Modeling the Endothelial Glycocalyx Layer in the Human Conventional Aqueous Outflow Pathway.

A layer of proteoglycans and glycoproteins known as glycocalyx covers the surface of the trabecular meshwork (TM), juxtacanalicular tissue (JCT), and Schlemm's canal (SC) inner wall of the conventional aqueous outflow pathway in the eye. This has been shown to play a role in the mechanotransduction of fluid shear stress and in the regulation of the outflow resistance. The outflow resistance in the conventional outflow pathway is the main determinant of the intraocular pressure (IOP) through an active, two-way, fluid-structure interaction coupling between the outflow tissues and aqueous humor. A 3D microstructural finite element (FE) model of a healthy human eye TM/JCT/SC complex with interspersed aqueous humor was constructed. A very thin charged double layer that represents the endothelial glycocalyx layer covered the surface of the elastic outflow tissues. The aqueous humor was modeled as electroosmotic flow that is charged when it is in contact with the outflow tissues. The electrical-fluid-structure interaction (EFSI) method was used to couple the charged double layer (glycocalyx), fluid (aqueous humor), and solid (outflow tissues). When the IOP was elevated to 15 mmHg, the maximum aqueous humor velocity in the EFSI model was decreased by 2.35 mm/s (9%) compared to the fluid-structure interaction (FSI) model. The charge or electricity in the living human conventional outflow pathway generated by the charged endothelial glycocalyx layer plays a minor biomechanical role in the resultant stresses and strains as well as the hydrodynamics of the aqueous humor.

The Effect of Intraocular Pressure Load Boundary on the Biomechanics of the Human Conventional Aqueous Outflow Pathway.

BACKGROUND: Aqueous humor outflow resistance in the trabecular meshwork (TM), juxtacanalicular connective tissue (JCT), and Schlemm's canal (SC) endothelium of the conventional outflow pathway actively contribute to intraocular pressure (IOP) regulation. Outflow resistance is actively affected by the dynamic outflow pressure gradient across the TM, JCT, and SC inner wall tissues. The resistance effect implies the presence of a fluid-structure interaction (FSI) coupling between the outflow tissues and the aqueous humor. However, the biomechanical interactions between viscoelastic outflow tissues and aqueous humor dynamics are largely unknown. METHODS: A 3D microstructural finite element (FE) model of a healthy human eye TM/JCT/SC complex was constructed with elastic and viscoelastic material properties for the bulk extracellular matrix and embedded elastic cable elements. The FE models were subjected to both idealized and a physiologic IOP load boundary using the FSI method. RESULTS: The elastic material model for both the idealized and physiologic IOP load boundary at equal IOPs showed similar stresses and strains in the outflow tissues as well as pressure in the aqueous humor. However, outflow tissues with viscoelastic material properties were sensitive to the IOP load rate, resulting in different mechanical and hydrodynamic responses in the tissues and aqueous humor. CONCLUSIONS: Transient IOP fluctuations may cause a relatively large IOP difference of ~20 mmHg in a very short time frame of ~0.1 s, resulting in a rate stiffening in the outflow tissues. Rate stiffening reduces strains and causes a rate-dependent pressure gradient across the outflow tissues. Thus, the results suggest it is necessary to use a viscoelastic material model in outflow tissues that includes the important role of IOP load rate.

Relative Contributions of Intraocular and Cerebrospinal Fluid Pressures to the Biomechanics of the Lamina Cribrosa and Laminar Neural Tissues.

