Currently most treatments for retinal diseases are based on frequent intravitreal injections, which are invasive, and could lead to serious complications such as endophthalmitis and retinal detachment. The frequent injections are necessary because the drugs delivered through the injection are cleared from the vitreous by multiple pathways. The frequency of injections in real-world experience may be lower than recommended resulting in poorer-than-expected treatment outcomes. It is ideal to administer ophthalmic drugs topically as eye drops but due to low bioavailability, they are not suitable to achieve therapeutic benefits in the back of the eye. Contact lenses have been extensively investigated for delivering drugs to treat anterior segment diseases because about 50% of the drug in the lenses permeates into the cornea compared to about 1-5% with eye drops. Delivery of drugs to the back of the eye including sustained delivery by contact lenses has received considerably less attention. Here we propose to advance contact lenses for back of the eye delivery, by determining the underlying mechanisms of delivery, evaluating enhanced and sustained delivery with the lenses relative to eye drops, developing models predictive of contact lens-based drug delivery, and developing novel lenses for delivery of biologics. We have preliminary data showing feasibility of contact lens mediated delivery of drugs to the back of the eye. The proposal will investigate two major pathways that can contribute to the back of the eye delivery from a contact lens: a) diffusion across cornea into anterior chamber followed by uveoscleral outflow into sclera-choroid and b) non-corneal transport involving diffusion into the tears followed by transverse diffusion across sclera and choroid into retina and vitreous. This proposal combines in vitro, ex vivo, in vivo and in silico studies to determine the relative importance of these pathways. We use a pharmacology-based approach in Aim 1 to evaluate the uveoscleral outflow pathway and a lens engineering-based approach entailing piggyback lenses in Aim 2 to understand the non-corneal pathway and to deliver drugs via one of the two pathways. Further, in Aim 2, we will develop and validate a novel, mechanistic, in-silico model incorporating drug and tissue properties. The model will allow design of contact lenses for delivering drugs to the back of the eye at therapeutic concentrations. In Aim 3, we will develop novel porous annulus lenses to deliver anti VEGF antibodies that are commonly used for treating wet age-related macular degeneration. All in vivo and ex vivo experiments will be conducted in New Zealand white rabbits that are commonly used for measuring ocular pharmacokinetics. In Aims 1 and 3, dexamethasone, which is used for treating diabetic macular edema is investigated, and in Aim 2, a series of corticosteroids with Log(P) ranging from 0.53 to 3.2 are used to explore the effect of hydrophobicity. In each of the Aims we us...