Scleral structure and biomechanics Boote, Craig; Sigal, Ian A.; Grytz, Rafael ...
Progress in retinal and eye research,
01/2020, Letnik:
74
Journal Article
Recenzirano
Odprti dostop
As the eye's main load-bearing connective tissue, the sclera is centrally important to vision. In addition to cooperatively maintaining refractive status with the cornea, the sclera must also provide ...stable mechanical support to vulnerable internal ocular structures such as the retina and optic nerve head. Moreover, it must achieve this under complex, dynamic loading conditions imposed by eye movements and fluid pressures. Recent years have seen significant advances in our knowledge of scleral biomechanics, its modulation with ageing and disease, and their relationship to the hierarchical structure of the collagen-rich scleral extracellular matrix (ECM) and its resident cells. This review focuses on notable recent structural and biomechanical studies, setting their findings in the context of the wider scleral literature. It reviews recent progress in the development of scattering and bioimaging methods to resolve scleral ECM structure at multiple scales. In vivo and ex vivo experimental methods to characterise scleral biomechanics are explored, along with computational techniques that combine structural and biomechanical data to simulate ocular behaviour and extract tissue material properties. Studies into alterations of scleral structure and biomechanics in myopia and glaucoma are presented, and their results reconciled with associated findings on changes in the ageing eye. Finally, new developments in scleral surgery and emerging minimally invasive therapies are highlighted that could offer new hope in the fight against escalating scleral-related vision disorder worldwide.
•Reviews the state of the art in structural, biomechanical and in silico techniques for characterising the sclera.•Presents a comprehensive view of physiological biomechanical loads on the sclera , including fluid pressures and eye movements.•Discusses recent findings on scleral changes in ageing, glaucoma and myopia.•Challenges current thinking about the relationship between scleral structure and biomechanical function.•Summarises recent therapeutic breakthroughs and predicts future areas of progress.
The purpose of this study was to leverage polarized light microscopy (PLM) to visualize the collagen fiber architecture of posterior pole and optic nerve head with micrometer-scale resolution and to ...identify and quantify major organizational components.
Eight sheep posterior poles were cryosectioned and imaged using PLM. Collagen fiber orientation was determined by using custom scripts, and the resulting orientation maps were inspected and quantified to identify major structural elements and tested for differences in mean fiber orientation and anisotropy, using linear mixed effect models.
Images revealed an intricate organization of collagen fibers in the posterior pole. In the lamina cribrosa, interweaving fibers formed large knots and wrapped around nerve fiber pores, with beam insertions into the scleral canal wall that were either narrow and straight or wide. In the peripapillary sclera, three significantly different (P < 0.0001) components were identified: fibers oriented circumferentially proximal to the canal, radially in the innermost sclera, and unaligned with interweaving fibers. The radial fibers were between 60 and 180 μm thick, extending at least 3 mm from the canal.
PLM revealed structural aspects of the lamina cribrosa and sclera that may have important biomechanical roles but that were previously unreported or not characterized quantitatively. In the lamina cribrosa, these roles included wide and narrow beam insertions and details of collagen fibers interweaving and wrapping around the pores. In the sclera, we described regions of circumferential, radial, and unaligned "random" fibers. Although there is consensus that circumferential fibers protect neural tissues by resisting canal expansion, the role of the radial fibers remains unclear.
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.
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), Bruch's 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).
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.
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.
To determine the relative strength, independently and in interaction, of the influence of factors representing the geometry and mechanical properties on the IOP-induced stresses and strains within ...the optic nerve head (ONH).
A computational model of the eye was developed such that 21 factors could be varied independently or simultaneously. A fractional factorial screening analysis was used to identify the factors and interactions with the largest influences on the lamina cribrosa (LC) and prelaminar neural tissue (PLNT).
Nine factors and their interactions accounted for the majority of the variance in the responses (between 95% and 99.8%). These factors were: the properties of the sclera (modulus, eye radius, and shell thickness), LC (modulus and radius), PLNT (modulus and compressibility), and optic nerve (modulus), and IOP. The interactions were stronger on the PLNT than on the LC (up to 16.4% and 9.0% of the response variances, respectively). No factor was the most influential on all the responses or sufficient to ensure high or low levels of strain or stress. Although the modulus of the sclera was among the most influential factors, its effects could be outweighed by other factors.
There were strong interactions between and within the geometry and mechanical properties of the tissues of the ONH. This suggests that to ascertain individual susceptibility to IOP it may be necessary to determine several properties of the eye, as well as their interactions. The influential factors and their covariances should be better characterized.
