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Xiaokun Wang, Jeeyeon Sohn, Garret Ma, Samuel C Yiu, Jennifer Elisseeff; Biocompatible Chondroitin sulfate-based cross-linker restores corneal mechanics and collagen alignment. Invest. Ophthalmol. Vis. Sci. 2016;57(12):2888.
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© 2017 Association for Research in Vision and Ophthalmology.
Collagen crosslinking initiated by riboflavin and UVA irradiation has recently been developed as a clinical treatment to slow the corneal ectasia progression. However, there are clinical complications of the UVA crosslinking, such as corneal scarring, and corneal tissue thinning ect., indicating a safer and more biocompatible method to reinforce the cornea is in demand. Chondroitin sulfate is a biological polymer that is abundant in the extracellular matrix of tissues throughout the body, including corneas. In this study we developed a functionalized chondroitin sulfate N-hydroxysuccinimide (CS-NHS) as a biocompatible, non-UVA initiated crosslinker to crosslink ectatic corneas.
Cadaver rabbit eyes were crosslinked in 2, 5, 10mg/ml CS-NHS in PBS buffer for 30 and 60 min respectively. CS-NHS penetration, swelling ratio and ultrastructural change were evaluated to optimize the crosslinking time and crosslinker concentration.As for crosslinking of ectatic corneas, rabbit eyes were treated with collagenase and chondroitinase enzymes to generate the ectatic models, and then crosslinked in 5mg/ml CS-NHS solution for 60 min. Corneal mechanics, ultrastructure, thermal stability, and inflammatory gene expression were evaluated before and after crosslinking.
The enzyme treatment significantly decreased the corneal mechanics and also damaged collagen fibril. The CS-NHS crosslinker was able to effectively penetrate into corneal stroma, restored corneal strength by 20~30%, decreased swelling ratio by 60%, and significantly increased collagen fibril thickness and density. Furthermore, qPCR results demonstrated that conventional UVA crosslinking significantly up-regulated TNFa and MMP9 gene expression, which raised the risk of complications such as corneal scarring and melting, whereas CS-NHS did not trigger any inflammatory response, and exhibited a protective potential of keratocytes during crosslinking, as it up-regulated keratocan and biglican gene expression.
In this study, we generated an ex vivo corneal ectatic model that simulates the structural disorder of keratoconus. CS-NHS crosslinking effectively stabilized the corneas without triggering inflammatory response. These findings indicate CS-NHS will benefit the ectatic corneas not only in the conventional structural stabilizing way, but also in a more versatile, non-invasive and potentially protective way.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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