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Abstract Background Astronauts undergoing long-duration spaceflight are exposed to numerous health risks, including Spaceflight-Associated Neuro-Ocular Syndrome (SANS), a spectrum of ophthalmic changes that can result in permanent loss of visual acuity. The etiology of SANS is not well understood but is thought to involve changes in cerebrovascular flow dynamics in response to microgravity. There is a paucity of knowledge in this area; in particular, cerebrospinal fluid (CSF) flow dynamics have not been well characterized under microgravity conditions. Our study was designed to determine the effect of simulated microgravity (head-down tilt [HDT]) on cerebrovascular flow dynamics. We hypothesized that microgravity conditions simulated by acute HDT would result in increases in CSF pulsatile flow. Methods In a prospective cohort study, we measured flow in major cerebral arteries, veins, and CSF spaces in fifteen healthy volunteers using phase contrast magnetic resonance (PCMR) before and during 15° HDT. Results We found a decrease in all CSF flow variables [systolic peak flow (p = 0.009), and peak-to-peak pulse amplitude (p = 0.001)]. Cerebral arterial average flow (p = 0.04), systolic peak flow (p = 0.04), and peak-to-peak pulse amplitude (p = 0.02) all also significantly decreased. We additionally found a decrease in average cerebral arterial flow (p = 0.040). Finally, a significant increase in cerebral venous cross-sectional area under HDT (p = 0.005) was also observed. Conclusions These results collectively demonstrate that acute application of −15° HDT caused a reduction in CSF flow variables (systolic peak flow and peak-to-peak pulse amplitude) which, when coupled with a decrease in average cerebral arterial flow, systolic peak flow, and peak-to-peak pulse amplitude, is consistent with a decrease in cardiac-related pulsatile CSF flow. These results suggest that decreases in cerebral arterial inflow were the principal drivers of decreases in CSF pulsatile flow.

The biomechanical properties of the cornea and sclera are important in the onset and progression of multiple ocular pathologies and vary substantially between individuals, yet the source of this variation remains unknown. Here we identify genes putatively regulating corneoscleral biomechanical tissue properties by conducting high-fidelity ocular compliance measurements across the BXD recombinant inbred mouse set and performing quantitative trait analysis. We find seven cis-eQTLs and non-synonymous SNPs associating with ocular compliance, and show by RT-qPCR and immunolabeling that only two of the candidate genes, Smarce1 and Tns4, showed significant expression in corneal and scleral tissues. Both have mechanistic potential to influence the development and/or regulation of tissue material properties. This work motivates further study of Smarce1 and Tns4 for their role(s) in ocular pathology involving the corneoscleral envelope as well as the development of novel mouse models of ocular pathophysiology, such as myopia and glaucoma.

Summary: Controlling intraocular pressure (IOP) remains the mainstay of glaucoma therapy. The trabecular meshwork (TM), the key tissue responsible for aqueous humor (AH) outflow and IOP maintenance, is very sensitive to mechanical forces. However, it is not understood whether Piezo channels, very sensitive mechanosensors, functionally influence AH outflow. Here, we characterize the role of Piezo1 in conventional AH outflow. Immunostaining and western blot analysis showed that Piezo1 is widely expressed by TM. Patch-clamp recordings in TM cells confirmed the activation of Piezo1-derived mechanosensitive currents. Importantly, the antagonist GsMTx4 for mechanosensitive channels significantly decreased steady-state facility, yet activation of Piezo1 by the specific agonist Yoda1 did not lead to a facility change. Furthermore, GsMTx4, but not Yoda1, caused a significant increase in ocular compliance, a measure of the eye's transient response to IOP perturbation. Our findings demonstrate a potential role for Piezo1 in conventional outflow, likely under pathological and rapid transient conditions.

