The sclera the white part of the eye constitutes the rest of the globe. It is a tough connective tissue and is continuous with the cornea.
Scleral collagen is, in composition and arrangement, more similar to that seen in skin, with wider fibrils and a much more interwoven structure than cornea. It has no optical role other than to provide a support for the retina on the back of the eye but has important physiological functions it contains fluid outflow channels to prevent excessive pressure within the eye and mechanical functions it maintains eye shape during ocular movement. This chapter describes the structure of the corneal stroma from the macroscopic level to the nanoscopic level and focuses on the role of collagen in determining the mechanical and optical properties of this fascinating connective tissue.
The chapter ends with a section describing the sclera and what is currently known about the changes in collagen that accompany the development of shortsightedness myopia. Unable to display preview. Download preview PDF. Skip to main content. Advertisement Hide. Authors Authors and affiliations K. This process is experimental and the keywords may be updated as the learning algorithm improves.
This is a preview of subscription content, log in to check access. Structure Google Scholar. Butterworth Heinemann, Oxford, UK. Benedek GB Theory of transparency of the eye. A keratan sulfate-containing isoform of decorin is developmentally regulated. J Biol Chem.
CrossRef Google Scholar. Biomechanical instability or chronic disease process? Cataract Refract. Bovine corneal keratan sulphate proteoglycan 37A. Normal and staphylomatous sclera of high myopia. Daxer A and Fratzl P Collagen fibril orientation in the human corneal stroma and its implications in keratoconus. Eye Res. Butterworth-Heinemann, Boston. Feuk T On the transparency of the stroma in the mammalian cornea. IEEE Trans. BME Fratzl P and Daxer A Structural transformation of collagen fibrils in corneal stroma during drying. An x-ray scattering study.
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Science Hjordtal JO Biomechanical studies of the human cornea: Development and application of a method for experimental studies of the extensibility of the intact human cornea. Acta Ophthalmol Scand Hjortdal JO Regional elastic performance of the human cornea. SaundersCompany, Philadelphia. PNAS Huang Y The effects of alkali burns and other pathological conditions on the ultrastructure of the cornea. PhD Thesis.
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Albrecht von Graefes. Komai Y and Ushiki T The three-dimensional organisation of collagen fibrils in the human cornea and sclera. The development of high myopia is associated with scleral thinning and changes in the diameter of scleral collagen fibrils in humans. In the present study, the association between these scleral changes and the losses in scleral tissue that have previously been reported in animal models were investigated to determine the relationship between changes in collagen fibril architecture and thinning of the sclera in high myopia.
Myopia was induced in young tree shrews by monocular deprivation of pattern vision for short-term 12 days or long-term 3—20 months periods. Scleral tissue from normal animals over a wide age range birth to 21 months was also collected to provide data on the normal development of the sclera. Light and electron microscopy were used to measure scleral thickness and to determine the frequency distribution of collagen fibril diameters in the sclera.
Tissue loss was monitored through measures of scleral dry weight. Significant scleral thinning and tissue loss, particularly at the posterior pole of the eye, were associated with ocular enlargement and myopia development after both short- and long-term treatments. However, collagen fibril diameter distribution was not significantly altered after short-term myopia treatment, whereas, from 3 months of monocular deprivation onward, significant reductions in the median collagen fibril diameter were noted, particularly at the posterior pole.
The results of this study demonstrated that loss of scleral tissue and subsequent scleral thinning occurred rapidly during development of axial myopia. However, this initial tissue loss progressed in a way that did not result in significant alterations to the collagen fibril diameter distribution. In the longer term, there was an increased number of small diameter collagen fibrils in the sclera of highly myopic eyes, which is consistent with findings in humans and is likely to contribute to the weakened biomechanical properties of the sclera that have previously been reported. Purchase this article with an account.
Jump To Materials and Methods Results Discussion. McBrien ; Lynn M. Cornell ; Alex Gentle. Author Affiliations Neville A. Alerts User Alerts. You will receive an email whenever this article is corrected, updated, or cited in the literature. You can manage this and all other alerts in My Account. This feature is available to authenticated users only.
Get Citation Citation. Get Permissions. The prevalence of high myopia myopia in excess of 6 diopters [D] in world populations has been estimated to be between 0. This conclusion is supported by evidence that the incidence of retinal disease in high myopia is greater with increasing eye size.
