Inka Tertinegg

Modeling individual-specific human optic nerve head biomechanics. Part II: influence of material properties

Biomechanical factors acting within the optic nerve head (ONH) likely play a role in the loss of vision that occurs in glaucoma. In a companion paper (Sigal et al. 2008), we quantified the biomechanical environment within individual-specific ONH models reconstructed from human post mortem eyes. Our goal in this manuscript was to use finite element modeling to investigate the influence of tissue material properties on ONH biomechanics in these same individual-specific models. A sensitivity analysis was carried out by simulating the effects of changing intraocular pressure on ONH biomechanics as tissue mechanical properties were systematically varied over ranges reported in the literature. This procedure was repeated for each individual-specific model described in the companion paper (Sigal et al. 2008). The outcome measures of the analysis were first and third principal strains, as well as the derived quantity of maximum shear strain, in ONH tissues. Scleral stiffness had by far the largest influence in ONH biomechanics, and this result was remarkably consistent across ONH models. The stiffnesses of the lamina cribrosa and pia mater were also influential. These results are consistent with those obtained using generic ONH models. The compressibility of the pre-laminar neural tissue influenced compressive and shearing strains. Overall, tissue material properties had a much greater influence on ONH biomechanics than did tissue geometry, as assessed by comparing results between our individual-specific models. Material properties of ONH tissues, particularly of the peripapillary sclera, play a dominant role in the mechanical response of an ONH to acute changes in IOP and may be important in the pathogenesis of glaucoma. We need to better understand inter-individual differences in scleral biomechanical properties and whether they are clinically important.

Dimensions of the human sclera: thickness measurement and regional changes with axial length

Scleral thickness, especially near the region of the optic nerve head (ONH), is a potential factor of interest in the development of glaucomatous optic neuropathy. Our goal was to characterize the scleral thickness distribution and other geometric features of human eyes. Eleven enucleated human globes (7 normal and 4 ostensibly glaucomatous) were imaged using high-field microMRI, providing 80 microm isotropic resolution over the whole eye. The MRI scans were segmented to produce 3-D corneoscleral shells. Each shell was divided into 15 slices along the anterior-posterior axis of the eye, and each slice was further subdivided into the anatomical quadrants. Average thickness was measured in each region, producing 60 thickness measurements per eye. Hierarchical clustering was used to identify trends in the thickness distribution, and scleral geometric features were correlated with globe axial length. Thickness over the whole sclera was 670 +/- 80 microm (mean +/- SD; range: 564 microm-832 microm) over the 11 eyes. Maximum thickness occurred at the posterior pole of the eye, with mean thickness of 996 +/- 181 microm. Thickness decreased to a minimum at the equator, where a mean thickness of 491 +/- 91 microm was measured. Eyes with a reported history of glaucoma were found to have longer axial length, smaller ONH canal dimensions and thinner posterior sclera. Several geometrical parameters of the eye, including posterior scleral thickness, axial length, and ONH canal diameter, appear linked. Significant intra-individual and inter-individual variation in scleral thickness was evident. This may be indicative of inter-individual differences in ocular biomechanics.

Finite element modeling of the human sclera: Influence on optic nerve head biomechanics and connections with glaucoma

Scleral thickness, especially near the optic nerve head (ONH), is a potential factor of interest in the development of glaucomatous optic neuropathy. Large differences in the dimensions of the sclera, the principal load-bearing tissue of the eye, have been observed between individuals. This study aimed to characterize the effects of these differences on ONH biomechanics. Eleven enucleated human globes (7 normal and 4 ostensibly glaucomatous) were imaged using high-field microMRI and segmented to produce 3-D individual-specific corneoscleral shells. An identical, idealized ONH geometry was inserted into each shell. Finite element modeling predicted the effects of pressurizing the eyes to an IOP of 30 mmHg, with the results used to characterize the effect of inter-individual differences in scleral dimensions on the biomechanics of the ONH. Measurements of the individual-specific corneoscleral shells were used to construct a 2-D axisymmetric idealized model of the corneoscleral shell and ONH. A sensitivity analysis based on this model quantified the relative importance of different geometrical characteristics of the scleral shell on the biomechanics of the ONH. Significant variations were observed in various measures of strain in the idealized lamina cribrosa (LC) across the seven normal corneoscleral shells, implying large differences in individual biomechanics due to scleral anatomy variations alone. The sensitivity analysis revealed that scleral thickness adjacent to the ONH was responsible for the vast majority of variation. Remarkably, varying peripapilary scleral thickness over the physiologically measured range changed the peak (95th percentile) first principal strain in the LC and radial displacement of the ONH canal by an amount that was equivalent to a change in IOP of 15 mmHg. Inter-individual variations in scleral thickness, particularly peripapillary scleral thickness, can result in vastly different biomechanical responses to IOP. These differences may be significant for understanding the interactions between IOP and scleral biomechanics in the pathogenesis of glaucomatous optic neuropathy. The relationship between scleral thickness and material properties needs to be studied in human eyes.

