The sclera is a tough barrier that supports and anchors the more delicate intraocular structures and prevents them from sustaining injury. In fulfilling this role, the sclera is regionally compromised by the positioning of the cornea, intraocular entry and exit of important nerves and vessels, and to serve as an attachment for the extraocular muscles. Despite these regional variations in structure, the sclera must be able to control eye shape during significant events that promote deformation of the globe, such as eye movements, accommodation, and intraocular pressure fluctuations. In doing so, it ensures that vision remains stable and that the globe does not rupture.1,2 To fulfill all of these roles the mammalian sclera must have both good strength and a degree of elasticity. Furthermore, it must retain these properties while remodelling, to allow the eye to grow in proportion to its refractive power and to replace ageing or damaged extracellular matrix components. This is particularly important in ensuring that the eye remains free from significant refractive error throughout life.
The extracellular matrix and cellular constituents of the sclera contribute to the unique biomechanical environment that allows the sclera to fulfill the above requirements. Changes in scleral mechanical properties have been documented during normal ocular development, as well as in pathological conditions such as high myopia. In the case of high myopia, the mammalian sclera thins, becomes weaker and more extensible, resulting in its inability to withstand the expansive forces of intraocular pressure.3–6 Historically, these changes in scleral biomechanics have been attributed to changes in the biochemical makeup of the extracellular matrix. Although these biochemical alterations are important in defining scleral mechanical properties, this article will highlight more recent advances in our understanding of the role that the scleral cells play in detecting matrix stress and tissue contraction and, in doing so develop a model highlighting how scleral cells may contribute mechanically to the development of myopia.
Biomechanics of the Normal Sclera and Changes during Myopia Development
The sclera is a viscoelastic structure, displaying an elastic component, in that it stretches linearly under increasing load and returns to its original state when the load is reduced, and a viscosity component, which results in the sclera slowly stretching, or creeping under a constant load over time.7,8 Scleral elasticity is tested through the application of an incremental load, and the measurement of the amount of scleral extension immediately after this increment is applied (Fig. 1). Creep properties of the sclera are revealed by specialized equipment which is able to keep scleral strips under a constant load as it extends, or creeps, in response to that load (Fig. 1). Experiments have demonstrated that the biomechanical properties of the mammalian sclera vary regionally, with the posterior sclera displaying differing elasticity and creep properties compared with the equatorial regions of the sclera.3,4 Overlayed on this regional variation, is an age-dependent change in scleral biomechanical properties, with lower creep rates coinciding with the time at which adult eye size is attained.5 These data support the hypothesis that the tensile properties of the sclera, in conjunction with a normal intraocular pressure, are capable of contributing to regulation of the normal growth patterns of the eye.
Similarly, where there is abnormal ocular growth, as in myopia development, the sclera’s mechanical properties are altered. Studies of the elastic properties of the sclera in myopic eyes, showed an increase in scleral elasticity early in the development of myopia (Fig. 2).4 However, most of the difference in elasticity between myopic and normal eyes was accounted for by the change in mammalian scleral thickness (the sclera from myopic eyes is significantly thinner). Finite element modeling of the change in eye size relative to the elastic change demonstrated that this change in scleral elasticity could only account for 20% of the change in eye size. This evidence suggested that other biomechanical factors were of more importance in myopia development. Recently, several studies have reported that the mammalian sclera becomes more extensible (increased creep) in eyes developing myopia, particularly at the posterior pole of the eye (Fig. 3).5,6,9 Unlike the changes in elasticity, the altered creep properties remained a significant factor in the process of ocular enlargement, even after thickness changes in the sclera were taken into account. This finding is important as it implicates changes in the scleral matrix properties, independent of the changes in thickness of the sclera.
