Differential Effects of Trabecular Meshwork Stiffness on Outflow Facility in Normal Human and Porcine Eyes

Camras, Lucinda J.; Stamer, W. Daniel; Epstein, David L.; González, Pedro; Yuan, Fan

doi:10.1167/iovs.12-9825

Cited by 59 publications

(76 citation statements)

References 37 publications

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“…Domestic pigs, even ones used as breeders, are not known to develop glaucoma. A study by Camras et al suggested that TM stiffness was correlated with outflow facility in human eye perfusion but not in the pig specimens 54 . Second, this ex vivo study does not account for important factors that can only be examined in vivo., this study focused on the effect of RKI-1447 on the TM but is is possible that dilation of post-trabecular outflow tract structures also exhibit a hypotensive effect in human open angle glaucoma where a high resistance of often remains after trabecular ablation [55][56][57][58] .…”

Section: Discussionmentioning

confidence: 98%

Ocular Hypotension, Actin Stress Fiber Disruption and Phagocytosis Increase by RKI-1447, a Rho-Kinase Inhibitor

Dang¹,

Wang²,

Shah³

et al. 2018

Preprint

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Objective: The Rho GTPase/Rho kinase pathway is an important target in glaucoma treatment. This study investigated the hypotensive effect of RKI-1447, a Rho kinase inhibitor developed for cancer treatment, in a porcine ex vivo pigmentary glaucoma model. Materials and Methods:Twenty-eight fresh porcine anterior chambers were perfused with pigment medium (1.67×10 7 pigment particles/ml) for 48 hours before being subjected to the RKI-1447 (n=16) or the vehicle control (n=12). Another twelve eyes with normal medium perfusion served as the control. The intraocular pressure (IOP) was recorded at two-minute intervals and the outflow facility was calculated. To investigate the intracellular mechanism of the IOP reduction, primary trabecular meshwork cells were exposed to RKI-1447 or the vehicle control and then analyzed for changes in cytoskeleton, motility, and phagocytosis.

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Section: Discussionmentioning

confidence: 98%

Ocular Hypotension, Actin Stress Fiber Disruption and Phagocytosis Increase by RKI-1447, a Rho-Kinase Inhibitor

Dang¹,

Wang²,

Shah³

et al. 2018

Preprint

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“…The morphology and stiffness of the TM correlate with outflow facility 14,15 , emphasizing the need to measure the biomechanical characteristics of outflow pathway. In the future, such measurements may provide insights currently unavailable in the management of glaucoma.…”

Section: Discussionmentioning

confidence: 99%

“…While TM stiffness may contribute to the prevention of SC collapse in the face of IOP elevation, Overby et al 12 recently demonstrated that gene expression in glaucoma is altered, resulting in increased SC endothelial stiffening, impeding formation of pores, leading to IOP elevation in glaucomatous eyes 13 . TM morphology and stiffness correlate with outflow facility 14,15 , emphasizing the need to measure its biomechanical characteristics.…”

Section: Introductionmentioning

confidence: 99%

Trabecular Meshwork Response to Pressure Elevation in the Living Human Eye

Kagemann

Wang

Wollstein

et al. 2015

JoVE

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The mechanical characteristics of the trabecular meshwork (TM) are linked to outflow resistance and intraocular pressure (IOP) regulation. The rationale behind this technique is the direct observation of the mechanical response of the TM to acute IOP elevation. Prior to scanning, IOP is measured at baseline and during IOP elevation. The limbus is scanned by spectral-domain optical coherence tomography at baseline and during IOP elevation (ophthalmodynamometer (ODM) applied at 30 g force). Scans are processed to enhance visualization of the aqueous humor outflow pathway using ImageJ. Vascular landmarks are used to identify corresponding locations in baseline and IOP elevation scan volumes. Schlemm canal (SC) cross-sectional area (SC-CSA) and SC length from anterior to posterior along its long axis are measured manually at 10 locations within a 1 mm segment of SC. Mean inner to outer wall distance (short axis length) is calculated as the area of SC divided by its long axis length. To examine the contribution of adjacent tissues to the effect IOP elevations, measurements are repeated without and with smooth muscle relaxation with instillation of tropicamide. TM migration into SC is resisted by TM stiffness, but is enhanced by the support of its attachment to adjacent smooth muscle within the ciliary body. This technique is the first to measure the living human TM response to pressure elevation in situ under physiological conditions within the human eye. Video LinkThe video component of this article can be found at