Excessive ocular enlargement must be facilitated by the outer coat of the eye, namely the sclera, and high myopia in humans has been found to be associated with a thinner sclera, particularly at the posterior pole of the eye. The thinning of the sclera in highly myopic humans was previously believed to occur as a result of passive stretching of the tissue to cover the enlarged globe 9 ; however, data from animal models of refractive development have forced a reinterpretation of this hypothesis. A study in monkeys with experimentally induced high myopia has established that marked scleral thinning is associated with smaller collagen fibril diameters, 11 as found in humans.
Furthermore, the study defined inner, middle, and outer layers of the sclera and determined that there is a gradient in fibril diameter across these layers and that this gradient is absent in myopic eyes. More recent studies in animals, such as the tree shrew and chick, have demonstrated that scleral dry tissue weight alters in conjunction with changes in scleral thickness and that this is associated with both biochemical and biomechanical changes in the scleral extracellular matrix.
In addition, studies have shown that this scleral thinning is associated with tissue loss, even during the earliest stages of myopia development. Scleral thinning and changes in scleral collagen fibril morphology have been reported, in abstract form, in the eyes of tree shrews developing myopia over the short term. In the present study, we investigated changes in scleral thickness and collagen fibril morphology, during both short and extended periods of myopia development, to examine how the short-term changes in scleral biochemistry observed in young tree shrews develop into long-term scleral pathology in adult animals.
These findings bring us closer to an understanding of the mechanisms of scleral pathology in highly myopic humans. The animals used in this study were maternally reared tree shrews Tupaia belangeri , raised in our own breeding colony.
Animals were maintained on a hour light—9-hour dark cycle, and food and water were available ad libitum. Tree shrew pups were randomly assigned to one of seven experimental groups, three of which were used to investigate scleral collagen fibril morphology and scleral thickness and four of which were used to monitor changes in scleral dry weight. Differences in the tissue processing requirements dictated that collagen fibril and dry weight data could not be collected from the same animals.
Myopia was induced by monocular deprivation MD of pattern vision, either through the use of a head-mounted goggle and translucent diffuser, 25 for short periods of monocular visual deprivation up to 3 months , or by monocular eyelid closure using lid suture, 18 for longer periods of monocular visual deprivation. The untreated contralateral eye served as a genetic control. Treatment commenced 15 days after natural eye opening, the time from which tree shrews are most susceptible to the induction of axial myopia. It is important from the point of view of the present study to note, however, that both of these methods of myopia induction result in a refractive error that is caused predominantly by enlargement of the vitreous chamber.
Myopia was induced in two of the three groups of animals allocated to this part of the study. Some of these animals served as age-matched control subjects for the monocularly deprived animals, and the remaining animals were used to establish the normal course of scleral development. The ages examined covered a number of critical points in the ocular development of the tree shrew and were as follows: birth, 19 days eye opening ; 34 days start of period when animals are most susceptible to myopia induction ; 45 days control subjects for short-term—deprived group ; 6 months, 7 months, Myopia was induced in two of the four groups that were used to monitor scleral dry weight changes.
After the designated period of treatment, ocular refraction and biometry data were gathered and the ocular tissue collected for processing. As previously described, ocular refractive error was measured by retinoscopy and corneal curvature by keratometry. Internal ocular dimensions were measured through the use of A-scan ultrasound. The only variation from this procedure was necessary in animals killed at birth, in which ocular biometry measurements were not possible with a sufficient degree of accuracy. Eyes were enucleated and residual orbital tissue carefully removed.
The eyes were immersed in the sodium cacodylate—buffered glutaraldehyde for 1 hour. At the end of this period, the cornea and lens were dissected away, with care taken to leave the mark in the limbal region. Guided by the limbal mark and the position of the optic nerve head, a 1. A crescent-shaped sector was then cut, extending anteroposteriorly along the medial aspect of the eye cup from the limbus to the cut edge of the posterior punch.
Scleral thickness measurements were obtained from thin sections stained with toluidine blue under light microscopy. Oblique sectioning was avoided by monitoring photoreceptor orientation in the sections, and variability was minimized by taking thickness readings from 25 serial sections, beginning approximately 0. Ultrathin sections were cut from both the posterior tissue punches and the equatorial 2. Electron micrographs were taken of collagen fibrils in transverse section from the outer fourth collagen fibril bundle inward from the sclera—episclera boundary , middle center bundle , and inner layers fourth layer out from the lamina fusca.
Two of these micrographs were obtained from separate areas in one section and two from a later section. Care was taken to ensure that each of these sample micrographs constituted a different collagen fiber bundle. As a result, approximately fibrils were sampled per defined scleral layer, which amounted to approximately scleral fibrils being sampled from each eye. Fibers were measured with a digitizing tablet, and where fibers were elliptical, the smallest diameter was measured. Collagen D-periodicity was measured in 90 to fibrils from the treated and control eye sclera of these animals, using the digitizing tablet.
