Publications
75 results found
Li G, Mukherjee D, Navarro I, et al., 2016, Visualization of conventional outflow tissue responses to netarsudil in living mouse eyes, European Journal of Pharmacology, Vol: 787, Pages: 20-31, ISSN: 0014-2999
Visual impairment due to glaucoma currently impacts 70 million people worldwide. While disease progression can be slowed or stopped with effective lowering of intraocular pressure, current medical treatments are often inadequate. Fortunately, three new classes of therapeutics that target the diseased conventional outflow tissue responsible for ocular hypertension are in the final stages of human testing. The rho kinase inhibitors have proven particularly efficacious and additive to current therapies. Unfortunately, non-contact technology that monitors the health of outflow tissue and its response to conventional outflow therapy is not available clinically. Using optical coherence tomographic (OCT) imaging and novel segmentation software, we present the first demonstration of drug effects on conventional outflow tissues in living eyes. Topical netarsudil (formerly AR-13324), a rho kinase/ norepinephrine transporter inhibitor, affected both proximal (trabecular meshwork and Schlemm’s Canal) and distal portions (intrascleral vessels) of the mouse conventional outflow tract. Hence, increased perfusion of outflow tissues was reliably resolved by OCT as widening of the trabecular meshwork and significant increases in cross-sectional area of Schlemm’s canal following netarsudil treatment. These changes occurred in conjunction with increased outflow facility, increased speckle variance intensity of outflow vessels, increased tracer deposition in conventional outflow tissues and decreased intraocular pressure. This is the first report using live imaging to show real-time drug effects on conventional outflow tissues and specifically the mechanism of action of netarsudil in mouse eyes. Advancements here pave the way for development of a clinic-friendly OCT platform for monitoring glaucoma therapy.
Sherwood JM, Reina-Torres E, Bertrand J, et al., 2016, Measurement of outflow facility using iPerfusion, PLoS One, Vol: 11, Pages: 1-29, ISSN: 1932-6203
Elevated intraocular pressure (IOP) is the predominant risk factor for glaucoma, and reducing IOP is the only successful strategy to prevent further glaucomatous vision loss. IOP is determined by the balance between the rates of aqueous humour secretion and outflow, and a pathological reduction in the hydraulic conductance of outflow, known as outflow facility, is responsible for IOP elevation in glaucoma. Mouse models are often used to investigate the mechanisms controlling outflow facility, but the diminutive size of the mouse eye makes measurement of outflow technically challenging. In this study, we present a new approach to measure and analyse outflow facility using iPerfusion™, which incorporates an actuated pressure reservoir, thermal flow sensor, differential pressure measurement and an automated computerised interface. In enucleated eyes from C57BL/6J mice, the flow-pressure relationship is highly non-linear and is well represented by an empirical power law model that describes the pressure dependence of outflow facility. At zero pressure, the measured flow is indistinguishable from zero, confirming the absence of any significant pressure independent flow in enucleated eyes. Comparison with the commonly used 2-parameter linear outflow model reveals that inappropriate application of a linear fit to a non-linear flow-pressure relationship introduces considerable errors in the estimation of outflow facility and leads to the false impression of pressure-independent outflow. Data from a population of enucleated eyes from C57BL/6J mice show that outflow facility is best described by a lognormal distribution, with 6-fold variability between individuals, but with relatively tight correlation of facility between fellow eyes. iPerfusion represents a platform technology to accurately and robustly characterise the flow-pressure relationship in enucleated mouse eyes for the purpose of glaucoma research and with minor modifications, may be applied in vivo to mice
Kaliviotis E, Sherwood JM, Dusting J, et al., 2016, Quantification of local blood flow characteristics in microfluidic applications, Pages: 5-14, ISSN: 1313-2458
Advances in microfluidic applications have made it possible to design microsystems in which various processes, including diagnostics and fundamental research in biofluids, can be performed. In the majority of the studies the effect of red blood cell aggregation in blood flow characteristics has not received much attention and the relationship between the local microstructure and local flow characteristics has not been investigated extensively. In this work local velocity, local aggregation and local hematocrit of human red blood cells (RBC) have been simultaneously, resolved and quantified in a microchannel. The experimental system involved simple brightfield microscopy, a pressure driven microfluidic system, and RBCs suspended in Dextran and phosphate buffer saline solutions to control the aggregation intensity. Local aggregation characteristics were investigated at bulk and local levels using statistical and edge-detection image processing techniques. Aggregation intensity was found to strongly correlate with local variations in velocity in both the central and wall regions. The results suggest a combined effect of haematocrit and velocity distributions on local aggregation characteristics and showed that using multiple methods for aggregation quantification, could help towards a robust characterisation of the structural properties of the fluid.
