Ocular Compliance Research Articles

Higher intraocular pressure is associated with slower axial growth in children with non-pathological high myopia

ObjectivesTo investigate the association between intraocular pressure (IOP) and axial elongation rate in highly myopic children from the ZOC-BHVI High Myopia Cohort Study.Methods162 eyes of 81 healthy children (baseline spherical equivalent: −6.25 D to −15.50 D) aged 7–12 years with non-pathological high myopia were studied over five biennial visits. The mean (SD) follow-up duration was 5.2 (3.3) years. A linear mixed-effects model (LMM) was used to assess the association between IOP (at time point t−1) and axial elongation rate (annual rate of change in AL from t−1 to t), controlling for a pre-defined set of covariates including sex, age, central corneal thickness, anterior chamber depth and lens thickness (at t−1). LMM was also used to assess the contemporaneous association between IOP and axial length (AL) at t, controlling for the same set of covariates (at t) as before.ResultsHigher IOP was associated with slower axial growth (β = −0.01, 95% CI −0.02 to −0.005, p = 0.001). There was a positive contemporaneous association between IOP and AL (β = 0.03, 95% CI 0.01–0.05, p = 0.004), but this association became progressively less positive with increasing age, as indicated by a negative interaction effect between IOP and age on AL (β = −0.01, 95% CI −0.01 to −0.003, p = 0.001).ConclusionsHigher IOP is associated with slower rather than faster axial growth in children with non-pathological high myopia, an association plausibly confounded by the increased influence of ocular compliance on IOP.

Modeling the compliance of the human eye with elastic membranes based on a bionic approach.

Together with the corneoscleral shell the intraocular pressure maintains the shape of the human eyeball and thus ensures both mechanical and optical integrity, whereby the relationship between the intraocular volume and pressure is described by the so-called ocular compliance. The compliance of the human eye is of significance insituations where a variation of the intraocular volume leads to a change in pressure or vice versa, as this is the case in many clinical settings. In order to provide a framework and set-up for experimental investigations and testing this paper presents a bionic inspired approach to simulate the ocular compliance by using elastomeric membranes- based on physiological behaviour. For parameter studies and for validation, the numerical analysis with hyperelastic material models shows good agreement with reported compliance curves. In addition, the compliance curves of six different elastomeric membranes have been measured. The results show that the characteristics of the compliance curve of the human eye can be modeled within a 5 % range using the proposed elastomeric membranes. A set-up for experimental investigations is presented that allows the simulation of the compliance curve of the human eye without simplifications in terms of shape, geometry, and deformation behaviour.

Corneal Hysteresis, Intraocular Pressure, and Progression of Glaucoma: Time for a "Hyst-Oric" Change in Clinical Practice?

It is known that as people age their tissues become less compliant and the ocular structures are no different. Corneal Hysteresis (CH) is a surrogate marker for ocular compliance. Low hysteresis values are associated with optic nerve damage and visual field loss, the structural and functional components of glaucomatous optic neuropathy. Presently, a range of parameters are measured to monitor and stratify glaucoma, including intraocular pressure (IOP), central corneal thickness (CCT), optical coherence tomography (OCT) scans of the retinal nerve fibre layer (RNFL) and the ganglion cell layer (GCL), and subjective measurement such as visual fields. The purpose of this review is to summarise the current evidence that CH values area risk factor for the development of glaucoma and are a marker for its progression. The authors will explain what precisely CH is, how it can be measured, and the influence that medication and surgery can have on its value. CH is likely to play an integral role in glaucoma care and could potentially be incorporated synergistically with IOP, CCT, and visual field testing to establish risk stratification modelling and progression algorithms in glaucoma management in the future.

Assessment of Commercial Off-the-Shelf Tissue Adhesives for Sealing Military-Relevant Corneal Perforation Injuries.