Purpose: The laminar region of the optic nerve head (ONH), thought to be the site of damage to the retinal ganglion cell axons in glaucoma, is continuously loaded on its anterior and posterior surfaces by dynamic intraocular pressure (IOP) and orbital cerebrospinal fluid pressure (CSFP), respectively. Thus, translaminar pressure (TLP; TLP = IOP-CSFP) has been proposed as a glaucoma risk factor. Methods: Three eye-specific finite element models of the posterior human eye were constructed, including full 3D microstructures of the load-bearing lamina cribrosa (LC) with interspersed laminar neural tissues (NTs), and heterogeneous, anisotropic, hyperelastic material formulations for the surrounding peripapillary sclera and adjacent pia. ONH biomechanical responses were simulated using three combinations of IOP and CSFP loadings consistent with posture change from sitting to supine. Results: Results show that tensile, compressive, and shear stresses and strains in the ONH were higher in the supine position compared to the sitting position (P < 0.05). In addition, LC beams bear three to five times more TLP-driven stress than interspersed laminar NT, whereas laminar NT exhibit three to five times greater strain than supporting LC (P < 0.05). Compared with CSFP, IOP drove approximately four times greater stress and strain in the LC, NT, and peripapillary sclera, normalized per mm Hg pressure change. In addition, IOP drove approximately three-fold greater scleral canal expansion and anterior-posterior laminar deformation than CSFP per mm Hg (P < 0.05). Conclusions: Whereas TLP has been hypothesized to play a prominent role in ONH biomechanics, the IOP and CSFP effects are not equivalent, as IOP-driven stress, strain, and deformation play a more dominant role than CSFP effects.

Viscoelastic Biomechanical Properties of the Conventional Aqueous Outflow Pathway Tissues in Healthy and Glaucoma Human Eyes.

BACKGROUND: Although the tissues comprising the ocular conventional outflow pathway have shown strong viscoelastic mechanical response to aqueous humor pressure dynamics, the viscoelastic mechanical properties of the trabecular meshwork (TM), juxtacanalicular connective tissue (JCT), and Schlemm's canal (SC) inner wall are largely unknown. METHODS: A quadrant of the anterior segment from two human donor eyes at low- and high-flow (LF and HF) outflow regions was pressurized and imaged using optical coherence tomography (OCT). A finite element (FE) model of the TM, the adjacent JCT, and the SC inner wall was constructed and viscoelastic beam elements were distributed in the extracellular matrix (ECM) of the TM and JCT to represent anisotropic collagen. An inverse FE-optimization algorithm was used to calculate the viscoelastic properties of the ECM/beam elements such that the TM/JCT/SC model and OCT imaging data best matched over time. RESULTS: The ECM of the glaucoma tissues showed significantly larger time-dependent shear moduli compared to the heathy tissues. Significantly larger shear moduli were also observed in the LF regions of both the healthy and glaucoma eyes compared to the HF regions. CONCLUSIONS: The outflow tissues in both glaucoma eyes and HF regions are stiffer and less able to respond to dynamic IOP.

Ocular Pulse Amplitude Correlates With Ocular Rigidity at Native IOP Despite the Variability in Intraocular Pulse Volume With Each Heartbeat.

Purpose: The purpose of this study was to assess ocular coat mechanical behavior using controlled ocular microvolumetric injections (MVI) of 15 µL of balanced salt solution (BSS) infused over 1 second into the anterior chamber (AC) via a syringe pump. Methods: Intraocular pressure (IOP) was continuously recorded at 200 Hz with a validated implantable IOP telemetry system in 7 eyes of 7 male rhesus macaques (nonhuman primates [NHPs]) during 5 MVIs in a series at native (3 trials), 15 and 20 mm Hg baseline IOPs, repeated in 2 to 5 sessions at least 2 weeks apart. Ocular rigidity coefficients (K) and ocular pulse volume (PV) were calculated for each trial. Data were averaged across sessions within eyes; PV was analyzed with a three-level nested ANOVA, and parameter relationships were analyzed with Pearson Correlation and linear regression. Results: After MVI at native baseline IOP of 10.4 ± 1.6 mm Hg, IOP increased by 9.1 ± 2.8 mm Hg (∆IOP) at a 9.6 ± 2.7 mm Hg/s slope, ocular pulse amplitude (OPA) was 0.70 ± 0.13 mm Hg on average; the average K was 0.042 ± 0.010 µL-1 and average PV was 1.16 ± 0.43 µL. PV varied significantly between trials, days, and eyes (P ≤ 0.05). OPA was significantly correlated with K at native IOP: Pearson coefficients ranged from 0.71 to 0.83 (P ≤ 0.05) and R2 ranged from 0.50 to 0.69 (P ≤ 0.05) during the first trial. Conclusions: The MVI-driven ∆IOP and slope can be used to assess ocular coat mechanical behavior and measure ocular rigidity. Translational Relevance: Importantly, OPA at native IOP is correlated with ocular rigidity despite the significant variability in PV between heartbeats.

