Bevacizumab-loaded Polyurethane Subconjunctival Implants: Effects on Experimental Glaucoma Filtration Surgery

Abstract

Purpose: : Vascular endothelial growth factor (VEGF) has been suggested to be involved in the scarring process due to the proliferation of fibroblasts. The polyurethanes have been extensively investigated for biomedical applications, as scaffold for tissue regeneration and as controlled/sustained release drug delivery systems, because of their excellent biocompatibility, chemical versatility and mechanical properties. The aim of this study was to evaluate the effect of the bevacizumab-loaded polyurethane implant (BPUI) as a new drug delivery system in a rabbit model of glaucoma filtration surgery.

Methods: : Polyurethane was obtained in aqueous dispersion through the conventional process. Bevacizumab (1.5mg) was incorporated into the dispersion with subsequent drying to form the polymeric film. Films of 3x3x1 mm containing (group 1, n=5) or not bevacizumab (group 2, n=5) were placed in the subconjunctival space, at the surgical site. The in vitro release of bevacizumab was evaluated with high-performance liquid chromatography (HPLC) and its in vivo effects was investigated in an experimental model of trabeculectomy by measuring the intraocular pressure (IOP, with Tonopen), bleb area (using Moorfields bleb grading system) and collagen deposition (Image J measurements of sirius red staining), and by immunohistological analysis of VEGF.

Results: : HPLC showed that 100% of bevacizumab was released until day 5. In vivo studies demonstrated no adverse effect, however no significant difference was observed in terms of IOP reduction (2.7 vs 2.2 mmHg), bleb area scores (2.6 vs 2.0) and collagen deposition intensity proportion (0.23 vs 0.20) between group 1 and 2 respectively, at day 5. BPUI was associated with a significant lower proportion of VEGF-expressing fibroblasts (0.17 vs 0.35 cells/field, P=0.005; Mann Whitney U test).

Conclusions: : This study demonstrated that the BPUIs allowed a short-term release of bevacizumab in vitro, were well tolerated in rabbits' eyes and promoted a reduction of VEGF-expressing fibroblasts. Further pharmacokinetic studies with BPUI will be necessary to improve our results in terms of optimizing its bioavailability with minimal side effects.

Keywords: wound healing • conjunctiva • drug toxicity/drug effects