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Chengxin Zhou, Marie-Claude Robert, Fengyang Lei, Vassiliki Kapoulea, James Chodosh, Claes H Dohlman, Eleftherios I Paschalis; Evaluation of a therapeutic anti-TNF-α drug delivery system for ocular alkali burns. Invest. Ophthalmol. Vis. Sci. 2016;57(12):1271. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Ocular burns cause corneal inflammation, neovascularization (CNV) and scarring. We have shown that tumor necrosis factor alpha (TNF-α) is upregulated after burn and that prompt TNF-α inhibition improves corneal wound healing. However, systemic administration of TNF-α inhibitors can cause significant adverse events, while topical administration is limited by poor corneal bioavailability and the need for frequent drug application. This study was designed to test a novel drug delivery system (DDS) for sustained-release of TNF-α inhibitor to the ocular surface. We used a rabbit ocular alkali burn model to assess the efficacy of the DDS in terms of reduction of corneal CNV, opacity and improvement of corneal wound healing.
DDS was prepared using porous PDMS/PVA composite fabrication that was loaded with 80μg infliximab. Evaluation was performed in 6 Dutch-belted pigmented rabbits that received ocular alkali burn with 2N NaOH. Three rabbits received subconjunctival implantation of anti-TNF-α DDS and 3 sham DDS immediately after the burn. Rabbits were followed with photography for 3 months and analyzed for CNV, opacity and re-epithelialization. Inflammation was assessed using CD45 antibody in tissue sections.
Rabbits treated with anti-TNF-α DDS achieved complete corneal re-epithelialization within 63.6 ± 7.5 days of burn, reduced CNV (0.13 ± 0.05 % of cornea area) and corneal opacity (central score = 2.17 ± 0.85; peripheral score = 0.33 ± 0.41 in a 0-4 scale), while sham DDS treated rabbits exhibited persistent epithelial defect until the end of the study (92 days), increased CNV (0.31 ± 0.14 % of cornea area, p<0.05) and corneal opacity (central score = 3.5 ± 0.57, p>0.05; peripheral score = 2.44 ± 1.41, p<0.05). Anti-TNF-α DDS was well tolerated. The number of CD45+ cells in anti-TNF-α DDS treated eyes was significantly lower (mean=4322 cells/ cornea) compared to sham DDS eyes (mean=17049 cells/ cornea, p<0.05). Infliximab was still present in the DDS 3 months after implantation, evident by anti-human IgG immunolocalization.
Sustained topical delivery of anti-TNF-α for the treatment of ocular alkali burn is feasible using the described DDS. Local anti-TNF-α therapy suppresses corneal inflammation and CNV, and improves wound healing. The described DDS may be beneficial to a variety of ocular surface diseases amenable to biologic therapy.
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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