Modeling the biomechanics of the conventional aqueous outflow pathway microstructure in the human eye.

BACKGROUND AND OBJECTIVE: Intraocular pressure (IOP) is determined by aqueous humor outflow resistance, which is a function of the combined resistance of Schlemm's canal (SC) endothelium and the trabecular meshwork (TM) and their interactions in the juxtacanalicular connective tissue (JCT) region. Aqueous outflow in the conventional outflow pathway results in pressure gradient across the TM, JCT, and SC inner wall, and induces mechanical stresses and strains that influence the geometry and homeostasis of the outflow system. The outflow resistance is affected by alteration in tissues' geometry, so there is potential for active, two-way, fluid-structure interaction (FSI) coupling between the aqueous humor (fluid) and the TM, JCT, and SC inner wall (structure). However, our understanding of the biomechanical interactions of the aqueous humor with the outflow connective tissues and its contribution to the outflow resistance regulation is incomplete. METHODS: In this study, a microstructural finite element (FE) model of a human eye TM, JCT, and SC inner wall was constructed from a segmented, high-resolution histologic 3D reconstruction of the human outflow system. Three different elastic moduli (0.004, 0.128, and 51.5 MPa based on prior reports) were assigned to the TM/JCT complex while the elastic modulus of the SC inner wall was kept constant at 0.00748 MPa. The hydraulic conductivity was programmed separately for the TM, JCT, and SC inner wall using a custom subroutine. Cable elements were embedded into the TM and JCT extracellular matrix to represent the directional stiffness imparted by anisotropic collagen fibril orientation. The resultant stresses and strains in the outflow system were calculated using fluid-structure interaction method. RESULTS: The higher TM/JCT stiffness resulted in larger stresses, but smaller strains in the outflow connective tissues, and resulted in a 4- and 5-fold larger pressure drop across the SC inner wall, respectively, compared to the most compliant model. Funneling through µm-sized SC endothelial pores was evident in the models at lower tissue stiffness, but aqueous flow was more turbulent in models with higher TM/JCT stiffness. CONCLUSIONS: The mechanical properties of the outflow tissues play a crucial role in the hydrodynamics of the aqueous humor in the conventional outflow system.

Ocular biomechanics during improvised explosive device blast: A computational study using eye-specific models.

BACKGROUND: Eye injuries comprise 10-13% of civilian improvised explosive device (IED) injuries. The bomb blast wave induces a normal and shear forces on the tissues, causing a large acute IOP elevation. This study calculated the biomechanical stresses and strains in the eye due to IED explosion via eye-specific fluid-structure interaction (FSI) models. METHODS: Blast occurred at 2, 3, and 4 m from the front and side of the victim and the weights of the IED were 1 and 2 kg. The ground was covered with the deformable soil to mimic the realistic IED explosion condition and reflect the blast wave. RESULTS: The IOP elevation of ∼6,000-48,000 mmHg was observed in the eyes while the highest IOP was occurred with the IED weight and distance of 2 kg and 2 m (front) and the lowest was occurred with the IED weight and distance of 1 kg and 4 m (side). Our findings suggest the importance of the victim location and orientation concerning the blast wave when it comes to ocular injury assessment. IOP elevation of ∼2900 and ∼2700 mmHg were observed in ∼1.6 ms after the blast for the IEDS weight of 2 kg and a victim distance of 2 m in front and side blasts, respectively, in consistence with the literature. Nonetheless, IOPs were considerably higher after ∼1.6 ms due to the merging of the bomb blast wave and its reflection off the ground. CONCLUSIONS: The stresses and strains were highest for the frontal blast. Both side and frontal blasts caused higher stresses and strains at the rectus muscle insertions where the sclera is thinnest and prone to rupture. Blast angle has no considerable role in the resultant IOP. Front blast with a heavier IED resulted a higher stresses and deformations in the eye connective tissues compared to the side blast.

Ocular biomechanics due to ground blast reinforcement.