Open-globe ocular injuries have increased in frequency in recent combat operations due to increased use of explosive weaponry. Unfortunately, open-globe injuries have one of the worst visual outcomes for the injured warfighter, often resulting in permanent loss of vision. To improve visual recovery, injuries need to be stabilized quickly following trauma, in order to restore intraocular pressure and create a watertight seal. Here, we assess four off-the-shelf (OTS), commercially available tissue adhesives for their ability to seal military-relevant corneal perforation injuries (CPIs). Adhesives were assessed using an anterior segment inflation platform and a previously developed high-speed benchtop corneal puncture model, to create injuries in porcine eyes. After injury, adhesives were applied and injury stabilization was assessed by measuring outflow rate, ocular compliance, and burst pressure, followed by histological analysis. Tegaderm dressings and Dermabond skin adhesive most successfully sealed injuries in preliminary testing. Across a range of injury sizes and shapes, Tegaderm performed well in smaller injury sizes, less than 2 mm in diameter, but inadequately sealed large or complex injuries. Dermabond created a watertight seal capable of maintaining ocular tissue at physiological intraocular pressure for almost all injury shapes and sizes. However, application of the adhesive was inconsistent. Histologically, after removal of the Dermabond skin adhesive, the corneal epithelium was removed and oftentimes the epithelium surface penetrated into the wound and was adhered to inner stromal tissue. Dermabond can stabilize a wide range of CPIs; however, application is variable, which may adversely impact the corneal tissue. Without addressing these limitations, no OTS adhesive tested herein can be directly translated to CPIs. This highlights the need for development of a biomaterial product to stabilize these injuries without causing ocular damage upon removal, thus improving the poor vision prognosis for the injured warfighter.

Smarce1 and Tensin 4 Are Putative Modulators of Corneoscleral Stiffness.

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.

The role of Piezo1 in conventional aqueous humor outflow dynamics

SummaryControlling 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.

An Open-Globe Porcine Injury Platform for Assessing Therapeutics and Characterizing Biological Effects.

Open-globe injuries can result in permanent vision loss, partly due to extended delays between injury and medical intervention. Even with early intervention, the management of open-globe injuries remains a challenge for ophthalmologists, mostly due to inadequate or suboptimal current therapies. To aid in the development of novel therapeutics and track toxicological and pathophysiological changes, this article details an open-globe injury platform capable of inducing injuries in enucleated porcine eyes. The injury platform relies on a high-speed solenoid device to mimic explosive injury scenarios, allowing for large, complex injury shapes and sizes that are often observed in casualties and are more difficult to treat. The system can be implemented with precise computer control of the injury mechanism to allow for more complex setups. Also, the system can make use of real-time intraocular pressure measurement to track changes during injury induction and to assess therapeutic efficacy for restoring intraocular pressure and the integrity of the eye. These protocols will assist with implementation of the injury model in prospective laboratories seeking to develop therapeutics or studying biological changes that occur from this type of traumatic injury. Published 2020. U.S. Government. Basic Protocol 1: Preparing gelatin molds and porcine eye tissue Basic Protocol 2: Creating an open-globe injury using a solenoid device Alternate Protocol 1: Constructing a computer-controlled system for open-globe injury Alternate Protocol 2: Constructing a pressure measurement system for tracking intraocular pressure Support Protocol 1: Assessing ocular compliance in porcine eyes Support Protocol 2: Assessing outflow rate from the anterior chamber Support Protocol 3: Assessing burst pressure in porcine eyes.

Integral role for lysyl oxidase-like-1 in conventional outflow tissue function and behavior.

Lysyl oxidase-like-1 (LOXL1), a vital crosslinking enzyme in elastin fiber maintenance, is essential for the stability and strength of elastic vessels and tissues. Variants in the LOXL1 locus associate with a dramatic increase in risk of exfoliation syndrome (XFS), a systemic fibrillopathy, which often presents with ocular hypertension and exfoliation glaucoma (XFG). We examined the role of LOXL1 in conventional outflow function, the prime regulator of intraocular pressure (IOP). Using Loxl1-/- , Loxl1+/- , and Loxl1+/+ mice, we observed an inverse relationship between LOXL1 expression and IOP, which worsened with age. Elevated IOP in Loxl1-/- mice was associated with a larger globe, decreased ocular compliance, increased outflow facility, extracellular matrix (ECM) abnormalities, and dilated intrascleral veins, yet, no dilation of arteries or capillaries. Interestingly, in living Loxl1-/- mouse eyes, Schlemm's canal (SC) was less susceptible to collapse when challenged with acute elevations in IOP, suggesting elevated episcleral venous pressure (EVP). Thus, LOXL1 expression is required for normal IOP control, while ablation results in altered ECM repair/homeostasis and conventional outflow physiology. Dilation of SC and distal veins, but not arteries, is consistent with key structural and functional roles for elastin in low-pressure vessels subjected to cyclical mechanical stress.

