J. Crawford Downs

Mechanical environment of the optic nerve head in glaucoma.

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.

Premise and Prediction—how Optic Nerve Head Biomechanics Underlies the Susceptibility and Clinical Behavior of the Aged Optic Nerve Head

We propose that age-related alterations in optic nerve head (ONH) biomechanics underlie the clinical behavior and increased susceptibility of the aged ONH to glaucomatous damage. The literature which suggests that the aged ONH is more susceptible to glaucomatous damage at all levels of intraocular pressure is reviewed. The relevant biomechanics of the aged ONH are discussed and a biomechanical explanation for why, on average, the stiffened peripapillary scleral and lamina cribrosa connective tissues of the aged eye should lead to a shallow (senile sclerotic) form of cupping is proposed. A logic for why age-related axon loss and the optic neuropathy of glaucoma in the aged eye may overlap is discussed. Finally, we argue for a need to characterize all forms of clinical cupping into prelaminar and laminar components so as to add precision to the discussion of clinical cupping which does not currently exist. Such characterization may lead to the early detection of ONH axonal and connective tissue pathology in ocular hypertension and eventually aid in the assessment of etiology in all forms of optic neuropathy including those that may be purely age-related.

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.

IOP-induced lamina cribrosa displacement and scleral canal expansion: an analysis of factor interactions using parameterized eye-specific models.

PURPOSE To study the anterior-posterior lamina cribrosa deformation (LCD) and the scleral canal expansion (SCE) produced by an increase in IOP and identify the main factors and interactions that determine these responses in the monkey. METHODS Eye-specific baseline models of the LC and sclera of both eyes of three normal monkeys were constructed. Morphing techniques were used to generate 888 models with controlled variations in LC thickness, position and modulus (stiffness), scleral thickness and modulus, and scleral canal size and eccentricity. Finite element modeling was used to simulate an increase in IOP from 10 to 15 mm Hg. A two-level, full-factorial experimental design was used to select factor combinations and to determine the sensitivity of LCD and SCE to the eight factors, independently and in interaction. RESULTS LCD was between 53.6 μm (posteriorly) and -12.9 μm (anteriorly), whereas SCE was between 0.5 and 15.2 μm (all expansions). LCD was most sensitive to laminar modulus and position (24% and 21% of the variance in LCD, respectively), whereas SCE was most sensitive to scleral modulus and thickness (46% and 36% of the variance in SCE, respectively). There were also strong interactions between factors (35% and 7% of the variance in LCD and SCE, respectively). CONCLUSIONS IOP-related LCD and SCE result from a complex combination of factors, including geometry and material properties of the LC and sclera. This work lays the foundation for interpreting the range of individual sensitivities to IOP and illustrates that predicting individual ONH response to IOP will require the measurement of multiple factors.

Correlation between Local Stress and Strain and Lamina Cribrosa Connective Tissue Volume Fraction in Normal Monkey Eyes

PURPOSE To investigate the biomechanical response to IOP elevation of normal monkey eyes using eye-specific, three-dimensional (3-D) finite element (FE) models of the ONH that incorporate lamina cribrosa (LC) microarchitectural information. METHODS A serial sectioning and episcopic imaging technique was used to reconstruct the ONH and peripapillary sclera of four pairs of eyes fixed at 10 mm Hg. FE models were generated with local LC material properties representing the connective tissue volume fraction (CTVF) and predominant LC beam orientation and used to simulate an increase in IOP from 10 to 45 mm Hg. An LC material stiffness constant was varied to assess its influence on biomechanical response. RESULTS Strains and stresses within contralateral eyes were remarkably similar in both magnitude and distribution. Strain correlated inversely, and nonlinearly, with CTVF (median, r (2) = 0.73), with tensile strains largest in the temporal region. Stress correlated linearly with CTVF (median r(2) = 0.63), with the central and superior regions bearing the highest stresses. Net average LC displacement was either posterior or anterior, depending on whether the laminar material properties were compliant or stiff. CONCLUSIONS The results show that contralateral eyes exhibit similar mechanical behavior and suggest that local mechanical stress and strain within the LC are correlate highly with local laminar CTVF. These simulations emphasize the importance of developing both high-resolution imaging of the LC microarchitecture and next-generation, deep-scanning OCT techniques to clarify the relationships between IOP-related LC displacement and CTVF-related stress and strain in the LC. Such imaging may predict sites of IOP-related damage in glaucoma.

