Sclera

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Vijay Sharma - One of the best experts on this subject based on the ideXlab platform.

Thomas T. Norton - One of the best experts on this subject based on the ideXlab platform.

  • The Sclera and myopia.
    Experimental Eye Research, 2005
    Co-Authors: Jody A. Summers Rada, Setareh Shelton, Thomas T. Norton
    Abstract:

    Myopia is a very common ocular problem, affecting perhaps one billion people worldwide. Most myopia is produced by lengthening of the vitreous chamber of the ocular globe. High myopia is characterized by Scleral thinning and localized ectasia of the posterior Sclera. The Sclera is a dense, fibrous, viscoelastic connective tissue that forms the outer coat of the eye and consists of irregularly arranged lamellae of collagen fibrils interspersed with proteoglycans and non-collagenous glycoproteins. Scleral fibroblasts are located between Scleral lamellae, and are responsible for synthesizing the extracellular matrix in which they reside. Research highlighted in this review clearly demonstrates that the Sclera is not a static container of the eye, but rather is a dynamic tissue, capable of altering extracellular matrix composition and its biomechanical properties in response to changes in the visual environment to regulate ocular size and refraction. Based on these studies, a strategy directed at reversing myopia-associated Scleral extracellular matrix remodeling events would be warranted, particularly in cases of high myopia in humans.

  • selective regulation of mmp and timp mrna levels in tree shrew Sclera during minus lens compensation and recovery
    Investigative Ophthalmology & Visual Science, 2005
    Co-Authors: John T Siegwart, Thomas T. Norton
    Abstract:

    Previous studies have provided evidence that a visually guided emmetropization mechanism adjusts the growth of the eye to reduce any mismatch between the eye's axial length and optical power.1-4 Experimental manipulation of refractive state in animal models provides particularly strong evidence for the existence of this mechanism. For example, the eyes of avians5-8 and mammals9-13 can be induced to increase their axial elongation rate within days or weeks by placing a minus-power lens or diffuser in front of the eye. In response to a minus lens, the eye elongates until the increase in vitreous chamber depth “compensates” for the decrease in optical power and then adjusts its elongation rate to maintain the match. When the minus lens is removed, the eye is myopic and responds by slowing its axial elongation rate producing refractive recovery. Manipulations of the visual environment that trigger a response from the emmetropization mechanism also induce tissue remodeling in the Sclera.14-19 In tree shrews, which, like other eutherian mammals, have an all-fibrous Sclera,20 the tissue remodeling does not appear to modulate growth per se, but rather alters the mechanical properties of the Sclera and, as a consequence, alters the ability of the Sclera to resist the relatively low but constant expansive force of intraocular pressure.21,22 In a previous study,21 it was found that changes in creep rate (a quantitative measure of viscoelasticity) were closely associated with changes in axial elongation rate during minus-lens treatment (creep rate higher) and recovery (creep rate lower), suggesting that modulation of the mechanical properties of the Sclera may control axial elongation. Precisely controlled Scleral tissue remodeling is probably responsible for the changes in the mechanical properties of the Sclera. Tissue remodeling is a complex process that involves both synthesis and degradation of the extracellular matrix (ECM). Numerous proteins are involved, including structural components such as collagen and proteoglycans,23 enzymes such as the matrix metalloproteinases (MMPs) that degrade ECM proteins,24 and tissue inhibitors of metalloproteinases (TIMPs) which bind to and inhibit the activity of the MMPs. In tree shrews, Scleral remodeling in eyes developing induced myopia is characterized by decreased levels of collagen,16,25 decreased levels of sulfated and unsulfated glycosaminoglycans (GAGs)16,19 (Norton TT et al. IOVS 1998;39:ARVO Abstract 2312; German A et al. IOVS 1999;40:ARVO Abstract 2387), and increased levels of gelatinase-A (MMP-2).26 In a previous study in tree shrews that involved monocular form deprivation (MD) to induce myopia,27 we found that mRNA levels for MMP-2, MMP-3, collagen 1(I), and TIMP-1 were altered during form deprivation and recovery, suggesting that modulation of Scleral gene expression may control Scleral tissue remodeling and Scleral extensibility. When MD is used to induce myopia in one eye, the axial elongation rate and Scleral creep rate increase and remain elevated. When minus-power lenses are used, axial elongation and Scleral extensibility rise at first. Then, as the axial length reaches its new target, they return to normal.21 If the pattern of changes in mRNA levels is causally related to the tissue remodeling and Scleral extensibility, then inducing myopia with a minus-power lens should cause changes in mRNA levels for the same proteins as occurs when MD is used to induce myopia. However, the time course of the changes should differ, in keeping with the different time course of the changes in Scleral extensibility and axial elongation rate. In the present study, we focused on the mRNA levels of MMPs and TIMPs that data suggest are involved in the remodeling of fibrous tissue such as Sclera. For example, MMP-2 appears to be involved in Scleral remodeling,26-28 and an important mechanism for the activation of pro-MMP-2 is thought to be cell surface activation by MT1-MMP,29,30 a mechanism that also involves TIMP-2 and possibly TIMP-3. Activation of MMP-2 through this mechanism is dependent on the relative levels of these molecules, and appropriate changes in their mRNA levels can suggest that this mechanism is active. MT1-MMP may also directly degrade Scleral ECM components. Fibroblasts from MT1-MMP deficient mice have virtually no degradative effect on type I collagen,31 suggesting that MT1-MMP may be critical in producing the loss of collagen that occurs during the development of experimental myopia in tree shrews.16,25

