Investigation of neurodegeneration in glaucoma, a leading cause of irreversible blindness worldwide, has been obfuscated by the lack of an efficient model that provides chronic, mild to moderate elevation of intraocular pressure (IOP) with preservation of optical media clarity for long term, in vivo interrogation of the structural and functional integrity of the retinal ganglion cells (RGCs). Here, we designed and formulated an injectable hydrogel based on in situ cross-linking of hyaluronic acid functionalized with vinyl sulfone (HA-VS) and thiol groups (HA-SH). Intracameral injection of HA-VS and HA-SH in C57BL/6J mice exhibited mild to moderate elevation of IOP with daily mean IOP ranged between 14 ± 3 and 24 ± 3 mmHg, which led to progressive, regional loss of RGCs evaluated with in vivo, time-lapse confocal scanning laser ophthalmoscopy; a reduction in fractional anisotropy in the optic nerve and the optic tract projected from the eye with increased IOP in diffusion tensor magnetic resonance imaging; a decrease in positive scotopic threshold response in electroretinography; and a decline in visual acuity measured with an optokinetic virtual reality system. The proportion of RGC loss was positively associated with the age of the animals, and the levels and the duration of IOP elevation. The new glaucoma model recapitulates key characteristics of human glaucoma which is pertinent to the development and pre-clinical testing of neuroprotective and neuroregenerative therapies. Statement of Significance: A new model to study chronic neurodegeneration in glaucoma has been developed via intracameral injection of a specifically designed hyaluronic acid functionalized with vinyl sulfone and thiol groups for cross-linking. Intracameral injection of the chemically cross-linked hydrogel generates mild to moderate IOP elevation, resulting in progressive degeneration of the retinal ganglion cells, optic nerve, and optic tract, and a decline in visual function. The model recapitulates the key features of neurodegeneration in human glaucoma, which will facilitate and expedite the development of neuroprotective and neuroregenerative therapies.
Bibliographical noteFunding Information:
Funding for this work was supported by The Chinese University of Hong Kong Direct Grant 2015, National Institutes of Health [R01-EY028125], BrightFocus Foundation [G2013077 and G2016030], and Research to Prevent Blindness/Stavros Niarchos Foundation International Research Collaborators Award. C.L. Y.C. and Y. Yu have patents filed related to this study (Induction of chronic elevation of intraocular pressure with intracameral cross-linking hydrogel US 20150250815). There are no competing interests for K.C. S.N. H.M. Y. Yip, Y.VDM. T.R. J.Y. S.B. and X.C.
Funding for this work was supported by The Chinese University of Hong Kong Direct Grant 2015 , National Institutes of Health [ R01-EY028125 ], BrightFocus Foundation [ G2013077 and G2016030 ], and Research to Prevent Blindness/Stavros Niarchos Foundation International Research Collaborators Award.
- Magnetic resonance imaging
- Optokinetic response
- Retinal ganglion cells