Significance: Glaucoma is a leading cause of blindness. The elevated intraocular pressure characteristic of many cases of glaucoma is attributable to increased resistance to aqueous humor outflow. However, the cause of this increased flow resistance has eluded investigators for over 140 y. Here we demonstrate that cells from the canal of Schlemm of glaucomatous eyes have altered gene expression and increased cytoskeletal stiffness that leads to reduced pore formation in these cells, likely accounting for increased outflow resistance associated with glaucoma. These findings thus establish that dysfunctional cytoskeletal mechanics may lie at the heart of this disease process and thereby motivate development of glaucoma therapeutics that target cell stiffness.

The 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. Patient-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. The 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. Through 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 altered by the wall motion, however, certain collocated regions of low and oscillatory wall shear stress which may be critical for disease progression were only identified in the FSI simulation. We conclude that, if patient-tailored simulations of aortic dissection are to be used as an interventional planning tool, then the additional complexity, expertise and computational expense required to model wall motion is indeed justified.

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, as well as to eyes from other species or different biofluidic systems.

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.

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.