  • the time course of changes in mrna levels in tree shrew Sclera during induced myopia and recovery
    Investigative Ophthalmology & Visual Science, 2002
    Co-Authors: John T Siegwart, Thomas T. Norton
    Abstract:

    Current evidence indicates that a visually guided emmetropization mechanism fine tunes the growth of the juvenile eye to match the eye’s axial length to its optical power.1,2 The eyes of avians3–6 and mammals7–11 can be induced to increase their axial elongation rate (producing myopia) by placement of a diffuser (monocular form deprivation [MD]) or a minus power lens in front of the eye. Removing the treatment causes slowed axial elongation rate (producing refractive recovery). These manipulations of the visual environment induce tissue remodeling in the Sclera.12–18 In tree shrews, which, similar to other eutherian mammals, have an all-fibrous Sclera,19 the tissue remodeling does not appear to modulate growth per se, but rather, alters the extensibility of the Sclera (measured as change in creep rate).20,21 In a previous study,20 it was found that changes in Scleral creep rate developed rapidly after the onset of MD and were closely associated with changes in axial elongation rate, suggesting that modulation of Scleral extensibility may control axial elongation. Precisely controlled Scleral tissue remodeling may be responsible for the changes in Scleral extensibility and, hence, the changes in the axial elongation rate. Tissue remodeling is a complex process that involves both synthesis and degradation of the extracellular matrix (ECM). A number of proteins are involved, including structural components such as collagen and proteoglycans22; enzymes, such as the matrix metalloproteinases (MMPs), that are known to degrade ECM proteins23; and tissue inhibitors of metalloproteinases (TIMPs) that bind to and inhibit the activity of the MMPs. In tree shrews, Scleral remodeling in eyes with induced myopia is characterized by decreased levels of type I collagen,18 decreased levels of sulfated and unsulfated glycosaminoglycans (GAGs),14,17,24,25 and increased levels of gelatinase-A (MMP-2).26 In a previous study in tree shrews,27 we found that mRNA levels for MMP-2, collagen α1(I), and TIMP-1 were altered by 11 days of form deprivation and 4 days of recovery. This finding suggests that modulation of Scleral gene expression may control Scleral tissue remodeling and Scleral extensibility. If a change in gene expression triggers the Scleral tissue remodeling that changes Scleral creep rate, then mRNA changes should be temporally associated with changes in creep rate. In the present study, we tested this hypothesis by examining the time course for changes in mRNA levels during MD and recovery and comparing it with the time course of changes in creep rate from a previous study.20

Thao D Nguyen - One of the best experts on this subject based on the ideXlab platform.

