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From the Department of Optometry and Vision Sciences, The University of Melbourne, Victoria, Australia.
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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METHODS. 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.
RESULTS. 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.
CONCLUSIONS. 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.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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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.6 Previous studies have shown that this scleral thinning is associated with a narrowing and dissociation of the collagen fiber bundles and a reduction in collagen fibril diameter.7 In addition, it has been reported that there is an increase in the occurrence of collagen fibrils that are stellate in cross-sectional profile.7 Changes in the biochemical structure of the sclera, such as altered glycosaminoglycan (GAG) and collagen content,8 have also been reported in the sclera of highly myopic post-mortem human eyes and are further evidence of scleral pathology in high myopia. 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 globe9 ; however, data from animal models of refractive development have forced a reinterpretation of this hypothesis.10
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.10 12 13 14 15
Collagen accounts for at least 90% of the dry weight of the mammalian sclera, and the tree shrew model of myopia exhibits a fibroblast-maintained scleral extracellular matrix that, similar to that of humans, consists of predominantly type I collagen associated with smaller amounts of other fibrillar and fibril-associated collagens.16 17 Studies in the tree shrew have shown that during development of myopia the vitreous chamber enlarges,18 the sclera thins at the posterior pole,19 and there is a reduction in scleral collagen and GAG content,13 changes that are also found in the sclera of human high myopes. In addition, studies have shown that this scleral thinning is associated with tissue loss, even during the earliest stages of myopia development.10 20 This loss of scleral tissue occurs in conjunction with rapid reductions in scleral GAG synthesis20 and cell proliferation.21 In addition, investigators have shown that the activity of matrix metalloproteinase (MMP)-2, an enzyme involved in the breakdown and turnover of collagen, is rapidly upregulated in the sclera of eyes with developing myopia.22
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.19 23 24 However, most data on the human sclera have been obtained from older post-mortem eyes. 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.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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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.26 Although the use of a diffuser is preferable in this type of study, because it does not induce the changes in corneal curvature found after eyelid closure,18 it is impractical to maintain the head-mounted goggle and diffuser over longer periods. 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.18 25 All the procedures were performed in accordance with the ARVO Statement for the use of Animals in Ophthalmic and Vision Research.
Collagen Fibril Morphology and Scleral Thickness Groups
Myopia was induced in two of the three groups of animals
allocated to this part of the study. Animals in the first group wore a
diffuser over a 12-day period (short-term–deprived; n = 5)
whereas animals in the second group either wore a diffuser for 3 months
or underwent eyelid closure for periods of 6 to 20 months
(long-term–deprived, n = 5). The final group consisted of
animals that had normal visual experience and varied in age from birth
to 21 months (normal, n = 10). 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, 13.5 months, and 21
months (control subjects for long-term–deprived group).
Scleral Dry Weight Groups
Myopia was induced in two of the four groups that were used to
monitor scleral dry weight changes. These animals were treated
identically with those just described, in that monocular deprivation
was induced, either over a 12-day period, through the use of a
head-mounted goggle and translucent diffuser (n = 11), or
for periods of 6 to 8 months, through the use of monocular eyelid
closure techniques (n = 10). Two groups of age-matched
normal animals were used as control subjects (n = 4 each
group).
Refractive and Biometric Ocular Measures
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.25
Measures were performed with animals under
ketamine-xylazine (90 and 10 mg/kg, respectively), anesthesia and 1%
topical atropine sulfate was used as a cycloplegic-mydriatic to aid the
measurement process. 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.
Processing of Ocular Tissue for Microscopy
After ocular refractive and biometric data had been collected,
the animals were administered a lethal dose of pentobarbital sodium
(120 mg/kg) and perfused by intracardial administration of 4 mg/ml
heparin, 4 mg/ml isoxsuprine in rabbit Ringer solution at 37°C, and
3.5% glutaraldehyde buffered with 0.15 M sodium cacodylate. A small
mark was made at the 12-o’clock position on the cornea and limbus,
with an indelible ink marker pen, to allow orientation of the eye cup
after enucleation. 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 1.5-mm diameter trephine was used
to excise a punch of retina, choroid, and sclera from the posterior
pole of the eye, to enable the measurement of scleral thickness. 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. Tissue samples were postfixed in 1% osmium tetroxide
for 2 hours at 4°C, and then rinsed and dehydrated in graded ethanols
before embedding in Araldite.
