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Tools & Techniques Diagnostics & prognostics

Unplugging the Donut of Drainage

Malfunction in the trabecular meshwork (TM), leading to blockage of Schlemm’s canal (SC), often leads to a dangerously increased IOP in primary open angle glaucoma (POAG) – and yet we don’t even know why this problem occurs. Although surgical removal of the blockage through trabeculotomy is an option, it’s common for the blockage to reappear down the line and for IOP to jump back up. Glaucoma is already the most common cause of blindness globally and the number of people affected is projected to increase (thanks to our aging population), so we can surely no longer ignore an important question: Why does this donut shaped tissue become dysfunctional for so many people? 

It’s true that there have been plenty of attempts to investigate the root cause of this pathological factor in the past with various in vitro and animal models for glaucoma – but nothing gleaned from these studies has been effectively translated into preventing or treating the tissue malfunction. 

Put simply, we need to use modern biotechnology to create better tissues in the lab to discover exactly what is going wrong in aqueous humor drainage – and how we can fix it (1).

Unveiling the problem

Our aim, within Lisa J. Hill’s lab at the University of Birmingham, UK, is to create a human 3D model of the primary site of POAG pathology – the blockage at the juxtacanalicular TM layer and SC inner wall, to be precise – and dig into the root cause of TM dysfunction. 

The main challenge? As far as drainage systems go, the TM and SC are remarkably complex – from both a biological and mechanical perspective. It is not simply a biochemical issue (which would still not be simple), but a combination of biological, physical, and mechanical properties that affect the bulk function of the tissue.

Donut of drainage

Both the TM and SC are located at the intersection of the iris and the cornea – forming a donut shaped tissue that is supposed to mediate drainage of aqueous humor in the eye. The TM and SC meet at the endothelial membrane, a key site in the TM with three distinct layers – the uveal meshwork, the corneoscleral meshwork, and the juxtacanalicular tissue – that all work to filter and flow aqueous humor into the SC.

One aspect that has boggled my mind – and, at the same time, further inspired our research – is that the TM cells differ in architecture and functionality throughout the tissue layers; indeed, they are highly adaptable and able to alter their characteristics dependent on their physical location; the cells adopt endothelial or phagocytic like behavioral roles in the uveal and corneoscleral meshwork, but the same cells in the juxtacanalicular tissue section take on the role of fibroblast and smooth-muscle cells. It is clear that the surrounding extracellular matrix is pulling the strings and enabling the cells of the TM to become social butterflies, with their amazing plasticity and stem cell-like characteristics.

The future is 3D

There are myriad biological and physical factors that work in synchronicity to regulate fluid outflow. To develop the complexity of the TM and SC in the lab requires the adoption of tissue engineering principles to produce both biological and mechanical aspects of the human tissue. This complexity is what has taken our project from solely investigating the TM, to the co-modular culture of both TM and SC that can recreate fluid outflow regulation. The next step is to create POAG models that also assess how optic nerve and retinal ganglion cell death occurs during increased pressure scenarios.

Creating 3D, humanized in vitro models that can replicate the complexity of these tissues in a controlled, reproducible manner would allow thorough investigations into basic mechanisms of the pathological processes as well as facilitate pre-clinical drug testing. As a byproduct of developing more sophisticated models of POAG, with TM and SC endothelial co-culture, we can start to fill gaps within the understanding of fluid flow regulation and pinpoint how physical cues complement the biological outputs of these cells within the fluid outflow pathway. Crucially, it will enable us to start tackling the high levels of POAG by treating the underlying causes rather than just alleviating the symptoms. A deeper understanding of tissue functionality may also help guide us to regenerative capabilities. Wherever we end up, we hope we are able to limit the prevalence and reduce the burden of current eye diseases for patients and healthcare systems.

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  1. HC Lamont et al., “Fundamental Biomaterial Considerations in the Development of a 3D Model Representative of Primary Open Angle Glaucoma,” Bioengineering, 8, 147 (2021). PMID: 34821713.
About the Author
Hannah C. Lamont

Hannah C. Lamont is a candidate at the EPSRC-SFI Centre for Doctoral Training in Engineered Tissues for Discovery, Industry and Medicine, University of Birmingham, UK.

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