Building the human cornea on a chip.

The rising prevalence of eye diseases and our increasing life expectancy has accelerated the demand for ophthalmic therapeutics. While there is a clear market for novel ophthalmic medicines, these drugs must also be safe. There are two standard approaches to preclinical drug testing; 1) the in vitro approach where human cells or cell lines are tested in cultures on mostly plasticware, and 2) in vivo testing using healthy animals or animal models of disease. Neither of these approaches are ideal as both deviate significantly from the true human in vivo status and the native environment of the cells. Moreover, side effects can present in human subjects that did not occur in either in vitro or in vivo models which can have devastating effects to the patients. Organ-on-chip (OoC) technology is an emerging biomedical field that aims to provide a 3-dimensional dynamic tissue environment to more closely model human physiology. OoC emerged from computer technology disciplines and aims to reproduce the smallest functional unit possible to represent the chemical, mechanical and functional aspects of human organs. These "smallest functional units" are microfluidic cell culture chips where multiple human cell types can grow together and interact as tissue would. The potential of OoC in Ophthalmology, and in particular the cornea, has not yet been properly exploited. The cornea is of distinct pharmacological interest, as the majority of ocular medications are administered as an eyedrop. Current ophthalmological in vitro models are limited to just one or two layers of the cornea. In reality, the cornea is a highly complex 'organ' consisting of five layers, each of which has a very specific physiology, functional role and cellular pathways. There is an unmet need to create a complete in vitro cornea model with adequate complexity. OoC technology allows to create a true cornea-on-a-chip including every corneal layer, mimicking the natural state as close as possible from the anterior chamber all the way through to the epithelium at an air-liquid interface, just like the surface of our eyes. The transparency of the cornea results from the complex interplay between the cells and the surrounding supporting structures. When one of the layers is compromised, it directly affects the integrity of the corneal system, possibly resulting in cellular damage or death which in turn directly impacts vision. Each layer of the cornea plays a role in the drug absorption process. The epithelial layer of the cornea is lipoidal in nature and acts as the first tissue barrier to drug absorption. On the other hand, the stroma is hydrophilic in nature and comprises 90% of the corneal thickness. Endothelium is the innermost layer separating barrier between the stroma and aqueous humour. This layer helps to maintain the corneal transparency due to its pump-and-leak mechanism that keeps the stroma in a relatively dehydrated state. In addition to difficulties related to the absorption of the drugs, metabolization through corneal enzymes also reduces drug bioavailability. The joined action of the three corneal layers maintains homeostasis and thus transparency. The drugs applied to treat eye-related conditions as well as those applied post-operatively (hypotensive drops, antibiotics, mydriatics and anti-inflammatory drugs) are applied topically and have to travel through the cornea where they could cause off-target damage. Therefore, the cornea model envisioned in this project includes the three main corneal layers: epithelium, stroma and endothelium. This is markedly different to existing in vitro models where mostly only the epithelium and in very few cases a part of the stroma is included. The aim of the project is to deliver a proof-of-concept for the design, production and validation of a cornea-on-chip model of the complete human cornea including all cell layers, that recreates the physiological environment precisely to adequately mimic the native human cornea.

Keywords:OPHTHALMOLOGY, CORNEA, ORGAN-ON-CHIP, IN VITRO MODEL

Disciplines:Cell growth and development, Cellular interactions and extracellular matrix, Ophthalmology, Tissue engineering