Assessment of Scleral Tissue
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 0.4 to 0.5 mm into the tissue
punch. Ultrathin sections were cut from both the posterior tissue
punches and the equatorial (2.0 mm from the limbus in
long-term–deprived animals only) region of the tissue crescents,
collected on coated copper grids, and stained for transmission electron
microscopy with uranyl acetate, lead citrate, and phosphotungstic acid.
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). Four electron micrographs
(x40,000 magnification) of approximately equal area were taken of each
defined scleral layer. 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 400 fibrils
were sampled per defined scleral layer, which amounted to approximately
1200 scleral fibrils being sampled from each eye. Fibers were measured
with a digitizing tablet, and where fibers were elliptical, the
smallest diameter was measured.
Electron micrographs (x100,000 magnification) were also taken of scleral collagen fibrils in longitudinal section, cut from the posterior region of the scleral tissue collected from two long-term–deprived animals. Collagen D-periodicity was measured in 90 to 160 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.
Scleral Dry Weight
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. 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). Samples were dried
at 105°C in an oven under an atmosphere of phosphorous pentoxide for
a period of 18 to 24 hours. Dry weights were recorded to the nearest
0.01 mg. The presented values are the mean of three readings obtained
with a five-figure balance (Mettler HK-60).
Data Analysis
Ocular refraction and biometric measures, as well as scleral
thickness and dry weight data, are represented as the mean of the right
or left treated or contralateral control eyes ± SEM or as the
mean or percentage mean (treated - control/control) difference
between paired right and left or treated and control eyes ± SEM.
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.
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Results |
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After longer periods of form deprivation, the relative myopia between treated and contralateral control eyes was significantly greater than that found in short-term–deprived animals (-14.7 ± 0.9 D vs. -11.8 ± 0.7 D, P < 0.05). 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 (3.21 ± 0.05 mm vs. 2.71 ± 0.05 mm, P < 0.01). 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.18 The measured degree of myopia in the treated eye was reduced by 4.9 ± 0.7 D in the present study, due to this corneal flattening (Table 1) .
Scleral Thickness and Collagen Fibril Morphology in the Normal
Developing Eye
Dehydrated scleral thickness at the posterior pole was found to
increase from 33 µm at birth to 79 µm at eye opening. Thereafter,
scleral thickness remained relatively steady at approximately 80 µm,
indicating that the sclera had reached its adult thickness by the time
of eye opening (Fig. 1A) . The age at which scleral thickness at the posterior pole reached
adult levels was in good agreement with the age at which both the
number of collagen fiber bundles across the scleral thickness (
23
bundles, Fig. 1B
) and the median collagen fibril diameter at the
posterior pole (78 nm [62–98] median value with interquartile range
of first and third quartiles in brackets; Fig. 1C
) also reached adult
levels. The distribution of collagen fibril diameters present at birth,
although approximating a normal distribution, was not found to be
gaussian when tested for normality (P = 0.01). The
distribution changed rapidly up to the age of 45 days, with a
positively skewed profile developing (Fig. 2A)
. During this period, there was a significant increase in the median
collagen fibril diameter from 62 nm (interquartile range, 53–70) at
birth to 80 nm (interquartile range, 62–115) by 45 days
(P < 0.001), although the distribution profile
remained skewed toward the smaller diameter fibers. 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. 2B
; at 6 months, 74 nm [51–130], and at 21 months, 85 nm
[52–129]; P = 0.36).
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Scleral Thickness in Myopia
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. 3A
; myopic eye 95 ± 12 µm vs. control eye 120 ± 13 µm;
-21%; P = 0.001). Significant differences in scleral
thickness between myopic and control eyes were also apparent in
long-term–deprived animals (Figs. 3A
3B
; 68 ± 5 µm vs.