BACKGROUND AND OBJECTIVE: Bomb blast injuries exerts a shearing force on the air-tissue interfaces, causing devastating ocular injury from the blast wave. Improvised explosive devices (IEDs) are usually placed at different heights from the ground to induce more severe injury through ground blast reinforcement (GBR). However, there is still a lack of knowledge of the role of GBR and IED height from the ground on ocular biomechanics, and how they can affect the intraocular pressure (IOP) in the eye. This study aimed to estimate the IOP due to frontal IED explosion at different heights from the ground using a fluid-structure interaction model with and without GBR effects. METHODS: A 2 kg IED was placed within 5 m of the victim at 5 different heights from the ground, including 0, 0.42, 0.85, 1.27, and 1.70 m. Two different blast formulations were used to simulate the IED explosion: (a) spherical airburst, with no amplification of the initial shock wave due to interaction with the ground-surface, and (b) hemispherical surface-burst, where the initial blast wave is immediately reflected and reinforced by the ground (GBR). RESULTS: Results revealed that the blast wave due to GBR reaches to the skull prior to the IED blast itself. The GBR also reached to the skull ∼ 0.6 ms earlier when the IED was on the ground compared to the height of 1.70 m. The highest and lowest IOPs of ∼ 17,000 and ∼ 15,000 mmHg were observed at the IED heights of 1.70 and 0 m from the ground considering GBR. However, when the role of the GBR is ignored, IOP of ∼ 9,000 mmHg was observed regardless of the IED height from the ground. The deformation in the apex of the cornea was higher when considering the GBR (∼ 0.75 cm) versus no GBR (∼ 0.65 cm). Considering GBR led to higher stresses and strains in the sclera. CONCLUSIONS: When the role of GBR was ignored, the results showed similar patterns and magnitudes of stresses and deformations in the skull and eye regardless of the height of the IED from the ground, which was not the case when GBR was considered. The findings of this study suggest the critical role of GBR in ocular blast simulations.

Strain by virtual extensometers and video-imaging optical coherence tomography as a repeatable metric for IOP-Induced optic nerve head deformations.

PURPOSE: To determine if in vivo strain response of the Optic Nerve Head (ONH) to IOP elevation visualized using Optical Coherence Tomography (OCT) video imaging and quantified using novel virtual extensometers was able to be provided repeatable measurements of tissue specific deformations. METHODS: The ONHs of 5 eyes from 5 non-human primates (NHPs) were imaged by Spectralis OCT. A vertical and a horizontal B-scan of the ONH were continuously recorded for 60 s at 6 Hz (video imaging mode) during IOP elevation from 10 to 30 mmHg. Imaging was repeated over three imaging sessions. The 2D normal strain was computed by template-matching digital image correlation using virtual extensometers. ANOVA F-test (F) was used to compare inter-eye, inter-session, and inter-tissue variability for the prelaminar, Bruch's membrane opening (BMO), lamina cribrosa (LC) and choroidal regions (against variance the error term). F-test of the ratio between inter-eye to inter-session variability was used to test for strain repeatability across imaging sessions (FIS). RESULTS: Variability of strain across imaging session (F = 0.7263, p = 0.4855) and scan orientation was not significant (F = 1.053, p = 0.3066). Inter session variability of strain was significantly lower than inter-eye variability (FIS = 22.63, p = 0.0428) and inter-tissue variability (FIS = 99.33 p = 0.00998). After IOP elevation, strain was highest in the choroid (-18.11%, p < 0.001), followed by prelaminar tissue (-11.0%, p < 0.001), LC (-3.79%, p < 0.001), and relative change in BMO diameter (-0.57%, p = 0.704). CONCLUSIONS: Virtual extensometers applied to video-OCT were sensitive to the eye-specific and tissue-specific mechanical response of the ONH to IOP and were repeatable across imaging sessions.

Modeling the biomechanics of the lamina cribrosa microstructure in the human eye.

