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P. D. Lamar, M. Hornof, M. Hoffer, A. Clausen; In vitro Ocular Safety Studies With Different Thiolated Chitosan Derivatives. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5774.
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To evaluate the potential toxicity of different thiolated chitosan derivatives in vitro using isolated rabbit corneas.
Three different thiol-modified chitosans were synthesized: chitosan-N-acetylcysteine (chito-NAC), chitosan-thioethylamidine (chito-TEA) and chitosan-thiobutylamidine (chito-TBA). Chito-NAC and chito-TBA were prepared with different degrees of thiol modification. Isotonic 0.5% and 0.75% solutions of these polymers were freshly prepared and adjusted to pH 6.5. These solutions were then incubated for 3 h with the epithelial side of freshly excised rabbit corneas in Ussing-type diffusion chambers under physiological conditions. Unmodified chitosan and GBR buffer were used as control. After incubation water content of each cornea was determined using a gravimetric method.
The degrees of modification with thiol groups were 35 µM/g and 80 µM/g for chito-NAC, 100 µM/g for chito-TEA, and 100 µM/g and 200 µM/g for chito-TBA. Corneal hydration level of control corneas was 79.0±1.0%. After 3 h incubation with 0.5% solutions of thiolated chitosan derivatives no significant increase in corneal hydration was observed, which indicates that the corneal epithelium remained intact. The same result was obtained with unmodified chitosan. Increasing the polymer concentration and the degree of modification with thiol groups had no negative effect on corneal integrity.
Determination of the corneal hydration level is a quick method to assess the influence of novel (polymeric) excipients on corneal epithelial integrity in an in vitro/"ex vivo" setting, because increased hydration of the cornea is a sensitive indicator for corneal damage. None of the tested thiolated chitosans displayed any damaging effect on the corneal epithelium in the tested concentrations. Further studies will be conducted to assess the potential of these polymers as tear film substitutes or polymeric excipients for drug delivery to the cornea and conjunctiva.
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