Biaxial mechanical testing of human sclera.

The biomechanical environment of the optic nerve head (ONH), of interest in glaucoma, is strongly affected by the biomechanical properties of sclera. However, there is a paucity of information about the variation of scleral mechanical properties within eyes and between individuals. We thus used biaxial testing to measure scleral stiffness in human eyes. Ten eyes from 5 human donors (age 55.4+/-3.5 years; mean+/-SD) were obtained within 24h of death. Square scleral samples (6mm on a side) were cut from each ocular quadrant 3-9 mm from the ONH centre and were mechanically tested using a biaxial extensional tissue tester (BioTester 5000, CellScale Biomaterials Testing, Waterloo). Stress-strain data in the latitudinal (toward the poles) and longitudinal (circumferential) directions, here referred to as directions 1 and 2, were fit to the four-parameter Fung constitutive equation W=c(e(Q)-1), where Q=c(1)E(11)(2)+c(2)E(22)(2)+2c(3)E(11)E(22) and W, cs and E(ij) are the strain energy function, material parameters and Green strains, respectively. Fitted material parameters were compared between samples. The parameter c(3) ranged from 10(-7) to 10(-8), but did not contribute significantly to the accuracy of the fitting and was thus fixed at 10(-7). The products cc(1) and cc(2), measures of stiffness in the 1 and 2 directions, were 2.9+/-2.0 and 2.8+/-1.9 MPa, respectively, and were not significantly different (two-sided t-test; p=0.795). The level of anisotropy (ratio of stiffness in orthogonal directions) was 1.065+/-0.33. No statistically significant correlations between sample thickness and stiffness were found (correlation coefficients=-0.026 and -0.058 in directions 1 and 2, respectively). Human sclera showed heterogeneous, near-isotropic, nonlinear mechanical properties over the scale of our samples.

Progesterone-mediated stimulation of osteoprogenitor proliferation and differentiation in cell populations derived from adult or fetal rat bone tissue depends on the serum component of the culture media

We have shown previously that progesterone (Prog) and dexamethasone (Dex) stimulate osteoprogenitor proliferation and differentiation in cell populations derived from adult rat vertebrae and in primary cultures of fetal rat calvariae. In these two in vitro systems, osteoprogenitors can be identified by the appearance of colonies of differentiated osteoblasts producing bone (bone nodule formation). Culture conditions supporting proliferation and differentiation of osteoprogenitors include a requirement for the presence of serum in the culture media. Our major interest in the present study was to investigate whether Prog- and Dex-mediated osteoprogenitor proliferation and differentiation was observed to the same degree in different lots of fetal bovine serum (FBS). In addition, we wanted to investigate whether osteoprogenitors present in cell populations derived from fetal calvarial bone and those present in populations derived from adult vertebral bone would respond similarly under the different culture conditions. We found that, in populations derived from adult rat vertebrae, the effects of the serum component of the culture medium on the number of bone nodules induced by Prog and on the dose-dependency of the Prog effect were striking: in culture media containing the most effective serum the number of bone nodules was 22-fold higher than that in the least effective serum. In addition, Prog responses were detectable at 10−5 M only in some sera but were significant at 10−7 M in others. The effect of Dex in the adult rat vertebrae-derived populations was much less dependent on the serum used: the number of bone nodules in culture media containing the most effective serum was only 1.3 times greater than that in media containing the least effective serum. In cell populations derived from fetal calvariae, the serum dependence of the Prog response was less pronounced: a 4.3-fold increase over control was observed in the most effective serum, and a 2.4-fold increase in the least effective serum. No effects of the serum component of the culture medium on the Dex response were detectable. Thus, Prog-induced bone nodule formation appears to be strongly dependent on the particular type of FBS used for osteoprogenitors present in bone cell populations derived from adult rat vertebrae but much less so in populations obtained from fetal rat calvariae. Preliminary experiments suggest that the estrogen content of the culture media may be one of the determinants regulating Prog responsiveness of the osteoprogenitors. Dex-induced proliferation and differentiation of osteoprogenitors in bone cell populations derived from both adult rat vertebrae and fetal rat calvariae, on the other hand, did not appear to be strongly dependant on factor(s) present in the FBS component of the culture medium.