Low-magnification scleral electron micrograph montages were assembled from a selection of short- and long-term—deprived and normal animals. Estimates of both the number of collagen fibril bundles along a perpendicular through the scleral thickness and the mean maximum thickness of these bundles were obtained from multiple measurements across the montages.
In the separate groups of animals that were used to assess scleral dry weight, ocular refraction and biometry measurements were collected, as detailed earlier, before eyes were enucleated in animals under deep anesthesia. Extraneous orbital tissue was dissected from the globe, and the cornea was removed by careful dissection around the pigment ring that defines the limbus in the tree shrew, by an investigator viewing through an operating microscope.
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The iris, lens, and vitreous were carefully removed, and a 5-mm surgical trephine was used to remove a region of the posterior pole of the eye. Retina and choroid were cleaned from both this sample posterior sclera and from the remaining sclera anterior—equatorial sclera. Dry weights were recorded to the nearest 0. The presented values are the mean of three readings obtained with a five-figure balance Mettler HK In the absence of evidence for a skewed distribution, these values were analyzed using paired t -tests, and comparison between groups was performed using a one-way ANOVA with a Tukey post hoc test.
Collagen fibril diameter distributions in the sclera were analyzed using a Kolmogorov-Smirnov normality test and found to be positively skewed. As a result, nonparametric statistics were applied to these data. Median fibril diameter and the first and third quartiles were used to represent the fibril data in individual eyes and grouped data. The Mann-Whitney test was used to compare individual or grouped right and left or treated and control eye data. The Kruskal-Wallis test with a Dunn post hoc test were used to make comparisons between multiple data sets.
Fibril frequency distribution plots were used to represent the data spread graphically after data had been normalized to the total number of fibrils sampled in each eye. Representative ocular biometric data from the animals in this study are presented in Table 1. These refractive error data were not corrected for the small-eye artifact of retinoscopy 27 and, consequently, it should be noted that the true values of ocular refraction in the treated and control eyes of both young and adult tree shrews are likely to be approximately 5 D 28 more myopic than those reported in Table 1.
Development of myopia in the treated eye was found to be a consequence of increased axial length relative to contralateral control eyes 7. This ocular enlargement was primarily due to a significant increase in the vitreous chamber depth of the treated eye 2. As was the case in short-term—deprived animals, development of myopia was primarily a result of increased axial length in the treated, relative to the contralateral control, eye and this was mainly due to increased vitreous chamber depth 3. However, there was also a small, but significant, thinning of the lens in these animals Table 1 , as previously reported, 18 which when modeled was found to account for just 1 D of the induced myopia.
The induction of myopia through the use of eyelid closure has previously been shown to result in a slight flattening and subsequent reduction in power of the cornea in the treated eye. The distribution changed rapidly up to the age of 45 days, with a positively skewed profile developing Fig. The appearance of larger diameter fibers and the skewing of fibril distribution was found to occur in each of the defined scleral layers inner, middle, and outer during development. Between the ages of 6 and 21 months, no significant alterations were found in the median fibril diameter Fig. Median collagen fibril diameter was assessed between the defined inner, middle, and outer scleral layers to determine whether differences were present across layers.
In the present study, the specific variation in fibril diameter across layers is referred to as a gradient, and it was found that the gradient at birth was minimal inner 59 nm vs. Significant reductions in scleral thickness were apparent in the posterior pole region of myopic, compared with contralateral control, eyes in short-term—deprived animals Fig.
Significant differences in scleral thickness between myopic and control eyes were also apparent in long-term—deprived animals Figs. Total scleral dry weight was found to be significantly reduced in the myopic eyes, compared with contralateral control eyes, of both short-term 5. The largest change in scleral dry weight was always found at the posterior pole of myopic eyes in both short-term 0. It should be noted that the mean percentage reductions in dry scleral weight found at the posterior pole were consistent with the percentage changes in scleral thickness.
Scleral fibril diameter distributions were found to be positively skewed, with a longer tail of larger diameter fibrils, in both treated and control eyes of short-term— and long-term—deprived animals Figs. No significant differences were found in the median collagen fibril diameter between treated and control eyes of short-term—deprived animals Fig.
After 3 months of monocular deprivation, a significant difference was apparent in the median collagen fibril diameters in the posterior sclera Fig. However, the reductions between myopic and control eyes in any of the individual scleral layers did not reach significance, with the greatest difference apparent in the outer posterior scleral layer 94 nm[ 63—] vs. In the animals that had been monocularly deprived for 6 months or more, there were significant changes in the median fibril diameter of myopic eyes, compared with contralateral control eyes, both in the posterior sclera overall Fig.