Age and Menopause Effects on Ocular Compliance and Aqueous Outflow

PurposeGlaucoma is the second leading cause of blindness worldwide. Recent work suggests that estrogen and the timing of menopause play a role in modulating the risk of developing glaucoma. Menopause is known to cause modest changes in intraocular pressure; yet, whether this change is mediated through the outflow pathway remains unknown. Menopause also affects tissue biomechanical properties throughout the body; however, the impact of menopause on ocular biomechanical properties is not well characterized.MethodsHere, we simultaneously assessed the impact of menopause on aqueous outflow facility and ocular compliance, as a measure of corneoscleral shell biomechanics. We used young (3–4 months old) and middle-aged (9–10 months old) Brown Norway rats. Menopause was induced by ovariectomy (OVX), and control animals underwent sham surgery, resulting in the following groups: young sham (n = 5), young OVX (n = 6), middle-aged sham (n = 5), and middle-aged OVX (n = 5). Eight weeks postoperatively, we measured outflow facility and ocular compliance.ResultsMenopause resulted in a 34% decrease in outflow facility and a 19% increase in ocular compliance (P = 0.011) in OVX animals compared with sham controls (P = 0.019).ConclusionsThese observations reveal that menopause affects several key physiological factors known to be associated with glaucoma, suggesting that menopause may contribute to an increased risk of glaucoma in women.

Measurement of Ocular Compliance Using iPerfusion.

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.

Quantification of Scleral Biomechanics and Collagen Fiber Alignment.

The stiffness of the sclera is important in several ocular disorders, and there is hence a need to quantify the biomechanical properties of this tissue. Here, we present two methods for measuring the stiffness of scleral ocular tissues: ocular compliance testing and digital image correlation strain mapping. In tandem with these approaches, we provide two methods to spatially quantify the anisotropic alignment of collagen fibers making up the sclera, using second harmonic generation microscopy and small-angle light scattering. Together, these approaches allow specimen-specific measurement of tissue stiffness and collagen alignment, which are key factors in determining how the eye responds to mechanical loads.

The impact of ocular hemodynamics and intracranial pressure on intraocular pressure during acute gravitational changes.

Exposure to microgravity causes a bulk fluid shift toward the head, with concomitant changes in blood volume/pressure, and intraocular pressure (IOP). These and other factors, such as intracranial pressure (ICP) changes, are suspected to be involved in the degradation of visual function and ocular anatomical changes exhibited by some astronauts. This is a significant health concern. Here, we describe a lumped-parameter numerical model to simulate volume/pressure alterations in the eye during gravitational changes. The model includes the effects of blood and aqueous humor dynamics, ICP, and IOP-dependent ocular compliance. It is formulated as a series of coupled differential equations and was validated against four existing data sets on parabolic flight, body inversion, and head-down tilt (HDT). The model accurately predicted acute IOP changes in parabolic flight and HDT, and was satisfactory for the more extreme case of inversion. The short-term response to the changing gravitational field was dominated by ocular blood pressures and compliance, while longer-term responses were more dependent on aqueous humor dynamics. ICP had a negligible effect on acute IOP changes. This relatively simple numerical model shows promising predictive capability. To extend the model to more chronic conditions, additional data on longer-term autoregulation of blood and aqueous humor dynamics are needed.NEW & NOTEWORTHY A significant percentage of astronauts present anatomical changes in the posterior eye tissues after spaceflight. Hypothesized increases in ocular blood volume and intracranial pressure (ICP) in space have been considered to be likely factors. In this work, we provide a novel numerical model of the eye that incorporates ocular hemodynamics, gravitational forces, and ICP changes. We find that changes in ocular hemodynamics govern the response of intraocular pressure during acute gravitational change.