89 ± 4 µm; -23%; P < 0.05), whereas no
differences were found in the thickness of the posterior sclera between
control or age-matched normal eyes (P = 0.42).
Furthermore, no significant difference was found between the thickness
of the sclera in the equatorial region of myopic and control eyes of
long-term–deprived animals (64 ± 8 µm vs. 66 ± 3 µm,
P = 0.85), which suggests that scleral thickness
changes in myopic eyes were regionally specific.
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Scleral Collagen Fibril Distribution in Myopia
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. 4A
4B
4C)
, as was the case in the two groups of age-matched control subjects. No
significant differences were found in the median collagen fibril
diameter between treated and control eyes of short-term–deprived
animals (Fig. 4A) in the posterior scleral region (95 nm [64–156]
vs. 97 nm [64–154]; P = 0.94). As might be expected
from these data, no differences in median fibril diameter were found in
the inner (P = 0.96), middle (P =
0.52), or outer (P = 0.52) scleral layers between
myopic and control eyes. A significant gradient in fibril diameter was
found in both myopic (inner 84 nm versus middle 106 nm versus outer 128
nm, P < 0.001) and control eyes (84 vs. 111 vs. 120
nm, respectively; P < 0.001) of short-term–deprived
animals.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Normal Scleral Development
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. Scleral thickness
increased steadily from birth, in conjunction with these fibril
diameter changes, and stable adult thickness was reached at a time
comparable to that at which collagen fibril distribution stabilized
(45 days). 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.16
28
After this period of rapid development, the
collagen fibril diameter distribution did not alter significantly with
time. 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 human31
and monkey11
sclera.
However, this gradient was minimal at birth and became substantially
more pronounced in older animals.
Short-Term Development of Myopia
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.31
The findings demonstrate that early loss of
scleral tissue, and consequent scleral thinning, is not associated with
detectable changes in the scleral collagen fibril diameter
distribution. Indeed, because some 90% of scleral dry weight is
accounted for by scleral collagen17
and the activity of
collagen-degrading enzymes is elevated early in myopia
development,22
this implies that most of this rapid tissue
loss in the posterior segment of short-term–treated animals must be
attributable to a general scleral collagen fibril degradation, rather
than to degradation of specific fibril populations of certain
diameters. 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.
Long-Term Development of Myopia
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.20
Of particular note in the
long-term group of animals was the marked reduction in scleral fibril
diameter in myopic eyes, found particularly at the posterior pole of
the eye, which is consistent with previous findings in the
equatorial30
and posterior7
regions of highly
myopic human eyes. 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.28
The shift toward smaller
diameter collagen fibrils was most apparent in the outer layer of the
sclera, which is illustrated by the fact that the normal fibril
diameter gradient across the defined scleral layers had markedly
declined at the posterior pole of myopic eyes (Fig. 6)
. 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.11
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 (0.29 mm after 12 days), mid-term (0.34 mm after 3 months), and long-term (0.37 mm after 9 months) animal were associated with marked differences in the significance of the interocular change in collagen fibril diameter (P = 0.86 short-term, P = 0.03 mid-term; and P = 0.002 long-term). 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. Indeed, similar proportions of larger diameter fibrils were found in both the myopic and control eyes of short-term–deprived animals (Fig. 4A) and in longer term normal (Fig. 2B) and deprived (Figs. 4B 4C) animals, demonstrating that deprivation per se does not prevent the development of larger diameter fibrils. Furthermore, evidence from a limited sample suggests that, after the initial short-term losses of fibril bundles across the sclera, bundle thickness also reduced over time, supporting the hypothesis that initial short-term degradation of whole fibril bundles is followed by subtler long-term changes in scleral remodeling.
Data from the present study were equivocal in resolving the issue of whether the untreated control eye of form-deprived tree shrews responds to deprivation of its fellow eye, as has recently been suggested.32 Indeed, data from long-term normal and myopic animals unequivocally demonstrate that contralateral control eye values for median scleral collagen fibril diameter, fibril diameter gradient, scleral thickness, scleral dry weight, ocular refraction, and ocular axial length were similar to those of normal animals. However, the smaller data set for short-term normal and myopic animals suggests that values of control eye scleral thickness, dry weight, and ocular refraction differed from those of normal eyes, although changes in ocular axial length and refractive error were mainly a feature of the treated eye.