Abstract Glaucoma is the leading cause of irreversible blindness. Current treatments use drugs or surgery to reduce intraocular pressure (IOP). In this study, a drug‐free, nonsurgical method is developed that lowers IOP for 4 months without requiring daily patient adherence. The approach involves expanding the suprachoroidal space (SCS) of the eye with an in situ‐forming hydrogel injected using a microneedle. This study tests the hypothesis that SCS expansion increases the drainage of aqueous humor from the eye via the unconventional pathway, which thereby lowers IOP. SCS injection of a commercial hyaluronic acid (HA) hydrogel reduces the IOP of normotensive rabbits for more than 1 month and an optimized HA hydrogel formulation enables IOP reduction for 4 months. Safety assessment by clinical ophthalmic examinations indicate the treatment is well tolerated. Histopathology shows minor hemorrhage and fibrosis at the site of injection. Further analysis by ultrasound biomicroscopy demonstrates a strong correlation of IOP reduction with SCS expansion. Outflow facility measurements show no difference in pressure‐dependent outflow by the conventional pathway between treated and untreated eyes, supporting the hypothesis. In conclusion, SCS expansion with an in situ‐forming hydrogel can enable extended IOP reduction for treating ocular hypertension and glaucoma without drugs or surgery.

A Correction to this paper has been published: https://doi.org/10.1038/s42003-021-01958-w

The pressure-volume relationship of the eye is determined by the biomechanical properties of the corneoscleral shell and is classically characterised by Friedenwald's coefficient of ocular rigidity or, alternatively, by the ocular compliance (OC), defined as dV/dP. OC is important in any situation where the volume (V) or pressure (P) of the eye is perturbed, as occurs during several physiological and pathological processes. However, accurately measuring OC is challenging, particularly in rodents. We measured OC in 24 untreated enucleated eyes from 12 C57BL/6 mice using the iPerfusion system to apply controlled pressure steps, whilst measuring the time-varying flow rate into the eye. Pressure and flow data were analysed by a “Discrete Volume” (integrating the flow trace) and “Step Response” method (fitting an analytical solution to the pressure trace). OC evaluated at 13 mmHg was similar between the two methods (Step Response, 41 [37, 46] vs. Discrete Volume, 42 [37, 48] nl/mmHg; mean [95% CI]), although the Step Response Method yielded tighter confidence bounds on individual eyes. OC was tightly correlated between contralateral eyes (R2 = 0.75, p = 0.0003). Following treatment with the cross-linking agent genipin, OC decreased by 40 [33, 47]% (p = 0.0001; N = 6, Step Response Method). Measuring OC provides a powerful tool to assess corneoscleral biomechanics in mice and other species.

A Correction to this paper has been published: https://doi.org/10.1038/s42003-021-01957-x

Glucocorticoids are widely used as an ophthalmic medication. A common, sight-threatening adverse event of glucocorticoid usage is ocular hypertension, caused by dysfunction of the conventional outflow pathway. We report that netarsudil, a rho-kinase inhibitor, decreased glucocorticoid-induced ocular hypertension in patients whose intraocular pressures were poorly controlled by standard medications. Mechanistic studies in our established mouse model of glucocorticoid-induced ocular hypertension show that netarsudil both prevented and reduced intraocular pressure elevation. Further, netarsudil attenuated characteristic steroid-induced pathologies as assessed by quantification of outflow function and tissue stiffness, and morphological and immunohistochemical indicators of tissue fibrosis. Thus, rho-kinase inhibitors act directly on conventional outflow cells to prevent or attenuate fibrotic disease processes in glucocorticoid-induced ocular hypertension in an immune-privileged environment. Moreover, these data motivate the need for a randomized prospective clinical study to determine whether netarsudil is indeed superior to first-line anti-glaucoma drugs in lowering steroid-induced ocular hypertension.

