Ian A. Sigal

Biomechanics of the optic nerve head

Biomechanical factors acting at the level of the lamina cribrosa (LC) are postulated to play a role in retinal ganglion cell dysfunction and loss in glaucoma. In support of this postulate, we now know that a number of cell types (including lamina cribrosa cells) are mechanosensitive. Here we briefly review data indicating cellular stretching, rate of stretching and substrate stiffness may be important mechanosensitivity factors in glaucoma. We then describe how experiments and finite element modeling can be used to quantify the biomechanical environment within the LC, and how this environment depends on IOP. Generic and individual-specific models both suggest that peripapillary scleral properties have a strong influence on LC biomechanics, which can be explained by the observation that scleral deformation drives much of the IOP-dependent straining of the LC. Elegant reconstructions of the LC in monkey eyes have shown that local strains experienced by LC cells depend strongly on laminar beam microarchitecture, which can lead to large local strain elevations. Further modeling, suitably informed by experiments, is needed to better understand lamina cribrosa biomechanics and how they may be involved in glaucomatous optic neuropathy.

Longitudinal change detected by spectral domain optical coherence tomography in the optic nerve head and peripapillary retina in experimental glaucoma.

PURPOSE To investigate whether longitudinal changes deep within the optic nerve head (ONH) are detectable by spectral domain optical coherence tomography (SDOCT) in experimental glaucoma (EG) and whether these changes are detectable at the onset of Heidelberg Retina Tomography (HRT; Heidelberg Engineering, Heidelberg, Germany)-defined surface topography depression. METHODS Longitudinal SDOCT imaging (Spectralis; Heidelberg Engineering) was performed in both eyes of nine rhesus macaques every 1 to 3 weeks. One eye of each underwent trabecular laser-induced IOP elevation. Four masked operators delineated internal limiting membrane (ILM), retinal nerve fiber layer (RNFL), Bruchs membrane/retinal pigment epithelium (BM/RPE), neural canal opening (NCO), and anterior lamina cribrosa surface (ALCS) by using custom software. Longitudinal changes were assessed and compared between the EG and control (nonlasered) eyes at the onset of HRT-detected surface depression (follow-up 1; [FU1]) and at the most recent image (follow-up 2; [FU2]). RESULTS Mean IOP in EG eyes was 7.1 to 24.6 mm Hg at FU1 and 13.5 to 31.9 mm Hg at FU2. In control eyes, the mean IOP was 7.2 to 12.6 mm Hg (FU1) and 8.9 to 16.0 mm Hg (FU2). At FU1, neuroretinal rim decreased and ALCS depth increased significantly (paired t-test, P < 0.01); no change in RNFL thickness was detected. At FU2, however, significant prelaminar tissue thinning, posterior displacement of NCO, and RNFL thinning were observed. CONCLUSIONS Longitudinal SDOCT imaging can detect deep ONH changes in EG eyes, the earliest of which are present at the onset of HRT-detected ONH surface height depression. These parameters represent realistic targets for SDOCT detection of glaucomatous progression in human subjects.

Chirality in Bare and Passivated Gold Nanoclusters

Detailed knowledge of the lattice structure, shape, morphology, surface structure, and bonding of bare and passivated gold clusters is fundamental to predict and understand their electronic, optical, and other physical and chemical properties. This information is essential to optimizing their utilization as novel nanocatalysts, 1 and as building-blocks of new molecular nanostructured materials, 2 with potential applications in nanoelectronics 3 and biological diagnostics. 4 An effective theoretical approach to determine gold cluster structures is to combine genetic algorithms and many-body potentials ~to perform global structural optimizations!, and first-principles density functional theory ~to confirm the energy ordering of the local minima!. Using this procedure we recently found many topologically interesting disordered gold nanoclusters with energy near or below the lowestenergy ordered isomer. 5‐ 8 The structures of these clusters

Glaucomatous Cupping Of The Lamina Cribrosa: A Review Of The Evidence For Active Progressive Remodeling As A Mechanism

