The optic nerve head as a biomechanical structure: a new paradigm for understanding the role of IOP-related stress and strain in the pathophysiology of glaucomatous optic nerve head damage.

We propose here a conceptual framework for understanding the optic nerve head (ONH) as a biomechanical structure. Basic principles of biomechanical engineering are used to propose a central role for intraocular pressure (IOP)-related stress and strain in the physiology of ONH aging and the pathophysiology of glaucomatous damage. Our paradigm suggests that IOP-related stress and strain (1) are substantial within the load-bearing connective tissues of the ONH even at low levels of IOP and (2) underlie both ONH aging and the two central pathophysiologies of glaucomatous damage--mechanical failure of the connective tissues of the lamina cribrosa, scleral canal wall, and peripapillary sclera, and axonal compromise within the lamina cribrosa by a variety of mechanisms. Modeling the ONH as a biomechanical structure generates a group of testable hypotheses regarding the central mechanisms of glaucomatous damage and provides a logic for classifying the principal components of the susceptibility of an individual ONH to a given level of IOP.

Viscoelastic material properties of the peripapillary sclera in normal and early-glaucoma monkey eyes.

PURPOSE: To test the hypothesis that changes in the viscoelastic material properties of peripapillary sclera are present within monkey eyes at the onset of early experimental glaucoma detected by confocal scanning laser tomography (CSLT). METHODS: Short-term (3-9 weeks), moderate (< or =44 mm Hg) intraocular pressure (IOP) elevation was induced in one eye of each of eight male monkeys by lasering the trabecular meshwork. This procedure generated early experimental glaucoma, defined as the onset of CSLT-detected optic nerve head (ONH) surface change, in the treated eye. Scleral tensile specimens from the superior and inferior quadrants of the eight early-glaucoma eyes were subjected to uniaxial stress relaxation and tensile tests to failure and the results compared with similar data obtained in a previous study of 12 normal (nonglaucomatous) eyes. Linear viscoelastic theory was used to characterize viscoelastic material property parameters for each specimen. Differences in each parameter due to quadrant and treatment were assessed by analysis of variance (ANOVA). RESULTS: Peripapillary sclera from the early-glaucoma eyes exhibited an equilibrium modulus (7.46 +/- 1.58 MPa) that was significantly greater than that measured in normal eyes (4.94 +/- 1.22 MPa; mean +/- 95% confidence interval, P < 0.01, ANOVA). Quadrant differences were not significant for the viscoelastic parameters within each treatment group. CONCLUSIONS: The long-term viscoelastic material properties of monkey peripapillary sclera are altered by exposure to moderate, short-term, chronic IOP elevations and these alterations are present at the onset of CSLT-detected glaucomatous damage to the ONH. Damage to and/or remodeling of the extracellular matrix of these tissues may underlie these changes in scleral material properties.

Three-dimensional reconstruction of normal and early glaucoma monkey optic nerve head connective tissues.

PURPOSE: To introduce high-resolution, digital three-dimensional (3-D) reconstruction of the connective tissues of the optic nerve head (ONH). METHODS: Trephinated ONH and peripapillary sclera from both eyes of three monkeys with early glaucoma (EG; one eye normal, one eye given laser-induced EG) were embedded in paraffin and serial sectioned at 3-mum thickness from the vitreous surface through the orbital optic nerve, with the embedded tissue block face stained and imaged after each cut. Each image was aligned, and then the scleral canal wall, sclera, border tissue of Elschnig, Bruch's membrane, lamina cribrosa, optic nerve septa, pial sheath, and vasculature were delineated as unique objects. Delineated images were stacked, color mapped, and volume rendered and then serial sagittal and transverse digital sections of the resultant voxel geometries were viewed and measured. RESULTS: Substantial differences in the 3-D architecture of the peripapillary sclera, scleral canal wall, and lamina cribrosa were present among the three normal eyes. All three EG eyes displayed permanent posterior deformation of the central lamina cribrosa, as well as expansion of the anterior and posterior neural canal openings in comparison with their respective contralateral normal control eyes. Peripherally, whereas laminar deformation was greatest inferiorly or superiorly in all three EG eyes, statistically significant deformation was present in all four quadrants of all three eyes. CONCLUSIONS: High-resolution, digital 3-D reconstructions of the load-bearing connective tissues of the monkey ONH confirm that the ONH connective tissues are profoundly altered at the onset of detectable ONH surface change in experimental glaucoma.

