David C. Pye

Assessment of Corneal Biomechanical Properties and Their Variation with Age

Purpose: The aim of this study was to determine the stress-strain behavior of corneal tissue and how the behavior was affected by age. Methods: Human corneal specimens ranging in age between 50 and 95 years were tested under inflation conditions to determine their stress-strain behavior. The corneas were subjected to two load rates that represent dynamic and static loading conditions. The pressure-deformation results were analyzed using shell theory to derive the stress-strain behavior. Results: The corneas demonstrated clear nonlinear behavior with an initial low stiffness stage and a final high stiffness stage. The transition between the two stages coincided with intraocular pressures between 12 and 20 mmHg. There was a considerable increase in stiffness associated with both age and load rate. Equations were derived to describe the nonlinear stress-strain relationship of corneal tissue for any age between 50 and 95 years, and these equations are presented in a form suitable for use in numerical simulations. Conclusions: The cornea demonstrates considerable stiffening with age with the behavior closely fitting an exponential power function typical of collagenous tissue. The increase in stiffness could be related to the additional age-related nonenzymatic cross-linking affecting the stromal collagen fibrils.

Determination of the modulus of elasticity of the human cornea.

PURPOSE To determine the material behavior of the human cornea in the form of simple relationships between the modulus of elasticity and intraocular pressure (IOP) and to establish the effect of age on the material behavior. METHODS Human corneal specimens with age between 50 and 95 years were tested under inflation conditions to determine their behavior. The corneas were subjected to two extreme load rates to represent dynamic and static loading conditions. The pressure-deformation results were analyzed using shell theory to derive the relationship between the modulus of elasticity and IOP. RESULTS The corneas demonstrated a nonlinear hyperelastic behavior pattern with an initial low stiffness stage and a final high stiffness stage. Despite the nonlinearity of the pressure deformation results, the relationship between the modulus of elasticity and the applied pressure was almost linear. A considerable increase was noted in the values of the modulus of elasticity associated with both age and load rate. General equations were derived to calculate the values of the secant and tangent moduli of elasticity in terms of IOP for any age greater than 50 years, and these equations are presented in a simple form suitable for use in numerical simulations. CONCLUSIONS Adequate representation of corneal material behavior is essential for the accurate predictive modeling of corneal biomechanics. The material models developed in this work could be implemented in numerical simulations of refractive surgery procedures, corneal shape changes due to contact lens wear, and other applications.

Proteases, proteolysis and inflammatory molecules in the tears of people with keratoconus

Purpose:  To investigate the expression of proteases, proteolytic activity and cytokines in the tear film of people with keratoconus.

Are proteinases the reason for keratoconus

Purpose: Keratoconus is a degenerating disease of the eye that results in an irregularly-shaped cornea. The etiology of the disease is unknown and the prognosis is difficult due to the variability in outcome. Keratoconus has been associated with eye rubbing, atopy, contact lens wear, as well as genetic conditions, such as Down’s syndrome, Ehlers-Danlos syndrome, and Marfan’s syndrome. Thinning of the cornea in keratoconus has been well studied and is documented to occur as a result of degradation of corneal collagen. The reason for this tissue degradation is unknown but has been hypothesized to be linked with proteases. Methods: This study used a literature search to review the role of proteases and inflammatory molecules in the aetiology of keratoconus. Results: Early studies demonstrated elevated levels of collagenolytic and gelatinolytic activities in laboratory cultures of keratoconic corneas. Matrix metalloproteinases (MMPs) are a family of zinc-dependent proteins that include collagenases and gelatinases. MMPs levels are altered in keratoconus corneas compared to normal corneas and the level of tissue inhibitor of metalloproteinases-1 (TIMP-1) is decreased in keratoconic corneas. Recent studies have demonstrated the involvement of Cathepsin B, G, and K in keratoconus. Although thought to be a non-inflammatory disease, inflammatory molecules, such as interleukins and tumor necrosis factor have been shown to be elevated in keratoconus, and these inflammatory molecules may mediate production and activation of proteases. Conclusions: Proteases may be implicated in keratoconus. An in-depth investigation of these proteases may help in better understanding the course of the disease.

