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Comparison of Collagen Fiber Anisotropy by Scleral Region between Non-glaucoma and Glaucoma Groups, as Measured Using WAXS.
Source publication
The posterior sclera has a major biomechanical influence on the optic nerve head, and may therefore be important in glaucoma. Scleral material properties are influenced significantly by collagen fiber architecture. Here we quantitatively map fiber orientation in non-glaucoma and glaucoma posterior human sclerae.
Wide-angle x-ray scattering quantifi...
Contexts in source publication
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... minimum peripapillary anisotropy was observed in the superior-nasal quadrant in 6/7 of non-glaucoma and 4/5 of glaucoma sclerae (Fig. 6). Regional and average fiber anisotro- py did not differ significantly between non-glaucoma and glaucoma groups in the midposterior sclera (Table 2). In contrast, fiber anisotropy was significantly reduced in the superior-temporal (P < 0.01) and inferior-nasal (P < 0.05) quadrants of the peripapillary tissue in glaucoma eyes compared with non-glaucoma eyes (Table 2). ...
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... and average fiber anisotro- py did not differ significantly between non-glaucoma and glaucoma groups in the midposterior sclera (Table 2). In contrast, fiber anisotropy was significantly reduced in the superior-temporal (P < 0.01) and inferior-nasal (P < 0.05) quadrants of the peripapillary tissue in glaucoma eyes compared with non-glaucoma eyes (Table 2). Regional measures of fiber anisotropy were not statistically different between the four diabetic eyes and the eight nondiabetic eyes studied (P > 0.05). ...
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... further interesting result of the current study was that the degree of fiber anisotropy within the peripapillary ring varied markedly (up to 4-fold) with circumferential position around the scleral canal (Fig. 6), and that weakest circumferential alignment was consistently observed in the superior-nasal quadrant ( Fig. 6 and Table 2). Moreover, the multiphoton imaging we carried out revealed that this structure does not extend through the full thickness of the tissue, but instead is formed mainly by fibers lying in the mid-to-outer stroma and encompassing only approximately 50% of the total scleral thickness (Figs. 7, 8). ...
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... the context of our observation, it is interesting to note that a recent modeling study using monkey sclera has also suggested no change in bulk fiber direction between non-glaucoma and glaucoma eyes. 31 However, the present study did indicate significant regional differences in mean fiber anisotropy within the peripapillary sclera between non-glaucoma and glaucoma eyes; while, in contrast, no such differences were found in the midposterior tissue (Table 2). It is possible that these differences represent some adaptive change in response to glaucoma, or else might be baseline structural properties that associate with predisposition to glaucomatous axon damage. ...
Citations
... Remodeling of the extracellular matrix (ECM)-including collagen-also occurs at the optic nerve head (ONH), a critical juncture in glaucoma pathophysiology [12,13]. Collagen fiber density is diminished in glaucomatous lamina cribrosa [14], changing the biological and biomechanical properties of the tissue to impact retinal ganglion cell (RGC) vulnerability at ONH [15][16][17][18][19]. An interdependence exists between the sclera and lamina cribrosa; collagen fibers of the PPS intersect with collagen fibers at the border of the lamina cribrosa [20,21], together forming the ONH connective tissue framework [22]. ...
The structural and biomechanical properties of collagen-rich ocular tissues, such as the sclera, are integral to ocular function. The degradation of collagen in such tissues is associated with debilitating ophthalmic diseases such as glaucoma and myopia, which often lead to visual impairment. Collagen mimetic peptides (CMPs) have emerged as an effective treatment to repair damaged collagen in tissues of the optic projection, such as the retina and optic nerve. In this study, we used atomic force microscopy (AFM) to assess the potential of CMPs in restoring tissue stiffness in the optic nerve head (ONH), including the peripapillary sclera (PPS) and the glial lamina. Using rat ONH tissue sections, we induced collagen damage with MMP-1, followed by treatment with CMP-3 or vehicle. MMP-1 significantly reduced the Young’s modulus of both the PPS and the glial lamina, indicating tissue softening. Subsequent CMP-3 treatment partially restored tissue stiffness in both the PPS and the glial lamina. Immunohistochemical analyses revealed reduced collagen fragmentation after MMP-1 digestion in CMP-3-treated tissues compared to vehicle controls. In summary, these results demonstrate the potential of CMPs to restore collagen stiffness and structure in ONH tissues following enzymatic damage. CMPs may offer a promising therapeutic avenue for preserving vision in ocular disorders involving collagen remodeling and degradation.
