Mechanical environment of the optic nerve head in glaucoma

Abstract

The optic nerve head (ONH) is of particular interest from a biomechanical perspective because it is a weak spot within an otherwise strong corneo-scleral envelope. The lamina cribrosa provides structural and functional support to the retinal ganglion cell axons as they pass from the relatively high-pressure environment in the eye to a low-pressure region in the retrobulbar cerebrospinal space. To protect the retinal ganglion cell axons within this unique environment, the lamina cribrosa in higher primates has developed into a complex structure composed of a three-dimensional network of flexible beams of connective tissue. The ONH is nourished by the short posterior ciliary arteries, which penetrate the immediate peripapillary sclera to feed capillaries contained within the laminar beams. This intrascleral and intralaminar vasculature is unique in that it is encased in load-bearing connective tissue, either within the scleral wall adjacent to the lamina cribrosa, or within the laminar beams themselves. Glaucoma is a multifactorial disease, and we believe that biomechanics not only determines the mechanical environment in the ONH, but also mediates IOP-related reductions in blood flow and cellular responses through various pathways. Our current understanding of the mechanical environment of the ONH is described, with particular emphasis on the influence of biomechanics in glaucoma.

Figures

Figure 1. The optic nerve head (ONH) is a three-dimensional (3D) structure comprised of multiple interactive tissue systems that exist on different scales. This complexity has been a formidable deterrent to characterizing its mechanical environment

(A) While clinicians are familiar with the clinically visible surface of the optic nerve head (referred to as the optic disc), in fact the ONH (B) is a dynamic, 3D structure (seen here in an illustrated sectional view) in which the retinal ganglion cell (RGC) axons in bundles (white) surrounded by glial columns (red), pass through the connective tissue beams of the lamina cribrosa (light blue), isolated following trypsin digestion in an scanning electron micrograph (SEM) of the scleral canal in (C). The blood supply for the connective tissues of the lamina cribrosa (D) derives from the posterior ciliary arteries and the circle of Zinn-Haller (Z-H). (E-F) The relationship of the laminar beams to the axon bundles is shown in schematic form in (E). (F) Individual beams of the lamina cribrosa are lined by astrocytes. Together they provide structural and metabolic support for the adjacent axon bundles. Within the lamina, the RGC axons have no direct blood supply. Axonal nutrition requires diffusion of nutrients from the laminar capillaries (solid red), across the endothelial and pericyte basement membranes, through the extracellular matrix (ECM) of the laminar beam (stippled), across the basement membranes of the astrocytes (thick black), into the astrocytes (yellow), and across their processes (not shown) to the adjacent axons (vertical lines). Chronic age-related changes in the endothelial cell and astrocyte basement membranes, as well as intraocular pressure (IOP)-induced changes in the laminar ECM and astrocyte basement membranes may diminish nutrient diffusion to the axons in the presence of a stable level of laminar capillary volume flow. In advanced glaucoma, the connective tissues of the normal lamina cribrosa (sagittal view of the center of the ONH; vitreous above, orbital optic nerve below), G) remodel and restructure into a cupped and excavated configuration (H). (B) Reprinted with permission from Doug Anderson; (C) reprinted with permission from Quigley HA; (D) reprinted with permission from Cioffi GA; (E) reprinted with permission from Quigley HA; (F) reprinted with permission from Morrison JC (G, H) Courtesy of Harry A. Quigley, MD.

Figure 2. IOP-related stress and strain are a constant presence within the ONH at all levels of IOP

In a biomechanical paradigm, IOP-related strain influences the ONH connective tissues and the volume flow of blood (primarily), and the delivery of nutrients (secondarily) through chronic alterations in connective tissue stiffness and diffusion properties (explained in Figure 1). Non-IOP related effects such as auto-immune or inflammatory insults (yellow) and retrobulbar determinants of ocular blood flow (red) can primarily damage the ONH connective tissues and/or axons, leaving them vulnerable to secondary damage by IOP-related mechanisms at normal or elevated levels of IOP. (Based in part on Fig. 5, Journal of Glaucoma Editorial, in press)

Figure 3. Normal and shear components of stress and strain

(A) The normal tensile and compressive stresses acting on a small square in the manner shown will act to elongate the region in one direction and compress it in the other. (B) The shear stresses acting on a similar region will act to distort the shape of the region.

Figure 4. The material properties of the peripapillary sclera are influenced by nonlinearity and collagen fiber orientation (anisotropy)

Separate from its thickness, the behavior of the sclera is governed by its material properties, which in turn are influenced by nonlinearity and fiber orientation. (A) Nonlinearity is an engineering term for tissues or structures whose material properties are altered by loading. Figure A demonstrates that the sclera becomes stiffer as it is loaded uniaxially (in one direction). In the case of the sclera, this is likely due to the fact collagen fibers embedded within the surrounding ground matrix start out crimped and progressively straighten as the load is increased. This conformational change in the fibrils accounts for the transition from an initially compliant, nonlinear response to a stiffened linear response as IOP increases. (B) Apart from nonlinearity, collagen fiber orientation (anisotropy) within the sclera strongly influences its mechanical behavior. Fiber orientation can be totally random (isotropic - not shown) or have a principal direction (anisotropic – 3 idealized cases shown). Finite element (FE) models of an idealized posterior pole with principal collagen fiber orientation in the circumferential, helicoidal, and longitudinal directions are shown. As the displacement plots show, the underlying fiber orientation can have profound effects on the deformation that occurs for a given IOP. Note that the displacement scale is exaggerated for illustrative purposes. (Figure courtesy of Michael Girard)