Agrawal R, Sherwood J, Chhablani J, et al., 2016, Red blood cells in retinal vascular disorders, Blood Cells, Molecules, and Diseases, Vol: 56, Pages: 53-61, ISSN: 1079-9796
Microvascular circulation plays a vital role in regulating physiological functions, such as vascular resistance, and maintaining organ health. Pathologies such as hypertension, diabetes, or hematologic diseases affect the microcirculation posing a significant risk to human health. The retinal vasculature provides a unique window for non-invasive visualisation of the human circulation in vivo and retinal vascular image analysis has been established to predict the development of both clinical and subclinical cardiovascular, metabolic, renal and retinal disease in epidemiologic studies.Blood viscosity which was otherwise thought to play a negligible role in determining blood flow based on Poiseuille's law up to the 1970s has now been shown to play an equally if not a more important role in controlling microcirculation and quantifying blood flow. Understanding the hemodynamics/rheology of the microcirculation and its changes in diseased states remains a challenging task; this is due to the particulate nature of blood, the mechanical properties of the cells (such as deformability and aggregability) and the complex architecture of the microvasculature.In our review, we have tried to postulate a possible role of red blood cell (RBC) biomechanical properties and laid down future framework for research related to hemorrheological aspects of blood in patients with retinal vascular disorders.
Boussommier-Calleja A, Li G, Wilson A, et al., 2015, Physical factors affecting outflow facility measurements in mice, Investigative Ophthalmology & Visual Science, Vol: 56, Pages: 8331-8339, ISSN: 1552-5783
Purpose: Mice are commonly used to study conventional outflow physiology. This study examined how physical factors (hydration, temperature, and anterior chamber [AC] deepening) influence ocular perfusion measurements in mice.Methods: Outflow facility (C) and pressure-independent outflow (Fu) were assessed by multilevel constant pressure perfusion of enucleated eyes from C57BL/6 mice. To examine the effect of hydration, seven eyes were perfused at room temperature, either immersed to the limbus in saline and covered with wet tissue paper or exposed to room air. Temperature effects were examined in 12 eyes immersed in saline at 20°C or 35°C. Anterior chamber deepening was examined in 10 eyes with the cannula tip placed in the anterior versus posterior chamber (PC). Posterior bowing of the iris (AC deepening) was visualized by three-dimensional histology in perfusion-fixed C57BL/6 eyes and by spectral-domain optical coherence tomography in living CD1 mice.Results: Exposure to room air did not significantly affect C, but led to a nonzero Fu that was significantly reduced upon immersion in saline. Increasing temperature from 20°C to 35°C increased C by 2.5-fold, more than could be explained by viscosity changes alone (1.4-fold). Perfusion via the AC, but not the PC, led to posterior iris bowing and increased outflow.Conclusions: Insufficient hydration contributes to the appearance of pressure-independent outflow in enucleated mouse eyes. Despite the large lens, AC deepening may artifactually increase outflow in mice. Temperature-dependent metabolic processes appear to influence conventional outflow regulation. Physical factors should be carefully controlled in any outflow studies involving mice.
