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J. Schwartzkopff, A. J. Hyatt, L. Bredow, C. Noack, P. Eberwein, K. R. Martin, T. Reinhard; Evaluation of a New Fibrin Based Drug Delivery System to Prevent Allograft Rejection in Rat Keratoplasty. Invest. Ophthalmol. Vis. Sci. 2010;51(13):1616.
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Many immunosupressives have been shown to prevent rejection following keratoplasty if given systemically. To avoid known toxic side effects, local drug administration (eye drops) was also tested but not proven similarly effective. Therefore, a fibrin based depot system was analyzed for its efficacy to deliver Cyclosporine A (CsA) after subconjunctival implantation in the rat keratoplasty model.
In vitro: Fibrin-gels were loaded with CsA or left empty. CsA release into storage medium was measured daily by mass spectrometry. The bioactivity of released CsA was verified by analyzing its capacity to inhibit T cells in a standard CFSE-proliferation assay. In vivo: The inflammatory reaction following subconjunctival implantation was examined histologically after one week by HE staining. Keratoplasty was performed between Fisher donor and Lewis recipient rats. On the day of surgery, CsA-fibrin gels were implanted next to the limbus. Control animals received fibrin gel without CsA. Animals were followed clinically until rejection occurred.
CsA was released over two weeks in vitro at a relatively constant rate. Released CsA inhibited T cell proliferation and was therefore proven to be bioactive. Implanted gels stayed stable for more than one week and caused only a mild concomitant infiltration of mononuclear cells. A single implantation of a CsA-gel statistically significantly improved allograft survival whereas all control treated animals rejected a corneal graft (p<0.001).
Our results show that bioactive CsA is released continously from a fibrin-gel delivery system. Moreover, CsA loaded fibrin-gels can be implanted without causing a significant immunological side reaction. A single CsA-fibrin-gel implantation is sufficient to promote allograft survival without causing unspecific side effects. We therefore propose fibrin as a carrier system for immunosuppressive drugs in the treatment of keratoplasty.
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