Median fibril diameter in the posterior sclera of these long-term—deprived animals was significantly reduced in myopic, compared with contralateral control, eyes Fig. This reduction in fibril diameter was most pronounced in the outer layers of the sclera 65 nm [45—] vs. In long-term—deprived animals, a significant decrease in median collagen fibril diameter was also found in the outer layer only of the equatorial scleral region of myopic, relative to control, eyes 67 nm[ 36—] vs.
Mean D-periodicity of scleral collagen fibrils, as determined in collagen fibrils from the four eyes, was found to be However, the number of collagen fibril bundles across the scleral thickness was slightly less in myopic eyes of both groups of deprived animals, when compared with the contralateral control eyes short-term, 44 vs. Furthermore, median fibril bundle thickness was less in myopic eyes of long-term—deprived animals 1. The present study provides a comprehensive picture of how the regional collagen fibril diameter distribution in the developing mammalian sclera alters, both during normal development and under conditions that induce myopic eye growth.
The main finding of this study was that the changes in scleral thickness and dry weight, in eyes developing myopia, occurred before significant changes in the collagen fibril distribution profile, as indicated by changes in the median collagen fibril diameter in defined regions of the sclera. The long-term changes in scleral fibril diameter in highly myopic tree shrew eyes are consistent with those reported in highly myopic human and monkey eyes, particularly with respect to the marked reduction in collagen fibril diameter in the posterior sclera.
The normal tree shrew sclera was found, at birth, to consist of a collagen fibril population that displayed a relatively normal distribution profile of fibril size. With increasing age, the distribution of fibril size became positively skewed, due to the appearance of larger diameter collagen fibrils. It is interesting to note that 45 days was also the age at which previous reports showed both ocular axial growth and scleral type I collagen production in young tree shrews to have markedly slowed.
A gradient in median scleral fibril diameter was encountered across the defined layers of the sclera at all ages, with larger fibrils found in the outer scleral layers, which is consistent with reports of the human 31 and monkey 11 sclera. However, this gradient was minimal at birth and became substantially more pronounced in older animals. In tree shrews that had relatively high degrees of axial enlargement and myopia induced over only 12 days, significant thinning of the posterior sclera and comparable reductions in both the posterior and total scleral dry weight were found.
No significant changes in the median collagen fibril diameter were detectable after this period of induced myopia, even in the outer layer of the posterior pole region of the sclera. A gradient in median collagen fibril diameter was found across the layers of the sclera in both myopic and control eyes and was similar to that seen both in normal animals and normal human sclera.
Furthermore, limited evidence from electron micrograph montages of the myopic and control eyes from a single animal suggests that short-term scleral thinning and tissue loss may occur through degradation of whole collagen fibril bundles across the scleral thickness, rather than through diffuse degradation of fibrils within existing bundles. In tree shrews with high myopia for 6 months or more, it was found that the thinned sclera persisted at the posterior pole of the eye, as did the reduced total scleral dry weight. The magnitude and pattern of scleral thinning and scleral dry weight reduction in short- and long-term—deprived animals suggests that scleral thinning and loss of tissue is most aggressive during the early stages of myopia development.
However, it is also apparent that scleral tissue lost during this more aggressive phase is not replaced if the myopia persists. In previous studies it has been found that animals allowed to recover from induced myopia replace the lost scleral tissue as emmetropia is re-established. In the tree shrew, these changes in scleral collagen fibril diameter became apparent after 3 months of form deprivation, an age that has previously been estimated to be the equivalent of the early teenage years in humans.
This finding is consistent with reports in highly myopic monkey eyes, which also lose the gradient in scleral collagen fibril diameter at the posterior pole. It is unlikely that the change in size of myopic eyes in the present study affected scleral collagen fibril diameter per se, given that similar degrees of relative axial enlargement in a short-term 0. However, a significant correlation was found between eye size and fibril diameter, particularly in myopic eyes, perhaps suggesting that scleral collagen fibril diameter plays some role in determining eye size.
The shift in collagen fibril distribution in myopic eyes may either indicate that the primary target in a continuing degradative process are larger diameter fibrils, or that long-term changes in the synthesis of the scleral extracellular matrix result in a predominance of smaller diameter fibrils. Given that there is no apparent wholesale disappearance of large diameter fibrils in these myopic sclerae, it seems that, in the long term, the process at work is one of aberrantly regulated remodeling of the sclera, resulting in smaller diameter fibrils.