  • glaucoma related changes in the mechanical properties and collagen micro architecture of the human Sclera
    PLOS ONE, 2015
    Co-Authors: Baptiste Coudrillier, Harry A Quigley, Joan L Jefferys, Jacek K Pijanka, Adhiraj Goel, Craig Boote, Thao D Nguyen
    Abstract:

    Objective The biomechanical behavior of the Sclera determines the level of mechanical insult from intraocular pressure to the axons and tissues of the optic nerve head, as is of interest in glaucoma. In this study, we measure the collagen fiber structure and the strain response, and estimate the material properties of glaucomatous and normal human donor Scleras. Methods Twenty-two posterior Scleras from normal and diagnosed glaucoma donors were obtained from an eyebank. Optic nerve cross-sections were graded to determine the presence of axon loss. The specimens were subjected to pressure-controlled inflation testing. Full-field displacement maps were measured by digital image correlation (DIC) and spatially differentiated to compute surface strains. Maps of the collagen fiber structure across the posterior Sclera of each inflated specimen were obtained using synchrotron wide-angle X-ray scattering (WAXS). Finite element (FE) models of the posterior Scleras, incorporating a specimen-specific representation of the collagen structure, were constructed from the DIC-measured geometry. An inverse finite element analysis was developed to estimate the stiffness of the collagen fiber and inter-fiber matrix. Results The differences between glaucoma and non-glaucoma eyes were small in magnitude. Sectorial variations of degree of fiber alignment and peripapillary Scleral strain significantly differed between normal and diagnosed glaucoma specimens. Meridional strains were on average larger in diagnosed glaucoma eyes compared with normal specimens. Non-glaucoma specimens had on average the lowest matrix and fiber stiffness, followed by undamaged glaucoma eyes, and damaged glaucoma eyes but the differences in stiffness were not significant. Conclusion The observed biomechanical and microstructural changes could be the result of tissue remodeling occuring in glaucoma and are likely to alter the mechanical environment of the optic nerve head and contribute to axonal damage.

  • the effects of glycosaminoglycan degradation on the mechanical behavior of the posterior porcine Sclera
    Acta Biomaterialia, 2015
    Co-Authors: Barbara J Murienne, Harry A Quigley, Joan L Jefferys, Thao D Nguyen
    Abstract:

    Pathological changes in Scleral glycosaminoglycan (GAG) content and in Scleral mechanical properties have been observed in eyes with glaucoma and myopia. The purpose of this study is to investigate the effect of GAG removal on the Scleral mechanical properties to better understand the impact of GAG content variations in the pathophysiology of glaucoma and myopia. We measured how the removal of sulphated GAG (s-GAG) affected the hydration, thickness and mechanical properties of the posterior Sclera in enucleated eyes of 6–9 month-old pigs. Measurements were made in 4 regions centered on the optic nerve head (ONH) and evaluated under 3 conditions: no treatment (control), after treatment in buffer solution alone, and after treatment in buffer containing chondroitinase ABC (ChABC) to remove s-GAGs. The specimens were mechanically tested by pressure-controlled inflation with full-field deformation mapping using digital image correlation (DIC). The mechanical outcomes described the tissue tensile and viscoelastic behavior. Treatment with buffer alone increased the hydration of the posterior Sclera compared to controls, while s-GAG removal caused a further increase in hydration compared to buffer-treated Scleras. Buffer-treatment significantly changed the Scleral mechanical behavior compared to the control condition, in a manner consistent with an increase in hydration. Specifically, buffer-treatment led to an increase in low-pressure stiffness, hysteresis, and creep rate, and a decrease in high-pressure stiffness. ChABC-treatment on buffer-treated Scleras had opposite mechanical effects than buffer-treatment on controls, leading to a decrease in low-pressure stiffness, hysteresis, and creep rate, and an increase in high-pressure stiffness and transition strain. Furthermore, s-GAG digestion dramatically reduced the differences in the mechanical behavior among the 4 quadrants surrounding the ONH as well as the differences between the circumferential and meridional responses compared to the buffer-treated condition. These findings demonstrate a significant effect of s-GAGs on both the stiffness and time-dependent behavior of the Sclera. Alterations in s-GAG content may contribute to the altered creep and stiffness of the Sclera of myopic and glaucoma eyes.