Ma S, Sherwood JM, Huck WTS, et al., 2015, The microenvironment of double emulsions in rectangular microchannels, Lab on a Chip, Vol: 15, Pages: 2327-2334, ISSN: 1473-0197
The flow environment in inner cores of water-in-oil-in-water (w/o/w) microfluidic double emulsions has a significant impact on industrial applications of such systems. For example, in the case of shear sensitive cells compartmentalised in the cores, high shear conditions may be deleterious. This study reports on the flow characteristics of w/o/w inner cores in comparison to those in single water-in-oil (w/o) microdroplets of equal size moving in the same microchannel, resolved by means of micro-particle image velocimetry (μPIV). The multiphase flow system employed in the study had a viscosity ratio, λ, between aqueous and oil phase of the order of unity (λ = 0.78) and both single droplets and inner cores of double emulsions filled the channel. This configuration resulted in a weak recirculating flow inside the w/o single droplet: the measured flow field exhibited a uniform low velocity flow field in the central region surrounded by small regions of reversed flow near the channel walls. This flow topology was maintained in the inner cores of w/o/w double emulsions for intermediate capillary numbers (Ca) ranging from 10−3 to 10−2, and core morphologies varying from large plugs to pancake cores. The core morphology affected the magnitude and distribution of the velocity in the droplets. The similarity in the flow topology resulted from the fact that inner cores were located at the back of the outer droplet in such a way that inner and outer interfaces were in contact for over half of core surface area and separated only by a thin lubricating film. Both single droplets and inner cores exhibited a narrow shear rate distribution characterised by small regions of maximum shear confined near the channel walls. Shear rate magnitude values were found to be an order of magnitude lower than those in the channel and hence capable of reducing stresses in flow cytometry to far below reported values for cell damage. Hence, it can be concluded that doubl
Alimohammadi M, Sherwood JM, Karimpour M, et al., 2015, Aortic dissection simulation models for clinical support: fluid-structure interaction vs. rigid wall models, Biomedical Engineering Online, Vol: 14, ISSN: 1475-925X
BackgroundThe management and prognosis of aortic dissection (AD) is often challenging and the use of personalised computational models is being explored as a tool to improve clinical outcome. Including vessel wall motion in such simulations can provide more realistic and potentially accurate results, but requires significant additional computational resources, as well as expertise. With clinical translation as the final aim, trade-offs between complexity, speed and accuracy are inevitable. The present study explores whether modelling wall motion is worth the additional expense in the case of AD, by carrying out fluid-structure interaction (FSI) simulations based on a sample patient case.MethodsPatient-specific anatomical details were extracted from computed tomography images to provide the fluid domain, from which the vessel wall was extrapolated. Two-way fluid-structure interaction simulations were performed, with coupled Windkessel boundary conditions and hyperelastic wall properties. The blood was modelled using the Carreau-Yasuda viscosity model and turbulence was accounted for via a shear stress transport model. A simulation without wall motion (rigid wall) was carried out for comparison purposes.ResultsThe displacement of the vessel wall was comparable to reports from imaging studies in terms of intimal flap motion and contraction of the true lumen. Analysis of the haemodynamics around the proximal and distal false lumen in the FSI model showed complex flow structures caused by the expansion and contraction of the vessel wall. These flow patterns led to significantly different predictions of wall shear stress, particularly its oscillatory component, which were not captured by the rigid wall model.ConclusionsThrough comparison with imaging data, the results of the present study indicate that the fluid-structure interaction methodology employed herein is appropriate for simulations of aortic dissection. Regions of high wall shear stress were not significantly al
Overby DR, Zhou EH, Vargas-Pinto R, et al., 2014, Altered mechanobiology of Schlemm's canal endothelial cells in glaucoma, Proceedings of the National Academy of Sciences of the United States of America, Vol: 111, Pages: 13876-13881, ISSN: 0027-8424
Increased flow resistance is responsible for the elevated intraocular pressure characteristic of glaucoma, but the cause of this resistance increase is not known. We tested the hypothesis that altered biomechanical behavior of Schlemm’s canal (SC) cells contributes to this dysfunction. We used atomic force microscopy, optical magnetic twisting cytometry, and a unique cell perfusion apparatus to examine cultured endothelial cells isolated from the inner wall of SC of healthy and glaucomatous human eyes. Here we establish the existence of a reduced tendency for pore formation in the glaucomatous SC cell—likely accounting for increased outflow resistance—that positively correlates with elevated subcortical cell stiffness, along with an enhanced sensitivity to the mechanical microenvironment including altered expression of several key genes, particularly connective tissue growth factor. Rather than being seen as a simple mechanical barrier to filtration, the endothelium of SC is seen instead as a dynamic material whose response to mechanical strain leads to pore formation and thereby modulates the resistance to aqueous humor outflow. In the glaucomatous eye, this process becomes impaired. Together, these observations support the idea of SC cell stiffness—and its biomechanical effects on pore formation—as a therapeutic target in glaucoma.