Scleral Biochemistry and Collagen Fibril Diameter
Previous studies have shown that certain proteoglycans, such as
decorin,33
and fibril-associated collagens34
are important factors in the control of collagen fibril synthesis—in
particular influencing the diameter of newly synthesized fibrils.
Indeed, it is implied from measures of sulfate incorporation in the
sclera that the synthesis of proteoglycans, such as decorin, is reduced
in mammalian eyes with developing myopia,20
35
36
37
and this is supported by the finding that overall proteoglycan content
of the scleral tissue also alters over time, as is the case in the
sclera of highly myopic human eyes.8
13
Therefore, it may
be that, in the short-term, the collagen fibril diameter profile in the
sclera of myopic eyes is relatively unaffected by the protease-driven
degradative process and that longer term shifts in collagen fibril
distribution are mediated by the changing scleral extracellular matrix
biochemistry.
Ocular Enlargement and Scleral Collagen Fibrils
Changes in scleral collagen fibril diameter distribution were
found to be associated with the most rapid periods of eye growth in
normally developing animals, which may suggest that the rate of growth
of the eye is related to the profile of collagen fibril diameters
within the scleral matrix. It has previously been reported that smaller
diameter collagen fibrils are present in developing tissues, giving way
to larger diameter fibrils as the tissue matures.38
Recent
theories explaining this phenomenon suggest that larger diameter
fibrils develop through lateral accumulation of collagen on existing
fibrils as the collagen matrix matures and the fibril
elongates.39
We suggest that the large numbers of smaller
diameter fibers in the sclera, seen during early ocular development and
myopic eye growth in older eyes, are indicative of collagen fibril
maturation during eye growth. Indeed, this hypothesis may explain why
the developing eye, in which the collagen matrix is developing, has
been shown to be most susceptible to the stimuli that induce myopic eye
growth.18
Furthermore, this hypothesis suggests that the
shift to a preponderance of smaller diameter fibers in older animals
with high degrees of induced myopia is consistent with a collagen
matrix that is still actively changing. However, the fact that no
significant change in fibril profile was encountered in young animals
in which myopia was developing suggests that additional factors are
involved in facilitating accelerated ocular elongation during the early
stages of myopic eye growth.
Changes in the material properties of the sclera have recently been reported in tree shrew eyes with developing myopia.14 15 40 These changes were detectable after 4 days of myopia development and were, to a large extent, independent of changes in the thickness of the scleral tissue itself. Furthermore, specifically in mammals, the degree of axial myopia was found to correlate with the degree of change in the mechanical properties of the sclera.15 Because the results of the present study suggest that the collagen fibril profile does not alter significantly in short-term–deprived eyes, the mechanical properties of the sclera must be controlled by additional factors, such as proteoglycans,41 during the initial stages of myopia development. However, we suggest that during the later stages of myopia development, the increased numbers of small-diameter fibers, in conjunction with the reduced proteoglycan content of the tissue, contribute to a scleral matrix that is less resistant to imposed mechanical stresses (such as the normal intraocular pressure). Indeed, studies in other fibrous matrices have shown that a preponderance of smaller diameter collagen fibrils is associated with lower tensile strength of the tissue.42 It may be that these smaller fibrils in the posterior sclera of eyes with long-term myopia underlie both the changes in refractive error seen in progressive myopia and the formation of posterior staphyloma.
In summary, the findings of the present study showed that ocular enlargement and scleral tissue loss during myopia development were not accompanied by significant changes in scleral collagen fibril diameter in the short term. However, longer periods of myopia development were accompanied by alterations in the collagen fibril diameter profile, resulting in more small-diameter fibrils. These findings may account for changes that are found in the material properties of the sclera from myopic eyes, indicating a mechanism for the formation of posterior staphyloma in highly myopic humans.
