Microstructure Motivated Growth and Remodeling of the Lamina Cribrosa in Early Glaucoma

Glaucoma is a leading cause of blindness in the world and is due to the loss of retinal ganglion cell axons. These axons deteriorate in a region in the posterior pole of the eye known as the optic nerve head (ONH). The axons pass through the lamina cribrosa (LC) as they exit the eye at the ONH. The LC is characterized by a porous, connective tissue structure composed of laminar beams. The function of the LC is unclear, but is believed to include providing mechanical support to the axons as they transition from inside the pressurized globe to the lower pressure orbital space. Early experimental glaucoma studies have shown that the LC remodels into a thicker, more posterior structure which incorporates more connective tissue after chronic IOP elevation [1,2]. The process by which this occurs is unknown. These structural changes are assumed to play an important role in the pathophysiology of the ocular disease glaucoma, where elevated IOP is known to be the most relevant risk factor.

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Biomechanics of the Posterior Pole During the Remodeling Progression From Normal to Early Experimental Glaucoma

ASME 2009 Summer Bioengineering Conference, Parts A and B ◽

10.1115/sbc2009-206518 ◽

2009 ◽

Author(s):

Ian A. Sigal ◽

Hongli Yang ◽

Michael D. Roberts ◽

Claude F. Burgoyne ◽

J. Crawford Downs

Keyword(s):

Visual Information ◽

Lamina Cribrosa ◽

Posterior Pole ◽

Glaucomatous Optic Neuropathy ◽

Retinal Ganglion ◽

Experimental Glaucoma ◽

Pass Through ◽

Mechanical Insult ◽

The Brain ◽

Connective Tissue Structure

Glaucoma is one of the leading causes of blindness worldwide. The loss of vision associated with glaucoma is due to damage to the retinal ganglion cell axons, which transmit visual information to the brain. Damage to these axons is believed to occur as the axons pass through the lamina cribrosa (LC), a connective tissue structure in the optic nerve head at the back of the eye. Elevated intraocular pressure (IOP) has been identified as the main risk factor for the development of the neuropathy, but the mechanism(s) by which a mechanical insult (elevated IOP) is translated into a biological effect (glaucomatous optic neuropathy) is not well understood.

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Early Functional Impairment in Experimental Glaucoma Is Accompanied by Disruption of the GABAergic System and Inceptive Neuroinflammation

International Journal of Molecular Sciences ◽

10.3390/ijms22147581 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7581

Author(s):

Oliver W. Gramlich ◽

Cheyanne R. Godwin ◽

David Wadkins ◽

Benjamin W. Elwood ◽

Markus H. Kuehn

Keyword(s):

Axon Guidance ◽

Gene Expression Analysis ◽

Adenoviral Vectors ◽

Significant Loss ◽

Aminobutyric Acid ◽

Complement Cascade ◽

Retinal Ganglion ◽

Functional Changes ◽

Experimental Glaucoma ◽

Iop Elevation

Glaucoma is a leading cause of irreversible blindness worldwide, and increased intraocular pressure (IOP) is a major risk factor. We aimed to determine if early functional and molecular differences in the glaucomatous retina manifest before significant retinal ganglion cell (RGC) loss is apparent. Adenoviral vectors expressing a pathogenic form of myocilin (Ad5.MYOC) were used to induce IOP elevation in C57BL/6 mice. IOP and pattern electroretinograms (pERG) were recorded, and retinas were prepared for RNA sequencing, immunohistochemistry, or to determine RGC loss. Ocular injection of Ad5.MYOC leads to reliable IOP elevation, resulting in significant loss of RGC after nine weeks. A significant decrease in the pERG amplitude was evident in eyes three weeks after IOP elevation. Retinal gene expression analysis revealed increased expression for 291 genes related to complement cascade, inflammation, and antigen presentation in hypertensive eyes. Decreased expression was found for 378 genes associated with the γ-aminobutyric acid (GABA)ergic and glutamatergic systems and axon guidance. These data suggest that early functional changes in RGC might be due to reduced GABAA receptor signaling and neuroinflammation that precedes RGC loss in this glaucoma model. These initial changes may offer new targets for early detection of glaucoma and the development of new interventions.

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Large Scale Voxel-Based Finite Element Modeling of Normal and Early Glaucomatous Monkey Lamina Cribrosa

ASME 2008 Summer Bioengineering Conference, Parts A and B ◽

10.1115/sbc2008-192984 ◽

2008 ◽

Author(s):

Sanjay Kodiyalam ◽

Michael D. Roberts ◽

Ian A. Sigal ◽

Richard T. Hart ◽

Claude F. Burgoyne ◽

...

Keyword(s):

Finite Element ◽

Intraocular Pressure ◽

Connective Tissue ◽

Large Scale ◽

Lamina Cribrosa ◽

Posterior Pole ◽

Stress And Strain ◽

Structural Support ◽

Elevated Intraocular Pressure ◽

Related Stress

Glaucoma is a leading cause of blindness worldwide. Some of the chief clinical hallmarks of glaucoma are the permanent posterior cupping of the optic nerve head, in the posterior pole of the eye, and the accompanying damage to the lamina cribrosa — the fenestrated structure of connective tissue spanning the scleral canal that provides structural support to the axon bundles passing through it. While elevated intraocular pressure (IOP) is associated with this disease, its role remains unclear. It has been hypothesized that IOP-related stress and strain within the laminar connective tissue (LCT) underlie the onset and progression of glaucoma [1] and that they may be used to predict the location of axonal insult and the pattern of damage within the LCT.