Human lamina cribrosa insertion and age.

PURPOSE To test the hypothesis that in healthy human eyes the lamina cribrosa (LC) insertion into the pia mater increases with age. METHODS The optic nerve heads (ONHs) of donor eyes fixed at either 5 or 50 mm Hg of IOP were sectioned, stained, and imaged under bright- and dark-field conditions. A 3-dimensional (3D) model of each ONH was reconstructed. From the 3D models we measured the area of LC insertion into the peripapillary scleral flange and into the pia, and computed the total area of insertion and fraction of LC inserting into the pia. Linear mixed effect models were used to determine if the measurements were associated with age or IOP. RESULTS We analyzed 21 eyes from 11 individuals between 47 and 91 years old. The LC inserted into the pia in all eyes. The fraction of LC inserting into the pia (2.2%-29.6%) had a significant decrease with age (P = 0.049), which resulted from a nonsignificant increase in the total area of LC insertion (P = 0.41) and a nonsignificant decrease in the area of LC insertion into the pia (P = 0.55). None of the measures was associated with fixation IOP (P values 0.44-0.81). Differences between fellow eyes were smaller than differences between unrelated eyes. CONCLUSIONS The LC insertion into the pia mater is common in middle-aged and older eyes, and does not increase with age. The biomechanical and vascular implications of the LC insertion into the pia mater are not well understood and should be investigated further.

MEASURING THE BIAXIAL STRESS-STRAIN CHARACTERISTICS OF HUMAN SCLERA

Glaucoma is a common ocular disease that causes irreversible loss of vision. Elevated intraocular pressure (IOP) is the primary risk factor for developing glaucoma. It is believed that increased IOP causes mechanical strain on the glial cells that support the retinal ganglion cell axons and thereby causes ganglion cell apoptosis [1,2]. This damage occurs in the optic nerve head (ONH) region of the eye, and is important for understanding ONH biomechanics.Copyright

The Effect of Nonlinear Scleral Properties on Optic Nerve Head Biomechanics

Glaucoma is a group of potentially blinding ocular diseases caused by gradual and progressive damage to the optic nerve, and is usually associated with elevated intraocular pressure (IOP) [1]. This damage occurs at the optic nerve head (ONH), the site where the optic nerve axons leave the posterior eye. IOP-related biomechanical factors are hypothesized to play a key role in the pathogenesis of glaucomatous damage [2].Copyright

Investigation of the biomechanical environment within the optic nerve head by finite element modelling

Publisher Summary This chapter aims at evaluating the role of mechanical stresses in the development of glaucomatous optic neuropathy. It uses methods, such as a simplified “generic” model of the optic nerve head was created—consisting of sclera, pre-laminar neural tissue, lamina cribrosa, and post-laminar neural tissue. The biomechanical environment is simulated using the finite element method, and results are compared with experimental measurements of pressure-induced deformation of optic nerve head tissues. The result obtained from the method is that the computed pattern of pressure-induced deformation of the anterior retinal surface is similar to that measured experimentally and the changes in optic nerve head topography as a function of pressure are similar to differences in topography between parameterized normal and glaucomatous eyes. The qualitative correspondence between results from the simplified model; experimental topographic change, and parameterized topographic change are consistent with the assumption that pressure-induced mechanical stress is related to the development of glaucomatous optic neuropathy.

Mechanics of Individual-Specific Corneoscleral Shell Models

Glaucoma is a group of diseases involving a progressive optic neuropathy of unknown etiology. It is one of the leading causes of blindness worldwide. It has been postulated that glaucomatous optic neuropathy may result from mechanical stresses on the optic nerve fibers passing through the lamina cribrosa (LC), from ischemia in the LC region, or from a combination of these two.Copyright