The biomechanical environment within the optic nerve head (ONH) may play a role in retinal ganglion cell loss in glaucomatous optic neuropathy. This was a systematic analysis in which finite element ...methods were used to determine which anatomic and biomechanical factors most influenced the biomechanical response of the ONH to acute changes in IOP.
Based on a previously described computational model of the eye, each of 21 input factors, representing the biomechanical properties of relevant ocular tissues, the IOP, and 14 geometric factors were independently varied. The biomechanical response of the ONH tissues was quantified through a set of 29 outcome measures, including peak and mean stress and strain within each tissue, and measures of geometric changes in ONH tissues. Input factors were ranked according to their aggregated influence on groups of outcome measures.
The five input factors that had the largest influence across all outcome measures were, in ranked order: stiffness of the sclera, radius of the eye, stiffness of the lamina cribrosa, IOP, and thickness of the scleral shell. The five least influential factors were, in reverse ranked order: retinal thickness, peripapillary rim height, cup depth, cup-to-disc ratio, and pial thickness. Factor ranks were similar for various outcome measure groups and factor ranges.
The model predicts that ONH biomechanics are strongly dependent on scleral biomechanical properties. Acute deformations of ONH tissues, and the consequent high levels of neural tissue strain, were less strongly dependent on the action of IOP directly on the internal surface of the ONH than on the indirect effects of IOP on the sclera. This suggests that interindividual variations in scleral properties could be a risk factor for the development of glaucoma. Eye size and lamina cribrosa biomechanical properties also have a strong influence on ONH biomechanics.
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Our goal was to quantify and characterize how the collagen fiber crimp waviness of the lamina cribrosa (LC) and peripapillary sclera (PPS) changes with intraocular pressure (IOP). ...Thirteen sheep (ovine) eyes were immersion and perfusion fixed while maintaining IOP at 0, 10, 15, 20, or 50 mmHg. Coronal optic nerve head (ONH) sections (30 µm) were imaged with polarized light microscopy (PLM) and analyzed for collagen fiber orientation and waviness (SD of fiber orientation). In the LC, the waviness of every LC beam was measured. In the PPS, at least 900 collagen bundles were measured per eye. Using the waviness at 50 mmHg IOP, we defined tissue-specific thresholds to determine the fraction of loaded or recruited fibers. We found that fiber waviness decreased with IOP (P < 0.001). At every IOP, the waviness of the collagen fibers, and the fraction of fibers recruited in the LC were smaller or equal than those of the PPS (P < 0.001). At 15 mmHg IOP, both LC and PPS had ¾ recruited fibers and ¼ left in reserve. The decreased waviness with IOP and associated fiber recruitment is experimental evidence of fiber-based nonlinear biomechanical behavior of the ONH. At all IOPs the PPS had an equal or larger fraction of fibers recruited than the LC. That both LC and PPS had the same fraction of recruited and reserve fibers at normal IOP suggests that this may be an optimal fraction of recruitment for healthy eyes. Whether this extends to human eyes remains unknown.
Collagen fibers exhibit a natural waviness or crimp that largely determine the nonlinear biomechanics of soft tissue. Experimental measurements of crimp morphology in the sheep eye, and how it changes with intraocular pressure (IOP), however, are exceedingly sparse. We quantified how posterior eye crimp changes with increasing IOP. We found that the lamina cribrosa and peripapillary sclera have fundamentally different crimp, and with increasing IOP, have different proportions of fibers that straighten, or get recruited, versus remaining wavy, or in reserve. Interestingly, at physiologic IOP of 15 mmHg, both tissues had about ¾ fibers recruited and ¼ fibers in reserve, indicating there may be an optimal fraction of fibers.
There is increasing clinical evidence that the eye is not only affected by intraocular pressure (IOP), but also by intracranial pressure (ICP). Both pressures meet at the optic nerve head of the eye, ...specifically the lamina cribrosa (LC). The LC is a collagenous meshwork through which all retinal ganglion cell axons pass on their way to the brain. Distortion of the LC causes a biological cascade leading to neuropathy and impaired vision in situations such as glaucoma and idiopathic intracranial hypertension. While the effect of IOP on the LC has been studied extensively, the coupled effects of IOP and ICP on the LC remain poorly understood. We investigated in-vivo the effects of IOP and ICP, controlled via cannulation of the eye and lateral ventricle in the brain, on the LC microstructure of anesthetized rhesus monkeys eyes using the Bioptigen spectral-domain optical coherence tomography (OCT) device (Research Triangle, NC). The animals were imaged with their head upright and the rest of their body lying prone on a surgical table. The LC was imaged at a variety of IOP/ICP combinations, and microstructural parameters, such as the thickness of the LC collagenous beams and diameter of the pores were analyzed. LC microstructure was confirmed by histology. We determined that LC microstructure deformed in response to both IOP and ICP changes, with significant interaction between the two. These findings emphasize the importance of considering both IOP and ICP when assessing optic nerve health.