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“…Recent data show that a stiffer TM in terms of circumferential or axial Young's modulus is more likely to be observed in normal donor eyes with higher outflow facility and less variation in outflow resistance in response to IOP elevation. 1 On the other hand, microscopic or local stiffness, measured at juxtacanalicular tissue (JCT) and inner wall of Schlemm's canal (SC) with atomic force microscopy (AFM), is higher and more heterogeneous in glaucomatous eyes than in normal eyes, 2 suggesting that a higher local stiffness of JCT correlates to a lower outflow facility in glaucomatous eyes. The two studies may appear conflicting to each other, but it has been well established that manner, rate, and direction in which a mechanical load is applied to tissue can result in very different stiffnesses.…”

mentioning

confidence: 99%

“…The two studies may appear conflicting to each other, but it has been well established that manner, rate, and direction in which a mechanical load is applied to tissue can result in very different stiffnesses. 3 Tensile stiffness measured by Camras et al 1 reflected resistance of the whole TM as an interconnected structure, including all cells and extracellular matrix (ECM), to mechanical stretch, whereas microindentation stiffness determined by Last et al 2 depended only on resistance of a region, smaller than a cell, to mechanical compression by the AFM probe. It is well known that the stiffness of a cell is several orders of magnitude smaller than that of a collagen fibril [3][4][5][6] ; thus, results from the two studies reflect completely different mechanical properties of the TM and cannot be compared directly.…”

mentioning

confidence: 99%

Circumferential Tensile Stiffness of Glaucomatous Trabecular Meshwork

Camras

Stamer

Epstein

et al. 2014

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Our previous work indicated that a larger circumferential Young's modulus (E) of trabecular meshwork (TM) correlated with a higher outflow facility (C) in normal human donor eyes. The current study investigated the influence of glaucomatous TM stiffness and cellularity on C.METHODS. Eight left eyes from glaucomatous human donors were perfused within 48 hours post mortem. Values of C were determined at pressures of 10, 20, 30, and 40 mm Hg. The TM was then dissected and imaged with optical coherence tomography to determine its crosssectional area. Uniaxial tensile stress was applied longitudinally to TM segments to determine stress-strain curves. E was calculated at zero strain, representing the circumferential stiffness of the TM at a relaxed state. Confocal images of DAPI-stained TM segments were used to determine cellularity after mechanical stretching.RESULTS. C (lL/min/mm Hg) of glaucomatous eyes was 0.18 6 0.02 (mean 6 SE) at 10 mm Hg and decreased to 0.11 6 0.02 when the pressure was increased to 40 mm Hg. C measured at 30 and 40 mm Hg correlated with TM cellularity. E was 12.5 MPa and 1.4 (geometric mean and SE) and did not statistically correlate with postmortem time, age, C, or cellularity.CONCLUSIONS. Compared with data of normal eyes observed in a previous study, C in glaucomatous eyes was reduced significantly, and the amount of reduction increased with increasing the pressure. E of glaucomatous TM was approximately one-fifth that of normal TM. Prospective studies are needed to further investigate the influence of TM tensile stiffness on outflow regulation.

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Differential Effects of Trabecular Meshwork Stiffness on Outflow Facility in Normal Human and Porcine Eyes

Cited by 59 publications

References 37 publications

Ocular Hypotension, Actin Stress Fiber Disruption and Phagocytosis Increase by RKI-1447, a Rho-Kinase Inhibitor

Ocular Hypotension, Actin Stress Fiber Disruption and Phagocytosis Increase by RKI-1447, a Rho-Kinase Inhibitor

Trabecular Meshwork Response to Pressure Elevation in the Living Human Eye

Circumferential Tensile Stiffness of Glaucomatous Trabecular Meshwork

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