Glaucoma is among the leading causes of blindness worldwide that is characterized by irreversible damage to the retinal ganglion cell axons in the lamina cribrosa (LC) region of the optic nerve head (ONH), most often associated with elevated intraocular pressure (IOP). The LC is a porous, connective tissue structure that provides mechanical support to the axons as they exit the eye and the biomechanics of the LC microstructure likely play a crucial role in protecting the axons passing through it. There is a limited knowledge of the IOP-driven biomechanics of the LC microstructure, primarily due to its small size and the difficulty with imaging the LC both in vitro and in vivo. We present finite element (FE) models of three human eye posterior poles that include the LC microstructure and interspersed neural tissues (NT) composed of retinal axons that are constructed directly from segmented, binary images of the LC. These models were used to estimate the stresses and strains in the LC and NT for an acute IOP elevation from 0 to 45 mmHg and compared with identical models except that the LC was represented as a homogenized continuum material with either homogeneous isotropic neo-Hookean properties or heterogeneous properties derived from local connective tissue volume fraction (CTVF) and predominant LC beam orientation. Stresses and strains in the LC and NT microstructure were investigated, and results were compared against those from the models wherein the LC was represented as a homogenized continuum. The regionalized volumetric average stresses and strains showed that the microstructural model yielded similar patterns to our prior approach using an LC continuum representation with mapped LC CTVF/anisotropy, but the microstructural modeling approach allows analysis of the stresses and strains in the LC and NT separately. As expected, the LC beams carried most of the IOP load in the microstructural models but exhibited less strain, while the encapsulated NT exhibited lower stresses and much higher strains. Results also revealed that the continuum models underestimate the maximum strains in the LC beams and NT by a factor of 2-3. Microstructural modeling should provide greater insight into the biomechanical factors driving damage to the axons (NT) and LC connective tissue remodeling that occur in glaucoma. The methods presented are ideal for modeling any structure with a complex microstructure composed of different materials, such as trabecular bone, lung, and tissue engineering scaffolds such as decellularized LC. Matlab code for mesh generation from a segmented image stack of the microstructure is included as Supplemental Material. STATEMENT OF SIGNIFICANCE: Glaucoma is among the leading causes of blindness worldwide that is characterized by axon damage in the lamina cribrosa (LC) region of the eye. We present a new approach for finite element modeling the entire eye-specific 3D LC microstructure and the interspersed neural tissues, incorporated into an eye-specific posterior eye model that provides appropriate boundary and loading conditions. Results are presented for three human donor eyes, showing that prior modeling approaches underestimate the stresses and strains in the laminar microstructure. We constructed models from image stacks of the segmented microstructure (Matlab code included) using an approach that is ideal for modeling any structure with a complex microstructure composed of different materials, such as trabecular bone, lung, and tissue engineering scaffolds.

Histologic validation of optical coherence tomography-based three-dimensional morphometric measurements of the human optic nerve head: Methodology and preliminary results.

PURPOSE: To compare the three-dimensional (3D) morphology of the deep load-bearing structures of the human optic nerve head (ONH) as revealed in vivo by spectral domain optical coherence tomography (SDOCT) with ex vivo quantitative 3D histology. METHODS: SDOCT imaging of the ONH was performed in six eyes from three brain-dead organ donors on life-support equipment awaiting organ procurement (in vivo conditions). Following organ procurement (ex vivo conditions), the eyes were enucleated and underwent a pars plana vitrectomy followed by pressurization to physiologic IOP and immersion fixation. Ex vivo ONH morphology was obtained from high-fidelity episcopic fluorescent 3D reconstruction. Morphologic parameters of the observed ONH canal geometry and peripapillary choroid, as well as the shape, visibility and depth of the lamina cribrosa were compared between ex vivo and in vivo measurements using custom software to align, scale, and manually delineate the different regions of the ONH. RESULTS: There was significant correspondence between in vivo and ex vivo measurements of the depth and shape of the lamina cribrosa, along with the size and shape of Bruch's membrane opening (BMO) and anterior scleral canal opening (ASCO). Weaker correspondence was observed for choroidal thickness; as expected, a thinner choroid was seen ex vivo due to loss of blood volume upon enucleation (-79.9%, p < 0.001). In addition, the lamina was shallower (-32.3%, p = 0.0019) and BMO was smaller ex vivo (-3.38%, p = 0.026), suggesting post mortem shrinkage of the fixed tissue. On average, while highly variable, only 31% of the anterior laminar surface was visible in vivo with SDOCT (p < 0.001). CONCLUSIONS: Morphologic parameters by SDOCT imaging of the deep ONH showed promising correspondence to histology metrics. Small but significant shrinkage artifact, along with large effects of exsanguination of the choroid, was seen in the ex vivo reconstructions of fixed tissues that may impact the quantification of ex vivo histoarchitecture, and this should be considered when developing models and biomarkers based on ex vivo imaging of fixed tissue. Lack of visibly of most of the lamina surface in SDOCT images is an important limitation to metrics and biomarkers based on in vivo images of the ONH deep tissues.