Figure 5. The thickness of the peripapillary sclera, and the size and shape of the scleral canal influence the magnitude and distribution of IOP-related stress within the peripapillary sclera

Stress plots within 3D biomechanical models of the posterior sclera and ONH demonstrate that stress concentrates around a defect (scleral canal) in a pressure vessel (eye) and varies according to the geometry of the peripapillary sclera and scleral canal. The idealized model in (A) shows the stress concentration around a circular canal in a perfectly spherical pressure vessel with uniform wall thickness (the ONH has been removed from these images for visualization purposes). The model in (B) shows the IOP-related stress concentration around an anatomically shaped scleral canal with realistic variation in peripapillary scleral thickness. In this case, the highest stresses (red) occur where the sclera is thinnest and the lowest stresses (blue) occur where the sclera is thickest, and also tend to concentrate around areas of the scleral canal with the smallest radius of curvature. The response of the sclera to this load is determined by its structural stiffness, which is the combination of geometry (how much tissue is bearing the load) and material properties (how rigid or compliant is the tissue).

Figure 6. In-wall stress engendered by IOP loading

In an idealized spherical shell, the majority of the stress generated by IOP is transferred into a hoop stress borne within the thickness of the wall. Laplace's Law, which relates the in-wall hoop stress to the internal pressure, is only applicable to spherical pressure vessels with isotropic material properties and uniform wall thickness, and can only be used to calculate very rough estimates of hoop stress in actual eyes. In pressure vessel geometries like the eye, with variable wall thickness, aspherical shape, and anisotropic material properties, the hoop stress may vary substantially by location.

Figure 7. Stress, relative to IOP (red arrows) in the lamina cribrosa (light green) and peripapillary sclera (grey) engendered by IOP loading

Cut-away diagram of IOP-induced stress in an idealized spherical scleral shell with a circular scleral canal spanned by a more compliant lamina cribrosa. In this case, the majority of the stress generated by IOP (red arrows) is transferred into a hoop stress borne within the thickness of the sclera and lamina (blue arrows) that is concentrated circumferentially around the scleral canal (green arrows). Note that the difference between IOP (red arrows) and the retrolaminar cerebrospinal fluid pressure (pink arrows) is the translaminar pressure gradient that generates both a net posterior force on the surface of the lamina and a hydrostatic pressure gradient within the neural and connective tissues of the pre-laminar and laminar regions. Most importantly, note that the in-plane hoop stress transferred to the lamina from the sclera is much larger than stress induced by the translaminar pressure gradient.

Figure 8. There are two components of acute IOP-induced ONH deformation in normal and early glaucoma eyes

(A) Sagittal section diagram of the ONH, showing the peripapillary sclera (hatched) and the lamina cribrosa for normal (upper) and early glaucoma (lower) eyes. Note that the early glaucoma eye has undergone permanent changes in ONH geometry including thickening of the lamina, posterior deformation of the lamina and peripapillary sclera, and posterior scleral canal expansion. Upon acute IOP elevation we believe two phenomena occur simultaneously and with interaction: the lamina displaces posteriorly due to the direct action of IOP (B), but much of this posterior laminar displacement is counteracted as the lamina is pulled taut by simultaneous scleral canal expansion (C). It is important to note that even though the net result of these IOP-related deformations is a small amount of posterior displacement of the lamina, substantial levels of IOP-related strain are induced in both the peripapillary sclera and lamina in this scenario.

Figure 9. Remodeling and restructuring of the ONH in early experimental glaucoma

Sagittal section diagrams of the ONH, showing the peripapillary sclera (hatched) and the lamina cribrosa for normal and early glaucoma eyes. (Left) The early glaucoma eye has undergone permanent changes in ONH geometry including thickening of the lamina, posterior deformation of the lamina and peripapillary sclera, and posterior scleral canal expansion. (Right) Recent work has also shown that although the cup deepens relative to Bruch's membrane opening (dotted orange line) as can be detected by longitudinal confocal scanning laser tomography imaging (solid brown versus dotted brown line) in early glaucoma, the prelaminar neural tissues (grey) are actually thickened (black arrows) rather than thinned. (Reprinted with permission from Yang, et al.25)

Figure 10. Progression of connective tissue morphology from normal health to early glaucoma to end-stage glaucoma

(A) Diagram of normal ONH connective tissue showing the thickness of the lamina cribrosa (x) and the in-wall hoop stress generated by IOP in the peripapillary sclera. (B) In early experimental glaucoma, our data to date suggests that rather than catastrophic failure of the laminar beams, there is permanent posterior deformation and thickening (y) of the lamina which occurs in the setting of permanent expansion of the posterior scleral canal. These changes indicate that a combination of mechanical yield and subsequent remodeling of the connective tissues occur very early in glaucoma that is not yet accompanied by physical disruption of the beams or frank excavation. (C) As the disease progresses to end-stage damage, we believe that the anterior laminar beams eventually fail, the lamina compresses (z) and scars, the laminar insertion into the sclera displaces posteriorly, and the scleral canal enlarges to the typical cupped and excavated morphology. Very little is known about the biomechanics, cellular processes, and remodeling that drives the morphological progression from the earliest detectable stage of glaucoma to end-stage damage, but it is likely that these processes continue to be driven by the distribution of IOP-related stress and strain within the connective tissues either primarily or through their effects on the capillaries contained within the laminar beams and the adjacent astrocytes. (Modified from Burgoyne, et al.8)