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Purpose: Demonstrate in vivo that controlled and extended release of a low dose of anti-vascular endothelial growth factor (anti-VEGF) from a microsphere-hydrogel drug delivery system (DDS) has a therapeutic effect in a laser-induced rat model of choroidal neovascularization (CNV)., Methods: Anti-VEGF (ranibizumab or aflibercept) was loaded into poly(lactic-co-glycolic acid) microspheres that were then suspended within an injectable poly(N-isopropylacrylamide)-based thermo-responsive hydrogel DDS.The DDS was shown previously to release bioactive anti-VEGF for ~200 days. CNV was induced using an Ar-green laser. The four experimental groups were as follows: (i) non-treated, (ii) drug-free DDS, (iii) anti-VEGF-loaded DDS, and (iv) bolus injection of anti-VEGF. CNV lesion areas were measured based on fluorescein angiograms and quantified using a multi-Otsu thresholding technique. Intraocular pressure (IOP) and dark-adapted electroretinogram (ERG) were also obtained pre- and post-treatment (1, 2, 4, 8, and 12 weeks)., Results: The anti-VEGF-loaded DDS group had significantly smaller (60%) CNV lesion areas than non-treated animals throughout the study. A small transient increase in IOP was seen immediately after injection; however, all IOP measurements at all time points were within the normal range. There were no significant changes in ERG maximal response compared to pre-treatment measurements for the drug-loaded DDS, which suggests no adverse effects on retinal cellular function., Conclusions: The current study demonstrates that the DDS can effectively decrease laser-induced CNV lesions in a murine model. Controlled and extended release from our DDS achieved greater treatment efficacy using an order of magnitude less drug than what is required with bolus administration. This suggests that our DDS may provide a significant advantage in the treatment of posterior segment eye diseases.