... The presence of structural birefringence in the sclera is associated with factors such as collagen fibril thickness, diameter, and orientation 13,24,25 . The collagen fiber architecture of the posterior human sclera demonstrates significant anisotropy and inhomogeneity 10 . Fiber anisotropy in the peripapillary sclera is 37% higher than that in the mid-posterior sclera 10 . ...
... The collagen fiber architecture of the posterior human sclera demonstrates significant anisotropy and inhomogeneity 10 . Fiber anisotropy in the peripapillary sclera is 37% higher than that in the mid-posterior sclera 10 . The intricate nature of scleral collagen fibrils surrounding the optic disc results in a diverse composition of birefringence-derived artifacts characterized by their heterogeneity. ...
We investigated birefringence-derived artifacts that potentially mimic focal defects of the lamina cribrosa (focal LC defects) in optical coherence tomography (OCT) imaging of eyes with glaucoma. This study included 74 eyes of 48 patients with glaucoma. Five horizontal line B-scan images of the optic disc were obtained using commercial swept-source OCT. From a dataset of prototype swept-source polarization-diversity OCT, we calculated the following types of OCT images: polarization-dependent, polarization-dependent attenuation-coefficient, polarization-independent, and polarization-independent attenuation-coefficient. We assessed the commercial OCT images for the presence of birefringence-derived artifacts by comparison with the polarization-diversity OCT images. Commercial OCT showed suggestive findings of focal LC defects in 17 of 74 eyes. Reevaluation using polarization-independent OCT revealed that the focal LC defects in one of 17 eyes (5.9%) were actually birefringence-derived artifacts. This study demonstrated the existence of birefringence-derived artifacts mimicking focal LC defects in commercial OCT imaging and indicated that polarization-diversity OCT is an effective tool to evaluate the presence of these artifacts.
... This study was the first to compare organisation of the three principle cytoskeletal components in scleral fibroblasts exposed to either a physiological or pathological strain, representative of in vivo IOP experienced in scleral tissue. Whilst it has been extensively documented in human glaucoma and experimental animal models that elevated IOP disrupts the typical scleral ECM organisation [41][42][43][44][45], less is known regarding the scleral fibroblast response. Therefore, these novel findings suggest that pathological CTS, recapitulating in vitro the glaucomatous levels of IOP had a reversible and inhibitory influence on remodelling of the F-actin cytoskeletal architecture and induction of chromatin condensation, which may compromise cell behaviour and contribute to glaucomatous pathology. ...
Mechanical loading regulates the functional capabilities of the ocular system, particularly in the sclera (‘white of the eye’) – the principal load-bearing tissue of the ocular globe. Resident fibroblasts of the scleral eye wall are continuously subjected to fluctuating mechanical strains arising from eye movements, cerebrospinal fluid pressure and, most influentially, intra-ocular pressure (IOP). Whilst fibroblasts are hypothesised to actively participate in scleral biomechanics, to date limited information has been reported on how the macroscopic stresses and strains are transmitted via their cytoskeletal networks. In this study, the effect of applying either a ‘physiological load’ (simulating healthy IOP) or a ‘pathological load’ (simulating an elevated glaucomatous IOP) to bovine scleral fibroblasts, as a model of human glaucoma, was conducted to characterise cytoskeletal organisation, chromatin condensation and cell dimensions using immunofluorescence confocal microscopy. Quantification of cell parameters and cytoskeletal element anisotropy were subsequently performed using FibrilTool, and chromatin condensation parameter assessment through a bespoke MATLAB script. The novel findings suggest that physiological load-induced F-actin rearrangement is transient, whereas pathological load, recapitulating in vivo glaucomatous IOP levels, had a reversible and inhibitory influence on remodelling of the cytoskeletal architecture and, further, induction of chromatin condensation. Ultimately, this could compromise cell behaviour. These findings could provide valuable insight into the mechanism(s) used by scleral fibroblasts to mechanically adapt to support biomechanical tissue integrity, and how it could be potentially modified for therapeutic avenues targeting mechanically mediated ocular pathologies such as glaucoma.