Peripapillary scleral thickness in perfusion-fixed normal monkey eyes.

PURPOSE: To characterize the thickness of the peripapillary sclera in perfusion-fixed normal monkey eyes so as to build accurate computational models of intraocular pressure (IOP)-related stress and strain within these tissues. METHODS: Nine rhesus monkeys were perfusion fixed, each with one normal eye set to an IOP of 10 mm Hg by manometer. A 6-mm-diameter specimen containing the optic nerve head and peripapillary sclera was trephined from each scleral shell and cut into 4-microm serial sagittal sections across the scleral canal opening, either horizontally (four eyes) or vertically (five eyes). The thickness of the peripapillary sclera was measured on every 24th section at 100-microm intervals from the posterior scleral canal opening (PSCO) to the peripheral edge of the specimen. The data were pooled by quadrant (superior, inferior, nasal, and temporal), regions within each quadrant, and distance from the PSCO, overall and for individual eyes, and subjected to analysis of variance. RESULTS: In terms of distance from the PSCO, the peripapillary sclera was thinnest nearest the PSCO (201 microm, nasal; 201 microm, temporal; 240 microm, inferior; 249 microm, superior), thickened progressively to a maximum in the midperiphery approximately 600 to 1000 microm from the PSCO (326 microm, nasal; 415 microm, superior; 420 microm, temporal; 422 microm, inferior), and thinned again peripherally in all quadrants. The peripapillary sclera was thinner in the nasal quadrant when compared with the other quadrants superiorly, inferiorly, and temporally (central region means of 291 microm, nasal; 369 microm, superior; 372 microm, inferior; and 369 microm, temporal; P < 0.0001). CONCLUSIONS: In the normal monkey eye, peripapillary scleral thickness varies significantly with distance from the posterior scleral canal opening and is thinner in the nasal quadrant than in the other quadrants. These differences are substantial and are likely to affect the magnitude of IOP-related stress and strain within these tissues for a given level of IOP.

Deformation of the lamina cribrosa and anterior scleral canal wall in early experimental glaucoma.

PURPOSE: To test the hypothesis that pathophysiologic deformation of the lamina cribrosa and anterior scleral canal wall underlies the onset of confocal scanning laser tomography (CSLT)-detected optic nerve head (ONH) surface change in early experimental glaucoma. METHODS: Both eyes of four normal (two normal eyes) monkeys and four with early glaucoma (one eye with laser-induced IOP elevation, observed until the onset of CSLT-detected ONH surface change) were enucleated immediately after death and immersion fixed at IOP 0 mm Hg. In an additional four normal monkeys and five with early glaucoma, both eyes were cannulated, and IOP set to 10 mm Hg in one normal eye and either 30 or 45 mm Hg in the other (normal or early-glaucoma) eye. After 15 to 80 minutes of acute IOP elevation, these nine monkeys were perfusion-fixed. Within images of serial sagittal sections of the ONH tissues in all 17 monkeys, anterior lamina cribrosa position, laminar thickness, and scleral canal diameter were measured. For each parameter, differences between the two eyes of each monkey and between treatment groups were assessed by ANOVA. RESULTS: Within the eyes of the eight monkeys with IOP 0 mm Hg, the lamina cribrosa was posteriorly displaced and thicker and the scleral canal was enlarged at Bruch's membrane and at the anterior laminar insertion in the early-glaucoma eyes compared with the contralateral normal eyes (plastic deformation). Within the high-IOP normal eyes, the lamina cribrosa was posteriorly displaced compared with that in the low-IOP normal eyes, but there were no significant differences in laminar thickness or scleral canal diameter (normal compliance). Within the high-IOP early-glaucoma eyes, the lamina cribrosa was posteriorly displaced and thicker and the scleral canal enlarged, compared with both low-IOP normal eyes and high-IOP normal eyes (hypercompliant deformation). Differences in laminar position between the high-IOP early-glaucoma eyes and the contralateral low-IOP normal eyes (hypercompliant plus plastic deformation) were more than eight times greater than the differences between the high-IOP normal eyes and the contralateral low-IOP normal eyes (normal compliance). CONCLUSIONS: Both plastic (permanent) and hypercompliant deformation of the lamina cribrosa and anterior scleral canal wall are present in young adult monkey eyes with early experimental glaucoma. These findings suggest that damage to the ONH connective tissues occurs early in the monkey model of experimental glaucoma.