System for Rapid, Precise Modulation of Intraocular Pressure, toward Minimally-Invasive In Vivo Measurement of Intracranial Pressure

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 <0.1 mmHg resolution and settling times less than 2 seconds. In vitro tests were carried out to characterize system performance. Then, as a proof of concept, we used the system to manipulate IOP in tree shrews (Tupaia belangeri) while video of the retinal vessels was recorded and the caliber of a selected vein was quantified. Modulating IOP using our system elicited a rapid change in the appearance of the retinal vein of interest: IOP was lowered from 10 to 3 mmHg, and retinal vein caliber sharply increased as IOP decreased from 7 to 5 mmHg. Another important feature of this technology is its capability to measure ocular compliance and outflow facility in vivo, as demonstrated in tree shrews. Collectively, these proof-of-concept demonstrations support the utility of this system to manipulate IOP for a variety of useful applications in ocular biomechanics, and provide a framework for further study of the mechanisms of retinal venous pulsation.

The Dynamic Response of Intraocular Pressure and Ocular Pulse Amplitude to Acute Hemodynamic Changes in Normal and Glaucomatous Eyes

To evaluate the effects of acute arterial blood pressure (ABP) and venous pressure changes on IOP in rats with experimental glaucoma. Unilateral experimental ocular hypertension was established in Sprague-Dawley rats by weekly intracameral injection of microbeads. Ocular pulse amplitude (OPA) and IOP were recorded from the anterior chamber using 1.2-Fr microsensors under urethane anesthesia. The effects on IOP during hemodynamic challenges using phenylephrine (PE) (50 μg/kg/min intravenous [IV]) and rapid saline loading (20 mL/kg/min IV) were studied. Over an 8-week period, IOP was significantly elevated by 60% in the unilateral ocular hypertensive eyes. Both ABP and IOP were significantly increased by PE infusion. A significantly greater IOP increase was found in the experimental eyes compared with control eyes (1.32 ± 0.18 mm Hg vs. 0.90 ± 0.09 mm Hg). Correspondingly, higher OPAs and an amplification of the OPA during arterial hypertension were found in the experimental eyes. A sustained rise in IOP secondary to IV saline loading was observed, with a greater rise observed among experimental eyes (0.74 ± 0.13 mm Hg vs. 0.37 ± 0.005 mm Hg). Sympathetic acceleration of ABP using PE resulted in surges in IOP and OPA. In contrast, increased venous pressure resulted in a more sustained rise in IOP but to a lesser extent. These responses were more pronounced in eyes with experimental glaucoma compared with control eyes, which may reflect the higher starting IOP contributing to a reduced ocular compliance. Our results suggest that eyes with ocular hypertension are more susceptible to IOP variability induced by hemodynamic fluctuations.

Eye Vessel Compliance as a Function of Intraocular and Arterial Pressure and Eye Compliance

The purpose of our study is to develop and validate a methodology to measure the compliance of the vascular network in the eye using biomechanical parameters, namely arterial pressure, intraocular pressure (IOP), and ocular compliance of the eyeball (OC). In vitro experiments were conducted on 6 freshly enucleated rabbit eyes. An inflatable catheter was inserted in the posterior chamber. The balloon was inflated and its volume changed periodically at a rate of 1-2 Hz, yielding variations in the intraocular volume; thus, emulating the volume pulsations of the vascular network in the eye. The IOP was measured continuously with a pressure transducer and the OC was calculated using the outflow facility. The compliance of the balloon, mimicking the compliance of the vascular network, was estimated indirectly from the measurements of IOP, balloon pressure, and OC. The estimated balloon compliance was compared to direct estimates of balloon compliance, based on the balloon pressure-volume curve. In vivo study included 5 white New-Zealand rabbits. The method to estimate the vascular compliance of the eye was tested under normal conditions and after administration of norepinephrine, which induced a vasoconstriction leading to reduction in vascular compliance. In vitro comparison of direct versus indirect estimates of compliance showed a difference that was not significant (0.075 vs. 0.077 μL/mm Hg, P = 0.86). Results from the in vivo study indicated that norepinephrine significantly increased the arterial pulse pressure amplitude, while compliance of vascular network of the eye decreased from 0.18 ± 0.12 to 0.10 ± 0.08 μL/mm Hg (P = 0.001). The eye vascular compliance can be predicted using the IOP, arterial pressure, and OC of the eyeball.

Outflow physiology of the mouse eye: pressure dependence and washout.

