Building the trabecular outflow pathway on-a-chip to dissect the mechanism of aqueous outflow dysfunction in glaucoma

Brief Lay Background

Glaucoma is a collective term for a group of diseases that cause irreversible sight loss. Glaucoma affects ~80 million people globally, and with an aging population this is set to increase to 120 million people by 2040.

Glaucoma is often, although not always, caused by elevated eye pressure. Our eyes contain fluid called aqueous humour, which helps to nourish and provide energy to the eye. This fluid needs to circulate in the same way as blood does throughout the body. Elevated pressure in the eye is caused when the fluid cannot flow out of the eye as it should do.

What problem/knowledge gap does it help address

Dr Overby’s team has a theory to explain why the aqueous humour cannot flow out of the eye properly. There are two tissues that control the outflow of fluid from the eye: an inner wall of cells called Schlemm’s canal (SC) and another tissue caused the juxtacanicular trabecular meshwork (TM). It is thought that when the inner wall senses pressure it forms tiny pores to allow fluid flow, which in turn ‘funnels’ the flow of fluid through the TM.

Dr Overby’s theory is that the stiffness of the SC tissue and the amount of physical contact between cells in the SC and TM layers influences the flow of fluid out of the eye, and ultimately, eye pressure.

This PhD project aims to develop a tiny model of the SC and TM outflow structure in the eye, so that this theory can be tested in detail.

Aim of the research project

A PhD student will develop a model based on ‘organ-on-a-chip’ technology, in which cell and tissue structures are miniaturized and built on tiny circuit boards. They will then use the model to study how different factors affect fluid flow, including cell stiffness and amount of contact between SC and TM cells.

Key procedures/objectives

1. A chip will be built that is made of three parallel channels. The central channel will be filled with gel. The side channels will contain fluid that cells can grow in. The SC cells will be grown on one side of the gel and the TM cells will grow within the gel.
2. The PhD student will alter the number of cells, the stiffness of the gel layer and the pressure between the channels, to explore how fluid flows through the TM layer and across the SC cell ‘wall’.
3. They will also compare SC and TM cells from people with and without glaucoma, to see whether altered cell stiffness in glaucoma is responsible for restricted fluid flow out of the eye.

This award will also contribute to building capacity in glaucoma research as it will lead to a PhD for an early career researcher. 

Potential impact on people with sight loss

There are treatments approved for treating glaucoma that work by reducing the stiffness of cells to lower pressure in the eye. However, because they affect all the cells in the eye, they often cause side-effects such as red or bloodshot eyes. It would be better to reduce the stiffness only of cells involved in fluid outflow to prevent these side effects, but the first step to doing so is to fully understand the mechanisms that prevent normal fluid outflow in the eye.

This organ-on-a-chip model will help scientists understand how fluid flow in the eye is regulated, which could pave the way for new treatments. The chips will also make it possible to quickly test potential treatments for their effects on fluid flow. This is important because there are currently few appropriate models for testing large numbers of potential drugs efficiently. If successful, the organ-on-a-chip will help to speed up the drug development process for glaucoma.