24-Hour IOP Telemetry in the Nonhuman Primate: Implant System Performance and Initial Characterization of IOP at Multiple Timescales

PURPOSE IOP is the most common independent risk factor for development and progression of glaucoma, but very little is known about IOP dynamics. Continuous IOP telemetry was used in three nonhuman primates to characterize IOP dynamics at multiple time scales for multiple 24-hour periods. METHODS An existing implantable telemetric pressure transducer system was adapted to monitoring anterior chamber IOP. The system records 500 IOP, ECG, and body temperature measurements per second and compensates for barometric pressure in real time. The continuous IOP signal was digitally filtered for noise and dropout and reported using time-window averaging for 19, 18, and 4 24-hour periods in three animals, respectively. Those data were analyzed for a nycthemeral pattern within each animal. RESULTS Ten-minute time-window averaging for multiple 24-hour periods showed that IOP fluctuated from 7 to 14 mm Hg during the day, and those changes occurred frequently and quickly. Two-hour time-window averages of IOP for multiple 24-hour periods in three animals showed a weak nycthemeral trend, but IOP was not repeatable from day-to-day within animals. CONCLUSIONS The measured IOP was successfully measured continuously by using a new, fully implantable IOP telemetry system. IOP fluctuates as much as 10 mm Hg from day to day and hour to hour in unrestrained nonhuman primates, which indicates that snapshot IOP measurements may be inadequate to capture the true dynamic character of IOP. The distributions, magnitudes, and patterns of IOP are not reproducible from day to day within animals, but IOP tends to be slightly higher at night when IOP data are averaged across multiple 24-hour periods within animals.

Changes in the Biomechanical Response of the Optic Nerve Head in Early Experimental Glaucoma

PURPOSE To investigate the biomechanical response of the optic nerve head (ONH) connective tissues to IOP elevation in three pairs of monkey eyes in which one eye had early experimental glaucoma (EG). METHODS A serial imaging technique was used to reconstruct the ONH and peripapillary sclera of three pairs of unilateral EG eyes fixed at 10 mm Hg. Eye-specific finite element models of the posterior pole were constructed with inhomogeneous material properties defined for the lamina cribrosa (LC) based on local connective tissue volume fraction (CTVF) and predominant LC beam orientation. These models were used to simulate an IOP increase from 10 to 45 mm Hg. A laminar material constant was varied to produce a range of LC displacements and scleral canal expansions, and the associated LC stress and strain were characterized. RESULTS The models suggest that the LC of normal and EG eyes can deform posteriorly or anteriorly when the LC material stiffness is low or high, respectively. Scleral canal expansion was generally, but not always, reduced in EG eyes. Strains in the EG eye were similar to or lower than those in the contralateral eye for the same average LC displacement and increased when the LC was more plaint. Laminar stresses were consistently lower in the EG eye, regardless of LC stiffness. CONCLUSIONS Connective tissue remodeling in EG alters the biomechanical response of the LC to IOP elevation in an eye-specific manner. The models indicated that the LC tissues in EG eyes were more plaint than those in the contralateral normal eyes in two of three monkeys.

Material properties of the posterior human sclera

To characterize the material properties of posterior and peripapillary sclera from human donors, and to investigate the macro- and micro-scale strains as potential control mechanisms governing mechanical homeostasis. Posterior scleral shells from 9 human donors aged 57-90 years were subjected to IOP elevations from 5 to 45mmHg and the resulting full-field displacements were recorded using laser speckle interferometry. Eye-specific finite element models were generated based on experimentally measured scleral shell surface geometry and thickness. Inverse numerical analyses were performed to identify material parameters for each eye by matching experimental deformation measurements to model predictions using a microstructure-based constitutive formulation that incorporates the crimp response and anisotropic architecture of scleral collagen fibrils. The material property fitting produced models that fit both the overall and local deformation responses of posterior scleral shells very well. The nonlinear stiffening of the sclera with increasing IOP was well reproduced by the uncrimping of scleral collagen fibrils, and a circumferentially aligned ring of collagen fibrils around the scleral canal was predicted in all eyes. Macroscopic in-plane strains were significantly higher in peripapillary region then in the mid-periphery. In contrast, the meso- and micro-scale strains at the collagen network and collagen fibril level were not significantly different between regions. The elastic response of the posterior human sclera can be characterized by the anisotropic architecture and crimp response of scleral collagen fibrils. The similar collagen fibril strains in the peripapillary and mid-peripheral regions support the notion that the scleral collagen architecture including the circumpapillary ring of collagen fibrils evolved to establish optimal load bearing conditions at the collagen fibril level.

Age-related changes in human peripapillary scleral strain

To test the hypothesis that mechanical strain in the posterior human sclera is altered with age, 20 pairs of normal eyes from human donors aged 20 to 90 years old were inflation tested within 48-h postmortem. The intact posterior scleral shells were pressurized from 5 to 45 mmHg, while the full-field three-dimensional displacements of the scleral surface were measured using laser speckle interferometry. The full strain tensor of the outer scleral surface was calculated directly from the displacement field. Mean maximum principal (tensile) strain was computed for eight circumferential sectors (