Young's modulus in normal corneas and the effect on applanation tonometry

Objectives. To determine the statistically normal range of corneal Young’s modulus in young healthy eyes in vivo, and to establish if this variation has a clinically significant influence on intraocular pressure (IOP) measurement using applanation tonometry. Methods. Central corneal curvature, central corneal thickness (CCT), and applanation IOP (Goldmann tonometer) were measured using standard clinical techniques in one eye of 100 normal human subjects (22.0 ± 2.9 years) in vivo. The Orssengo-Pye algorithm was used to calculate the corneal Young’s modulus of these experimental subjects, and to produce a theoretical model of potential errors in Goldmann applanation tonometry estimates of IOP due to variations of Young’s modulus and CCT. Results. Corneal Young’s modulus was 0.29 ± 0.06 MPa [95% confidence interval (CI) 0.17 to 0.40 MPa]. According to the Orssengo-Pye model, the relationship between Young’s modulus and the error in applanation IOP is linear; the slope was 23 mm Hg per MPa. An increase from the minimum to the maximum value of the calculated limits of agreement (95% CI) of Young’s modulus caused a variation in applanation IOP of 5.35 mm Hg. The anticipated error at the extremes of the limits of agreement (95% CI) of CCT was similar at 4.67 mm Hg. Conclusion. Physiological variations in corneal Young’s modulus may cause clinically significant errors in Goldmann applanation tonometry estimates of IOP.

Effects of eye rubbing on the levels of protease, protease activity and cytokines in tears: relevance in keratoconus.

Proteases, protease activity and inflammatory molecules in tears have been found to be relevant in the pathogenesis of keratoconus. We sought to determine the influence of eye rubbing on protease expression, protease activity and concentration of inflammatory molecules in tears.

Diurnal variation of central corneal thickness and Goldmann applanation tonometry estimates of intraocular pressure.

PurposeTo determine whether there is a temporal relationship between the diurnal variation of central corneal thickness (CCT) and intraocular pressure (IOP) by Goldmann applanation tonometry in young normal human participants in vivo. MethodsTwenty-five eyes of 25 young healthy normal participants were examined in a prospective observational cross-sectional study. IOP, CCT and corneal curvature were measured using standard clinical techniques over a 24-hour period, and the temporal interrelationships between these parameters were examined. ResultsThe overnight change in IOP measured by Goldmann tonometry was 3.1±2.4 mm Hg (P<0.001), CCT was 20.1±10.9 μm (P=0.016), with no statistical change in central corneal curvature (0.05 mm, P=0.477, paired t test with Bonferroni correction). Both IOP and CCT were highest on awakening at 7:00 then dropped rapidly to baseline levels by 9:00 (linear mixed models), and these two parameters were highly correlated (r=0.978, P<0.001). After 9:00, there was no correlation between these parameters (r=−0.453, P=0.260). ConclusionsThe results of this study have highlighted a potential link between the diurnal variation of CCT and the accuracy of Goldmann tonometry estimates of IOP during the first 2 hours after awakening. Clinicians should be wary of using Goldmann tonometry to estimate IOP until the overnight increase in CCT has resolved.

A Clinical Description of Ocular Response Analyzer Measurements

PURPOSE To examine the interrelationships among the Ocular Response Analyzer (ORA; Reichert Ophthalmic Instruments, Buffalo, NY), Goldmann applanation tonometer (GAT), and corneal geometry measurements in a young, healthy sample. METHODS Central corneal radius, ORA, GAT, and central corneal thickness (CCT) measurements were taken in 99 subjects (age, 21 ± 2 years) who were free of ocular and systemic disease. RESULTS The mean ± SD corneal hysteresis (CH) and corneal resistance factor (CRF) were 10.4 ± 1.2 and 10.1 ± 1.5 mm Hg, respectively. The Bland-Altman 95% limits of agreement of ORA Goldmann-correlated IOP (ORAg) and ORA corneal-compensated (ORAcc) IOP with reference to GAT were -4.5 to +6.0 and -4.1 to +6.8 mm Hg, respectively. The full equations used by the ORA to calculate ORAcc and CRF were reconstructed. The statistically significant effect of CCT on GAT became redundant if CRF was included in a multivariate regression analysis. Both CH and CRF were associated with CCT (R(2) = 0.252 and 0.290, respectively). CONCLUSIONS Sample CH and CRF were consistent with those reported in the literature. ORAg and ORAcc agreed poorly with GAT. CRF appears to be at least a partial description of corneal rigidity. The ocular determinants of CH are unclear.

