thin film composite membranes, Journal of Membrane Science, Vol: 520, Pages: 247-261, ISSN: 0376-7388
The HTI cellulose triacetate (CTA) and novel thin film composite (TFC) membranes are used to study the multifaceted interactions involved in the fouling and cleaning of forward osmosis (FO) membranes, using calcium alginate as a model foulant. Results show that fouling on the TFC membrane was more significant compared to CTA, arising from a variety of factors associated with surface chemistry, membrane morphology and structural properties. Interestingly, it was observed that in FO mode, membrane surface properties dominated over fouling layer properties in determining fouling behaviour, with some surface properties (e.g. surface roughness) having a greater effect on fouling than others (e.g. surface hydrophilicity). In pressure retarded osmosis (PRO) mode, structural properties of the support played a more dominant role whereby fouling mechanism was specific to the foulant size and aggregation as well as the support pore size relative to the foulant. Whilst pore clogging was observed in the TFC membrane due to its highly asymmetric and porous support structure, fouling occurred as a surface phenomenon on the CTA membrane support layer. Besides pore clogging, the severe fouling observed on the TFC membrane in PRO mode was due to a high specific mass of foulant adsorbed in its porous support. It was observed that a trade-off between enhanced membrane performance and fouling mitigation is apparent in these membranes, with both membranes providing improvement in one aspect at the expense of the other. Hence, significant developments in their surface and structural properties are needed to achieve high anti-fouling properties without compromising flux performance. Measured fouling densities on the studied surfaces suggest that there is not a strong correlation between foulant-membrane interaction and fouling density. Cleaning results suggest that physical cleaning was more efficient on the CTA membrane compared to the TFC membrane. Further, they implied that despite diff
Gu B, Adjiman C, Xu Y, 2014, An integrated model of a spiral-wound membrane module for reverse osmosis considering the effects of winding and spacers, Pages: 566-568
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