The purpose of this review is to examine the literature in an attempt to elucidate a biomechanical basis for glaucomatous cupping. In particular, this work focuses on the role of biomechanics in driving connective tissue remodeling in the progression of laminar morphology from a normal state to that of an excavated glaucomatous state. While there are multiple contributing factors to the pathogenesis of glaucoma, we focus on laminar extracellular matrix (ECM) remodeling in glaucoma and the feedback mechanisms and signals that may guide progressive laminar cupping. We review the literature on the potential mechanisms of glaucomatous changes in the laminar ECM at the anatomic, structural, cellular and subcellular levels in the context of the biomechanical paradigm of glaucomatous onset and progression. Several conclusions can be drawn from this review. First, extensive remodeling of the lamina cribrosa ECM occurs in primary open angle glaucoma. Second, there is surprisingly little evidence to support acute mechanical damage to the lamina as the principal mechanism of cupping. Third, ONH astrocytes and lamina cribrosa cells can sense their mechanical environment and respond to mechanical stimuli by remodeling the ECM. Fourth, there is evidence suggesting that chronic remodeling of the lamina results in a progressive posterior migration of the laminar insertion into the canal wall, which eventually results in the posterior lamina inserting into the pia mater. Finally, modeling studies suggest that laminar remodeling may be a biomechanical feedback mechanism through which cells modify their environment in an attempt to return to a homeostatic mechanical environment. It is plausible that biomechanics-driven connective tissue remodeling is a mechanism in the progression of laminar morphology from a normal state to that of a cupped, excavated glaucomatous state.

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.

Posterior (Outward) Migration of the Lamina Cribrosa and Early Cupping in Monkey Experimental Glaucoma

PURPOSE To quantify the lamina cribrosa insertion into the peripapillary sclera and optic nerve pia in normal (N) and early experimental glaucoma (EEG) monkey eyes. METHODS Perfusion-fixed optic nerve heads (ONHs) from 21 animals were digitally reconstructed three dimensionally and delineated. Anterior Laminar Insertion Position (ALIP), Posterior Laminar Insertion Position (PLIP), Laminar Insertion Length (LIL; distance between the anterior and posterior laminar insertions), and Scleral Thickness (at the Anterior Sub-arachnoid space) were calculated for each ONH. Animals were pooled into four groups based on the kill condition (N vs. EEG) and perfusion IOP (10, 30, or 45 mm Hg) of each eye: N10-N10 (n = 6), N30/45-N10 (n = 6), EEG10-N10 (n = 3), and EEG30/45-N10 (n = 6). Glaucomatous EEG versus N eye differences in each group and each animal were required not only to achieve statistical significance (P < 0.05) but also to exceed physiologic intereye differences within the bilaterally normal groups. RESULTS ALIP was significantly posterior (outward) in the EEG compared with N10 eyes of the EEG30/45-N10 group and 5 of 9 individual EEG eyes (difference range, 12-49 μm). PLIP was significantly posterior in the EEG eyes of both EEG groups and in 6 of 9 individual EEG eyes (range, 25-83 μm). LIL ranged from 90 to 190 μm in normal eyes and was significantly increased within the EEG eyes of both EEG groups and in 7 of 9 individual EEG eyes (difference range, 30-47 μm). CONCLUSIONS Posterior migration of the lamina cribrosa is a component of early cupping in monkey EEG.

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.

Deformation of the Early Glaucomatous Monkey Optic Nerve Head Connective Tissue after Acute IOP Elevation in 3-D Histomorphometric Reconstructions

PURPOSE To retest the hypothesis that monkey ONH connective tissues become hypercompliant in early experimental glaucoma (EEG), by using 3-D histomorphometric reconstructions, and to expand the characterization of EEG connective tissue deformation to nine EEG eyes. METHODS Trephinated ONH and peripapillary sclera from both eyes of nine monkeys that were perfusion fixed, with one normal eye at IOP 10 mm Hg and the other EEG eye at 10 (n=3), 30 (n=3), or 45 (n=3) mm Hg were serial sectioned, 3-D reconstructed, 3-D delineated, and quantified with 3-D reconstruction techniques developed in prior studies by the authors. Overall, and for each monkey, intereye differences (EEG eye minus normal eye) for each parameter were calculated and compared by ANOVA. Hypercompliance in the EEG 30 and 45 eyes was assessed by ANOVA, and deformations in all nine EEG eyes were separately compared by region without regard for fixation IOP. RESULTS Hypercompliant deformation was not significant in the overall ANOVA, but was suggested in a subset of EEG 30/45 eyes. EEG eye deformations included posterior laminar deformation, neural canal expansion, lamina cribrosa thickening, and posterior (outward) bowing of the peripapillary sclera. Maximum posterior laminar deformation and scleral canal expansion co-localized to either the inferior nasal or superior temporal quadrants in the eyes with the least deformation and involved both quadrants in the eyes achieving the greatest deformation. CONCLUSIONS The data suggest that, in monkey EEG, ONH connective tissue hypercompliance may occur only in a subset of eyes and that early ONH connective tissue deformation is maximized in the superior temporal and/or inferior nasal quadrants.

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.