Abstract Coronary artery bypass graft (CABG) failure has been linked to graft hemodynamics, in particular wall shear stress. This study characterizes the morphology, geometry and wall shear stress patterns in human CABGs. The intimal thickness (IT) in 49 human saphenous vein CABGs was measured by digital light microscopy. The geometry of six saphenous vein CABGs was replicated by post-mortem infusion of Batson’s #17 anatomical corrosion casting compound. Graft hemodynamics were evaluated in two flow models, fabricated from the casts, under steady (Re = 110) and pulsatile flow (Re = 110, a = 2) conditions. Saphenous vein CABGs in situ for more than 2 months had, on average, the greatest IT on the hood and suture sites of the distal anastomosis. Floor thickening was highly variable and significantly less than IT at the hood, suture site and graft body. All casts showed an indentation along the floor and 5/6 casts displayed a sharp local curvature on the hood. In both flow models, a large increase in wall shear rate occurred on the hood, just proximal to the toe. The local geometry of the hood created this large spatial gradient in wall shear stress which is a likely factor in hood intimal hyperplasia. [ABSTRACT FROM AUTHOR]

The purpose of this work was to investigate the effects of physiologically realistic cardiac-induced motion on hemodynamics in human right coronary arteries. The blood flow patterns were numerically simulated in a modeled right coronary artery (RCA) having a uniform circular cross section of 2.48 mm diam. Arterial motion was specified based on biplane cineangiograms, and incorporated physiologically realistic bending and torsion. Simulations were carried out with steady and pulsatile inflow conditions (mean \text{Re}_{D/math> ɑ =1.82) in both fixed and moving RCA models, to evaluate the relative importance of RCA motion, flow pulsation, and the interaction between motion and flow pulsation. RCA motion with a steady inlet flow rate caused variations in wall shear stress (WSS) magnitude up to 150% of the inlet Poiseuille value. There was significant spatial variability in the magnitude of this motion-induced WSS variation. However, the time-averaged WSS distribution was similar to that predicted in a static model representing the time-averaged geometry. Furthermore, the effects of flow pulsatility dominated RCA motion-induced effects; specifically, there were only modest differences in the WSS history between simulations conducted in fixed and moving RCA models with pulsatile inflow. RCA motion has little effect on time-averaged WSS patterns. It has a larger effect on the temporal variation of WSS, but even this effect is overshadowed by the variations in WSS due to flow pulsation. The hemodynamic effects of RCA motion can, therefore, be ignored as a first approximation in modeling studies. © 2003 Biomedical Engineering Society. PAC2003: 8719Uv, 8719Hh, 8719St, 8719Rr [ABSTRACT FROM AUTHOR]

Many experiments have documented the response of intraocular pressure (IOP) to postural change. External forces caused by gravitational orientation change produce a dynamic response that is encountered every day during normal activities. Tilting the body at a small downward angle is also relevant to studying the effects of hypogravity (spaceflight), including ocular changes. We examined data from 36 independent datasets from 30 articles on IOP response to postural change, representing a total population of 821 subjects (≥1173 eyes) with widely varying initial and final postures. We confirmed that IOP was well predicted by a simple quantity, namely the hydrostatic pressure at the level of the eye, although the dependence was complex (nonlinear). Our results show that posturally induced IOP change can be explained by hydrostatic forcing plus an autoregulatory contribution that is dependent on hydrostatic effects. This study represents data from thousands of IOP measurements and provides insight for future studies that consider postural change in relation to ocular physiology, intraocular pressure, ocular blood flow and aqueous humor dynamics.

Pathologic changes in intracranial pressure (ICP) are commonly observed in a variety of medical conditions, including traumatic brain injury, stroke, brain tumors, and glaucoma. However, current ICP measurement techniques are invasive, requiring a lumbar puncture or surgical insertion of a cannula into the cerebrospinal fluid (CSF)-filled ventricles of the brain. A potential alternative approach to ICP measurement leverages the unique anatomy of the central retinal vein, which is exposed to both intraocular pressure (IOP) and ICP as it travels inside the eye and through the optic nerve; manipulating IOP while observing changes in the natural pulsations of the central retinal vein could potentially provide an accurate, indirect measure of ICP. As a step toward implementing this technique, we describe the design, fabrication, and characterization of a system that is capable of manipulating IOP in vivo with