Ma S, Sherwood JM, Huck WTS, et al., 2014, On the flow topology inside droplets moving in rectangular microchannels, Lab on a Chip, Vol: 14, Pages: 3611-3620, ISSN: 1473-0197
The flow topology in moving microdroplets has a significant impact on the behaviour of encapsulated objects and hence on applications of the technology. This study reports on a systematic investigation of the flow field inside droplets moving in a rectangular microchannel, by means of micro-particle image velocimetry (μPIV). Various water/oil (w/o) fluid mixtures were studied in order to elucidate the effects of a number of parameters such as capillary number (Ca), droplet geometry, viscosity ratio and interfacial tension. A distinct change in flow topology was observed at intermediate Ca ranging from 10−3 to 10−1, in surfactant-laden droplets, which was attributed primarily to the viscosity ratio of the two phases rather than the Marangoni effect expected in such systems. W/o droplet systems of lower inner-to-outer viscosity ratios tend to exhibit the well-known flow pattern characterised by a parabola-like profile in the droplet bulk-volume, surrounded by two counter rotating recirculation zones on either side of the droplet axis. As the viscosity ratio between the two phases is increased, the flow pattern becomes more uniform, exhibiting low velocities in the droplet bulk-volume and higher-reversed velocities along the w/o interface. The Ca and droplet geometry had no effect on the observed flow topology change. The study highlights the complex, three-dimensional (3D) nature of the flow inside droplets in rectangular microchannels and demonstrates the ability to control the droplet flow environment by adjusting the viscosity ratio between the two phases.
Sherwood JM, Holmes D, Kaliviotis E, et al., 2014, Spatial Distributions of Red Blood Cells Significantly Alter Local Haemodynamics, PLOS ONE, Vol: 9, ISSN: 1932-6203
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Sherwood JM, Kaliviotis E, Dusting J, et al., 2014, Hematocrit, viscosity and velocity distributions of aggregating and non-aggregating blood in a bifurcating microchannel, BIOMECHANICS AND MODELING IN MECHANOBIOLOGY, Vol: 13, Pages: 259-273, ISSN: 1617-7959
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Reina-Torres E, Sherwood JM, Stamer WD, et al., 2014, Role of Vascular Endothelial Growth Factor (VEGF) in the regulation of conventional outflow facility in mice, Publisher: ASSOC RESEARCH VISION OPHTHALMOLOGY INC, ISSN: 0146-0404
Sherwood JM, Dusting J, Kaliviotis E, et al., 2012, The effect of red blood cell aggregation on velocity and cell-depleted layer characteristics of blood in a bifurcating microchannel, Biomicrofluidics, Vol: 6, ISSN: 1932-1058
Red blood cell (RBC) aggregation is a multifaceted phenomenon, and whether it is generally beneficial or deleterious remains unclear. In order to better understand its effect on microvascular blood flow, the phenomenon must be studied in complex geometries, as it is strongly dependent on time, flow, and geometry. The cell-depleted layer (CDL) which forms at the walls of microvessels has been observed to be enhanced by aggregation; however, details of the characteristics of the CDL in complex regions, such as bifurcations, require further investigation. In the present study, a microchannel with a T-junction was used to analyze the influence of aggregation on the flow field and the CDL. Micro-PIV using RBCs as tracers provided high resolution cell velocity data. CDL characteristics were measured from the same data using a newly developed technique based on motion detection. Skewed and sharpened velocity profiles in the daughter branches were observed, contrary to the behavior of a continuous Newtonian fluid. RBC aggregation was observed to increase the skewness, but decrease the sharpening, of the velocity profiles in the daughter branches. The CDL width was found to be significantly greater, with a wider distribution, in the presence of aggregation and the mean width increased proportionally with the reciprocal of the fraction of flow entering the daughter branch. Aggregation also significantly increased the roughness of the interface between the CDL and the RBC core. The present results provide further insight into how RBC aggregation may affect the flow in complex geometries, which is of importance in both understanding its functions invivo, and utilizing it as a tool in microfluidic devices.
Sherwood J, Dusting J, Konstantinidis E, et al., 2010, FLOW-INDUCED STREAMWISE VIBRATION OF A FLEXIBLY-MOUNTED CANTILEVERED CYLINDER IN STEADY AND PULSATING CROSSFLOW, Pressure Vessels and Piping Conference of the American-Society-of-Mechanical-Engineers, Publisher: AMER SOC MECHANICAL ENGINEERS, Pages: 203-210
Konstantinidis E, Giagopoulos D, Sherwood J, et al., 2010, THE EFFECT OF FLOW PULSATIONS ON THE STREAMWISE VIBRATION OF A CANTILEVERED RIGID CYLINDER, 7th Int Symposium on Fluid-Structure Interactions, Flow-Sound Interactions, and Flow-Induced Vibration and Noise/Summer Meeting of the Fluids Engineering Division of ASME, Publisher: AMER SOC MECHANICAL ENGINEERS, Pages: 65-73
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