... In addition, the scleral GAG content is varied in eye diseases and disorders such as myopia and glaucoma (Murienne et al. 2015;Norton and Rada 1995). It is noted that the orientation of collagen fibers changes because of aging, glaucoma, and myopia (Coudrillier et al. 2015;Markov et al. 2018;Pijanka et al. 2012); a numerical model such as the one that was developed here is capable of separating the effects of collagen fiber orientation and fixed charge density. In such studies, the actual fiber distribution, instead of the theoretical fiber distributions considered here, can be fed into the numerical model. ...
The sclera is a soft tissue primarily consisting of collagen fibers, elastin, and proteoglycans. The proteoglycans are composed of a core protein and negatively charged glycosaminoglycan side chains. The fixed electric charges inside the scleral extracellular matrix play a key role in its swelling and are expected to cause the tissue to deform in response to an electric field. However, the electroactive response of the sclera has not yet been investigated. The present work experimentally demonstrates that sclera behaves similar to an anionic electrosensitive hydrogel and develops a chemo-electro-mechanical (CEM) mathematical framework for its electromechanical response. In the numerical model, a hyperelastic constitutive law with distributed collagen fibers is used to capture the nonlinear mechanical properties of the sclera, and the coupled Poisson–Nernst–Planck equations represent the distribution of mobile ions throughout the domain. After calibrating the proposed numerical CEM model against the experimental measurements, we employ it to investigate the effects of different parameters on the scleral electromechanical response including the voltage and fixed charge density. The experimental and numerical findings of the present study confirm that sclera behaves as an electroactive hydrogel and provide new insight into the mechanical response of this ocular tissue.
... Indeed, previous data have demonstrated the ability of TPGS micelles loaded with NR to diffuse intact through a hyaluronic acid gel [27], possibly due to the presence of the pegylated corona [64]. The inner part of the sclera is made up of thinner and more regularly arranged collagen fibers that give rise to a more compact structure [65,66]. This compact structure, together with the tortuosity of the pores [67], makes it difficult for the micelles to quickly diffuse into the deepest sclera as evidenced by the absence of transscleral penetration of cyclosporine after 6 h of application; micelles can be slowed down or even get stuck in the sinuous and convoluted pores. ...
Cyclosporine is an immunomodulatory drug commonly used for the treatment of mild-to-severe dry eye syndrome as well as intermediate and posterior segment diseases as uveitis. The ocular administration is however hampered by its relatively high molecular weight and poor permeability across biological barriers. The aim of this work was to identify a micellar formulation with the ability to solubilize a considerable amount of cyclosporine and promote its transport across ocular barriers. Non-ionic amphiphilic polymers used for micelles preparation were tocopherol polyethylene glycol 1000 succinate (TPGS) and Solutol® HS15. Furthermore, the addition of alpha-linolenic acid was assessed. A second aim was to evaluate micelles fate in the ocular tissues (cornea and sclera) to shed light on penetration mechanisms. This was possible by extracting and quantifying both drug and polymer in the tissues, by studying TPGS hydrolysis in a bio-relevant environment and by following micelles penetration with two-photon microscopy. Furthermore, TPGS role as permeation enhancer on the cornea, with possible irreversible modifications of tissue permeability, was analyzed. Results showed that TPGS micelles (approx. 13 nm in size), loaded with 5 mg/ml of cyclosporine, promoted drug retention in both the cornea and the sclera. Data demonstrated that micelles behavior strictly depends on the tissue: micelles disruption occurs in contact with the cornea, while intact micelles diffuse in the interfibrillar pores of the sclera and form a reservoir that can sustain over time drug delivery to the deeper tissues. Finally, cornea quickly restore the barrier properties after TPGS removal from the tissue, demonstrating its potential good tolerability for ocular application.
