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J. M. Stewart, D. S. Schultz, O.-T. Lee, M. L. Trinidad; Collagen Crosslinks Are a Determinant of Scleral Permeability: Implications for Transscleral Drug Delivery Strategies. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5005. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
To evaluate the role of collagen crosslinks in permeability of sclera to both solute diffusion and fluid flow.
Porcine and rabbit sclera were subjected to exogenous crosslinking treatment in vitro using methylglyoxal. Scleral discs treated for 24 hours with control solution or 0.5% or 2% methylglyoxal were placed in a two-chamber diffusion apparatus, and fluorescein diffusion was measured over a 4 hour period with fluorescence spectrophotometry. Hydraulic permeability was evaluated utilizing a column of saline attached to a two-chamber system to generate a transscleral fluid pressure in a physiologic range. Flow across control and treated scleral samples was calculated according to the descent of the fluid column over a 24-hour period. Papain digests and fluorescence spectrophotometry were used to quantify non-enzymatic crosslinks in control and treated samples.
Methylglyoxal treatment resulted in impaired solute diffusion and fluid flow across the sclera. The permeability constant for fluorescein was reduced 9-fold by the 0.5% solution and 148-fold by the 2% solution. Hydraulic permeability was also markedly reduced. Fluorescence levels, an indicator of crosslink density, were found to increase with the concentration of methylglyoxal used.
Nonenzymatic glycation due to methylglyoxal results in reduced scleral permeability. It is expected that the effect upon solute diffusion will be more pronounced with larger molecules. These findings suggest that nonenzymatic crosslinks that accumulate due to age or diseases such as diabetes will similarly impair solute and fluid diffusion across the sclera. Crosslink density should be considered when modeling pharmacokinetics and dosing for transscleral drug administration.
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