Analysis of the effects of finite element type within a 3D biomechanical model of a human optic nerve head and posterior pole.

BACKGROUND AND OBJECTIVE: Biomechanical stresses and strains can be simulated in the optic nerve head (ONH) using the finite element (FE) method, and various element types have been used. This study aims to investigate the effects of element type on the resulting ONH stresses and strains. METHODS: A single eye-specific model was constructed using 3D delineations of anatomic surfaces in a high-resolution, fluorescent, 3D reconstruction of a human posterior eye, then meshed using our simple meshing algorithm at various densities using 4- and 10-noded tetrahedral elements, as well as 8- and 20-noded hexahedral elements. A mesh-free approach was used to assign heterogeneous, anisotropic, hyperelastic material properties to the lamina cribrosa, sclera and pia. The models were subjected to elevated IOP of 45 mmHg after pre-stressing from 0 to 10 mmHg, and solved in the open-source FE package Calculix; results were then interpreted in relation to computational time and simulation accuracy, using the quadratic hexahedral model as the reference standard. RESULTS: The 10-noded tetrahedral and 20R-noded hexahedral elements exhibited similar scleral canal and laminar deformations, as well as laminar and scleral stress and strain distributions; the quadratic tetrahedral models ran significantly faster than the quadratic hexahedral models. The linear tetrahedral and hexahedral elements were stiffer compared to the quadratic element types, yielding much lower stresses and strains in the lamina cribrosa. CONCLUSIONS: Prior studies have shown that 20-noded hexahedral elements yield the most accurate results in complex models. Results show that 10-noded tetrahedral elements yield very similar results to 20-noded hexahedral elements and so they can be used interchangeably, with significantly lower computational time. Linear element types did not yield acceptable results.

Comparison of extraocular and intraocular pressure transducers for measurement of transient intraocular pressure fluctuations using continuous wireless telemetry.

The optimal approach for continuous measurement of intraocular pressure (IOP), including pressure transducer location and measurement frequency, is currently unknown. This study assessed the capability of extraocular (EO) and intraocular (IO) pressure transducers, using different IOP sampling rates and duty cycles, to characterize IOP dynamics. Transient IOP fluctuations were measured and quantified in 7 eyes of 4 male rhesus macaques (NHPs) using the Konigsberg EO system (continuous at 500 Hz), 12 eyes of 8 NHPs with the Stellar EO system and 16 eyes of 12 NHPs with the Stellar IO system (both measure at 200 Hz for 15 s of every 150 s period). IOP transducers were calibrated bi-weekly via anterior chamber manometry. Linear mixed effects models assessed the differences in the hourly transient IOP impulse, and transient IOP fluctuation frequency and magnitude between systems and transducer placements (EO versus IO). All systems measured 8000-12,000 and 5000-6500 transient IOP fluctuations per hour > 0.6 mmHg, representing 8-16% and 4-8% of the total IOP energy the eye must withstand during waking and sleeping hours, respectively. Differences between sampling frequency/duty cycle and transducer placement were statistically significant (p < 0.05) but the effect sizes were small and clinically insignificant. IOP dynamics can be accurately captured by sampling IOP at 200 Hz on a 10% duty cycle using either IO or EO transducers.

Quantification of Translaminar Pressure Gradient (TLPG) With Continuous Wireless Telemetry in Nonhuman Primates (NHPs).