Glaucoma is the second leading cause of blindness worldwide and is characterized by the death of retinal ganglion cells (RGCs), the cells that send vision information to the brain. Their axons exit the eye at the optic nerve head (ONH), the main site of damage in glaucoma. The importance of biomechanics in glaucoma is indicated by the fact that elevated intraocular pressure (IOP) is a causative risk factor for the disease. However, exactly how biomechanical insult leads to RGC death is not understood. Although rat models are widely used to study glaucoma, their ONH biomechanics have not been characterized in depth. Therefore, we aimed to do so through finite element (FE) modeling. Utilizing our previously described method, we constructed and analyzed ONH models with individual-specific geometry in which the sclera was modeled as a matrix reinforced with collagen fibers. We developed eight sets of scleral material parameters based on results from our previous inverse FE study and used them to simulate the effects of elevated IOP in eight model variants of each of seven rat ONHs. Within the optic nerve, highest strains were seen inferiorly, a pattern that was consistent across model geometries and model variants. In addition, changing the collagen fiber direction to be circumferential within the peripapillary sclera resulted in more pronounced decreases in strain than changing scleral stiffness. The results from this study can be used to interpret data from rat glaucoma studies to learn more about how biomechanics affects RGC pathogenesis in glaucoma., (Copyright © 2021 by ASME.)

Glaucoma is the leading cause of irreversible blindness and involves the death of retinal ganglion cells (RGCs). Although biomechanics likely contributes to axonal injury within the optic nerve head (ONH), leading to RGC death, the pathways by which this occurs are not well understood. While rat models of glaucoma are well-suited for mechanistic studies, the anatomy of the rat ONH is different from the human, and the resulting differences in biomechanics have not been characterized. The aim of this study is to describe a methodology for building individual-specific finite element (FE) models of rat ONHs. This method was used to build three rat ONH FE models and compute the biomechanical environment within these ONHs. Initial results show that rat ONH strains are larger and more asymmetric than those seen in human ONH modeling studies. This method provides a framework for building additional models of normotensive and glaucomatous rat ONHs. Comparing model strain patterns with patterns of cellular response seen in studies using rat glaucoma models will help us to learn more about the link between biomechanics and glaucomatous cell death, which in turn may drive the development of novel therapies for glaucoma.

The posterior eye is a complex biomechanical structure. Delicate neural and vascular tissues of the retina, choroid, and optic nerve head that are critical for visual function are subjected to mechanical loading from intraocular pressure, intraocular and extraorbital muscles, and external forces on the eye. The surrounding sclera serves to counteract excessive deformation from these forces and thus to create a stable biomechanical environment for the ocular tissues. Additionally, the eye is a dynamic structure with connective tissue remodeling occurring as a result of aging and pathologies such as glaucoma and myopia. The material properties of these tissues and the distribution of stresses and strains in the posterior eye is an area of active research, relying on a combination of computational modeling, imaging, and biomechanical measurement approaches. Investigators are recognizing the increasing importance of the role of the collagen microstructure in these material properties and are undertaking microstructural measurements to drive microstructurally-informed models of ocular biomechanics. Here, we review notable findings and the consensus understanding on the biomechanics and microstructure of the posterior eye. Results from computational and numerical modeling studies and mechanical testing of ocular tissue are discussed. We conclude with some speculation as to future trends in this field.

The biomechanical environment of the optic nerve head (ONH), of interest in glaucoma, is strongly affected by the biomechanical properties of sclera. However, there is a paucity of information about the variation of scleral mechanical properties within eyes and between individuals. We thus used biaxial testing to measure scleral stiffness in human eyes. Ten eyes from 5 human donors (age 55.4+/-3.5 years; mean+/-SD) were obtained within 24h of death. Square scleral samples (6mm on a side) were cut from each ocular quadrant 3-9 mm from the ONH centre and were mechanically tested using a biaxial extensional tissue tester (BioTester 5000, CellScale Biomaterials Testing, Waterloo). Stress-strain data in the latitudinal (toward the poles) and longitudinal (circumferential) directions, here referred to as directions 1 and 2, were fit to the four-parameter Fung constitutive equation W=c(e(Q)-1), where Q=c(1)E(11)(2)+c(2)E(22)(2)+2c(3)E(11)E(22) and W, c's and E(ij) are the strain energy function, material parameters and Green strains, respectively. Fitted material parameters were compared between samples. The parameter c(3) ranged from 10(-7) to 10(-8), but did not contribute significantly to the accuracy of the fitting and was thus fixed at 10(-7). The products cc(1) and cc(2), measures of stiffness in the 1 and 2 directions, were 2.9+/-2.0 and 2.8+/-1.9 MPa, respectively, and were not significantly different (two-sided t-test; p=0.795). The level of anisotropy (ratio of stiffness in orthogonal directions) was 1.065+/-0.33. No statistically significant correlations between sample thickness and stiffness were found (correlation coefficients=-0.026 and -0.058 in directions 1 and 2, respectively). Human sclera showed heterogeneous, near-isotropic, nonlinear mechanical properties over the scale of our samples., (Copyright (c) 2010 Elsevier Ltd. All rights reserved.)