Factors Influencing the Biomechanical Properties of the Sclera
The mammalian sclera is a typical collagenous connective tissue, consisting of a framework of heterotypic collagen fibrils surrounded by a highly organized and complex structure of proteoglycans and glycoproteins. This collagenous extracellular matrix is enclosed in a lamellar structure of collagen fibril bundles, with the scleral cells (fibroblasts) that secrete and maintain this matrix located between the bundles.1,2 These lamellae form an interwoven mesh, resulting in the opaque appearance of the sclera (Fig. 4). In highly myopic eyes the sclera is significantly thinner, acutely so in those areas underlying a staphyloma. Ultrastructural evaluation shows a more layered, lamellar structure to the scleral collagen fibril bundles, with electron microscopic evidence of thinner collagen fibrils (Fig. 4).10–12 Although biochemical analyses of the scleral changes in myopia have been possible in postmortem human eyes,9 animal models of myopia have provided a better understanding of the mechanisms driving these changes during the development of myopia. Based on animal studies, it is hypothesized that the eye controls the scleral matrix based on the image quality falling on the retina; essentially the retina signals the sclera to weaken, or strengthen, to accelerate or slow eye growth. For example, in mammalian high myopia, this signal leads to biochemical remodelling of the scleral matrix, producing a thinner, weaker tissue.1,2
Mammalian scleral thinning is associated with a general loss of collagen and proteoglycans, in defined scleral areas (posterior pole).13,14 This demonstrates that changes in scleral biomechanics are not simply a function of tissue redistribution as the sclera stretches to accommodate the enlarging eye, but due to a physical loss of the scleral extracellular matrix. The mechanism of this collagen loss is two-fold. Firstly, the production of new collagen quickly reduces as the eye starts to develop myopia. These changes are largely a result of reduced production of type I collagen, which accounts for the vast majority of scleral collagen (approximately 99%).14–17 Secondly, existing collagen is degraded and eliminated from the scleral extracellular matrix, through increased activity of collagen-degrading enzymes (matrix metalloproteinases).18,19 The scleral proteoglycan profile follows a similar pattern in that there is reduced production of new proteoglycans, particularly the large proteoglycan aggrecan,20 in eyes developing myopia and a net reduction in proteoglycans within the scleral extracellular matrix of the myopic eye.13,21,22
Studies examining the time course of scleral changes in mammalian myopia reveal that changes in collagen fibril diameter start to occur only some time after a significant amount of myopia has developed, with an increase in the frequency of smaller diameter collagen fibrils being most apparent in the outer regions of the sclera.10–12 The reason for the delay in appearance of these smaller fibrils remains unclear. However, findings of the early stages of myopia development highlight the importance of altered expression ratios of the various fibrillar collagens (types I, V, and III),14 as well as the levels of certain small proteoglycans, such as lumican, which also interact with collagen fibrils.23
From the above overview of the biochemical and ultrastructural changes to the sclera in mammalian eyes developing myopia it will be noted these alterations are relatively well defined, with reduced collagen expression and fibril size, in addition to altered proteoglycan characteristics, producing a thinner, weaker sclera. It appears to be no accident that these changes arise around the same time as the alterations in scleral biomechanical properties. In fact, more recent studies in mammalian models of myopia have provided ample evidence that the increased tendency of the sclera to creep correlates with the onset of biochemical remodelling of the extracellular matrix of the sclera.24 Thus, it seems likely that the general tendency of matrices with less collagen or thinner collagen fibrils to creep more rapidly, coupled with the decreased negative charge density associated with the loss of proteoglycans from the sclera, make major contributions to the increased creep rate in the myopic eye (Fig. 5).25,26 Other contributory factors are alterations in the links between collagen fibrils and/or collagen fiber bundles and slippage of these fibers although further investigation is warranted.27
The discussion to date has centered on the role of extracellular matrix remodelling in determining the biomechanical response of the sclera during axial myopia development. Such evidence seems to leave little room for a role for the scleral cells in modulating tissue biomechanics, aside from modifying their gene expression patterns to regulate the biochemical remodelling itself. However, experiments assessing the in vivo scleral creep response provide evidence that scleral cells have an important role in the mechanical response of the mammalian sclera during eye growth. In such studies, intraocular pressure of the eye is manipulated in a controlled fashion, over an extended period of time, and the ocular axial length measured.28 Unlike data from the in vitro studies described earlier, changes in axial length act as a surrogate for the extensibility of the eye, and allow estimates of both the elastic and creep behavior of the eye to be determined in vivo. When intraocular pressure is increased, both avian and mammalian eyes exhibit an initial elastic response to the imposed intraocular pressure rise, followed, in the avian eye, by a gradual creep extension (Fig. 6).28 However, in the mammalian eye, this initial elastic enlargement of the eye is subsequently offset by a gradual shortening of the eye, yielding negative creep values (eye gets shorter). When the intraocular pressure was returned to normal, the eye had become shorter than its original starting value (Fig. 6). The rapidity of the shortening response (<1 h) cannot be explained in terms of scleral matrix remodelling, implicating the scleral cells themselves in the physical process of ocular shortening. Further investigation of scleral cells in the mammalian sclera via immunohistochemistry showed the sclera to contain a subset of cells which express a protein known as alpha-smooth muscle actin (α-SMA).28 This protein is typically expressed in highly contractile cells known as myofibroblasts.29 Given that α-SMA is typically found in muscles, this finding has led to the hypothesis that the scleral cells have an active role in the mechanical properties of the mammalian sclera, and that this may be of importance in a number of physiological and pathological ocular functions.
