Human Scleral Hydraulic Conductivity: Age-Related Changes, Topographical Variation, and Potential Scleral Outflow Facility

Jackson, Timothy L.; Hussain, Abir; Hodgetts, A; Morley, Ana M. S.; Hillenkamp, Jost; Sullivan, Paul; Marshall, John

doi:10.1167/iovs.06-0362

Cited by 41 publications

(35 citation statements)

References 28 publications

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“…39 In this study, we found that there was lower permeability to dextran in older CD1 than in younger CD1 mice. Related measures of scleral permeability, namely hydraulic conductivity and permeability to albumen, have been reported to decline with age in human eyes, 40,41 and these findings are consistent with our permeability data. We have recently found that older CD1 mice are more susceptible to experimental glaucoma damage than younger CD1 mice.…”

Section: Discussionsupporting

confidence: 92%

Scleral Permeability Varies by Mouse Strain and Is Decreased by Chronic Experimental Glaucoma

Pease

Oglesby

Cone-Kimball

et al. 2014

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. To determine differences in scleral permeability, as measured by diffusion of macromolecules, by using fluorescence recovery after photobleaching (FRAP), with reference to differences by mouse strain, scleral region, and the effect of experimental glaucoma.METHODS. In three mouse strains (B6, CD1, and B6 mice with mutation in collagen 8a2[Aca23]), we used FRAP to measure the diffusion of fluorescein isothiocyanate-dextran, molecular weight 40 kDa, into a photobleached zone of sclera. Scleral regions near the optic nerve head (peripapillary) and two successively more anterior regions were compared. Sclera from mouse eyes subjected to chronically elevated intraocular pressure after bead injection into the anterior chamber were compared to fellow eye controls. FRAP data were compared against estimated retinal ganglion cell axon loss in glaucomatous eyes.RESULTS. Diffusion rates of dextran molecules in the sclera were significantly greater in Aca23 and B6 mice than in CD1 mice in a multivariate model adjusted for region and axial length (P < 0.0001). Dextran diffusion significantly decreased in glaucomatous eyes, and the decline increased with greater axon loss (P ¼ 0.0003, multivariable model). Peripapillary scleral permeability was higher in CD1 than B6 and Aca23 mice (P < 0.05, multivariable model, adjusted by Bonferroni). CONCLUSIONS.Measurement of the diffusion rates of dextran molecules in the sclera showed that glaucoma leads to decreased scleral permeability in all three mouse strains tested. Among mouse strains tested, those that were more susceptible to glaucomatous loss of retinal ganglion cells had a lower scleral permeability at baseline.Keywords: glaucoma, mouse, experimental model, sclera, diffusion, permeability, photobleaching, dextran G laucoma is the second leading cause of world blindness and its principal risk factors include the effect of intraocular pressure (IOP) acting to decrease the number of retinal ganglion cells (RGCs). Intraocular pressure is a mechanical load that generates stress and strain in the sclera, which are magnified at the optic nerve head (ONH). The largest mechanical strains have been measured in in vitro inflation experiments in the peripapillary region, immediately adjacent to the ONH.1 The sclera acts on the ONH, where axons of RGCs pass out of the eye, and suffers damage related to the effects of IOP.2,3 Thus, the behavior of the sclera is highly relevant to glaucoma injury and its study may be useful in improved diagnosis as well as new therapeutic avenues.The sclera comprises three-quarters of the human ocular circumference and is 75% to 90% collagen, with additional elastin fibrils and proteoglycans. 4,5 The scleral proteoglycans include heparin sulfate, chondroitin sulfate, dermatan sulfate, keratan sulfate, hyaluronan, aggrecan, and several small leucinerich proteoglycans.6,7 These may have important functional significance for the mechanical responses of the sclera. 8 Scleral thickness is greatest at the peripapillary zone, followed by the limbus, and is...

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Section: Discussionsupporting

confidence: 92%

Scleral Permeability Varies by Mouse Strain and Is Decreased by Chronic Experimental Glaucoma

Pease

Oglesby

Cone-Kimball

et al. 2014

Invest. Ophthalmol. Vis. Sci.