Glaucoma is a common cause of blindness. Studies of this disease can involve collection of aqueous humor (AH) fluid from eyes of patients undergoing surgery, which involves aspirating a small fluid volume from the anterior region of the eye through a fine-bore needle. Unfortunately, the composition of the AH is spatially non-uniform in the eye, and thus the composition of the aspirated fluid is uncertain. Our goal was to numerically simulate the AH aspiration process to determine where the aspirated fluid was being collected from and thus gain insight into the composition of the collected fluid. A 3D computational model of the anterior region of the human eye was created and the Navier-Stokes equations were numerically solved during the aspiration process for a set of typical (baseline) conditions: 40 microl aspirated volume and needle placement in the central anterior chamber. We also ran variations of this baseline simulation. The main finding was that the aspirated fluid comes from a very localized region around the needle tip, so that for typical conditions, almost no aspirated fluid is withdrawn from the angle region of the anterior chamber. This is important because the AH in this angle region is protein-rich and directly interacts with the tissues that control fluid drainage from the eye. Recommendations for standardizing aspiration conditions are given.

The goal of the present study was to specifically modify protein expression in the resistance-generating region of the conventional outflow pathway, namely the inner wall of Schlemm's canal (SC) and the juxtacanalicular region of the trabecular meshwork, in perfused human anterior segments. Anterior segments from human cadaveric eyes were prepared for organ culture using standard techniques and were perfused at constant flow while recording pressure. After reaching a stable outflow facility within physiological limits, forward perfusion was stopped and a fluid-tight fence encircling the limbus was installed and filled with media containing an adenovirus encoding the lacZ reporter gene (either 2 x 10(6) or 6 x 10(6)PFU/ml). With the limbus submerged, pressure inside the chamber was lowered to -1 mmHg to facilitate reverse perfusion of virus into SC ("retroperfusion"). After 30-60 min at zero pressure (with some mixing), forward perfusion was restarted and continued for 5-7 days, after which anterior segments were fixed and processed for visualization of lacZ activity. Retroperfusion of nine anterior segments with adenovirus encoding a reporter gene did not appreciably alter baseline outflow facility (0.27+/-0.05 versus 0.29+/-0.08 microl/min per mmHg post-retroperfusion). Gross examination of outflow tissues showed focal distribution of lacZ activity around the circumference of SC, presumably near collector channels. In segments that were sequentially tilted during retroperfusion, the distribution of lacZ activity appeared more uniform. Sagittal histological sections showed lacZ activity in all portions of the conventional drainage tract, particularly cells in the resistance-generating region. Taken together, the results demonstrate that candidate protein expression by cells in the resistance-generating region of the conventional drainage pathway can be specifically modified by retroperfusion of adenovirus and examined for effects on outflow facility.

Endothelial cells regulate vascular tone and mural remodelling in a shear-dependent manner that is commonly assumed to keep wall shear stress constant across arteries and species. Allometric arguments show that aortic flow velocity is constant across species, a deduction that is consistent with much experimental data, but the same arguments also show that the shear stress experienced by aortic endothelium will depend inversely on body mass to the 3/8th power, and hence will be 20-fold higher in mice than in men. This conclusion is robust and has important implications for the study of shear-dependent vascular biology and pathology.