Myofibroblasts are generally defined as highly contractile cells that express the smooth muscle protein, α-SMA.30 Typically arising from fibroblast differentiation, these cells are capable of rapid contractile responses to imposed tissue stress, thus relieving tension within, and limiting expansion of, the surrounding matrix.29,31 These cells also control their local environment through remodelling of the surrounding extracellular matrix, strengthening it and relieving cellular stress.29 Myofibroblasts are important in the wound healing response, contracting wound openings and laying down scar tissue to strengthen the wound. Numerous studies have investigated the presence of these cells during the corneal wound response.32 In such instances, wounding initiates a differentiation process whereby fibroblasts alter their phenotype to form the highly contractile myofibroblast. These cells facilitate wound healing, then ‘self-destruct’ by the process of apoptosis once healing is complete.
Myofibroblasts in the Sclera
Characterization of the myofibroblast population of the sclera has thus far been limited. However, the presence of myofibroblasts in the sclera has to date been demonstrated in all the mammalian species assessed. Interestingly, it appears that myofibroblasts are absent from the sclera of the chick eye, possibly explaining the different creep response to raised intraocular pressure in vivo compared to mammalian eyes (Fig. 6).28 Studies in human, monkey and guinea pig sclera suggest that myofibroblasts comprise a subset of scleral cells, with one study suggesting an age-dependant increase in the proportion of myofibroblasts.33,34 Such findings imply that scleral myofibroblasts are less prevalent when the eye is growing most rapidly (the fetal and neonatal phase), but that they increase in number as eye growth slows and reaches its adult size. Interestingly, unlike the normal transience of these cells, the sclera contains a stable population of myofibroblasts.
In vitro scleral cell culture studies have also shed light on the contractile responses of these cells. Grown under normal cell culture conditions mammalian scleral cell populations do not display large numbers of myofibroblasts. However, this changes when the cells are grown in three dimensional collagen gels which are attached to the side of culture dishes to allow stresses to build up (these conditions approximate the in vivo scleral matrix). Upon release of the cell-populated gels from their attachment, there is a rapid cell-mediated contraction of the collagen matrix, which is associated with a concurrent increase in the proportion of scleral myofibroblasts (Fig. 7). The data suggest that important regulators of scleral myofibroblast differentiation exist and that the presence of these factors directly affects the contractile capacity of the scleral cells.
Regulators of Scleral Myofibroblast Differentiation
Fibroblast to myofibroblast differentiation is a complex process, with a number of signaling factors important in the fibroblast moving through the proto-myofibroblast to mature myofibroblast stage.35,36 However, at a basic level the process is initiated either by induced stress on the cell and matrix, or through stimulation with cell signaling factors, among the most important of which is the cytokine transforming growth factor-beta (TGF-β).36 The sclera, itself, is under constant and fluctuating stress due to intraocular pressure, while TGF-β is present within the scleral matrix and has been implicated in the remodelling that occurs during mammalian myopia development. In vitro cell culture studies using attached or stressed collagen gels (Fig. 7) have shown that scleral myofibroblasts are readily formed by increasing matrix stress. Similarly, the addition of TGF-β to scleral cell cultures brings about a rapid differentiation of fibroblasts into α-SMA-expressing myofibroblasts (Fig. 8). Careful assessment of the structural proteins within the cell cytoplasm shows that ‘stress fibers’ have developed within the cell that typically orient themselves parallel to the imposed stress.37 Work in other tissue systems have shown that these stress fibers may assemble or disassemble in periods of minutes,38 demonstrating how transient the function of these cells may be, and how responsive they are to changes in the extracellular matrix environment.
Myofibroblast-Extracellular Matrix Interactions
Myofibroblasts are capable of modifying their extracellular environment both through contraction and the production of new extracellular matrix. Once formed myofibroblasts produce collagen, proteoglycans and many other constituents and regulators of the extracellular matrix, in order to maintain or repair their extracellular environment.35 For this reason, myofibroblasts must be continually receiving information about the surrounding matrix. The major significance of this direct cell-matrix interaction is two-fold. Firstly, the cell is in a position to immediately sense any changes in the stress experienced by the extracellular matrix, and thus be in a position to change its production and regulation of the extracellular matrix accordingly. Secondly, the cell is in a position to physically respond to any imposed stresses, via contraction of its surrounding matrix.