The effect of contact lens induced corneal edema on Goldmann applanation tonometry measurements.

AimTo determine the effect of small increases in corneal hydration on the accuracy of Goldmann applanation tonometry estimates of intraocular pressure (IOP). Materials and MethodsTwenty-five young healthy subjects presented on 3 separate days approximately 1 week apart. On 2 visits, subjects were required to wear a hydrogel contact lens with either a center thickness of 0.3 and 0.7 mm (HEMA 38% water content, parallel surface curve) in 1 eye only under closed-eye conditions for 2 hours to induce corneal swelling. The third visit acted as a control. IOP, corneal thickness, and corneal curvature were measured in both eyes before and after contact lens wear on all visits. ResultsThere was a statistically significant increase in corneal thickness of 40.2±14.4 μm (P<0.001) and 41.9±16.4 μm (P<0.001) after wearing the 0.3 and 0.7 mm thick contact lenses, respectively (2-tailed paired t test). There was an increase in IOP of 2.8±2.2 mm Hg (P<0.001) after wearing the 0.3 mm thick contact lens, and a statistically insignificant difference of 1.3±3.0 mm Hg (P=0.058) after wearing the 0.7 mm thick contact lens (2-tailed paired t test). There was a statistically significant Pearson correlation between the change in corneal thickness and the change in IOP after lens wear (r=0.500, P<0.001, 0.3 mm lens and r=0.399, P<0.001, 0.7 mm lens). The corneal hydration-induced measurement error was 0.46 mm Hg per 10 μm change in corneal thickness (0.3 mm lens) and 0.35 mm Hg per 10 μm change in corneal thickness (0.7 mm lens). ConclusionA small increase in corneal hydration and thickness may cause a clinically significant overestimation of IOP when measured using Goldmann applanation tonometry.

The effect of corneal edema on dynamic contour and goldmann tonometry.

Purpose. To determine the effect of contact lens-induced corneal edema on measurements of intraocular pressure (IOP) using the Pascal dynamic contour tonometer (DCT), compared with the Goldmann tonometer. Methods. Thirty young healthy subjects (23.0 ± 3.0 years) were recruited from the student population at the University of New South Wales. Thick hydroxyethyl methacrylate contact lenses were worn monocularly for 2 hours under closed-eye conditions to induce corneal edema via hypoxia. IOP (Goldmann and Pascal DCT), ocular pulse amplitude (OPA), and central corneal thickness (CCT) were measured in both eyes before and after lens wear. Paired t-tests, Pearson correlation, and Bland-Altman plots were used to identify changes in, and relationships between, these parameters resulting from corneal edema. Results. Lens wear resulted in statistically significant changes in CCT (+48.3 ± 14.4 &mgr;m, p < 0.001), Goldmann IOP (+1.5 ± 2.8 mm Hg, p = 0.007), and Pascal DCT IOP (−0.7 ± 1.1 mm Hg, p = 0.001) but not OPA (0.0 ± 0.3 mm Hg, p = 0.721, two-tailed paired t-test). The Pascal DCT provided IOP readings that were 1.3 ± 2.0 mm Hg higher than the Goldmann IOP readings when hydration was normal, but the Goldmann tonometer provided readings that were 0.8 ± 2.5 mm Hg higher than the Pascal DCT readings when the cornea was edematous. The variation between the two instruments was weakly correlated to the change in CCT (r = −0.261, p = 0.044). Conclusions. Contact lens-induced corneal edema caused a small underestimation error in IOP measurements by the Pascal DCT, and an overestimation error in Goldmann tonometry measurements. The OPA measurement provided by the Pascal DCT is insensitive to corneal edema-induced changes in corneal properties.