Purpose: Recent retrospective clinical and animal studies suggest that cerebrospinal fluid pressure (CSFP) is important in glaucoma pathogenesis. Intraocular pressure (IOP) and CSFP are the driving components of translaminar pressure (TLP = IOP - CSFP), which acts across the lamina cribrosa (LC) thickness to create the translaminar pressure gradient (TLPG = TLP/LC thickness). Methods: We developed an implantable wireless telemetry system based on a small piezoelectric sensor with low temporal drift. IOP, measured in the anterior chamber, and intracranial pressure (ICP), measured in the brain parenchyma (as a surrogate for CSFP) were measured at 200 Hz in three male rhesus macaques (nonhuman primates, NHPs) on a 10% duty cycle (15 seconds of every 150-second period). Three-dimensional LC thickness was autosegmented as the mean thickness of the visible hyperreflective band in 48 radial spectral-domain optical coherence tomography b-scans centered on the optic nerve head. Results: Results indicated the rank order of IOP, ICP, TLP, and TLPG for waking, sleeping, and 24-hour periods averaged across all days. NHP 150110 had the highest IOP and ICP in all periods; however, it had the lowest TLPG in all periods due to its relatively thick LC. The other two NHPs showed similar shifts in the rank order of possible glaucoma risk factors. Conclusions: IOP is the only modifiable and readily measurable pressure-based risk factor for glaucoma. However, other potential risk factors such as ICP, TLP, and TLPG, as well as their rank-order patterns, differed compared to IOP across subjects, demonstrating that a comprehensive view of relevant risk factors is warranted. Translational Relevance: Future studies should consider including CSFP, TLP, and TLPG in addition to IOP as potential risk factors when assessing eye-specific glaucoma susceptibility.

Effect of Body Position on Intraocular Pressure (IOP), Intracranial Pressure (ICP), and Translaminar Pressure (TLP) Via Continuous Wireless Telemetry in Nonhuman Primates (NHPs).

Purpose: Recent retrospective clinical studies and animal experiments have suggested that cerebrospinal fluid pressure (CSFP) is important in glaucoma, acting through the translaminar pressure (TLP = IOP - CSFP), which directly affects the optic nerve head. In this study, IOP and intracranial pressure (ICP; a surrogate of CSFP) were measured at various body positions to quantify the determinants of TLP. Methods: We have developed an implantable wireless pressure telemetry system based on a small piezoelectric sensor with low temporal drift. Telemetry transducers were placed in the anterior chamber to measure IOP and in the brain parenchyma at eye height to measure ICP. IOP was calibrated against anterior cannulation manometry, and ICP/CSFP was calibrated against an intraparenchymal Codman ICP Express microsensor. We measured IOP, ICP, and TLP = IOP - ICP continuously at 200 Hz in three male nonhuman primates (NHPs) in three trials; pressures were then averaged for 30 seconds per body position. Relative change of IOP, ICP, and TLP from the supine (baseline) position to the seated, standing, and inverted positions were quantified. Results: TLP changed significantly and instantaneously from the supine to seated (+14 mm Hg), supine to standing (+13 mm Hg) and supine to inverted (-12 mm Hg) positions (P < 0.05). There was no significant TLP change for supine to prone. ICP showed greater relative change than IOP. Conclusions: TLP change due to body position change is driven more by ICP/CSFP than IOP. IOP, ICP, and TLP variability, coupled with telemetry, should allow us to test the hypotheses that IOP, ICP, or TLP fluctuations contribute independently to glaucoma onset or progression.

Intra-Subject Variability and Diurnal Cycle of Ocular Perfusion Pressure as Characterized by Continuous Telemetry in Nonhuman Primates.

