In Vitro and Ex Vivo Models for Assessing Drug Permeation across the Cornea

Abstract

Drug permeation across the cornea remains a major challenge due to its unique and complex anatomy and physiology. Static barriers such as the different layers of the cornea, as well as dynamic aspects such as the constant renewal of the tear film and the presence of the mucin layer together with efflux pumps, all present unique challenges for effective ophthalmic drug delivery. To overcome some of the current ophthalmic drug limitations, the identification and testing of novel drug formulations such as liposomes, nanoemulsions, and nanoparticles began to be considered and widely explored. In the early stages of corneal drug development reliable in vitro and ex vivo alternatives, are required, to be in line with the principles of the 3Rs (Replacement, Reduction, and Refinement), with such methods being in addition faster and more ethical alternatives to in vivo studies. The ocular field remains limited to a handful of predictive models for ophthalmic drug permeation. In vitro cell culture models are increasingly used when it comes to transcorneal permeation studies. Ex vivo models using excised animal tissue such as porcine eyes are the model of choice to study corneal permeation and promising advancements have been reported over the years. Interspecies characteristics must be considered in detail when using such models. This review updates the current knowledge about in vitro and ex vivo corneal permeability models and evaluates their advantages and limitations.

Enhancing paracellular and transcellular permeability using nanotechnological approaches for the treatment of brain and retinal diseases

“…1) acts as a natural protection against microorganisms and confers mechanical stability to the eye; it is a highly complex structure made of different layers. 26 The cornea, a transparent and avascular tissue with an average thickness of 500 mm in humans consists of several layers: (i) the corneal epithelium consisting of flattened superficial cells, wing cells, and columnar basal cells, (ii) Bowman's layer, (iii) the corneal stroma, (iv) the Descemet's membrane and (v) the corneal endothelium. Drug delivery is restricted in the cornea due to the presence of intercellular TJs between epithelial and endothelial cells, completely hindering the diffusion of macromolecules via the paracellular route.…”

“…10C) as the model of choice to study corneal penetration and promising advancements have been reported over the years. 26 An ex vivo bovine whole eye was used lately as model for corneal penetration studies of CQDs, in conjunction with confocal microscopy 91 (Fig. 6D).…”

“…Immortalized human cell lines, derived from corneal epithelial, conjunctival epithelial and retinal pigment epithelial cells, are currently available. 26,171 The use of retinal microvascular endothelial cells (HRMVEC/ACBRI181, cell systems), retinal pigment epithelium cells (RPE/ARPE-19, ATCC) and Mu ¨ller glial cells (Moorfield Institute of Ophthalmology-Mu ¨ller 1, UCL) is common for in vitro studies and considered promising for studying the drug transport into ocular tissues.…”