... 63 Other studies have shown that glaucomatous eyes exhibit a lower degree of scleral anisotropy. 64 However, detailed studies would be required to determine whether the decreased anisotropy is an effect or a cause of the onset of glaucoma. Additionally, viscoelastic effects were not included. ...
Purpose: To present the cyclic strains developed in the lamina cribrosa due to the cardiac cycle-driven fluctuations in the pressure conditions around the optic nerve head. Design: Finite element analysis on 3-D models of the human eye. Methods: Varying intraocular pressure and cerebrospinal fluid pressure over a cardiac cycle were provided as boundary conditions in the finite element models. The cyclic strains generated in the lamina cribrosa were compared at differentmean intraocular pressures representing normal and pathological conditions. Results: The peak maximum principal strains varied from 0.7% to 1.4% across all cases of normal and elevated intraocular pressure, and occurred along the periphery of the lamina cribrosa. The amplitude of the cyclic strains in the lamina cribrosa increased by 3.5% from the normal case to the pathological cases. The amplitudes did not change significantly for the pathological cases with mean intraocular pressures of 21.6 mmHg, 26.6 mmHg, and 31.6 mmHg. Conclusion and future perspective: The effect of short-term pressure changes on the tissues of the optic nerve head has not been studied extensively. In vitro and ex vivo experiments can be designed based on the results of computational studies to observe the eff ect of cyclic strains on mechanosensitive cells in the optic nerve head. Furthermore, the repetitive impact of cyclic strains in the lamina cribrosa over numerous cardiac cycles gives rise to the possibility of mechanical fatigue contributing to the structural damage around the optic nerve head. A cumulative damage model can be developed based on the results of this study.
... According to the biomechanical hypothesis of glaucoma, retinal nerve fibers are damaged mainly at the scleral lamina cribrosa. Evidence is becoming more consistent in recent years that the major determinants of biomechanical properties of the optic nerve head are the biomechanical behaviors of the sclera and lamina cribrosa [123,124] Pijanka et al. [125] showed that in human eyes, fiber alignment was decreased in the superior-temporal and inferior-nasal quadrants, while it was increased in the other two quadrants. These novel findings were later validated in a contralateral eye study that demonstrated a lower fiber anisotropy in the glaucoma sclera [126] Another study that included a larger number of specimens found that, as the disease progressed from normal to glaucoma with undamaged optic nerve and then to optic nerve injury, the collagen structure of the peripapillary sclera became more uniform overall [127] In addition, there was an increase in both small-and large-diameter collagen fibrils, as well in the cross-sectional area, in bead-glaucoma mouse eyes [128]. ...
... This tendency toward stiffer mechanical performance has been observed in previous animal experiments with glaucoma [129,130] In a more detailed inflation test, by measuring the full 3D deformation field in the posterior sclera based on electronic speckle pattern interferometry, Girard et al. confirmed the increased structural stiffness of the sclera and reported a larger elastic modulus in monkey eyes with early glaucoma [81] In human eyes, the posterior scleral deformation response has been evaluated by Coudrillier et al. [68] who performed a full field analysis and showed that the pressure-strain response was stiffer in the meridional direction, while the ratio of meridional strain to circumferential strain was smaller in the peripapillary sclera of patients with glaucoma, regardless of the presence of nerve damage. These results are in agreement with the lower anisotropy in the fiber organization of various peripapillary regions [125] By fitting the surface deformation field with a hyperelastic distributed fiber model based on inverse finite element modeling, Coudrillier et al. [127] reported that the matrix shear modulus and stiffness gradually increased as the optic nerve changed from normal to glaucomatous and then to glaucoma-damaged. ...