Mice are commonly used in glaucoma research, but relatively little is known about aqueous outflow dynamics in the species. To facilitate future use of the mouse as a model of aqueous humor outflow, several fundamental physiological parameters were measured in the mouse eye. Eyes from adult mice of either sex (C57BL/6 background) were enucleated, cannulated with a 33-gauge needle, and perfused at constant pressure while inflow was continuously measured. At 8 mm Hg, total outflow facility (C(total)) was 0.022 ± 0.005 μL/min/mm Hg (all values mean ± SD; n = 21). The flow-pressure relationship was linear up to 35 mm Hg. The conventional outflow facility (C(conv)) was 0.0066 ± 0.0009 μL/min/mm Hg, and the unconventional outflow (F(u)) was 0.114 ± 0.019 μL/min, both measured at room temperature. At 8 mm Hg, 66% of the outflow was via the unconventional pathway. In a more than 2-hour-long perfusion at 8 mm Hg, the rate of facility change was 2.4% ± 5.4% (n = 11) of starting facility per hour. The ocular compliance (0.086 ± 0.017 μL/mm Hg; n = 5) was comparable to the compliance of the perfusion system (0.100 ± 0.004 μL/mm Hg). Mouse eyes are similar to human eyes, in that they have no detectable washout rate and a linear pressure-flow relationship over a broad range of intraocular pressures. Because of the absence of washout and the apparent presence of a true Schlemm's canal, the mouse is a useful model for studying the physiology of the inner wall of Schlemm's canal and the conventional outflow tissues.

Effect of induced myopia on scleral mechanics and myofibroblast populations

Abstract Purpose: Determine the effect of induced refractive error on a) ocular compliance and b) scleral contractile cell populations in guinea pig. Methods: One week old guinea pigs (n = 29) were monocularly deprived of form vision (MD) for 14 days. Cycloplegic refractive error was measured with an IR Optometer. Ocular compliance (change in length/mmHg change in IOP) of MD and control eyes was compared by raising the IOP to 50 mmHg for one hour in 8 anaesthetised animals. A‐scan ultrasound measures of axial length were taken every 10 minutes with raised IOP, and after returning IOP to 15 mmHg. Antibodies to DAPI and α‐smooth muscle actin (α‐SMA) were used to determine the total cell population and cell contractile potential respectively in MD and control sclera. Results: MD induced ‐4.06 ± 1.88 D of myopia, which was correlated with 169 ± 267 μm of vitreous chamber depth (VCD) elongation (n = 29; R2 = 0.37). Both deprived and control eyes showed negative creep compliance (eye shortening) over one hour of raised IOP, equivalent to 1.44 μm shortening per minute. On returning the IOP to 15 mmHg the VCD of the control eye was shorter than baseline by 92.86 ± 88 μm while the deprived eye remained 83.48 ± 37 μm longer than baseline (± SEM; n = 8). These differences were not statistically significant (p = 0.173). There was however an increase of 6% in the percentage of the total cell population positive for α‐SMA in myopic versus control sclera (p = 0.015; n = 7). Conclusions: Myopic and control eyes show similar negative creep compliance in vivo with raised IOP, and no difference in their elastic compliance response. However the α‐SMA positive cell population is increased in myopic sclera, suggesting a role in scleral remodelling.

The Circadian Rhythm in Intraocular Pressure and its Relation to Diurnal Ocular Growth Changes in Chicks

Recent investigations have shown that growing chicken eyes elongate during the day and shorten during the night. We asked whether the chick, like a number of other animals, exhibits a rhythm in intraocular pressure (IOP) and whether this rhythm might be associated with this rhythm in elongation. We find that the intraocular pressure in normal eyes is high during the day and low in the middle of the night, similar to the rhythm in ocular elongation. The amplitude of this rhythm in IOP is approximately 8 mm Hg; it persists in constant darkness, albeit with a reduced amplitude, implying that the rhythm has a circadian component. Form deprivation by translucent diffusers does not affect the amplitude of the rhythm in IOP, but makes the phase of the rhythm more variable, such that the trough no longer consistently occurs at night.We find that the magnitude of the ocular compliance (the change in length induced by change in intraocular pressure) is consistent with the possibility that the diurnal changes in IOP might, through mechanical stretch, account for much of the diurnal changes in length. However, in individual eyes, we find consistent phase differences between the rhythms in IOP and ocular elongation. Therefore, we propose that the rhythm in IOP influences ocular elongation in ways other than by simply inflating the eye, for example, by influencing underlying rhythms in scleral extracellular matrix production. We conclude that the rhythm in IOP plays a role in the regulation of the growth of the eye.