Purpose: To characterize ocular perfusion pressure (OPP) fluctuations with continuous telemetry over 24-hour periods across multiple days in nonhuman primates (NHPs) to test the hypotheses that OPP differs among NHPs and that the diurnal cycle of OPP is characterized by low OPP during sleep. Methods: We have developed and validated two implantable radiotelemetry systems that allow continuous measurement of intraocular pressure (IOP), arterial blood pressure (BP), and OPP up to 500 Hz. OPP was measured unilaterally in 12 male NHPs for periods of 38 to 412 days. IOP transducers were calibrated directly via anterior chamber manometry, and OPP was calculated continuously as central retinal artery BP minus IOP. OPP data were corrected for signal drift between calibrations and averaged hourly. Results: OPP varied widely among animals, with daily averages ranging from ∼47 to 65 mm Hg. In eight of 12 NHPs, OPP was significantly lower during sleep compared to waking hours. In three animals, the diurnal cycle was reversed and OPP was significantly higher during sleep (P < 0.05), and one NHP showed no diurnal cycle. Day-to-day OPP variability within NHPs was the largest source of overall OPP variability, even larger than the differences between NHPs. Average daily OPP showed an unexplained ∼32-day cyclic pattern in most NHPs. Conclusions: Average OPP varied widely and exhibited differing diurnal cycles in NHPs, a finding that matches those of prior patient studies and indicates that OPP studies in the NHP model are appropriate. Infrequent snapshot measurements of either IOP or BP are insufficient to capture true IOP, BP, and OPP and their fluctuations.

Diurnal Cycle of Translaminar Pressure in Nonhuman Primates Quantified With Continuous Wireless Telemetry.

Purpose: Recent retrospective clinical studies and animal experiments have suggested that cerebrospinal fluid pressure (CSFP) is important in glaucoma pathogenesis. Intraocular pressure (IOP) and CSFP are the driving components of the translaminar pressure (TLP), which directly effects the optic nerve head. This study measured the diurnal cycle of TLP using continuous wireless telemetry in nonhuman primates (NHPs), a common animal model of glaucoma. Methods: We have developed an implantable wireless telemetry system based on a small piezoelectric pressure transducer with low drift. Unilateral IOP was measured in the anterior chamber of the eye, and intracranial pressure (ICP, a surrogate measure of CSFP) was measured in the brain parenchyma in four awake, behaving NHPs for periods of 22 to 281 days. IOP and ICP telemetry transducers were calibrated with direct pressure measurements in the eye (every 2 weeks) and brain (monthly). TLP was quantified in real time as IOP-ICP, and hourly means of IOP, ICP, and TLP were analyzed. Results: Results show that mean ICP is significantly higher by an average of 4.8 ± 0.8 mmHg during sleeping hours in NHPs (P < 0.01). IOP showed a small but significant nocturnal elevation in two of four animals despite NHPs sleeping upright (P < 0.05). TLP was significantly lower during sleep (7.1 ± 0.6 mmHg; P < 0.01) than when the animals were awake and active (11.0 ± 0.9 mmHg), driven primarily by the large increase in ICP during sleep. Conclusions: The 56% increase in TLP during waking hours in NHPs matches the increase in TLP due to postural change from supine to upright reported previously in humans.

A Mesh-Free Approach to Incorporate Complex Anisotropic and Heterogeneous Material Properties into Eye-Specific Finite Element Models.

Commercial finite element modeling packages do not have the tools necessary to effectively incorporate the complex anisotropic and heterogeneous material properties typical of the biological tissues of the eye. We propose a mesh-free approach to incorporate realistic material properties into finite element models of individual human eyes. The method is based on the idea that material parameters can be estimated or measured at so called control points, which are arbitrary and independent of the finite element mesh. The mesh-free approach approximates the heterogeneous material parameters at the Gauss points of each finite element while the boundary value problem is solved using the standard finite element method. The proposed method was applied to an eye-specific model a human posterior pole and optic nerve head. We demonstrate that the method can be used to effectively incorporate experimental measurements of the lamina cribrosa micro-structure into the eye-specific model. It was convenient to define characteristic material orientations at the anterior and posterior scleral surface based on the eye-specific geometry of each sclera. The mesh-free approach was effective in approximating these characteristic material directions with smooth transitions across the sclera. For the first time, the method enabled the incorporation of the complex collagen architecture of the peripapillary sclera into an eye-specific model including the recently discovered meridional fibers at the anterior surface and the depth dependent width of circumferential fibers around the scleral canal. The model results suggest that disregarding the meridional fiber region may lead to an underestimation of local strain concentrations in the retina. The proposed approach should simplify future studies that aim to investigate collagen remodeling in the sclera and optic nerve head or in other biological tissues with similar challenges.