Corneal and scleral biomechanical properties have important implications in the maintenance of normal ocular morphology and function. The cornea and sclera compose the outermost layer of the eyeball, forming a sphere with a certain degree of intraocular pressure, and are therefore under dynamic loading conditions. Recently, several major ophthalmic conditions have been shown to be linked to corneal and scleral biomechanical properties, such as ametropia, corneal pathologies, ocular surface disease, and glaucoma. A profound understanding of corneal and scleral biomechanics is essential to clarifying disease pathogenesis, improving diagnostic ability, and developing treatment strategies. This review aims to highlight the role of corneal and scleral biomechanics in ophthalmology and its clinical translation. Specifically, advances and prospects in corneal and scleral biomechanics and possible associated diseases are addressed.
... An important aspect of assessing the role of the sclera in glaucoma is better understanding scleral micro-and ultra-structure, and how they influence scleral biomechanical properties. For example, it has been long noted that the scleral canal is surrounded by a reinforcing 'ring' of collagen fibers [94][95][96], but recent imaging studies suggest that the situation is more complex [90], with collagen fibers forming a 'basket-weave' architecture around the scleral canal to protect the fragile cells of the ONH while efficiently transferring loads towards the equatorial sclera [97 98]. In addition to the role of collagen, we are coming to appreciate the role that other ECM components play in modulating scleral mechanics. ...
Purpose of review:
Biomechanics is an important aspect of the complex family of diseases known as the glaucomas. Here, we review recent studies of biomechanics in glaucoma.
Recent findings:
Several tissues have direct and/or indirect biomechanical roles in various forms of glaucoma, including the trabecular meshwork, cornea, peripapillary sclera, optic nerve head/sheath, and iris. Multiple mechanosensory mechanisms and signaling pathways continue to be identified in both the trabecular meshwork and optic nerve head. Further, the recent literature describes a variety of approaches for investigating the role of tissue biomechanics as a risk factor for glaucoma, including pathological stiffening of the trabecular meshwork, peripapillary scleral structural changes, and remodeling of the optic nerve head. Finally, there have been advances in incorporating biomechanical information in glaucoma prognoses, including corneal biomechanical parameters and iridial mechanical properties in angle-closure glaucoma.
Summary:
Biomechanics remains an active aspect of glaucoma research, with activity in both basic science and clinical translation. However, the role of biomechanics in glaucoma remains incompletely understood. Therefore, further studies are indicated to identify novel therapeutic approaches that leverage biomechanics. Importantly, clinical translation of appropriate assays of tissue biomechanical properties in glaucoma is also needed.
... The sclera has even been characterized by optomechanical birefringence (Shin et al. 2018). While there have been extensive investigations of anterior ocular tissues such as cornea (Carnell and Vito 1992;Liu and He 2009;Rahman et al. 2020), sclera Downs et al. 2005;Eilaghi et al. 2010;Elsheikh et al. 2010b;Pijanka et al. 2012;Wollensak and Spoerl 2004), and the lamina cribrosa (LC) of the optic disk (Brazile et al. 2018;Coudrillier et al. 2016;Feola et al. 2017;Midgett et al. 2020;Sigal et al. 2014), the biomechanical properties of tissues posterior to the globe have been comparatively neglected. Biomechanical properties of the bovine ON have been reported ), but human ON data are currently lacking, despite the presence of abundant connective tissue around and within the human ON that distinguishes it from other neural tissue such as brain (Karim et al. 2004). ...