  • the in vitro inflation response of mouse Sclera
    Experimental Eye Research, 2010
    Co-Authors: Kristin M Myers, Frances E. Cone, Harry A Quigley, Scott Gelman, Mary Ellen Pease, Thao D Nguyen
    Abstract:

    The purpose of this research was to develop a reliable and repeatable inflation protocol to measure the Scleral inflation response of mouse eyes to elevations in intraocular pressure (IOP), comparing the inflation response exhibited by the Sclera of younger and older C57BL/6 mice. Whole, enucleated eyes from younger (2 month) and older (11 month) C57BL/6 mice were mounted by the cornea on a custom fixture and inflated according to a load-unload, ramp-hold pressurization regimen via a cannula connected to a saline-filled programmable syringe pump. First, the tissue was submitted to three load-unload cycles from 6 mmHg to 15 mmHg at a rate of 0.25 mmHg/s with ten minutes of recovery between cycles. Next the tissue was submitted to a series of ramp-hold tests to measure the creep behavior at different pressure levels. For each ramp-hold test, the tissue was loaded from 6 mmHg to the set pressure at a rate of 0.25 mmHg/s and held for 30 minutes, and then the specimens were unloaded to 6mmHg for 10 minutes. This sequence was repeated for set pressures of: 10.5, 15, 22.5, 30, 37.5, and 45 mmHg. Scleral displacement was measured using digital image correlation (DIC), and fresh Scleral thickness was measured optically for each specimen after testing. For comparison, Scleral thickness was measured on untested fresh tissue and epoxy-fixed tissue from age-matched animals. Comparing the apex displacement of the different aged specimens, the Sclera of older animals had a statistically significant stiffer response to pressurization than the Sclera of younger animals. The stiffness of the pressure-displacement response of the apex measured in the small-strain (6-15 mmHg) and the large-strain (37.5-45 mmHg) regime, respectively, were 287 ± 100 mmHg/mm and 2381 ± 191 mmHg/mm for the older tissue and 193 ± 40 mmHg/mm and 1454 ± 93 mmHg/mm for the younger tissue (Student t-test, p < 0.05). The Scleral thickness varied regionally, being thickest in the peripapillary region and thinnest at the equator. Fresh Scleral thickness did not differ significantly by age in this group of animals. This study presents a reliable inflation test protocol to measure the mechanical properties of mouse Sclera. The inflation methodology was sensitive enough to measure Scleral response to changes in IOP elevations between younger and older C57BL/6 mice. Further, the specimen-specific Scleral displacement profile and thickness measurements will enable future development of specimen-specific finite element models to analyze the inflation data for material properties.

Josh Wallman - One of the best experts on this subject based on the ideXlab platform.

  • evidence that increased Scleral growth underlies visual deprivation myopia in chicks
    Investigative Ophthalmology & Visual Science, 1991
    Co-Authors: Anne Mette Christensen, Josh Wallman
    Abstract:

    : The authors evaluated three measures of Scleral growth in chicks that were visually deprived with the use of translucent occluders. The authors sought to determine whether the ocular elongation and myopia that results from this deprivation is associated with increased growth of the Sclera. The authors found that the dry weight of the Sclera of deprived eyes increased 65% faster than that of nondeprived eyes. Furthermore, the uptake of labeled methionine and thymidine was significantly increased by visual deprivation, whether expressed as incorporation per Sclera, per milligram of Sclera, per milligram of protein, or per milligram of DNA. In addition, the amount of DNA and soluble protein was significantly greater in the Scleras of deprived eyes than in those of nondeprived eyes. Finally, the degree of hydration of the Scleras from deprived eyes was greater relative to their weight than that of the Scleras from nondeprived eyes. These results suggest that visual deprivation causes increased cellular proliferation and increased protein synthesis in the Sclera of chicks.