The mechanical properties of the microstructural components of sclera are central to eye physiology and pathology. Because these parameters are extremely difficult to measure directly, they are often ...estimated using inverse-modeling matching deformations of macroscopic samples measured experimentally. Although studies of sclera microstructure show collagen fiber interweaving, current models do not account for this interweaving or the resulting fiber-fiber interactions, which might affect parameter estimates. Our goal was to test the hypothesis that constitutive parameters estimated using inverse modeling differ if models account for fiber interweaving and interactions. We developed models with non-interweaving or interweaving fibers over a wide range of volume fractions (36–91%). For each model, we estimated fiber stiffness using inverse modeling matching biaxial experimental data of human sclera. We found that interweaving increased the estimated fiber stiffness. When the collagen volume fraction was 64% or less, the stiffness of interweaving fibers was about 1.25 times that of non-interweaving fibers. For higher volume fractions, the ratio increased substantially, reaching 1.88 for a collagen volume fraction of 91%. Simulating a model (interweaving/non-interweaving) using the fiber stiffness estimated from the other model produced substantially different behavior, far from that observed experimentally. These results show that estimating microstructural component mechanical properties is highly sensitive to the assumed interwoven/non-interwoven architecture. Moreover, the results suggest that interweaving plays an important role in determining the structural stiffness of sclera, and potentially of other soft tissues in which the collagen fibers interweave.
The collagen fibers of sclera are interwoven, but numerical models do not account for this interweaving or the resulting fiber-fiber interactions. To determine if interweaving matters, we examined the differences in the constitutive model parameters estimated using inverse modeling between models with interweaving and non-interweaving fibers. We found that the estimated stiffness of the interweaving fibers was up to 1.88 times that of non-interweaving fibers, and that the estimate increased with collagen volume fraction. Our results suggest that fiber interweaving is a fundamental characteristic of connective tissues, additional to anisotropy, density and orientation. Better characterization of interweaving, and of its mechanical effects is likely central to understanding microstructure and biomechanics of sclera and other soft tissues.
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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.
The collagen fibers of the corneoscleral shell play a central role in the eye mechanical behavior. Although it is well-known that these fibers form a complex three-dimensional interwoven structure, ...biomechanical and microstructural studies often assume that the fibers are aligned in-plane with the tissues. This is convenient as it removes the out-of-plane components and allows focusing on the 2D maps of in-plane fiber organization that are often quite complex. The simplification, however, risks missing potentially important aspects of the tissue architecture and mechanics. In the cornea, for instance, fibers with high in-depth inclination have been shown to be mechanically important. Outside the cornea, the in-depth fiber orientations have not been characterized, preventing a deeper understanding of their potential roles. Our goal was to characterize in-depth collagen fiber organization over the whole corneoscleral shell. Seven sheep whole-globe axial sections from eyes fixed at an IOP of 50 mmHg were imaged using polarized light microscopy to measure collagen fiber orientations and density. In-depth fiber orientation distributions and anisotropy (degree of fiber alignment) accounting for fiber density were quantified over the whole sclera and in 15 regions: central cornea, peripheral cornea, limbus, anterior equator, equator, posterior equator, posterior sclera and peripapillary sclera on both nasal and temporal sides. Orientation distributions were fitted using a combination of a uniform distribution and a sum of π-periodic von Mises distributions, each with three parameters: primary orientation μ, fiber concentration factor k, and weighting factor a. To study the features of fibers that are not in-plane, i.e., fiber inclination, we quantified the percentage of inclined fibers and the range of inclination angles (half width at half maximum of inclination angle distribution). Our measurements showed that the fibers were not uniformly in-plane but exhibited instead a wide range of in-depth orientations, with fibers significantly more aligned in-plane in the anterior parts of the globe. We found that fitting the orientation distributions required between one and three π-periodic von Mises distributions with different primary orientations and fiber concentration factors. Regions of the posterior globe, particularly on the temporal side, had a larger percentage of inclined fibers and a larger range of inclination angles than anterior and equatorial regions. Variations of orientation distributions and anisotropies may imply varying out-of-plane tissue mechanical properties around the eye globe. Out-of-plane fibers could indicate fiber interweaving, not necessarily long, inclined fibers. Effects of small-scale fiber undulations, or crimp, were minimized by using tissues from eyes at high IOPs. These fiber features also play a role in tissue stiffness and stability and are therefore also important experimental information.
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