Remodeling of the connective tissue microarchitecture of the lamina cribrosa in early experimental glaucoma.

PURPOSE: To characterize the trabeculated connective tissue microarchitecture of the lamina cribrosa (LC) in terms of total connective tissue volume (CTV), connective tissue volume fraction (CTVF), predominant beam orientation, and material anisotropy in monkeys with early experimental glaucoma (EG). METHODS: The optic nerve heads from three monkeys with unilateral EG and four bilaterally normal monkeys were three dimensionally reconstructed from tissues perfusion fixed at an intraocular pressure of 10 mm Hg. A three-dimensional segmentation algorithm was used to extract a binary, voxel-based representation of the porous LC connective tissue microstructure that was regionalized into 45 subvolumes, and the following quantities were calculated: total CTV within the LC, mean and regional CTVF, regional predominant beam orientation, and mean and regional material anisotropy. RESULTS: Regional variation within the laminar microstructure was considerable within the normal eyes of all monkeys. The laminar connective tissue was generally most dense in the central and superior regions for the paired normal eyes, and laminar beams were radially oriented at the periphery for all eyes considered. CTV increased substantially in EG eyes compared with contralateral normal eyes (82%, 44%, 45% increases; P<0.05), but average CTVF changed little (-7%, 1%, and -2% in the EG eyes). There were more laminar beams through the thickness of the LC in the EG eyes than in the normal controls (46%, 18%, 17% increases). CONCLUSIONS: The substantial increase in laminar CTV with little change in CTVF suggests that significant alterations in connective and nonconnective tissue components in the laminar region occur in the early stages of glaucomatous damage.

The biomechanical effects of kyphoplasty on treated and adjacent nontreated vertebral bodies.

It remains unclear whether adjacent vertebral body fractures are related to the natural progression of osteoporosis or if adjacent fractures are a consequence of augmentation with bone cement. Experimental or computational studies have not completely addressed the biomechanical effects of kyphoplasty on adjacent levels immediately following augmentation. This study presents a validated two-functional spinal unit (FSU) T12-L2 finite element model with a simulated kyphoplasty augmentation in L1 to predict stresses and strains within the bone cement and bone of the treated and adjacent nontreated vertebral bodies. The findings from this multiple-FSU study and a recent retrospective clinical study suggest that changes in stresses and strains in levels adjacent to a kyphoplasty-treated level are minimal. Furthermore, the stress and strain levels found in the treated levels are less than injury tolerance limits of cancellous and cortical bone. Therefore, subsequent adjacent level fractures may be related to the underlying etiology (weakening of the bone) rather than the surgical intervention.

Viscoelastic characterization of peripapillary sclera: material properties by quadrant in rabbit and monkey eyes.

In this report we characterize the viscoelastic material properties of peripapillary sclera from the four quadrants surrounding the optic nerve head in both rabbit and monkey eyes. Scleral tensile specimens harvested from each quadrant were subjected to uniaxial stress relaxation and tensile ramp to failure tests. Linear viscoelastic theory, coupled with a spectral reduced relaxation function, was employed to characterize the viscoelastic properties of the tissues. We detected no differences in the stress-strain curves of specimens from the four quadrants surrounding the optic nerve head (ONH) below a strain of 4 percent in either the rabbit or monkey. While the peripapillary sclera from monkey eyes is significantly stiffer (both instantaneously and in equilibrium) and relaxes more slowly than that from rabbits, we detected no differences in the viscoelastic material properties (tested at strains of 0-1 percent) of sclera from the four quadrants surrounding the ONH within either species group.