Data from many different tissue systems show that extracellular matrix-producing cells, such as myofibroblasts, are closely related to their matrix through a variety of cell-matrix adhesion molecules. On the outside of the cell these adhesion molecules act as receptors, binding to various aspects of the extracellular matrix, such as collagen.39 These cell adhesion molecules also span the cell membrane and join, internally, to the cytoskeleton of the cell, forming a complete bridge between the extracellular matrix and the actin of the internal framework of the cell.40 The integrin family of receptors are perhaps the most important cell adhesion molecules in extracellular matrices such as the sclera. Collagen-binding integrins have been demonstrated on scleral cells (Fig. 9).41 Of further interest, integrin gene expression has been shown to be decreased in mammalian eyes developing myopia, suggesting that the cell-matrix bond is altered in myopic eyes (Fig. 9).42 Such a reduction in cell-matrix contact would have implications for the biomechanical response of the sclera.
Cellular and Matrix Contributions to Altered Scleral Biomechanics and Myopia
From the above discussion scleral myofibroblasts must be considered an integral part of the biochemical and biomechanical response of the mammalian sclera, both in normal and abnormal eye growth. These cells certainly have the potential to contribute to the matrix changes widely reported in the sclera of eyes developing myopia,1,2 and their mechanical interaction with the matrix, together with their contractile capability, indicate a mechanism whereby the sclera may control its elastic response to short term changes in stress, such as during fluctuations in intraocular pressure due to cardiac cycle, respiration and eye movement.
A proposed model for the significance of scleral myofibroblasts in myopic eye growth, incorporating the current data, is shown in Fig. 10. Black text and black arrows indicate that which has been demonstrated experimentally, whereas gray indicates areas currently subject to conjecture. A retino-scleral signaling mechanism43 drives the scleral cell population (a mixture of fibroblasts and myofibroblasts28,33) to initiate the process of scleral tissue loss, partly due to reduced synthesis of extracellular matrix components and partly a result of accelerated degradative pathways.14 As these pathways take hold the sclera starts to thin and its material properties weaken, increasing the capacity of the sclera to creep under normal intraocular pressure.5,6,12 This process increases the stresses present within the matrix, and presumably on the scleral cells. However, the reduced TGF-β in the extracellular environment of the myopic eye44 represents a competing influence, thus it is uncertain, at this stage, how scleral myofibroblast numbers change in myopia. Down-regulation of integrin expression early on in the process of myopia development42 may represent a mechanism whereby myofibroblasts disconnect from the scleral matrix, releasing the cells’ mechanical influence on the matrix and enhancing the capacity of the sclera to creep5,6 and the eye to grow. Such a response could also reflect a protective mechanism in response to the stresses the scleral cells are experiencing. As myopia progresses, the population of scleral myofibroblasts may try to reconnect with the creeping matrix. Similarly, they may remain disconnected from the matrix, de-differentiating to fibroblasts, due to their reduced experience of the stress in the matrix, and allowing further increase in the creep capacity of the sclera. Throughout this process, gene expression changes continue among the scleral cell population resulting in the changes in the collagenous matrix which manifest later in myopia development, such as reduced diameter of collagen fibrils,14 further enhancing scleral creep.
The biomechanical properties of the sclera are critical in maintaining normal ocular development. Alterations in these properties, such as those seen during myopia development, produce concurrent alterations in eye size. Although remodelling to the scleral matrix was considered to be the sole determinant of biomechanical change, recent data has highlighted the important role of scleral cells, particularly scleral myofibroblasts. Although there remains much work to do in characterizing the role of scleral myofibroblasts in normal and abnormal eye growth, proper identification of the factors involved in scleral weakening and subsequent increased eye size will enable treatments to be devised which will ultimately result in reducing the impact of high myopia on visual function.
The authors would like to acknowledge the technical assistance of Dr. Ravi Metlapally and Mr. Bryan McGowan.
This work was supported by a grant from the National Health and Medical Research Council of Australia (NHMRC) grant 454602.
The data presented in this manuscript was delivered at the 12th International Myopia Conference held in Palm Cove, Australia in July 2008.
Neville A. McBrien
Department of Optometry and Vision Sciences
The University of Melbourne
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