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Acknowledgements |
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Footnotes |
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Submitted for publication January 29, 2001; revised May 2, 2001; accepted May 23, 2001.
Commercial relationships policy: N.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be marked
"advertisement" in accordance with 18 U.S.C. 
1734
solely to indicate this fact.
Corresponding author: Neville A. McBrien, Department of Optometry and Vision Sciences, The University of Melbourne, Victoria 3010, Australia. n.mcbrien{at}optometry.unimelb.edu.au
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A. G. Moring, J. R. Baker, and T. T. Norton Modulation of Glycosaminoglycan Levels in Tree Shrew Sclera during Lens-Induced Myopia Development and Recovery Invest. Ophthalmol. Vis. Sci., July 1, 2007; 48(7): 2947 - 2956. [Abstract] [Full Text] [PDF]
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N. A. McBrien, R. Metlapally, A. I. Jobling, and A. Gentle Expression of Collagen-Binding Integrin Receptors in the Mammalian Sclera and Their Regulation during the Development of Myopia Invest. Ophthalmol. Vis. Sci., November 1, 2006; 47(11): 4674 - 4682. [Abstract] [Full Text] [PDF]
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J. Zhou, E. F. Rappaport, J. W. Tobias, and T. L. Young Differential Gene Expression in Mouse Sclera during Ocular Development Invest. Ophthalmol. Vis. Sci., May 1, 2006; 47(5): 1794 - 1802. [Abstract] [Full Text] [PDF]
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I. A. Sigal, J. G. Flanagan, and C. R. Ethier Factors Influencing Optic Nerve Head Biomechanics Invest. Ophthalmol. Vis. Sci., November 1, 2005; 46(11): 4189 - 4199. [Abstract] [Full Text] [PDF]
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J. T. Siegwart Jr and T. T. Norton Selective Regulation of MMP and TIMP mRNA Levels in Tree Shrew Sclera during Minus Lens Compensation and Recovery Invest. Ophthalmol. Vis. Sci., October 1, 2005; 46(10): 3484 - 3492. [Abstract] [Full Text] [PDF]
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 B C Chauhan, D M Hutchison, R P LeBlanc, P H Artes, and M T Nicolela Central corneal thickness and progression of the visual field and optic disc in glaucoma Br J Ophthalmol, August 1, 2005; 89(8): 1008 - 1012. [Abstract] [Full Text] [PDF]
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N. S. Logan, B. Gilmartin, C. F. Wildsoet, and M. C. M. Dunne Posterior Retinal Contour in Adult Human Anisomyopia Invest. Ophthalmol. Vis. Sci., July 1, 2004; 45(7): 2152 - 2162. [Abstract] [Full Text] [PDF]
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E Arranz-Marquez and M A Teus Relation between axial length of the eye and hypotensive effect of latanoprost in primary open angle glaucoma Br J Ophthalmol, May 1, 2004; 88(5): 635 - 637. [Abstract] [Full Text] [PDF]
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A. I. Jobling, M. Nguyen, A. Gentle, and N. A. McBrien Isoform-specific Changes in Scleral Transforming Growth Factor-{beta} Expression and the Regulation of Collagen Synthesis during Myopia Progression J. Biol. Chem., April 30, 2004; 279(18): 18121 - 18126. [Abstract] [Full Text] [PDF]
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S. Chakravarti, J. Paul, L. Roberts, I. Chervoneva, A. Oldberg, and D. E. Birk Ocular and Scleral Alterations in Gene-Targeted Lumican-Fibromodulin Double-Null Mice Invest. Ophthalmol. Vis. Sci., June 1, 2003; 44(6): 2422 - 2432. [Abstract] [Full Text] [PDF]
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A. Gentle, Y. Liu, J. E. Martin, G. L. Conti, and N. A. McBrien Collagen Gene Expression and the Altered Accumulation of Scleral Collagen during the Development of High Myopia J. Biol. Chem., May 2, 2003; 278(19): 16587 - 16594. [Abstract] [Full Text] [PDF]
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