Intracameral injection of cross‐linking hydrogel polymer as an animal model of IOP increase

Abstract

AbstractGlaucoma is a multifactorial neurodegenerative disease that leads to the progressive loss of retinal ganglion cells (RGCs) and their axons resulting in visual field damage and retinal and optic nerve head changes. Progression is generally slow but, in some patients, can lead to a ‘catastrophic’ reduction of visual function and in advanced cases may lead to blindness. Glaucoma is, in fact, the leading cause of irreversible blindness worldwide.Finding a model of retinal ganglion cell (RGC) loss or experimental glaucoma which accurately mimics human disease has been a challenge for researchers. There have been many attempts to produce a model of studying RGC pathophysiology or death longitudinally to study pharmacological treatments or neuroprotective interventions. There are many methods, both acute and chronic, that have been used to induce retinal ganglion cell death. Some methods made a direct injury to the optic nerve which causes rapid RGC death, while others are models try to increase the IOP with mechanical damage or injection of different agents into the anterior chamber to block aqueous humour outflow.Several models of chronic glaucoma, primarily in non‐human primates and rodents, in which IOP is elevated has been described. However, most of these animal models due to the opacification of the ocular medias as a result of the inflammation or intraocular pression increase only allow to perform a single time point for many different time ex vivo analysis of the RGCs. So, longitudinal changes in the number of RGCs in the same animal can only be performed in vivo. This is an important way to remove the between‐subject variability, but any aging effects will be compounded to those due to disease progression.A novel glaucoma model using a cross‐linking polymer result in a consistent and sustained elevation of IOP with preservation of optical media clarity for long term.This model is based on in situ temperature sensitive cross‐linking of a mixture of two components (hyaluronic acid functionalized with vinyl sulfone (HA‐VS) and thiol groups (HA‐SH)). When the mixture is injected into the anterior chamber, the higher temperature of aqueous humour compared to air causes the gel to solidify within the anterior chamber angle thereby blocking aqueous outflow through the trabecular meshwork and increasing the IOP. Furthermore, the hydrogel is localized to the anterior chamber angle with no noticeable media opacities, thereby allowing repeated in vivo imaging.It has been shown that the increased IOP and the optical media clarity produced in this animal model of glaucoma allows for in vivo study with the Confocal Scanning Laser Ophthalmoscope of the density and structural loss of RGCs, as well as functional loss of RGCs with electroretinography for more than 4 weeks after the hydrogel injection.