Ultrasonic Traveling Waves for Near-Wall Positioning of Single Microbubbles in a Flowing Channel.

Although microbubbles are used primarily in the medical industry as ultrasonic contrast agents, they can also be manipulated by acoustic waves for targeted drug delivery, sonothrombolysis and sonoporation. Acoustic waves can also potentially remove microbubbles from tubing systems (e.g., in hemodialysis) to prevent the negative effects associated with circulating microbubbles. A deeper understanding of the interactions between the acoustic radiation force, the microbubble and the channel wall could greatly benefit these applications. In this study, single air-filled microbubbles were injected into a flowing (polydimethylsiloxane) channel and monitored by a high-speed camera while passing through a pulsed ultrasonic wave zone (0.5 MHz). This study compared various bubble sizes, flow rates and acoustic pressure amplitudes to better understand the three physical regimes observed: free bubble translation (away from the wall); on-wall translation; and bubble-wall attachment. Comparison with a theoretical model revealed that the acoustic radiation force needs to exceed the combined repulsive forces (shear lift, wall lubrication and repulsive Van der Waal forces) for the dead state of bubble-wall attachment. The bubble dynamics revealed through this investigation provide an opportunity for efficient positioning of microbubbles in a channel flow, for either in vivo manipulation or removal in biological applications.

Tracking geometric and hemodynamic alterations of an arteriovenous fistula through patient-specific modelling.

BACKGROUND AND OBJECTIVE: The use of patient-specific CFD modelling for arteriovenous fistulae (AVF) has shown great clinical potential for improving surveillance, yet the use of imaging modes such as MRI and CT for the 3D geometry acquisition presents high costs and exposure risks, preventing regular use. We have developed an ultrasound based procedure to bypass these limitations. METHODS: A scanning procedure and processing pipeline was developed specifically for CFD modelling of AVFs, using a freehand ultrasound setup combining B-mode scanning with 3D probe motion tracking. The scanning procedure involves sweeping along the vasculature to create a high density stack of B-mode frames containing the lumen geometry. This stack is converted into a continuous volume and transient flow waveforms are recorded at the boundaries, synchronised with ECG and automatically digitised, forming realistic boundary conditions for the CFD models. This is demonstrated on a diseased patient-specific AVF. RESULTS: The three scans obtained using this procedure varied in geometry and flow behaviour, with regions of disease located in the first two scans. The outcome of the second procedure seen in the third scan indicated successful restoration with no sites of disease and higher flow. The models gave insight into the lumenal changes in diameter for both the artery and vein segments, as well as characterising hemodynamic behaviours in both the diseased and restored states. Vascular segment resistances obtained from the CFD models indicate a significant reduction once disease was removed, resulting in much higher flows enabling the patient to resume dialysis. CONCLUSION: The methodology described in this study allowed for a multifaceted analysis and high level tracking in terms of both geometry and flow behaviours for a patient case, demonstrating significant clinical utility and practicality, as well as enabling further research into vascular disease progression in AVFs through longitudinal analysis.

Flow-Mediated Drug Transport from Drug-Eluting Stents is Negligible: Numerical and In-vitro Investigations.

Prior numerical studies have shown that the blood flow patterns surrounding drug-eluting stents can enhance drug uptake in stented arteries. However, these studies employed steady-state simulations, wherein flow and drug transport parameters remained constant with respect to time. In the present study, numerical simulations and in-vitro experiments were performed to determine whether luminal blood flow patterns can truly enhance drug uptake in stented arteries. Unlike the aforementioned studies, the time-varying depletion of drug within the stent coating was modelled and the simulation results were validated qualitatively with the in-vitro experiments. The simulations showed that the non-Newtonian properties of blood, its complex near-wall behavior, and the pulsatility of its flow all affect drug uptake only modestly. Furthermore, flow-mediated drug transport was found to be negligible due to the rapid rate at which drug depletes at the stent coating surfaces that are exposed to arterial blood flow. For fluid dynamicists, these results show that steady-state simulations must be avoided when modelling drug transport in stented arteries. For device designers, these results may be used to optimize the shape of drug-eluting stent struts and coatings to improve stent efficacy.