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“…25 However, there is evidence to suggest that for some ethnic groups a significant age-dependent decrease in CCT occurs in later life. [26][27][28] In comparison, Jackson et al 24 reported that although ST showed a possible reduction with age, the trend was not significant. In our study in whites, we found that age did not influence CCT or ST measurements.…”

Section: Discussionmentioning

confidence: 92%

“…Perhaps, corneal thickness (and curvature) might be uniquely affected by hormonal changes even though sex-related difference in CCT remains to be adequately defined. 23 Jackson et al 24 reported that there were no difference in the ST between males and females. However, the site where the ST was measured on donor eyes was randomly selected.…”

Section: Discussionmentioning

confidence: 98%

Correlation Between Corneal and Scleral Thickness in Glaucoma

Mohamed-Noor

Bochmann

Siddiqui

et al. 2009

Journal of Glaucoma

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“…Previous studies have demonstrated the integrity of tissue clamped in this Ussing chamber. 13,15,16,17 A small glass encased magnetic stirrer was added to each hemi-chamber. Previous studies have demonstrated that stirring does not increase the scleral permeability of high MWT compounds.…”

Section: Diffusion Testing Apparatusmentioning

confidence: 99%

Influence of molecular shape, conformability, net surface charge, and tissue interaction on transscleral macromolecular diffusion

Srikantha

Mourad

Suhling

et al. 2012

Experimental Eye Research

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Purpose: To study the influence of molecular shape, conformability, net surface charge and tissue interaction on transscleral diffusion.Methods: Unfixed, porcine sclera was clamped in an Ussing chamber. Fluorophore labelled, neutral, albumin, dextran, or ficoll were placed in one hemi-chamber and the rate of transscleral diffusion was measured over 24 hours using a spectrophotometer. Experiments were repeated using dextrans and ficoll with positive, or negative, net surface charges.Fluorescence recovery after photobleaching (FRAP) was undertaken to compare transscleral diffusion with diffusion through a solution.All molecules were 70 kDa.Results: Using FRAP, mean ± SD diffusion coefficient (D) was highest for albumin, followed by ficoll, then dextran (p = 0.0005). Positive dextrans diffused fastest, followed by negative, then neutral dextrans (p = 0.0005). Neutral ficoll diffused the fastest, followed by positive then negative ficoll (p = 0.0008). For the neutral molecules, transscleral D was highest for albumin, followed by dextran, then ficoll (p < 0.0001). D was highest for negative ficoll, followed by neutral, then positive ficoll (p < 0.0001). By contrast, D was highest for positive dextran, followed by neutral, then negative dextran (p = 0.0021).Conclusions: Diffusion in free solution does not predict transscleral diffusion and the molecular-tissue interaction is important. Molecular size, shape, and charge may all markedly influence transscleral diffusion, as may conformability to a lesser degree, but all need to be considered when selecting or designing drugs for transscleral delivery.Drugs directed against vascular endothelial growth factor (VEGF) have proven efficacy in some of the most common retinal diseases. The ANCHOR and MARINA studies demonstrated efficacy in wet age-related macular degeneration (AMD), 1,2 and studies such as CRUISE, BRAVO 3,4 and several from the DRCnet Group have shown favourable results in retinal vein occlusion and diabetic macular oedema. Whilst the data in these studies have led to improved clinical care, the need for regular intravitreal injections represents a burdensome regimen of treatment. A less invasive mode of delivery would have potential advantages in terms of reduced cost, discomfort, and complication rate.Systemic administration is impeded by the blood-aqueous and blood-retinal-barriers. High drug concentrations may be required to overcome these barriers to diffusion, with the attendant risk of systemic side effects. 5 A topical route would have obvious advantages. Delivery to the retina is however difficult for several reasons, such as lacrimation, low corneal permeability to large molecules, counter directional intraocular convection, and importantly the long diffusional distance. 53 Blood flow in the conjunctiva, episclera and choroid can also reduce drug concentration. 33,50 Notwithstanding these potential difficulties, transscleral delivery has a number of potential advantages. 6,7,8,9 The sclera has a large and accessible surface area, and a high d...

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Human Scleral Hydraulic Conductivity: Age-Related Changes, Topographical Variation, and Potential Scleral Outflow Facility

Cited by 41 publications

References 28 publications

Scleral Permeability Varies by Mouse Strain and Is Decreased by Chronic Experimental Glaucoma

Scleral Permeability Varies by Mouse Strain and Is Decreased by Chronic Experimental Glaucoma

Correlation Between Corneal and Scleral Thickness in Glaucoma

Influence of molecular shape, conformability, net surface charge, and tissue interaction on transscleral macromolecular diffusion

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