... Variability of tangent moduli in the current study is in a comparable range to the data of Spoerl et al. Human peripapillary sclera consists of an annulus of predominantly circumferentially oriented fibers encircling the optic disk, as has been implemented in computational studies (Campbell et al. 2014;Coudrillier et al. 2013;Jones et al. 2015;Pijanka et al. 2012;Zhang et al. 2015). The current study directly evaluated tensile properties of peripapillary sclera in the circumferential direction. ...
... Although tangent modulus of peripapillary sclera in the 3% strain region was low, the nonlinear stiffness increased markedly with increasing strain, indicating that peripapillary sclera can absorb considerable deformational energy without failure. This high resistance to failure seems functionally appropriate, because peripapillary sclera functions as a reinforcing ring protecting the sensitive and compliant ON and LC (Campbell et al. 2014;Coudrillier et al. 2013;Jones et al. 2015;Pijanka et al. 2012;Zhang et al. 2015) against ON traction during eye movement (Clark et al. 2020;Demer 2016;Demer et al. 2017Demer et al. , 2020. It is notable that preconditioning of peripapillary sclera decreased the CV of its tangent modulus appreciably, from 1.27 to 0.42 at 3% strain, and from 1.08 to 0.40 at 7% strain. ...
The optic nerve (ON) is a recently recognized tractional load on the eye during larger horizontal eye rotations. In order to understand the mechanical behavior of the eye during adduction, it is necessary to characterize material properties of the sclera, ON, and in particular its sheath. We performed tensile loading of specimens taken from fresh postmortem human eyes to characterize the range of variation in their biomechanical properties and determine the effect of preconditioning. We fitted reduced polynomial hyperelastic models to represent the nonlinear tensile behavior of the anterior, equatorial, posterior, and peripapillary sclera, as well as the ON and its sheath. For comparison, we analyzed tangent moduli in low and high strain regions to represent stiffness. Scleral stiffness generally decreased from anterior to posterior ocular regions. The ON had the lowest tangent modulus, but was surrounded by a much stiffer sheath. The low-strain hyperelastic behaviors of adjacent anatomical regions of the ON, ON sheath, and posterior sclera were similar as appropriate to avoid discontinuities at their boundaries. Regional stiffnesses within individual eyes were moderately correlated, implying that mechanical properties in one region of an eye do not reliably reflect properties of another region of that eye, and that potentially pathological combinations could occur in an eye if regional properties are discrepant. Preconditioning modestly stiffened ocular tissues, except peripapillary sclera that softened. The nonlinear mechanical behavior of posterior ocular tissues permits their stresses to match closely at low strains, although progressively increasing strain causes particularly great stress in the peripapillary region.
... These fibers are the prominent components of extracellular matrix (ECM), which normally provides the underlying structural framework of biological tissues [5]. Alterations of collagen fibers organization parameters, specifically fiber orientation and alignment, play an integral role in many diseases including cancer [6,10,11], scaring [7], scleroderma [9], and glaucoma [8]. Thus, quantifying these parameters may be important to study the properties of healthy and diseased tissues and to develop a potential innovative diagnostic tool. ...
Collagen alignment has shown clinical significance in a variety of diseases. For instance, vulvar lichen sclerosus (VLS) is characterized by homogenization of collagen fibers with increasing risk of malignant transformation. To date, a variety of imaging techniques have been developed to visualize collagen fibers. However, few works focused on quantifying the alignment quality of collagen fiber. To assess the level of disorder of local fiber orientation, the homogeneity index (HI) based on limiting entropy is proposed as an indicator of disorder. Our proposed methods are validated by verification experiments on Poly Lactic Acid (PLA) filament phantoms with controlled alignment quality of fibers. A case study on 20 VLS tissue biopsies and 14 normal tissue biopsies shows that HI can effectively characterize VLS tissue from normal tissue (P < 0.01). The classification results are very promising with a sensitivity of 93% and a specificity of 95%, which indicated that our method can provide quantitative assessment for the alignment quality of collagen fibers in VLS tissue and aid in improving histopathological examination of VLS.