The Impact of Blood Rheology on Drug Transport in Stented Arteries: Steady Simulations.

BACKGROUND AND METHODS: It is important to ensure that blood flow is modelled accurately in numerical studies of arteries featuring drug-eluting stents due to the significant proportion of drug transport from the stent into the arterial wall which is flow-mediated. Modelling blood is complicated, however, by variations in blood rheological behaviour between individuals, blood's complex near-wall behaviour, and the large number of rheological models which have been proposed. In this study, a series of steady-state computational fluid dynamics analyses were performed in which the traditional Newtonian model was compared against a range of non-Newtonian models. The impact of these rheological models was elucidated through comparisons of haemodynamic flow details and drug transport behaviour at various blood flow rates. RESULTS: Recirculation lengths were found to reduce by as much as 24% with the inclusion of a non-Newtonian rheological model. Another model possessing the viscosity and density of blood plasma was also implemented to account for near-wall red blood cell losses and yielded recirculation length increases of up to 59%. However, the deviation from the average drug concentration in the tissue obtained with the Newtonian model was observed to be less than 5% in all cases except one. Despite the small sensitivity to the effects of viscosity variations, the spatial distribution of drug matter in the tissue was found to be significantly affected by rheological model selection. CONCLUSIONS/SIGNIFICANCE: These results may be used to guide blood rheological model selection in future numerical studies. The clinical significance of these results is that they convey that the magnitude of drug uptake in stent-based drug delivery is relatively insensitive to individual variations in blood rheology. Furthermore, the finding that flow separation regions formed downstream of the stent struts diminish drug uptake may be of interest to device designers.

Erratum: "Manufacturing and wetting low-cost microfluidic cell separation devices" [Biomicrofluidics 7, 056501 (2013)].

[This corrects the article on p. 056501 in vol. 7.].

Two-dimensional computational analysis of microbubbles in hemodialysis.

On average, an end-stage renal disease patient will undergo hemodialysis (HD) three or four times a week for 4-5 h per session. Any minor imperfection in the extracorporeal system may become significant in the treatment of these patients due to the cumulative exposure time. Recently, air traps (a safety feature of dialysis systems) have been reported to be inadequate in detecting microbubbles and may even create them. Microbubbles have been linked to lung injuries and damage to the brain in chronic HD patients; therefore the significance of microbubbles has been revisited. Bubbles may originate at the vascular access sites, sites of local turbulent blood flow, the air trap, or in the bloodlines after priming with saline prior to use. In this paper, computational fluid dynamics is used to model blood flow in the air trap to determine the likely mechanisms of microbubble dynamics. The results indicate that almost all bubbles with diameters less than 50 µm and most of the bubbles of 50-200 µm pass through the air trap. Consequently, the common air traps are not effective in removing bubbles less than 200 µm in diameter.

Impact of flow pulsatility on arterial drug distribution in stent-based therapy.

Drug-eluting stents reside in a dynamic fluid environment where the extent to which drugs are distributed within the arterial wall is critically modulated by the blood flowing through the arterial lumen. Yet several factors associated with the pulsatile nature of blood flow and their impact on arterial drug deposition have not been fully investigated. We employed an integrated framework comprising bench-top and computational models to explore the factors governing the time-varying fluid dynamic environment within the vasculature and their effects on arterial drug distribution patterns. A custom-designed bench-top framework comprising a model of a single drug-eluting stent strut and a poly-vinyl alcohol-based hydrogel as a model tissue bed simulated fluid flow and drug transport under fully apposed strut settings. Bench-top experiments revealed a relative independence between drug distribution and the factors governing pulsatile flow and these findings were validated with the in silico model. Interestingly, computational models simulating suboptimal deployment settings revealed a complex interplay between arterial drug distribution, Womersley number and the extent of malapposition. In particular, for a stent strut offset from the wall, total drug deposition was sensitive to changes in the pulsatile flow environment, with this dependence increasing with greater wall displacement. Our results indicate that factors governing pulsatile luminal flow on arterial drug deposition should be carefully considered in conjunction with device deployment settings for better utilization of drug-eluting stent therapy.