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Remodeling of the Connective Tissue Microarchitecture of the Lamina Cribrosa in Early Experimental Glaucoma

Investigative Opthalmology & Visual Science ◽

10.1167/iovs.08-1792 ◽

2009 ◽

Vol 50 (2) ◽

pp. 681 ◽

Cited By ~ 94

Author(s):

Michael D. Roberts ◽

Vicente Grau ◽

Jonathan Grimm ◽

Juan Reynaud ◽

Anthony J. Bellezza ◽

...

Keyword(s):

Connective Tissue ◽

Lamina Cribrosa ◽

Experimental Glaucoma

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Analysis of Experimental IOP-Induced Scleral Deformations at the Sub-Micrometer Scale Using Electronic Speckle Interferometry

ASME 2011 Summer Bioengineering Conference, Parts A and B ◽

10.1115/sbc2011-53633 ◽

2011 ◽

Author(s):

Massimo A. Fazio ◽

Luigi Bruno ◽

Rafael Grytz ◽

J. Crawford Downs

Keyword(s):

Visual Information ◽

Computational Models ◽

Speckle Interferometry ◽

Posterior Pole ◽

Retinal Ganglion ◽

Electronic Speckle Interferometry ◽

Ocular Biomechanics ◽

Pass Through ◽

Scleral Shell ◽

Micrometer Scale

The retinal ganglion cell axons carry visual information, and pass through the optic nerve head (ONH) as they traverse from inside the eye to the brain. The ONH is the site of axonal damage in glaucoma, the second leading cause of blindness in the world, and ONH biomechanics is hypothesized to play a crucial role in the development and progression of the disease. The load bearing tissues of the ONH insert into the surrounding sclera, which provides the boundary conditions for this important structure. It is therefore important to develop accurate experimental techniques to measure scleral shell deformations under intraocular pressure (IOP) loading that can be used to drive constitutive and computational models of scleral biomechanics. The overall goal of this project is to better understand the role of ocular biomechanics in the development of glaucoma by constructing eye-specific finite element models of the posterior pole and ONH.

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Finite Element Modeling of the Lamina Cribrosa Microarchitecture in the Normal and Early Glaucoma Monkey Optic Nerve Head

ASME 2007 Summer Bioengineering Conference ◽

10.1115/sbc2007-176193 ◽

2007 ◽

Cited By ~ 2

Author(s):

J. Crawford Downs ◽

Michael D. Roberts ◽

Claude F. Burgoyne ◽

Richard T. Hart

Keyword(s):

Optic Nerve ◽

Optic Nerve Head ◽

Nutritional Support ◽

Lamina Cribrosa ◽

Retinal Ganglion ◽

The Us ◽

Elevated Intraocular Pressure ◽

Pass Through ◽

The Brain ◽

Connective Tissue Structure

Glaucoma is the second leading cause of blindness in the US and is usually associated with elevated intraocular pressure (IOP). Glaucomatous damage is believed to occur at the optic nerve head (ONH) where the retinal ganglion cell axons pass through an opening in the back of the eye wall on their path to the brain. This opening is spanned by the lamina cribrosa, a fenestrated connective tissue structure that provides structural and nutritional support for the axons as they pass through the eye wall.

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Continuum-Level Finite Element Modeling of the Optic Nerve Head Using a Fabric Tensor Based Description of the Lamina Cribrosa

ASME 2007 Summer Bioengineering Conference ◽

10.1115/sbc2007-176656 ◽

2007 ◽

Cited By ~ 5

Author(s):

Michael D. Roberts ◽

Richard T. Hart ◽

Yi Liang ◽

Anthony J. Bellezza ◽

Claude F. Burgoyne ◽

...

Keyword(s):

Optic Nerve ◽

Optic Nerve Head ◽

Ganglion Cells ◽

Lamina Cribrosa ◽

Vision Impairment ◽

Porous Space ◽

Fabric Tensor ◽

Retinal Ganglion ◽

Pass Through ◽

Connective Tissue Structure

Glaucoma is a chronic disease of the eye that can progress to severe vision impairment or blindness if left untreated. The principal site of glaucomatous damage is believed to be within the optic nerve head (ONH) where the axons of the retinal ganglion cells pass through an opening in the back of the sclera (the eye wall) on their way to form the orbital optic nerve. This opening is spanned by the lamina cribrosa (LC), a fenestrated connective tissue structure which provides both a load bearing function for the eye as well as support (both structural and metabolic) for axonal bundles as they traverse the porous space of the LC.

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The Influence of Material Properties and Geometry on Optic Nerve Head Biomechanics

ASME 2009 Summer Bioengineering Conference, Parts A and B ◽

10.1115/sbc2009-206513 ◽

2009 ◽

Author(s):

Hongli Yang ◽

Ian A. Sigal ◽

Michael D. Roberts ◽

Claude F. Burgoyne ◽

J. Crawford Downs

Keyword(s):

Optic Nerve ◽

Optic Nerve Head ◽

Material Properties ◽

Lamina Cribrosa ◽

Stress And Strain ◽

Retinal Ganglion ◽

Biological Mechanisms ◽

The World ◽

Related Stress ◽

Pass Through

Glaucoma is the second leading cause of irreversible blindness in the world. The biological mechanisms of this disease are not well understood, and the factors contributing to its progression are not well characterized. It is generally accepted that the retinal ganglion cell axons are damaged in glaucoma as they pass through the optic nerve head (ONH). The ONH contains the lamina cribrosa (LC), a fenestrated connective tissue network that spans the scleral canal, through which the axons pass as they leave the eye. It has been postulated that intraocular pressure (IOP)-related stress and strain plays a central role in the pathophysiology of glaucoma [1], so the study of LC biomechanics is important in developing an understanding of the disease.

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