Changes in the biomechanical response of the optic nerve head in early experimental glaucoma

Glaucoma is a progressive degenerative disease of the eye that, among its other effects, results in extensive alterations of the connective tissues in and around the optic nerve head (ONH). In the advanced stages of glaucoma, the connective tissues of the lamina cribrosa (LC) become posteriorly displaced and excavated beneath Bruch's membrane opening (clinical “cupping”), and the laminar beam network appears compressed or collapsed.1 This change in laminar connective tissue anatomy represents a long-term remodeling process mediated by astrocytes and LC cells2–4 that can compromise axonal function and may result in blindness. Although there is still debate as to whether this remodeling process is driven by mechanical, vascular, or other factors,5,6 it is generally acknowledged that intraocular pressure (IOP) plays a central role in the disease.7–11 Various experimental animal models based on IOP elevation have been developed in attempts to better understand the tissue changes that underlie glaucoma. Of these, the monkey model of glaucoma is most used in studies of the ONH connective tissue, because the monkey has a highly developed LC that undergoes morphologic changes that are very similar to those in human glaucoma.1 Prior work with this model has shown that connective tissue changes begin very early, only weeks after the induction of sustained elevated IOP. Specifically, these changes include posterior migration of the LC surface, thickening of the LC (possibly through recruitment of the immediate retrolaminar septa into the three-dimensional [3-D] LC structure12), expansion of the scleral canal, and a marked increase in the amount of connective tissue comprising the lamina.12,13 Two of the changes that occur very early in the disease process—thickening of the LC and increase in total LC connective tissue volume—seem at odds with the longer term remodeling configuration associated with end-stage glaucoma and most likely represent a transient phase of disease progression. As such, they may provide important clues regarding the initiating events in this long-term remodeling process that eventually results in vision loss. In recent years we have proposed a biomechanical paradigm for glaucoma that integrates mechanical, vascular, and cellular influences to describe the multiple changes that occur over a lifetime within the optic nerve head (ONH) during health and disease.5,14,15 Within this paradigm, we hypothesize that IOP-related stresses and strains within the load-bearing connective tissues of the ONH play a key role in modulating local blood flow, diffusion processes, and cellular activity, such that a state of mechanical and biological homeostasis is maintained. As such, the mechanical and vascular hypotheses of glaucomatous damage become complementary rather than dichotomous, and the dynamics of the entire system as a mechanobiological entity are highlighted. We have described techniques for characterizing the microarchitecture of the LC12 and how this information can be used to computationally model the mechanical environment within the LC and peripapillary sclera by using finite element modeling.16 In the present study, we applied the same techniques to model the biomechanical response of three pairs of monkey eyes with unilateral early experimental glaucoma (EG) to acute IOP elevation. Because of the aforementioned changes in anatomy and microarchitecture of the ONH connective tissues that occur in EG, it is important to understand the concomitant changes in the IOP-related displacements, stresses, and strains that take place in these remodeled EG eyes compared with those in their contralateral normal controls. However, our modeling techniques require target deformations for each model that are ideally based on experimental data. Although there are numerous studies on IOP-related deformation of the ONH surface, there are no published data on in vivo ONH connective tissue mechanical deformation. Recent experimental data derived by using a postmortem, 3-D histomorphometric technique suggest that the LC of normal eyes can move either posteriorly or anteriorly, depending on eye-specific geometric and material property factors, and that the magnitude of this displacement is small (approximately ±7 μm).17 In EG eyes, however, determination of the LC displacement by such 3-D histomorphometric approaches is problematic because it is unclear how to separate the laminar deformation into its permanent (remodeled) and acute (mechanical) IOP-related components (Burgoyne CF, et al. IOVS 2010;51:ARVO E-Abstract 2137). In light of this uncertainty, in the present study we varied the LC material stiffness of each EG and contralateral normal eye to produce a wide range of target LC displacements, both posterior and anterior, and characterized the concomitant changes in scleral canal expansion, and stress and strain in the LC for IOP increase from 10 to 45 mm Hg.