PROJECT SUMMARY/ABSTRACT Chronic posterior eye diseases, such as diabetic macular edema (DME), macular edema (ME) caused by retinal vein occlusion, wet age-released macular degeneration (wet AMD) and non-infectious posterior uveitis (NU), are associated with high rates irreversible vision loss. Current standard of care for DME, ME and wet AMD is monthly intravitreal injections of anti-vascular endothelial growth factor (VEGF) monoclonal antibody, Bevacizumab (Bev), or the fragment, Ranibizumab (Ran). In addition, because those diseases are characterized by inflammation and fibrosis, intravitreal corticosteroid implant injections every 2~6 months is the mainstay to treat DME, ME, and NU. Recently, combination therapy of intravitreal anti-VEGF and corticosteroid implant (Ozurdex) injections has been extensively studied in clinical trials to expect better therapeutic efficacy in those chronic diseases. However, multiple frequent intravitreal injections are not only invasive and inconvenient for patients but also increase the risk of complications, such as conjunctival hemorrhage, and increased intraocular pressure (IOP). Especially, the intravitreal corticosteroid treatment causes serious local side effects, such as cataract and abnormally high IOP which can lead to glaucoma. Because the peak IOP is highly associated with the drug (dexamethasone, Dex) concentration in the vitreous/retina released from Ozurdex, we hypothesize that the local side effect is due to the inability to adjust dosage and burst release characterized by high concentration in shorter time than desired. The central hypothesis of this proposal is that our novel dose-controllable co-delivery implant of Dex/Ran would reduce the side effects due to uncontrollable dosage after intravitreal administration, and extend therapeutic efficacy. We recently developed a biodegradable light-activated implant that can be intravitreally injected and triggered by laser through the lens of the eye for dose-controlled drug release safely. The drug dosage can be precisely and easily controlled by varying laser parameters, such as power and duration. The overall goal of this research is to improve the treatment of chronic posterior eye diseases and reduce side effects caused by current corticosteroid treatment methods by developing a dose-controllable co-delivery drug implant. The focus of Aim 1 is to complete the development of a dose-controllable co-delivery Dex/Ran implant and investigate the drug release kinetics in vitro. Aim 2 focuses on defining effect of different drug delivery methods on reducing side effects, glaucoma, utilizing human trabecular meshwork cells. Aim 3 will determine in vivo efficacy and reduced side effects of the implant compared to the traditional methods, i.e. Ozurdex and monthly Ran injections, in a retinal vessel leakage/edema rabbit model. At the successful completion of this project, expected outcomes include identifying feasibility of the dose-controllable implants t...