Manufacturing and wetting low-cost microfluidic cell separation devices.

Deterministic lateral displacement (DLD) is a microfluidic size-based particle separation or filter technology with applications in cell separation and enrichment. Currently, there are no cost-effective manufacturing methods for this promising microfluidic technology. In this fabrication paper, however, we develop a simple, yet robust protocol for thermoplastic DLD devices using regulatory-approved materials and biocompatible methods. The final standalone device allowed for volumetric flow rates of 660 µl min(-1) while reducing the manufacturing time to <1 h. Optical profilometry and image analysis were employed to assess manufacturing accuracy and precision; the average replicated post height was 0.48% less than the average post height on the master mold and the average replicated array pitch was 1.1% less than the original design with replicated posts heights of 62.1 ± 5.1 µm (mean ± 6 standard deviations) and replicated array pitches of 35.6 ± 0.31 µm.

Analysis of drug distribution from a simulated drug-eluting stent strut using an in vitro framework.

The mechanisms of delivery of anti-proliferative drug from a drug-eluting stent are defined by transport forces in the coating, the lumen, and the arterial wall. Dynamic asymmetries in the localized flow about stent struts have previously been shown to contribute to significant heterogeneity in the spatial distribution of drug in in silico three-compartmental models of stent based drug delivery. A novel bench-top experiment has been created to confirm this phenomena. The experiment simulates drug release from a single stent strut, and then allows visualization of drug uptake into both lumen and tissue domains using optical techniques. Results confirm the existence of inhomogeneous and asymmetric arterial drug distributions, with this distribution shown to be sensitive to the flow field surrounding the strut.

Large eddy simulation of a stenosed artery using a femoral artery pulsatile flow profile.

Computational fluid dynamics simulation of stenosed arteries allows the analysis of quantities including wall shear stress, velocity, and pressure; detailed in vivo measurement is difficult yet the analysis of the fluid dynamics related to stenosis is important in understanding the likely causes and ongoing effects on the integrity of the vessel. In this study, a three-dimensional Large Eddy Simulation is conducted of a 50% occluded vessel, with a typical femoral artery profile used as the transient inlet conditions. The fluid is assumed to be homogenous, Newtonian and incompressible and the walls are assumed rigid. The stenosis is axisymmetric, however the three-dimensional study allows for a flow field that is not axisymmetric and results show significant three-dimensionality. High values of wall shear stress and oscillatory values of wall shear stress (varying in both space time) are observed. The results of the study give insight into the time-varying flow structures for a mildly stenosed artery and indicate that three-dimensional simulations may be important to gain a complete understanding of the flow field.

Development of an in vitro method for modeling drug release and subsequent tissue drug uptake and deposition in a pulsatile flow network.

A novel benchtop model of drug elution and arterial drug deposition following stent implantation has been developed. The model contains a single drug loaded strut and a compartment simulating the vessel wall, housed in a flow chamber under a pulsatile flow regime. Each component has programmable transport properties that can be implemented into a computational model of drug elution. An initial experiment determining the effects of luminal flow on drug deposition patterns was performed. The results show that spatial distribution of drug correlates with areas of low and recirculating flow surrounding the strut. This spatial distribution of drug was shown to be dependent on both transient release behavior and the local flow field surrounding the strut. Furthermore, these results showed that the novel method could be used to study the effects of luminal flow in the presence of single or multiple struts. The method could also be used to explore more complex drug release strategies.