Harry A Quigley - One of the best experts on this subject based on the ideXlab platform.

  • glaucoma related changes in the mechanical properties and collagen micro architecture of the human Sclera
    PLOS ONE, 2015
    Co-Authors: Baptiste Coudrillier, Harry A Quigley, Joan L Jefferys, Jacek K Pijanka, Adhiraj Goel, Craig Boote, Thao D Nguyen
    Abstract:

    Objective The biomechanical behavior of the Sclera determines the level of mechanical insult from intraocular pressure to the axons and tissues of the optic nerve head, as is of interest in glaucoma. In this study, we measure the collagen fiber structure and the strain response, and estimate the material properties of glaucomatous and normal human donor Scleras. Methods Twenty-two posterior Scleras from normal and diagnosed glaucoma donors were obtained from an eyebank. Optic nerve cross-sections were graded to determine the presence of axon loss. The specimens were subjected to pressure-controlled inflation testing. Full-field displacement maps were measured by digital image correlation (DIC) and spatially differentiated to compute surface strains. Maps of the collagen fiber structure across the posterior Sclera of each inflated specimen were obtained using synchrotron wide-angle X-ray scattering (WAXS). Finite element (FE) models of the posterior Scleras, incorporating a specimen-specific representation of the collagen structure, were constructed from the DIC-measured geometry. An inverse finite element analysis was developed to estimate the stiffness of the collagen fiber and inter-fiber matrix. Results The differences between glaucoma and non-glaucoma eyes were small in magnitude. Sectorial variations of degree of fiber alignment and peripapillary Scleral strain significantly differed between normal and diagnosed glaucoma specimens. Meridional strains were on average larger in diagnosed glaucoma eyes compared with normal specimens. Non-glaucoma specimens had on average the lowest matrix and fiber stiffness, followed by undamaged glaucoma eyes, and damaged glaucoma eyes but the differences in stiffness were not significant. Conclusion The observed biomechanical and microstructural changes could be the result of tissue remodeling occuring in glaucoma and are likely to alter the mechanical environment of the optic nerve head and contribute to axonal damage.

  • the effects of glycosaminoglycan degradation on the mechanical behavior of the posterior porcine Sclera
    Acta Biomaterialia, 2015
    Co-Authors: Barbara J Murienne, Harry A Quigley, Joan L Jefferys, Thao D Nguyen
    Abstract:

    Pathological changes in Scleral glycosaminoglycan (GAG) content and in Scleral mechanical properties have been observed in eyes with glaucoma and myopia. The purpose of this study is to investigate the effect of GAG removal on the Scleral mechanical properties to better understand the impact of GAG content variations in the pathophysiology of glaucoma and myopia. We measured how the removal of sulphated GAG (s-GAG) affected the hydration, thickness and mechanical properties of the posterior Sclera in enucleated eyes of 6–9 month-old pigs. Measurements were made in 4 regions centered on the optic nerve head (ONH) and evaluated under 3 conditions: no treatment (control), after treatment in buffer solution alone, and after treatment in buffer containing chondroitinase ABC (ChABC) to remove s-GAGs. The specimens were mechanically tested by pressure-controlled inflation with full-field deformation mapping using digital image correlation (DIC). The mechanical outcomes described the tissue tensile and viscoelastic behavior. Treatment with buffer alone increased the hydration of the posterior Sclera compared to controls, while s-GAG removal caused a further increase in hydration compared to buffer-treated Scleras. Buffer-treatment significantly changed the Scleral mechanical behavior compared to the control condition, in a manner consistent with an increase in hydration. Specifically, buffer-treatment led to an increase in low-pressure stiffness, hysteresis, and creep rate, and a decrease in high-pressure stiffness. ChABC-treatment on buffer-treated Scleras had opposite mechanical effects than buffer-treatment on controls, leading to a decrease in low-pressure stiffness, hysteresis, and creep rate, and an increase in high-pressure stiffness and transition strain. Furthermore, s-GAG digestion dramatically reduced the differences in the mechanical behavior among the 4 quadrants surrounding the ONH as well as the differences between the circumferential and meridional responses compared to the buffer-treated condition. These findings demonstrate a significant effect of s-GAGs on both the stiffness and time-dependent behavior of the Sclera. Alterations in s-GAG content may contribute to the altered creep and stiffness of the Sclera of myopic and glaucoma eyes.

  • Development of diagnostic and treatment strategies for glaucoma through understanding and modification of Scleral and lamina cribrosa connective tissue
    Cell and Tissue Research, 2013
    Co-Authors: Harry A Quigley, Frances E. Cone
    Abstract:

    Considerable evidence indicates that the state of ocular connective tissues and their response in glaucomatous disease affect the degree of glaucoma damage. Both experimental and clinical data suggest that improved diagnostic and prognostic information can be derived from the assessment of the mechanical responsiveness of the Sclera and lamina cribrosa to intraocular pressure (IOP). Controlled mutagenesis of the Sclera has produced a mouse strain that is relatively resistant to increased IOP. Alteration of the baseline Scleral state can be accomplished through either increased cross-linking of fibrillar components or their reduction. The Sclera is a dynamic structure, altering its structure and behavior in response to IOP change. The biochemical pathways that control these responses are fertile areas for new glaucoma treatments.

  • the in vitro inflation response of mouse Sclera
    Experimental Eye Research, 2010
    Co-Authors: Kristin M Myers, Frances E. Cone, Harry A Quigley, Scott Gelman, Mary Ellen Pease, Thao D Nguyen
    Abstract:

    The purpose of this research was to develop a reliable and repeatable inflation protocol to measure the Scleral inflation response of mouse eyes to elevations in intraocular pressure (IOP), comparing the inflation response exhibited by the Sclera of younger and older C57BL/6 mice. Whole, enucleated eyes from younger (2 month) and older (11 month) C57BL/6 mice were mounted by the cornea on a custom fixture and inflated according to a load-unload, ramp-hold pressurization regimen via a cannula connected to a saline-filled programmable syringe pump. First, the tissue was submitted to three load-unload cycles from 6 mmHg to 15 mmHg at a rate of 0.25 mmHg/s with ten minutes of recovery between cycles. Next the tissue was submitted to a series of ramp-hold tests to measure the creep behavior at different pressure levels. For each ramp-hold test, the tissue was loaded from 6 mmHg to the set pressure at a rate of 0.25 mmHg/s and held for 30 minutes, and then the specimens were unloaded to 6mmHg for 10 minutes. This sequence was repeated for set pressures of: 10.5, 15, 22.5, 30, 37.5, and 45 mmHg. Scleral displacement was measured using digital image correlation (DIC), and fresh Scleral thickness was measured optically for each specimen after testing. For comparison, Scleral thickness was measured on untested fresh tissue and epoxy-fixed tissue from age-matched animals. Comparing the apex displacement of the different aged specimens, the Sclera of older animals had a statistically significant stiffer response to pressurization than the Sclera of younger animals. The stiffness of the pressure-displacement response of the apex measured in the small-strain (6-15 mmHg) and the large-strain (37.5-45 mmHg) regime, respectively, were 287 ± 100 mmHg/mm and 2381 ± 191 mmHg/mm for the older tissue and 193 ± 40 mmHg/mm and 1454 ± 93 mmHg/mm for the younger tissue (Student t-test, p < 0.05). The Scleral thickness varied regionally, being thickest in the peripapillary region and thinnest at the equator. Fresh Scleral thickness did not differ significantly by age in this group of animals. This study presents a reliable inflation test protocol to measure the mechanical properties of mouse Sclera. The inflation methodology was sensitive enough to measure Scleral response to changes in IOP elevations between younger and older C57BL/6 mice. Further, the specimen-specific Scleral displacement profile and thickness measurements will enable future development of specimen-specific finite element models to analyze the inflation data for material properties.